Industrial pharmacy complete notes

Industrial pharmacy complete notes Pharm D. 4th professional

1. GHULAM MURTAZA HAMAD
FOURTH PROFF EVENING | PUNJAB UNIVERSITY COLLEGE OF PHARMACY, LAHORE
INDUSTRIAL
PHARMACY
4
TH
PROFESSIONAL


Reference
Lachman and Lieberman- The
Theory and Practice of
Industrial Pharmacy, 5
th
Edition
Aulton's Pharmaceutics- The
Design and Manufacture of
Medicines, 4
th
Edition
Martin’s Physical Pharmacy
and Pharmaceutical Sciences,
5
th
Edition

2. GM Hamad

TABLE OF CONTENTS

Contents
1. Mass Transfer
2. Heat Transfer
3. Drying
4. Comminution (Size Reduction)
5. Mixing
6. Clarification and Filtration
7. Evaporation
8. Compression and Compaction
9. Safety Methods in Pharmaceutical Industry
10. Emulsions
11. Suspensions
12. Semisolids
13. Sterile Products
14. Packing and Packaging

3. GM Hamad

MASS TRANSFER
INTRODUCTION
• It includes the transfer of mass from a solid to a fluid and from a fluid to
fluid which emphasis on the effect of boundary layer and influence of
mass transfer phenomenon on the unit operation.
• Three fundamental transfer processes:
­ Momentum transfer
­ Heat transfer
­ Mass transfer
• Mass transfer may occur in a gas mixture, a liquid solution or solid. Mass
transfer occurs whenever there is a gradient in the concentration of a
species. The basic mechanisms are the same whether the phase is a gas,
liquid, or solid. It usually occurs due to diffusion.
MODES OF MASS TRANSFER
• The two modes of mass transfer:
­ Molecular diffusion
­ Convective mass transfer
1. MOLECULAR DIFFUSION
• The diffusion of molecules is when the whole bulk fluid is not moving but
stationary. Diffusion of molecules is due to a concentration gradient.
A. FICK’S LAW
­ Linear relation between the rate of diffusion of chemical species and
the concentration gradient of that species. The general Fick’s law
Equation for binary mixture of A and B is:
??????
�
°
= − ��
��
�??????
�
�??????

B. THERMAL DIFFUSION
­ Diffusion due to a temperature gradient. Usually negligible unless
the temperature gradient is very large.
C. PRESSURE DIFFUSION
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4. GM Hamad

­ Diffusion due to a pressure gradient. Usually negligible unless the
pressure gradient is very large.
D. FORCED DIFFUSION
­ Diffusion due to external force field acting on a molecule. Forced
diffusion occurs when an external field is imposed on an electrolyte
(for example, in charging an automobile battery)
E. KNUDSEN DIFFUSION
­ Diffusion phenomena occur in porous solids.
2. CONVECTION MASS TRANSFER
• When a fluid flowing outside a solid surface in forced convection motion,
rate of convective mass transfer is given by:
??????
A=??????
??????(�
????????????−�
????????????)
­ Where, Kc = mass transfer coefficient, CLi = bulk fluid
concentration, CLI = conc. of fluid near the solid surface
• Kc depends on:
i. System Geometry
ii. Fluid properties
iii. Flow velocity
• Whenever there is concentration difference in a medium, nature tends
to equalize things by forcing a flow from the high to the low
concentration region. The molecular transport process of mass is
characterized by the general equation:
Rate of transfer process = driving force / resistance
TYPES OF MASS TRANSFER
• Different types of mass transfer are as follows:
1. SOLID- FLUID MASS TRANSFER
• Consider a crystal of soluble material immerged in solvent in which it is
dissolving. Where crystal is surrounded by a stationary boundary layer of
the solute with the bulk of fluid able to move. Such movement could be
natural convection arising from temperature or density changes or
forced convection resulting from agitation. Hence transport of the
molecules of dissolving solids will take place in 2 stages:
2

5. GM Hamad

I. First the molecules move through the boundary layer by molecular
diffusion with no mechanical mixing or movement process that is
analogous to heat transfer by conduction.
II. Secondary, once material has passed to the boundary layer mass
transfer takes place by bulk movement of solution known as eddy
diffusion. It is analogous to heat transfer by convection. Since there is
virtually no limit to vigorous movement of bulk of fluid.
• The controlling factor in the rate of crystal will be molecular diffusion
through the boundary layer. Eddy diffusion will not be considered
further. In general, molecular diffusion is the controlling process. Mass
transfer by this process can be represented in a similar manner to
conduction heat transfer but with a concentration gradient instead of
temperature gradient. Mass transfer by molecular diffusion can be
represented by an equation:
W=
DA (C
1−C
2)
L
O
­ Where, W = weight of solute diffusion, D = diffusion constant, A =
area, o = time, C1 = conc. of solute at interface, C2 = conc. of solute
in bulk, L = film thickness
2. SOLID-GAS MASS TRANSFER
• The term fluid includes gases and vapors as well as liquids and refer
equally to mass transfer from a solid to a gas. As an example of a solid is
drying in air to vapor molecule must be diffuse through the air boundary
layer to the atmosphere. The driving force in this case will be the partial
vapor pressure gradient through the air boundary layers.
W=
DA (P
1−P
2)
L
O
­ Where, W = weight of solute diffusion, D = diffusion constant, A =
area, o = time, P1 = partial pressure of vapor at interface, P2 =
partial pressure of vapor in atmosphere, L = film thickness
3. FLUID-FLUID MASS TRANSFER
• It occurs when mass transfer takes place between immiscible fluids.
Which may be two liquids or liquid and gas (vapor). In this case there will
3

6. GM Hamad

be boundary layer of fluids on each side of the interface where the slope
of concentration gradient depends on the diffusion co-efficient in two
materials as shown in figure, where slope of the concentration gradient
depends upon the diffusion coefficients in the two systems.
INFLUENCE ON UNIT OPERATION
• Mass transfer theory can be applied in any operation in which material
change phase. Where it is solid, liquid, vapor, liquid-liquid-vapor. The
effect can be seen in simple operation as making if a solution of a solid in
liquid where the rate of solution can be increases by different factors:
1. AGITATION
• It reduces the thickness of boundary layer and disperses any local
concentration of solution so increases the concentration gradient.
2. ELEVATED TEMPERATURE
• It will increase solubility of most materials but increase diffusion co-
efficient and decrease the viscosity of liquid so reduce the boundary layer
thickness.
3. SIZE REDUCTION OF SOLID
• It increases area over which diffusion can occur.
4. MASS TRANSFER EQUIPMENT
• Design of mass transfer equipment must confirm turbulent flow
conduction, maximum concentration of partial pressure gradient and
largest possible surface area.
4

7. GM Hamad

HEAT TRANSFER
DEFINITION
• Heat transfer is the study of exchange of thermal energy through a body
or between bodies which occurs when there is a temperature difference.
INTRODUCTION
• In pharmaceutical technology, in order to achieve a well-defined
technological purpose, heat is frequently transferred to some material
to change its temperature, state of matter or any other physical,
chemical and biological state.
• When two bodies at different temperature, thermal energy transfer
from the one with higher temperature to the one with low temperature.
Heat always transfers from hot to cold.
• Heat transfer is involved:
Sieving, mixing → heat transfer occurs (due to particle colloids/ collisions)
Tablets → Sieving – Mixing – Wetting – Drying – Sieving – Compression.
• it is typically given the symbol “Q” and is expressed in joules in SI units
the rate of heat transfer is measured in watts equals to joules per
Seconds denoted by “q”
• The heat flux, or the rate of heat transfer per unit area measured in
watts per area (W/m
2
) and uses q
n
for the symbol.
• Most common processes requiring heating are dissolving, melting,
evaporation, distribution, extraction, drying lyophilization and
sterilization.
• Temperature is non-additive physical property of material. Quantity of
heat Q is the quantity of energy absorbed or lost after thermal
interaction. The amount of heat Invested in to heating a body, in linear
proportion with mass off material (m) of specific heat (c).
Q=mc ∆t
• Heating can be performed directly or indirectly. Most common direct
heating is done with flame or other heating source. Example: Immersion
heaters, which means a heat transfer without any medium. Indirect heat
transfer with same medium.
5

8. GM Hamad

• Mixing of medium, which should be heated, assists more even and
consistent heat transfer in both cases. At heat transfer, magnitude of
transferred heat several phenomena can occur:
­ Phase transition
­ Polymorphism (property of material to exist in more than one
crystalline form)
­ Pyrolysis
TYPES OF HEAT TRANSFER
1. Conduction
2. Convection
3. Radiation
1. CONDUCTION
• Conduction is the transfer of heat through materials by the direct
contact of matter. Dense metals like copper and aluminum are very
good thermal conductors. The ability to conduct heat often depends
more on the structure of a material than on the material itself.
THERMAL CONDUCTIVITY
• The thermal conductivity of a material describe how well the material
conducts heat.
FOURIER FORMULA FOR CONDUCTION
φ=??????
A
L
∆T
• Where,
­ φ = heat transfer
­ λ = conduction factor
­ A = surface area
­ L = thickness
­ ∆T = temperature difference
CONDUCTION RATE
• Conduction rate is expressed as:
Rate=
Driving force
Resistance

• The temperature difference is driving force and resistance to heat
6

9. GM Hamad

increases by greater thickness and decrease as co-efficient of thermal
conductivities increase and area becomes larger.
RELATIONSHIP B/W CONDUCTIVITY AND RESISTANCE
• Conductivity is inversely proportional to resistance.
k∝
1
R

RESISTANCE OF COMPOUND LAYER
• The resistance of compound layer of material can be calculated as:
R∝L ,R∝
1
k
,R=
L
K

Total Resistence=
L
1+L
2+⋯L
n
K
1+K
2+⋯K
n

• The situation in a compound layer may be
represented in a convenient graphical form
using temperature and thickness as
ordinates, so that relative slopes of the
various sections of the temperature gradient
will be dependent upon the thermal
conductivity of the material of each layer as
shown in figure.
OVERALL COEFFICIENT OF HEAT TRANSFER
• To calculate heat transfer we have to know overall thermal conductivity
which can be obtained by reversing the process i.e. by taking reciprocal
of overall co-efficient of heat transfer "U" having unit w/m
2
k and is
represented by:
U=
1
L
1+L
2+⋯�
??????/�
1+K
2+⋯K
n

• To calculate heat transfer “U” is used instead of K/L, so that:
q=UA ∆T
2. CONVECTION
• Heat transfer by convection occurs due to movement of molecules and
their associated heat on a macroscopic level. It involves mixing of
7

10. GM Hamad

molecules and occurs within fluids where the molecules are free to
move.
HEAT TRANSFER BY NATURAL CONVECTION
• It occurs when there is a density difference within the fluid arising from
greater expansion and hence lower density of the fluid in hotter region.
HEAT TRANSFER BY FORCED CONVECTION
• It occurs when the fluid is forced to move e.g. by the movement of a
mixer blade or disruption caused by baffles.
• Heat transfer occurs more quickly by forced convection than by natural
convection owing to greater intensity of movement and therefore
increased velocity of fluid. Turbulence aids heat transfer.
HEAT CONVECTION EQUATION
• According to Newton's cooling law, specific formula for Convection heat
transfer
φ=αA ∆T
­ α = Convection factor, A = area contacting fluids, ∆T =
temperature difference.
FACTORS AFFECTING HEATING OF FLUIDS
• Factors that affect heat transfer of fluids are as follows:
1. Steam
2. Air film
3. Condensate film
4. Scale
5. Metal wall
6. Liquid film
7. Liquid
DESIGN OF HEATING EQUIPMENT
• Following are parameters to be taken in designing heating equipment:
I. AREA
• Heating should take place over as large surface as possible.
II. TEMPERATURE
• A suitable temperature should be employed because it is directly
proportional to heat transfer.
III. MATERIAL OF CONSTRUCTION
• The plant should be made of suitable thermal conductivity material.
IV. GENERAL DESIGN
8

11. GM Hamad

• The design of plant should be such that it would minimize the resistance
due to surface layer.
V. AIR REMOVAL
• Elimination of air in steam is extremely important.
VI. CLEANLINESS
• The surface of vessel should be clean from deposits of solid.
VII. CONDENSATE REMOVAL
• The system should be arranged to allow correct drainage and removal of
the condensate from the steam.
VIII. LIQUID CIRCULATION
• Liquid movement should be arranged to ensure turbulent flow by
avoiding awkward shape. Stagnation might occur using for circulation if
natural circulation is inadequate due to density or viscosity changes.
3. RADIATION
• Radiation is heat transfer by electromagnetic waves. Thermal radiation is
electromagnetic waves including light produced by objects because of
their temperature. The higher the temperature of an object the more
thermal radiation it gives off.
• A hot body emits heat energy in the form of electromagnetic waves. If it
falls on another body some of the radiation may transmitted, some
reflects and a part is absorbed.
• The quality of emission is dependent on absolute temperature, total
energy, heat, wavelength and intensity.
BOLTZMAN FORMULA
φ=ϵσA??????
• Where,
­ ε = emission capability, σ = radiation constant, T = absolute
temperature.
PHARMACEUTICAL APPLICATIONS OF HEAT TRANSFER
• Heat transfer is involved in many pharmaceutical processes:
­ Melting
­ Creating an elevated temperature during the production of
suppositories, creams and ointments.
­ Controlled cooling of the same products.
­ Heating of solvent to hasten dissolution process E.g. Dissolution of
9

12. GM Hamad

preservatives.
­ Sterilization E.g. Autoclaves.
­ Evaporation of liquids to concentrate the product.
­ Heating or cooling of air in air conditioning plant.
­ Drying of granules during tableting.
­ Heating air to facilitate coating.
­ Spray drying and freeze drying.
STEAM AS HEATING MEDIUM
• Steam is most commonly used in heating the pharmaceutical material to
affect drying and evaporation. In addition, it is most important in
sterilization.
REASONS FOR WIDE USE OF STEAM
• Steam has very high heat contents. Steam is given up at constant
temperature. The raw material water is cheap and plentiful.
• Steam is clean, odorless and tasteless so result of accidental
contamination is not serious.
• The alternative media oil could be very dangerous.
• Steam can be used as high pressure to generate electric power, at low
pressure it can be used for heating purpose.
HEAT IN VAPORS
• Vapors contain heat in 2 forms:
I. SENSIBLE HEAT
• Sensible Heat is that heat which can be detected by senses i.e.
temperature change is caused when heat is given up or given out.
II. LATENT HEAT
• Latent heat means invisible, which cannot be detected by change in
temperature. It is detected at constant temperature as a change of
phase occurs between solid and liquid or vapors.
PROPERTIES OF STEAM
• The properties can be discussed if one kg of water is taken in cylinder
enclosed in a friction less piston at constant temperature and pressure.
• When heat is added until the change occurs like water starts boiling, it
will take place at temperature (t) and amount of heat required is
sensible heat of water i.e. h = t – 0 KJ
• If more heat is added a fraction of water (q) will be vaporized.
10

13. GM Hamad

• If latent heat of vaporization is LKJ/kg then the amount of heat added is
qLKJ and total heat content is (steam water mixture) is h + qLKJ.
• Where q = dryness fraction of wet steam and can be expressed as
percentage or part of 1. Thus, steam may be expressed as 85% or 0.85
dry.
• If further heat is added a point will be reached when q = 1 i.e. all the
water has been evaporated and steam is dried, then total heat now
added is h + L = H x KJ at constant temperature.
PRACTICAL ASPECTS OF USES OF STEAM
• In practice, it is usual for steam to be generated centrally in the factory
and distributed in various items of process plant.
I. GENERATION OF STEAM
• High pressure to drive turbine for generating electric power. Low
pressure steam can be used for heating process. It is more economical.
II. DISTRIBUTION
• From boiler steam may be distributed through pipes which should be of
adequate size and length to avoid losses. The pipe should be (lagged)
cover with porous and poor conducting material like; asbestos or glass
wool. The best property of lagging is that it should be porous to trap a
stagnant layer of air as air is very poor conductor of heat. Sometimes
different layer of aluminum foil are used for insulation.
III. PRESSURE REDUCTION
• Generally, process plant uses steam at a pressure of 1.7-2 bars. So that a
reduction of pressure from boiler is necessary. This is done by reducing
valves. The pressure of spring attempts to open the valve against high
pressure steam. Closing of valve is caused by low pressure steam. A
balance will be reached in which low pressure steam acting on the
diaphragm closes the wall against the spring pressure.
• Expansion at the plant has advantage that some drying of steam can
place due to higher value of latent heat of vaporization at low pressure.
It is also known as throttling.
IV. USE OF STEAM IN PLANT
• It may be:
DIRECT
• In this case live steam is blown directly into the material; it has
advantage of direct efficiency and no boundary resistance to overcome.
11

14. GM Hamad

But the disadvantage is that condensate enters the material. It is useful
method of heating liquid if dilution is not important most specifically
used in steam distillation and sterilization.
INDIRECT
• In this case there is barrier between steam and material to be heated.
• This may be affected by means of jacket around the piece of plant or by
having a steam of coil or tubes through the vessels. The use of steam
jacket is convenient butt has the limitation, if vessel increases in size the
heating area decreases in volume.
V. CONDENSATE REMOVAL
• Indirect method of using steam in jackets or tubes must be enclosed
system to maintain the steam pressure and to prevent loss of steam.
This means condensate forms as steam gives up its latent heat, will
accumulate and water clog the system unless some arrangements are
made for condensate removal.
• Thus, a system must include a steam trap, a device to distinguish
between water and steam allowing former to discharge and later to be
retained. Steam traps may be divides into 2 classes:
MECHANICAL STEAM TRAPS
• It depends upon the critical difference between water and steam or
between vapor and liquid. It has advantage of possessing greater
strength and able to operate under variety of conditions than
thermostatic steam traps.
THERMOSTATIC STEAM TRAPS
• It depends upon that condensate can lose sensible heat and will be at
low temperature then steam. It is different from mechanical traps for
opening when the plant is not in use allowing condensate to drain and
air to sweep out from the system when starting up.
Moreover, mechanical traps are unable to distinguish between air and
steam.
VI. REMOVAL OF AIR
• It may be removed by use of thermostatic type of traps which will
operate when the proportional of air lower steam pressure sufficiently.
In addition, air vent can be used in same principle as in balance pressure
expansion trap.
12

15. GM Hamad

DRYING
DEFINITION
• ‘’A process in which the liquid is removed from a material by the
application of heat and is accomplished by the transfer of a liquid from a
surface into an unsaturated vapor phase’’
• This applies to the removal of small amount of water from moisture
bearing table salt as well as recovery of table salt from sea by
evaporation.
METHODS OF DRYING
• There are many non-thermal methods of drying:
1) Expression: of a solid to remove liquid.
2) Extraction: of liquid from a solid by use of solvent.
3) Adsorption: of water from a solvent by the use of desiccants.
4) Absorption: of moisture of gases by passing through sulfuric acid
(??????
2????????????
4)
5) Desiccation: of moisture from solids by placing it in a sealed
container with a moisture Removing material, (silica gel in a bottle)
THEORY
• It is an important process in almost all the pharmaceutical industries.
There is hardly any pharmaceutical plant engaged in the manufacture of
tablets or capsules, that does not use dryers.
• Drying is commonly last stage of the process before packing and has a
considerable effect on the properties of the product which may prevent
the deterioration, produce a readily soluble or free flowing product.
• Drying involves both heat and mass transfer operation. Heat must be
transferred to the material to be dried in order to supply the latent heat
required for vaporization of moisture. Mass transfer is involved in the
diffusion of water through the material to the evaporating surface, in
the subsequent evaporation of water from the surface and in the
diffusion of the resultant vapor into the passing air stream.
13

16. GM Hamad

• Drying involves:
­ Heat transfer
­ Mass transfer
HEAT TRANSFER
• Heat must be transferred to the material to be direct in order to supply
the latent heat required for the vaporization of the moisture, (phase
change). The rate of vaporization of the liquid film from the surface of
the material being dried depends upon:
dw
dQ(t)
=
q
λ

­ Where, dw/dt = rate of evaporation, 1b of H2O/hr, q = overall
rate of heat transfer, λ = latent heat of vaporization of water.
• Heat transfer takes place by:
­ Conduction
­ Convection
­ Radiation
• It means overall rate of heat transfer depends upon the sum of rate of
heat transfer by c, r, and k
S;q=qc+qr+qk
dw
dt
=qc+qr+qr/pi
­ Where, qk, qc and qr are the rate of heat transfer by conduction,
convection and radiation, respectively.
MASS TRANSFER
• Mass transfer involves:
­ Diffusion of water through the surface to the evaporation surface.
­ The subsequent evaporation of water from the surface.
­ The diffusion of resultant vapor into the passing air stream.
• Rate of diffusion of vapor into passing air stream depends on following
factors:
­ Area of evaporating surface (A)
­ Humidity difference (Hs-Hg)
14

17. GM Hamad

So,
dw
dt
∝A (Hs−Hg)
dw
dt
=KA (Hs−Hg)
­ Hs = absolute humidity of surface, Hg = absolute humidity of air
­ Where, K = coefficient of mass transfer, is not a constant but
depends upon volume of air stream passing over the surface as:
k∝V
??????

k=C V
??????

­ Where, V = volume, C = proportionality constant, n = fractional
exponent.
• After the start of drying there will be a production of initial adjustment.
After that, the rate of evaporation of liquid from the surface is equal to
the rate of diffusion of liquid from the body of solids. Which depends on
rate of heat transfer. So, the rate of heat transfer becomes equal to the
rate of mass transfer.
qc+qr+qk=KA (Hs−Hg)
Rate of diffusion
dw
dt
=K′A (Hs−Hg)
METHOD TO INCREASE RATE OF DRYING
• From the above equation we can increase the rate of by following ways:
­ By increasing qC: the rate of convection heat transfer qC can be
increased by increasing the air flow rate and raising the air inlet
temperature.
­ By increasing qr: the rate of radiation transfer can be speed up by
introducing the high temperature radiant heat source into the
drying chamber.
­ By increasing qk: by reducing the thickness of material being dried
and by allowing it to come in contact with the raised temperature
surface.
15

18. GM Hamad

­ By increasing K: increasing the air volume also speeds up the rate
of drying by increasing the coefficient of mass transfer K.
­ By increasing (Hs-Hg): if inlet air is determined, humidity gradient
can be increased which is other mean of speeding up the rate of
drying.
GENERAL CLASSIFICATION OF THE DRYERS
CLASSIFICATION BASED ON METHOD OF SOLID HANDLING
I. STATIC BED DRYERS
• Tray & Truck Dryers
• Vacuum Shelf Dryers
• Tunnel Dryers
• Belt Dryers
• Drum Dryers
II. MOVING BED DRYERS
• Turbo Tray Dryers
• Rotary Dryers
• Vibratory Conveyor
Dryers
• Vacuum Tumble Dryers
• Pan Dryers
III. FLUIDIZED BED DRYERS
• Vertical Dryers • Horizontal Dryers
IV. PNEUMATIC DRYERS
• Spray Dryers • Flash Dryers
V. SPECIALIZED DRYERS
• Freeze Dryer
CLASSIFICATION BASED ON HEAT TRANSFER MODE
I. CONVECTION
• Flash Dryer
• Spray Dryer
• Fluid Bed Dryer
• Cabinet Dryer
• Tunnel Dryer
• Rotary Dryer
II. CONDUCTION
• Drum Dryer
• Agitated Pan Dryer
• Rotary Dryer
• Tray Dryer
III. RADIATION
• Infrared Shelf Dryer • Sun Dryer
IV. DIELECTRIC
• Microwave Oven
• Microwave Tunnel
• Radiofrequency Dryer
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19. GM Hamad

V. COMBINED MODES
• Microwave Convective Dryer
• Infrared Convective Dryer
1. STATIC BED SYSTEM
I. TRAY AND TRUCK OR SHELF DRYERS
• They are also known as cabinet or compartment dryers. There are
usually hot air ovens.
PRINCIPLE
• In these types of dryers there is no static relative movement among the
solid particles being dried. Only a fraction of a total number of particles
is directly exposed to the heat sources.
• The exposed surface can be increased by decreasing the thickness of the
bed.
DESIGN AND WORKING
TRAY DRYERS
• Tray dryers consist of a cabinet in which the material to be dried is
spread on trays. The number of trays varies with the size of dryer.
• Dryers of laboratory size may contain as few as three trays.
TRUCK DRYER
• Truck dryer is one in which the trays are located in trucks which can be
rolled into and out of the drying cabinet in pharmaceutical industries.
Truck dryers are preferred over tray dryers because of convenience in
loading and unloading the drying cabinets.
TYPES OF TRAY DRYERS
DIRECT DRYER
• Most tray dryer used in pharmaceutical industry are direct dryers, in
which heating is accomplished by the forced circulation of large volume
of heated air.
INDIRECT DRYER
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20. GM Hamad

• They utilize heated shelves inside the drying chamber to evaporate the
moisture which is then removed by vacuum pump. The preferred
energy source for heating the drying air used on pharmaceutical
products are steam or electricity. Steam is preferred over electricity
because steam energy is cheaper.
ADVANTAGES
• Drying by tray dryer is a batch process rather than continuous drying in
industry, batch drying is preferred because each batch can be dried
separately.
• Same equipment can be used for drying a wide variety of materials.
• Used for damp solid material drying.
DISADVANTAGES
• Only few particles are exposed to heat.
• Electricity cost is high.
II. TUNNEL DRYER
• It is a modification of tray dryer in which oven Is replaced by a long
tunnel.
OPERATION
• The material to be dried is entered at one end and the dried material is
collected at the other end of the tunnel. The trays containing the wet
material is loaded on trucks which have an automatic speed control.
• In the multiple belt conveyer system, the partially dried material which
has completed one side moves automatically from the end of 1
st

conveyer on to the 2
nd
conveyer moving in opposite direction. In this
way the product may successfully travel five times along the tunnel
before its discharged at the other end of the tunnel.
ADVANTAGES AS COMPARED TO TRAY DRYERS
• It is semi continuous in operation and can be used for the large-scale
production.
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21. GM Hamad

2. MOVING BED SYSTEM
I. TURBO TRAY DRYERS
PRINCIPLE
• Drying particles are partially separated so that they flow over each
other. Motion may be induced either by gravity or mechanical agitation.
DESIGN AND WORKING
• Turbo dryer consist of a series of rotating angular
trays arranged in vertical stack. Heated air is
circulated over the trays by turbo-type fans. Wet
mass fed through the roof of the dryer and is leveled
by a stationary wiper. After about 7-8 of the
revolution the material being dried onto the tray
below where it is again spread and leveled. The
same procedure is continued throughout the height
of the dryer until the dried material is discharged at
the bottom.
ADVANTAGES
• Because turbo dryers continuously expose new surfaces to air, drying
rates are considerably faster than tray dryers.
DISADVANTAGES
• Expensive, Complicated.
II. ROTARY DRYERS
• The rotary dryer is modified form of tunnel dryer in which particles are
passed through a rotating cylinder, counter current to stream of heated
air. Due to the rotation of cylinder, the material is turned over and
drying takes place from individual particles and not from a static bed.
• The cylindrical shell is mounted with a slight slope so as to discharge the
material and make the operation continuous. Baffles or flights in the
shell may increase the rate of drying.
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22. GM Hamad

3. FLUIDIZED-BED SYSTEMS
• If a gas is allowed to flow upward through a bed of particulate solids at a
velocity greater than the settling velocity of the particles and less than
the velocity for pneumatic conveying, the solids are buoyed up and
become partially suspended in the gas stream.
• The resultant mixture of solids and gas behaves like a liquid, and the
solids are said to be fluidized.
• This is used for the granular solids because each particle is surrounded
by the drying gas.
PRINCIPLE
• Solid particles are partially suspended in an upward moving gas stream.
The particles are lifted and then fall back in a random manner, so that
the resultant, mixture of solid and gas acts like a boiling liquid and the
solid are said to be fluidized.
• This technique is very useful and efficient and it is used for drying
granular solids because each particle is surrounded by the drying gas.
TYPES OF FLUIDISED BED DRYERS
VERTICAL
• Used for batch drying.
HORIZONTAL
• Used for continuous drying.
DESIGN
• It consist of stainless-steel chamber
with a perforated bottom into which
the wet material to be dried is placed.
For loading and unloading, the drying
chamber is removed from the unit.
The air is introduced from below
which is heated by means of heaters
fitted there in and it is then passed
through the powder by means of fan
fitted in the upper part of the
apparatus.
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23. GM Hamad

REQUIREMENT
• The requirement is that:
­ Granules are not so wet that they stick together on drying.
WORKING
• The air is heated to the required temperature and its flow rate is
adjusted as the velocity of air is increased, the bed begins to expand.
• Further increase in velocity beyond this point will cause rapid expansion
of the bed and particles will begin to show turbulent motion.
FLUIDISATION
• The particles are not in direct contact with each other and efficient heat
exchange take place between the particles and the following air. The
moist air is carried away rapidly.
PURPOSE
• The purpose of this SOP is to describe the procedure to be followed
while operating the Fluid Bed Dryer to achieve the following objectives:
­ To fulfill the GMP requirement.
­ For personnel and machine safety.
­ For efficient operation.
­ To ensure proper washing and cleaning of equipment to produce
quality products.
SCOPE
• This SOP is valid for the Production department of SRP Plant.
PERSONNEL
• Wear mask, gloves and specified gown during all operations.
PRECAUTIONS
• During drying if lumps are observed, switch off the dryer. Take out the
trolley and paddle the product container, so to break the lumps and
level the product bed in the trolley.
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24. GM Hamad

• Observe that granules should not be over fluidized so as to avoid
attrition of granules.
STARTING
• Connect the air and electric supply.
• Load the Fluid Bed Dryer Bowl with product.
• The quantity should be appropriate for good fluidization.
• Introduce trolley into the space meant for it properly.
• Assure that bowl is well fitted in its space in the dryer.
RUNNING
• Adjust the drying temperature.
• Check that the product is completely fluidized then reduce the air flap
level until fluidization is just maintained.
• Observe that the granules are in fluidized state.
• If needed, press the shake device so as to maintain fluidization.
• Close the air flap and switch off the dryer, press shake device so if any
product that is remained in the filter should slide down into the trolley.
• Take out the trolley and observe the granules.
• Transfer the dried granules or material from Fluid Bed Dryer trolley into
polyethylene lined labeled drums.
ENDING (CLEANING)
• After completion of drying process, remove the trolley from dryer.
• Collect the dried granules in polyethylene lined labeled drums by means
of scoop.
• Clean and wash the trolley with hot water.
• Clean thoroughly inner and outer side of dryer with clean duster.
• In case of product change over, remove the filter ring and clean it.
• Wash the top and bottom of dryer thoroughly with hot water to remove
the traces of previous product.
• Also wash the trolley with hot water.
• Finally rinse with purified water.
ADVANTAGES
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25. GM Hamad

• They are efficient as 5-200kg material can be dried within 20-40 mins
compared with 24 hours in tray dryers
• Drying takes place from individual particles and not from whole bed
• The temperature of fluidized bed dryer can be controlled
• A free-flowing product is produced
• Due to short drying time unit has high output
• No caking or agglomeration
• Drying from all sides and not only surface.
DISADVANTAGES
• Complicated
• Skilled persons are required
• Too wet granules stick together
• Overheating causes brittle granules and tablet defects occur.
• Many organic powders develop electrostatic charges during fluidization
so efficient electrical earthing is necessary.
4. PNEUMATIC BED SYSTEM
SPRAY DRYERS
• They are used for drying only liquid materials such as solution, slurries,
pastes and suspensions.
PRINCIPLE
• In this method, the liquid is dispersed as fine droplets into a moving
stream of hot air, where they are evaporated rapidly before reaching the
wall of chamber. The product dries into a fine powder which is collected
into a collection system.
DESIGN
• All spray dryers consist of following components:
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26. GM Hamad

­ Feed delivery system
­ Drying chamber
­ Solid gas separator
­ Atomizer
­ Heated air supply
­ Product collector
­ Cyclone
WORKING
• The liquid to be dried is fed to atomizer by use of suitable pump. The
rate of feed adjusted in such a way that each droplet of sprayed liquid is
completely dried before reaching the walls of drying chamber and yet
the dried powder is not overheated in the process.
• The inlet air temperature is kept constant. Too high temperature can
result in improper drying. Similarly, excessive feed rates will lower the
outer temperature due to which the material will be collected on the
walls of the chamber.
• The disc of atomizer D is driven by an air turbine and spins at 35000 rpm.
Air is introduced with help of fan which is heated by means of electric
heaters to a maximum temperature of 350℃. The spray droplets from
atomizer come in contact with the hot air.
• The droplets rapidly evaporate in the drying chamber. The dried powder
is separated from the gas in cyclone separator and collected in
container.
ADVANTAGES
• Liquid material can be dried
• Drying is very rapid and fast
• Thermostable substances can easily be dried
• Sterile solution can be dried
• The dried powder will have uniform particle size and shape
• Powder formed has good flow properties
• Labor cost are low
• Material up to 200 kg per hour can be handled.
DISADVANTAGES
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27. GM Hamad

• The equipment is very bulky and costly
• There is a lot of wastage of heat.
5. SPECIALIZED DRYERS
FREEZE DRYING
• It is process by which water is removed from the liquid product after it is
frozen by sublimation. Hence this is also known as FREEZE DRYING or
SUBLIMATION.
PRINCIPLE
• Liquid is first frozen to ice before application of vacuum to avoid
frothing, then sublimation of frozen ice is carried out under reduced
pressure.
• The vaporization of ice occurs only at the surface; hence the frozen ice is
exposed to large surface area.
PROCEDURE
• Freeze drying on large scale may be carried out by freezing the product
in a container kept on the shelf of a chamber by circulating a refrigerant
like ammonia or ethylene glycol from the compressor through the pipes
fitted along the series of shelf.
• When freezing is complete; vacuum is applied to the chamber which has
been previously chilled by means of circulating the refrigerant from
large compressor.
• Heat is then supplied to the product by heating coils. The process is
continued till the product is dry and a spongy solid material is left
behind which is collected in container.
APPLICATIONS
• For the manufacturing of certain pharmaceuticals or biological products
which are thermolabile.
• For drying blood plasma, vitamins, hormones, enzymes and antibiotics,
thus preserving these for years.
• Freeze dried products have definite physical properties as compared to
other products derived by other methods.
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28. GM Hamad

• Freeze dried products are more stable and are readily soluble.
DISADVANTAGES
• Slow process
• Very costly
6. VACUUM DRYERS
• Also known as vacuum oven. It consists of jacketed vessel. It has to
withstand vacuum in the oven and steam present in the jacket.
• Oven and dryer can be loaded with air-tight seal. It is connected to a
vacuum pump through a condenser and receiver.
• At a vacuum of 0.03 to 0.06 bar water boils at 350℃.
ADVANTAGES
• Very suitable for heat sensitive products
• Porous and friable product is obtained
• Valuable solvents can be recovered
DISADVANTAGES
• Heat transfer may be low and non-uniform
• Limited capacity
• Labor and running costs are high
• Finely divided powder may be drawn into the vacuum pump.
APPLICATIONS OF DRYING
• Drying is an important process which is used by almost all the
pharmaceutical industries.
• Drying has following applications in pharmacy:
1. For the preparation of granules which can be dispensed in bulk,
compressed in the form of tablets or filled in capsules.
2. For the preparation of certain products like dried aluminum
hydroxide, dried lactose cad powdered extracts.
3. For reducing the bulk and weight of powder and thus reducing the
cost of transportation and storage.
4. Vegetable drugs are dried before extraction to facilitate grinding
and to avoid deterioration on storage.
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29. GM Hamad

5. As dried products are more stable than moist ones so stable
products are produced by drying.
6. Drying has the considerable effects on the properties of product
and it produces a readily soluble and free flowing products.
7. Thermolabile substances can be dried using spray dryer.
DRYING OF SOLIDS
1. LOSS ON DRYING
The moisture in a solid can be expressed on a wet weight or dry weight
basis. On wet weight basis, the water content of a material and is calculated
as a percentage of weight of the wet solid. whereas on the dry weight basis,
the water is expressed as a percentage of weight of the dry solid. The term
loss on drying is an expression of moisture content on a wet weight basis,
calculated as:
%LOD=
Weight of water in sample
Weight of wet sample
⨯100
2. MOISTURE BALANCE
• The LOD of a wet solid is often determined by the use of moisture
balance, which has a heat source of rapid heating and a scale calibrated
in percent LOD.
• A weigh sample is placed on a balance and is allowed to dry until a
constant weight is achieved. The water lost by evaporation is read
directly from the percent LOD scale. It is assumed that there are no
other volatile materials present.
3. MOISTURE CONTENT
• Another measurement of the moisture in a wet solid is that calculated
on a dry weight basis. This value is referred to as moisture content or
MC, calculated by:
%MC=
Weight of water in sample
Weight of dry sample
⨯100
• LOD value can vary in any solid fluid mixture from slightly above 0 to
above 100%. But the MC value can change from slightly above 0 and
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30. GM Hamad

approach infinity. Thus, percent MC is a far more realistic value than
LOD, in the determination of dryer and capacity.
BEHAVIOR OF SOLIDS DURING DRYING
• It helps in determine:
­ Time required to dry a certain batch in given dryer
­ Size of dryer required for certain drying process.
• It is done by using a cabinet with a weighing scale provided that
conditions are of a large dryer and are properly simulated. The
information's obtained in drying in such an environment can be plotted
on a graph between moisture contents and drying rate.
1. INITIAL ADJUSTMENT
• When a wet solid is first placed in an oven, it undergoes initial
adjustment to the environment. During the production, it absorbs heat
and at the same time losses some moisture. Drying rate begins to
increase.
2. CONSTANT RATE PERIOD
• Temperature remains constant, moisture evaporating from solid surface
is replaced by more moisture which diffuses through capillary force, as a
result drying rate remains constant.
3. FIRST FALLING RATE PERIOD
• At this point, the speed at which moisture evaporates from the surface
exceeds the speed at which moisture diffuses to surface from the
bottom. Hence, a continuous drying cannot be maintained. As a result,
dry spots are formed. The moisture content at which this occurs is
termed as “Critical Moisture Content” With the passage of time, the no.
of dry spots keeps on increasing. Hence, during this stage, rate falls
steadily. This period is also termed as unsaturated surface drying.
4. SECOND FALLING RATE PERIOD
• The whole solid surface dries out and the rate of drying depends upon
diffusion of the moisture to the surface which is very low. Therefore,
rate of drying falls even more sharply than in the previous period. Point
D is referred to as 'second critical point’
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31. GM Hamad

5. EQUILIBRIUM MOISTURE CONTENT
• Drying rate = 0, then an equilibrium is attained between moisture
content in the solid and in the air. There cannot be any further loss of
moisture and any further heating will be useless.
GRAPH BETWEEN MOISTURE CONTENTS AND DRYING RATE

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32. GM Hamad

COMMINUTION (SIZE REDUCTION)
MILLING
• “Milling is the mechanical process of reducing the particle size of solids.”
• Various terms (commination, crushing, disintegration, dispersion,
grinding, and pulverization) have been used synonymously with milling
depending on the product, equipment and the process.
• Milling equipment is usually classified as coarse, intermediate or fine
according to the size of the milled product.
WHY MILLING? / IMPORTANCE OF MILLING
• Milling or grinding offers a method by which these particles can be
produced.
• The surface area per unit weight, which is known as the specific surface,
is increased by size reduction. In general, a 10-fold increase in surface
area has been given by a 10-fold decrease in particle size. This increased
surface area affects:
I. DISSOLUTION AND THERAPEUTIC EFFICACY
• Dissolution and therapeutic efficiency of medicinal compounds that
possess low solubility in body fluids are increased due to increase in the
area of contact between the solid and the dissolving fluid.
EXAMPLES
• The control of fineness of griseofulvin led to an oral dosage regimen half
that of the originally marketed product.
• In inhalational products, the size of particles determines their position
and retention in the bronchopulmonary system.
• Transdermal delivery is also facilitated by particle size reduction.
II. EXTRACTION
• Extraction or leaching from animal glands (liver and pancreas) and crude
vegetable drugs is facilitated by communition. The control of particle
size in the extraction process provides for more complete extraction and
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33. GM Hamad

a rapid filtration rate when the solution is filtered through the mare.
III. DRYING
• The drying of wet masses may be facilitated by milling, which increases
the surface area and reduces the distance that the moisture must travel
within the particle to reach the outer surface. Micronization and
subsequent drying also increases the stability because the occluded
solvent is removed.
EXAMPLE
• In the manufacture of compressed tablets by wet granulation process,
the sieving of the wet mass is done to ensure more rapid and uniform
drying.
IV. FLOWABILITY
• The flow property of powders and granules is affected by particle size
and size distribution. The freely flowing powders and granules in high-
speed filling equipment and tablet presses produce a uniform product.
For suspensions of high disperse phase concentration, reduction in
particle size leads to increase in viscosity.
V. MIXING OR BLENDING
• The mixing or blending of several solid ingredients of a pharmaceutical is
easier and more uniform if the ingredients are of approximately the
same size. This provides a greater uniformity of dose.
• Solid pharmaceuticals that are artificially colored are often milled to
distribute the coloring agent to ensure that the mixture is not mottled
and uniform from batch-to-batch. Even the size of a pigment affects its
color.
VI. FORMULATION
• Lubricants used in compressed tablets and capsules function by virtue of
their ability to coat the surface of the granulation or powder. A fine
particle size is essential if the lubricant is to function properly.
VII. RATE OF ABSORPTION
• Smaller the particle size quicker and greater will be the rate of
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34. GM Hamad

absorption. For example: rectal absorption of aspirin from a theobroma
oil suppository is also related to particle size.
VIII. EMULSION STABILITY
• Stability of emulsions is increased by decreasing the size of oil globules.
E.g. microemulsions are more stable.
IX. FILLING EQUIPMENT
• The flowability of powders, granules in high speed filling equipment and
in tablets presses is dependent upon size of particles.
X. LUBRICANTS
• A fine particle size is necessary if a lubricant is to function properly in
compressed tablets or capsules.
DISADVANTAGES OF SIZE REDUCTION
• Loss of aromatic and volatile ingredients: On grinding aromatic and
volatile content of crude drugs maybe lost ducts elevated temperature.
• Increased oxidation and reduction: Increased surface area due to size
reduction when exposed to atmospheric conditions may result in
oxidation and hydrolysis of the product.
• Caking in suspension due to small particles.
• Decrease in flow ability due to decrease in particle size.
• Very fine particles are not favorable for tablet preparation.
• Surface gets charged and particles aggregate.
• Some drugs degrade on milling.
• Some drugs melts upon milling due to increased temperature during
milling.
• Polymorphism occurs and crystal’s habit is changed.
FACTORS INFLUENCING MILLING
I. HARDNESS
• It is the surface property of the materials in general; harder the material
difficult is to reduce the size. However, if the material is very hard and
brittle also the size reduction may present no special problem.
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35. GM Hamad

II. TOUGHNESS
• A soft but tough material may present more problems in size reduction
then hard and brittle substances. E.g. a blackboard chalk can be broken
more easily than a rubber. Toughness can be reduced by treating the
material with liquefied gas such as nitrogen.
III. ABRASIVENESS
• It is the property of hard materials. During grinding of some very
abrasive substances, the final powder may become contaminated with
more than 0.1% of metal worn from grinding mill.
IV. STICKINESS
• It may cause considerable difficulty in size reduction as materials may
adhere to grinding surfaces or the meshes of screen may become
choked. Complete dryness helps milling. Addition of inert substances
could be assistance e.g. addition of kaolin to sulfur and DDT has been
advantageous.
V. SOFTENING TEMPERATURE
• Heat generated during milling can cause some substances to melt thus
causing problems. E.g. gummy or resinous substances.
VI. MATERIAL STRUCTURE
• Material structure may have lines or weakness along which the material
splits to form flake like particles.
VII. MOISTURE CONTENT
• In general, materials should be dry or wet; not merely damp. For dry
grinding less than 5% moisture is suitable when for wet grinding more
than 50% moisture is suitable.
VIII. PHYSIOLOGICAL EFFECT
• For potent drugs e.g. podophyllum, hormones, small amount of dust
may affect the operators, thus and enclosed mill should be used.
IX. PURITY REQUIRED
• When high degree of purity of product is designed, apparatus causing
wear off the grinding surface should be avoided.
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36. GM Hamad

X. SIZE OF FEED MATERIAL
• For very fine product it may be necessary to carry out the size reduction
in several stages depending upon the size of feed material. E.g.
preliminary crushing followed by coarse grinding and then fine grinding.
XI. BULK DENSITY
• The capacities of most batch mills depend on volume, thus the output of
machine is related to bulk density of the substances.
PARTICLE SIZE DISTRIBUTION (PSD)
• The particle-size distribution (PSD) of a powder, or granular material, or
particles dispersed in fluid, is a list of values or a mathematical function
that defines the relative amount, typically by mass, of particles present
according to size.
• It has a specific range i.e. between 1-100um. Average is always taken out
by mean and median.
EXAMPLE
• For a powder if we take reference of 10um then D10 = 10% particles are
of 10um and remaining 90% are greater than 10um (coarse powder)
• D50 = 50% particles are of 10um and remaining 50% are greater than
10um (fine powder)
• D90 = 90% particles are of 10um and remaining 10% are greater than
10um (very-fine powder)
SIZE ANALYSIS
• Particle size analysis, particle size measurement, or simply particle sizing
is the collective name of the technical procedures, or laboratory
techniques which determines the size range, and/or the average, or
mean size of the particles/ particle size distribution in a powder or liquid
sample.
SIEVING
• Sieving is the most widely used method for measuring particle size
distribution because it is inexpensive, simple, and rapid with little
variation between operators. Although the lower limit of application is
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37. GM Hamad

generally considered to be 50 microns, micromesh sieves are available
for extending the lower limit to 10 microns.
• A sieve consists of a pan with a bottom of wire cloth with square
openings. The procedure involves the mechanical shaking of a sample
through a series of successively smaller sieves and the weighing of the
portion of the sample retained on each sieve. The type of motion
influences sieving: vibratory motion is most efficient, followed
successively by side-tap motion, bottom-tap motion, rotary motion with
tap, and rotary motion.
• The B.P. specifies five grades of powder are:
Grade of powder Sieve through which all particle must pass
Coarse 10
Moderately coarse 22
Moderately fine 44
Fine 85
Very fine 120

NUMBER OF SIEVES
• This is the number of meshes in a length of 25.4 mm (1in) in each
direction parallel to the wires.
OTHER METHODS
• Sedimentation Methods
• Elutriation Techniques
• Microscopic Sizing and Image Analysis
• Electrical Impedance Method
• Laser Diffraction Methods
THEORY OF COMMINUTION
STRESS-STRAIN CURVE
• Compression at any point along the line below the yield value, the
material
will go back and returns to its original shape and this is called elastic
deformation. However, compression above the yield value will result in
plastic deformation in which the substance break down and not go back
to its original shape after removing stress.
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38. GM Hamad

GRIFFITH THEORY
• The Griffith theory of cracks and flaws assumes that all solids contain
flaws and microscopic cracks, which increase the applied force according
to the crack length and focus the stress at the atomic bond of the crack
apex.
• The Griffith theory may be expressed as:
T=√
Yϵ
c

• Where, T is the tensile stress, Y is the Young's modulus, ?????? is the surface
energy of the wall of the crack and c is the critical crack depth required
for fracture
ENERGY OF COMMINUTION
• The energy required to reduce the size of particles is inversely
proportional to the size raised to some power. This general differential
equation may be expressed mathematically as:
dE
dD
=−
C
D
n

• Where, dE is the amount of energy required to produce a change in size,
dD, of unit mass of material, and C and n are constants.
KICK'S LAW
• In 1885, Kick suggested that the energy requirement, E, for size
reduction is directly related to the reduction ratio (D1/D2). Kick's theory
may be expressed as:
E=Cln
D
1
D
2

• Where, D1 and D2 are the diameters of the feed material and discharged
product, respectively. The constant C may be regarded as the reciprocal
efficiency coefficient.
• Kick's equation assumes that the material has flaws distributed
throughout its internal structure that are independent of the particle
volume.
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39. GM Hamad

RITTINGER'S LAW
• In 1867, von Rittinger proposed that the energy required for size
reduction is directly proportional to the increase in specific area surface
as expressed by the following relationship:
??????=??????
1(??????
2−??????
1)
• Where, k1 denotes the relationship between the particle surface and
diameter, and S1 and S2 are the specific surface before and after milling,
respectively.
• In terms of particle diameters:
E=C
′
[
1
D
2
−
1
D
1
]
• It is most applicable to brittle materials. Rittinger’s theory ignores
particle deformation before fracture although work is the product of
force and distance.
BOND'S LAW
• In 1952, Bond suggested that the energy required for size reduction is
inversely proportional to the square root of the diameter of the product.
This may be expressed mathematically as:
W
tα 1/√D
2
• Where, Wt is the total work of comminution in kilowatt hours per short
ton of milled material, and D2 is the size in micrometers through which
80% by weight of the milled product will pass.
MILLING RATE
• The mass and size of particles and the time in the mill affect the milling
rate. It has been reported that batch milling of brittle materials in small
mills follows the first-order law. The original particles are fractured to
produce first-generation particles, which are then fractured to produce
second-generation particles, which are also fractured, and so on.
MECHANISM OR COMMINUTION
• Mills are equipment designed to impart energy to the material and
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40. GM Hamad

cause its size reduction. There are four main methods of effecting size
reduction, involving different mechanisms:
I. CUTTING
• It involves application of force over a very narrow area of material using
a sharp edge of a cutting device.
II. COMPRESSION
• In compression, the material is gripped between the two surfaces and
crushed by application of pressure.
III. IMPACT
• It involves the contact of material with a fast-moving part which imparts
some of its kinetic energy to the material. This causes creation of
internal stresses in the particle, there by breaking it.
IV. ATTRITION
• In attrition, the material is subjected to pressure as in compression, but
the surfaces are moving relative to each other, resulting in shear forces
which break the particles.
EQUIPMENTS
• A mill consists of three basic parts:
­ Feed chute, which delivers the material
­ Grinding mechanism, usually consisting of a rotor and stator
­ A discharge chute.
• The principle of operation depends on cutting, compression, impact
from a sharp blow, and attrition. In most mills, the grinding effect is a
combination of these actions.
OPEN-CIRCUIT MILLING
• If the milling operation is carried out so that the material is reduced, to
the desired size by passing it once through the mill, the process is known
as open-circuit milling.
CLOSED-CIRCUIT MILL
• A closed-circuit mill is the one in which the discharge from the milling
chamber is passed through a size-separation device or classifier and the
oversize particles are returned to the grinding chamber for further
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41. GM Hamad

reduction of size. Closed-circuit operation is most valuable in reduction
to fine and ultra-fine size.
CLASSIFICATION TREE OF MILLS









1. CUTTER MILL
PRINCIPLE
• The basic principle of cutter mill is Cutting and shearing.
CONSTRUCTION
• The rotary knife cutter has a horizontal rotor with 2
to 12 knives spaced uniformly on its periphery turning
from 200 to 900 rpm and a cylindrical casing having
several stationary knives. The bottom of the casing
holds a screen that controls the size of the material
discharged from the milling zone.
• A disc mill consists of two vertical discs, each may be
rotating in the opposite directions (double-runner
disc mill), or only one may be rotating (single-runner
disc mill), with an adjustable clearance. The disc may be provided with
cutting faces, teeth, or convolutions. The material is pre-milled to
approximately 40-mesh size and is usually suspended in a stream of air
or liquid when fed to the mil.
• Cutting mills are used for tough, fibrous materials and provide a
successive cutting or shearing action rather than attrition or impact.
Mills
Cutting
Cutter
Compression
Roller
Colloid
Edge and end
runner
Impact
Hammer
Attrition
Pin
Ball
Vibro-energy
Fluid energy
Spiral jet
Homogenization
Simple
Silver son
Ultrasonic
High pressure
Microfluidizer
Low-pressure cyclone
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42. GM Hamad

WORKING
• Feeding of particle in the mill through the hopper. Milling is done
through the movement of rotating knives against stationary knives. Size
reduction occurs by fracture of particles between two sets of knives. The
screen retains the particles until a sufficient degree of size reduction
occurs.
OPERATION
• The feed size should be less than 1 inch in thickness and should not
exceed the length of the cutting knife. For sizes less than 20-mesh, a
pneumatic product-collecting system is required. Under the best
operating conditions, the size limit of a rotary cutter is 80-mesh.
USES
• Used to obtain a coarse degree of size reduction of soft materials such as
roots and peels before its extraction.
• Cutter mill is used for size reduction of tough & fibrous material like
animal tissues, medicinal plants, and plant parts. It is also used in the
manufacture of rubber, plastics and plastic material.
LIMITATIONS
• Not used for friable materials.
• The fed size should be less than 1 inch thick & should not exceed the
length of the cutting knife.
• The material is pre-milled and is usually suspended in a stream of air or
liquid when fed to the mill.
2. ROLLER MILLS
PRINCIPLE
• Roller mills consist of two to five smooth rollers operating at different
speeds. Thus, size reduction is effected by a combination of compression
and shearing action.
CONSTRUCTION AND WORKING
It consists of one or more rollers and is commonly used. Of these, the three-
roller types are preferred. In operation, rollers composed of a hard, abrasion-
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43. GM Hamad

resistant material, and arranged to come into close
proximity to each other are rotated at different rates.
Depending on the gap, the material that comes
between the rollers is crushed, and also sheared by the
difference in rates of movement of the two surfaces.
USES
• For crushing seeds before extraction of fixed oil
• Used to crush soft tissue to help in penetration of solvents.
VARIANTS
• Multiple smooth rollers or corrugated, ribbed, or saw-toothed rollers
can provide cutting action also
3. COLLOID MILL
PRINCIPLE
• The basic principle of colloid mill is compression and shearing.
CONSTRUCTION
I. ROTOR AND STATOR
• A high-speed rotor, fixed to the housing with a
shaft. Rotor moves at the speed of 3000-20,000
rpm. Rotor is with conical milling surfaces. Just
under the rotor, there is stator.
• Rotors and stators may be either smooth-
surfaced, or rough-surfaced. With smooth-
surfaced rotors and stators, there is a thin,
uniform film of material between them which is
subjected to maximum amount of shear. Rough-surfaced mills add
intense eddy currents, turbulence, and impaction to the shearing action.
Rough-surfaced mills are useful with fibrous materials because fibers
tend to interlock and clog smooth-surfaced mills.
II. MOTOR
• It rotates the rotor.
III. ADJUSTABLE CLEARANCE
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44. GM Hamad

• The gap between rotor and stator is fitted with adjustable clearance that
can be adjusted from 0.002-0.03 inches.
IV. HOPPER
• Just above the rotor, is a hopper for material input.
V. OUTLET
• In the periphery of housing, is an outlet for discharge of material.
WORKING
• It works on the principle of shearing consisting of conical rotor and
stator. A colloid mill consists of a high-speed rotor (3,000 to 20,000 rpm)
and a stator with conical milling surfaces between which an adjustable
clearance ranging from 0.002 to 0.03 inches is present.
• The material to be grounded should be pre-milled as finely as possible to
prevent damage to the colloid mill. The reduced material is then fed into
the machine through a hopper which is thrown outward by centrifugal
action. As the material pass through a narrow gap between rotor and
stator its size is reduced.
USES
• These are used primarily for the comminution for solids and dispersion
of suspensions containing wetted solids and preparations of viscous
emulsions.
ADVANTAGES
• Products with particle size less than 1um can be obtained.
• Useful for preparing pharmaceutical syrup, emulsions, lotions, ointments
and creams.
• Size reduction is always carried out in the presence of liquid.
DISADVANTAGES
• Not applicable for processing dry materials.
• Materials need to be milled previously.
• Suspensions may be aerated due to colloid mill.
4. EDGE-AND END-RUNNER MILL
EDGE RUNNER MILL
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45. GM Hamad

OTHER NAMES
• Chaser mill
PRINCIPLE
• It is basically a mechanical pestle and mortar for large scale production.
The basic principle of Edge-runner Mill is compression due to the weight
of the pestle and shear.
CONSTRUCTION
• It consists of the following parts:
­ Rollers
­ Shafts
­ Bed or base
­ Adjustable clearance
• The edge-runner mill consists of one or two heavy
granite or cast-iron wheels or mailers mounted on a horizontal shaft and
standing in a heavy pan.
I. ROLLERS
• Two heavy, steel or granite wheels revolve or chase each other on a
steel or granite the base giving the name chaser mill. The stone may be
as heavy as six tons and having a diameter of 0.5 to 2.5m.
• The large size roller may weigh up to 6 tons.
II. SHAFTS
• The rollers are mounted on a horizontal shaft and turns around a vertical
shaft.
III. BED OR BASE
• Made up of steel or granite. Usually the wheels are rotated but
sometimes the base is made to rotate.
IV. ADJUSTABLE CLEARANCE
• The height between the rollers and the base determines the particle size
of the material hence the fineness of the particles can be increased or
decreased by adjusting the height.
WORKING
• The material is fed into the center of the pan and is worked outward by
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the mulling action. Milling occurs by compression, due to the weight of
the muller, and by shearing.
• Both mills operate at slow speeds on a packed bed. Both produce
moderately fine powders and operate successfully with fibrous
materials. Wet grinding with very viscous materials such as ointments,
pastes are also possible.
USES
• Edge runner mill is used for grinding tough materials to fine powder. It is
still used for plant-based products.
ADVANTAGES
• Simple to operate, require less attrition.
• Easy maintenance
• No problem of jamming
• Used to reduce size of extremely tough and fibrous roots and barks.
DISADVANTAGES
• Require more floor space than other commercial machines
• Output is less
• Cannot accommodate wet grinding.
END RUNNER MILL
• End runner mill is used for grinding tough materials to fine powder. It is
suitable for fine grinding.
PRINCIPLE
• It works on the principle of crushing and shearing.
CONSTRUCTION
• The end-runner mill is similar in principle and
consists of a rotating pan or mortar made of cast
iron or porcelain. A heavy pestle is mounted
vertically within the pan in an off-center position.
• It consists of following parts:
I. MORTAR
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47. GM Hamad

• A moveable mortar made up of steel or granite.
II. PESTLE
• Made up of same material as that of mortar. It is dumble shaped and
heavy. It is mounted eccentrically in mortar through a hinged joint.
Pestle is free to rise and fall in mortar.
III. MOTOR
• It is needed to rotate the mortar.
IV. SCRAPPER
• Scrapper is attached to the mortar which constantly removes the
material from the pestle and thus returning them back to the mortar.
WORKING
• The material to be ground is put in the mortar, which is rotated
mechanically. The pestle rotates itself by friction. The material is crushed
and rubbed between the pestle and the rotating mortar. The scrapper
removes the sticking material from the pestle and returns back to the
mortar for grinding. The ground material is passed through the sieve to
get the powder of required size.
PHARMACEUTICAL APPLICATIONS
• They are used for reduction of tough and fibrous materials.
• Used also for coarse materials.
• Used for the reduction of roots and barks to form the powder.
ADVANTAGES
• Suitable for reducing particle size of coarse materials.
• Completely simple as compared to complex mills
DISADVANTAGES
• Output is less.
• More time consuming
5. HAMMER MILL
OTHER NAMES
• Fitz Patrick comminutor
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48. GM Hamad

PRINCIPLE
• The basic principle of hammer mill is impact.
CONSTRUCTION
• The hammer mill is an impact mill using a
high-speed rotor (up to 10,000 rpm) to
which a number of swinging hammers are
fixed. A universal mill employs a variety of
rotating milling elements such as a pin
disk, wing or blade beater, turbine rotor,
or hammer-type rotor, in combination
with either a matched pin disk (that may
or may not rotate), or perforated screen or stator.
• Criticality: The screens that retain the material in the milling chamber
are not woven but perforated. The particle size of the discharged
material is smaller than the screen hole or slot, as the particles exit
through the perforations on a path approximately tangential to the
rotor. Efforts to strengthen a screen by increasing its thickness influence
particle size. For a given rotor speed and screen opening, a thicker
screen produces a smaller particle, which is also illustrated in Fig.
WORKING
• The material is fed at the top or center, thrown out centrifugally, and
ground by impact of the hammers or against the plates around the
periphery of the casing. The clearance between the housing and the
hammers contributes to size reduction. The material is retained until it is
small enough to fall through the screen that forms the lower portion of
the casing. Particles fine enough to pass through the screen are
discharged almost as fast as they are formed.
• Some internal classification can be achieved by appropriate selection of
milling tools. The particle size that can be achieved will depend on the
type of milling tool selected, rotor speed (calculated as tip speed it the
outermost rotating part), and solid density in the mill or solid feed rate.
CRITICAL SPEED
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• Comminution is effected by impact at peripheral hammer speeds of up
to 7,600 meters per minute, at which speed most materials behave as if
they were brittle. In the preparation of wet granules for compressed
tablets, a hammer mill is operated at 2,450 rpm with knife edges, using
circular or square holes of a size determined by what will pass without
clogging (1.9 to 2.54 cm). In milling the dried granulation, the mill is
operated at 1,000 or 2,450 rpm with knife edges and circular holes in the
screen (0.23 to 0.27 cm).
• Speed is crucial. Below a critical impact speed, the rotor turns so slowly
that a blending action rather than comminution is obtained. This results
in overloading and a rise in temperature. Microscopic examination of the
particles formed when the mill is operating below the critical speed
shows them to be spheroidal, indicating not an impact action, but an
attrition action, which produces irregularly- shaped particles.
• At very high speeds, there is possibly insufficient time between
hammers for, the material to fail from the grinding zone. In wet milling
of dispersed systems with higher speeds, the swing hammers may lay
back with an increased clearance. For such systems, fixed hammers
would be more effective.
FACTORS AFFECTING PARTICLE SIZE OF A PRODUCT
• Rotor speed
• Feed rate
• Type and number of hammers
• Clearance between hammers and chamber wall
• Discharge opening of screens
EXAMPLES
• Afex comminuting mill
• Fitz comminuting mill
PHARMACEUTICAL APPLICATIONS
• The hammer mill can be used for almost any type of size reduction. Its
versatility makes it popular in the pharmaceutical industry, where it is
used to mill dry materials, wet filter-press cakes, ointments, and slurries.
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• A hammer mill can be used for granulation and close control of the
particle size of powders.
• They are used for preparation of wet granules for compressed tablets.
• They can be used for grinding of fibers.
• They can be used for crystalline material.
• Used in powdering the barks, leaves, roots, crystals and filter cakes.
ADVANTAGES
• They are simple to install and operate, the operation is continuous.
• They are rapid in action and many different types of materials can be
ground with them.
• There is no chance of contamination due to abrasion of metal from the
mill because no surfaces of the mill move against each other.
• The particle size of the material to be reduced can be easily controlled
by changing the speed of the rotor, hammer type, shape & size of the
screen.
• They are easy to clean and may be operated as a closed system to
reduce dust and explosion hazards.
DISADVANTAGES
• Heat buildup during milling is more, therefore, product degradation is
possible.
• Hammer mills cannot be employed to mill sticky, fibrous and hard
materials.
• The screens may get clogged. Wearing of mill and screen is more with
abrasive materials.
6. PIN MILL
PRINCIPLE
• The basic principle of pin mill is attrition.
CONSTRUCTION
• Pin mills Consist of two horizontal steel plates
with vertical projections arranged in concentric
circles on opposing faces and becoming more
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51. GM Hamad

closely spaced towards the periphery. The projections of the two faces
intermesh.
WORKING
• The feed is introduced at a controlled rate to the milling chamber
through the center of the stator and is propelled through intermeshing
rings of rotor and stator pins by centrifugal motion. The passage
between the pins leads to size reduction by impact and attrition. The
material is collected in the annular space surrounding the disks and
passes to a separator. The large volumes of air drawn through the mill
are discharged through the separator. The final particle size achieved in
a pin mill is governed by the rotor speed, solids feed rate, and air flow
rate through the mill.
• Smaller particles can be generated by maxi-mizing the rotor tip speed
and minimizing both product feed and air flow rate. The fineness of the
grind may be varied by the use of disks with different dispositions of
pins. As equipment scale is increased, maintaining rotor tip speed is one
reliable way to achieve milled particle sizes comparable to small-scale
results.
ADVANTAGES AND DISADVANTAGES
• Absence of screens and gratings provides a clog-free action.
• This type of milling is typically able to achieve smaller average particle
size than wet rotor-stator milling.
• The machine is suitable for grinding soft, non-abrasive powders, and low
milling temperatures permit heat-sensitive materials to be processed.
7. BALL MILL
OTHER NAMES
• Jar mill
PRINCIPLE
• The basic principle of ball mill is impact and attrition.
VARIANTS OF SIMPLE BALL MILL
TUBE MILL
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• The tube mill as its name implies has a long narrow cylinder and can
grind to a finer product than the conventional ball mill.
PEBBLE MILL
• If pebbles are used, it is known as a pebble mill.
ROD MILL
• If rods or bars are used, it is known as a rod mill. The rod mill is
particularly useful with sticky material that would hold the balls together
because the greater weight of the rods causes them to pull apart.
HANDING MILL
• The ball mill may be modified to a conical shape and tapered at the
discharge end. If balls of different size are used in a conical ball mill, they
segregate according to site and provide progressively finer grinding as
the material flows axially through the mill.
CONSTRUCTION
• The ball mill consists of a horizontally rotating hollow
vessel of cylindrical shape with the length slightly greater
than its diameter. The mill is partially filled with balls of
steel or pebbles, which act as the grinding medium.
BALLS
• The balls act as grinding medium. Balls are usually made up of stainless
steel or steel and occupy about 30 to 50% of the volume of cylinder.
• Balls are made up of:
­ Porcelain
­ Flint
­ Nylon
­ Rubber
METALLIC FRAME
• The cylindrical vessel is mounted on a metallic frame.
HANDLE
• It is needed for rotating the cylinder.
WORKING
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• The material to be grounded is put into the mill through the lid. The mill
is rotated at a slow speed for appropriate time until the desired size
reduction is achieved. The product is then taken out and passed through
the suitable sieve to get powder of desired size range.
• Most ball mills utilized in pharmacy are batch-operated, however,
continuous ball mills are available, which are fed through a hollow
trunnion at one end, with the product discharged through a similar
trunnion at the opposite end. The outlet is covered with a coarse screen
to prevent the loss of the balls.
CRITICAL SPEED
• The critical speed of a ball mill is the speed at which the balls just begin
to centrifuge with the mill.
• In a ball mill rotating at a slow speed, the balls roll and cascade over one
another, providing an attrition action.
• As the speed is increased, the balls are carried up the sides of the mill
and fall freely onto the material with an impact action, which is
responsible for most size reduction. If the speed is increased sufficiently,
the balls are held against the mill casing by centrifugal force and revolve
with the mill.
critical speed=76.6/√D
• Improving the efficacy of ball mill
• Efficiency of a ball mill is increased as amount of material is increased
until the space in the bulk volume of ball charge is and then, the
efficiency of milling is by further addition of material.
• Increasing the total weight of balls of a given size increases the fineness
of the powder. The weight of the ball charge can be increased by
increasing the number of balls or by using a ball composed of a material
with a higher density.
• Optimum milling conditions are usually obtained when the bulk volume
of the balls is equal to 50% of the volume of the mill, variation in weight
of the balls is normally affected by the use of materials of different
densities. Thus, steel balls grind faster than porcelain balls, as they are
three times denser.
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• Wetting agents may increase the efficiency of milling and physical
stability of the product by nullifying electrostatic forces produced during
comminution. For those products containing wetting agents, the
addition of the wetting agent at the milling stage may aid size reduction
and reduce aggregation.
USES
• Used for either wet or dry milling
• Ball mill at low speed is used for milling dyes, pigments and insecticides.
• Stainless steel balls are preferred in production of ophthalmic and
parenteral products.
ADVANTAGES
• Ball mill has the advantage of being used for batch or continuous
operation.
• In a batch operation, unstable or explosive materials may be sealed
within an inert atmosphere and satisfactorily ground.
• Ball mills may be sterilized and sealed for sterile milling in the
production of
• The installation, operation, and labor costs involved in ball milling are
low.
DISADVANTAGES
• The ball mill is very noisy machine.
• Ball mill is a slow process.
• Soft, tacky, fibrous material cannot be milled by ball mill.
8. FLUID-ENERGY MILL
OTHER NAMES
• Jet mill or micronizer
PRINCIPLE
• The basic principle of fluid-energy mill is impact and attrition.
CONSTRUCTION
• A fluid-energy mill consists of following parts:
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55. GM Hamad

­ Venturi injector
­ Nozzles
­ Grinding chamber
­ Discharge outlet
­ Cyclone separator
­ Bag collector
• The design of the fluid-energy mill provides
internal classification, which permits the finer
and lighter particles to be discharged and the
heavier oversized particles, under the effect of centrifugal force, to be
retained until reduced to a small size.
WORKING
• In the fluid-energy mill or micronizer, the material is suspended and
conveyed at high velocity by air or steam, which is passed through
nozzles at pressure of 100 to 150 pounds per square inch (psi). The
violent turbulence of the air and steam reduces the particle size chiefly
by inter-particular attrition. Air is usually used because most
pharmaceuticals have a low melting point or are thermolabile. As the
compressed air expands at the orifice, the cooling effect counteracts the
heat generated by milling.
• The material is fed near the bottom of the mill through a venturi injector
(A). As the compressed air passes through the nozzles (B), the material is
thrown outward against the wall of the grinding chamber (impact) (C)
and other particles (attrition). The air moves at high speed in an elliptical
path carrying with it the fine particles that pass out of the discharge
outlet (D) into a cyclone separator and a bag collector. The large
particles are carried by centrifugal force to the periphery, where they
are further exposed to the attrition action.
USES
• It is used to reduce particle size of antibiotics and vitamins.
• Moderately hard materials can be processed for size reduction.
• Ultra-fine grinding can be achieved.
ADVANTAGES
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• Powders with all particles below a few micrometers may be quickly
produced by this method.
• Cooling effect of grinding fluid as it expands in the chamber
compensates for the moderate heat generated during grinding process.
• Narrow range of particle size produced.
• No abrasion of the mill.
• For very sensitive materials, an inert gas can be used.
• Useful for thermolabile substances e.g. vitamins and enzymes.
DISADVANTAGES
• The disadvantage of high capital and running costs may not be so serious
in the pharmaceutical industry because of the high value of the
materials which are often processed.
• One drawback of this type of mill is the potential for build-up of
compressed product in the mill or on the classifier. This can affect milled
particle size by changing the open volume in the mill or open area in the
classifier, especially if classifier vanes or gas nozzles become plugged or
blocked.
9. DISINTEGRATOR
PRINCIPLE
• It works on the principle of impact and grinding.
CONSTRUCTION
• It consists of:
­ Chamber
­ Disc and shaft
­ Sieve
­ Hopper
• The disintegrator consists of a drum
shaped chamber made up of steel. In the chamber, there are four steel
beaters fixed to a disc through which passes a shaft which rotates at a
higher speed up to 5000-7000 rpm. The tower part of the chamber is
filled with a desired number sieve which can be easily attached or
detached. A hopper is attached at the upper surface of the chamber.
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WORKING
• The drug to be comminuted is fed into the chamber through the hopper
where it is broken by the direct blow of the beaters and by the impact of
the material, which is thrown with a great force against the surface of
the chamber. The reduced particles pass through the sieve of desired
size.
ADVANTAGES
• Can be used for powdering very bard drugs.
• Used for powdering crude vegetable drugs.
• Can be used for milling the ointments and for mixing the powdered
ingredients.
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MIXING
DEFINITION
“Mixing is a process that tends to result in a randomization of dissimilar
particles within a system.” (OR)
“The process in which two or more than two components in a separate or
roughly, mixed conditions is treated in such a way that each particle of anyone
ingredient lies as nearly as possible to the adjacent particles of other
ingredients is called mixing.”
OBJECTIVES OF MIXING
• To ensure uniformity of composition between mixed ingredients.
• To initiate or enhance physical or chemical reactions e.g. diffusion and
dissolution.
• To improve single phase and multiple phase system.
• To control heat and mass transfer.
RESULT OF MIXING
• When two or more than two miscible liquids are mixed true solutions
are obtained.
• When two immiscible liquids are mixed in the presence of emulsifying
agent, emulsions are produced.
• When a solid is mixed in a vehicle a solution is obtained.
• When an insoluble solid is mixed in a vehicle a suspension is obtained.
• When a solid/liquid is mixed in a semisolid base/ointment suppositories
are produced.
• When two or more than two solids are mixed together a solid dosage
form is obtained.
TYPES OF MIXTURES
1. POSITIVE MIXTURES
• Spontaneous, irreversible and complete mixing of two or more than two
gases or miscible liquids through diffusion, without the expenditure of
energy results in a positive mixture.
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2. NEGATIVE MIXTURES
• These are formed when insoluble solids are mixed with a vehicle to for a
suspension or when two immiscible liquids are mixed to form emulsion.
• These mixers require a high degree of mixing with external force.
3. NEUTRAL MIXTURES
• The components of neutral mixers do not have the tendency to mix
spontaneously but once mixed, they do not separate out immediately
e.g. ointments, pastes.
• Neither mixing nor de-mixing unless system is acted upon by an external
energy input.
DEGREE OF MIXING
• Degree of mixing is defined in terms of standard deviation.
Standard deviation=√
xy
N

• Here,
­ x and y are proportions of the major and minor constituents, N is
the number of particles in the sample taken.
• Mixing of powder should be continued until the amount of active drug
that is required in a dose is with in ± 35° of that found by assay in a
representative number of sample doses.
MECHANISM OF MIXING
• In all type of mixers mixing is achieved by applying one or more of the
following mechanisms:
1. CONVECTIVE MIXING
• During convective mixing, transfer of groups of particles in bulk take
place from one part of the powder bed to another.
2. SHEAR MIXING
• During shear mixing, shear forces are created within the mass of the
material by using agitator arm or a blast of air.
3. DIFFUSIVE MIXING
• During this mixing, the material are tilted so that the gravitational forces
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causes the upper layers to slip and diffusion of the individual particles
take place over newly developed surfaces. Mixing occur by diffusion
process by random movement of particle within a powder bed and
cause them to change their relative position.
CLASSIFICATION OF MIXING EQUIPMENTS
POWDER MIXERS / SOLID MIXERS
1. Pestle and Mortar
2. Spatula
3. Sieves
4. Tumbler Mixers
a) Cube Mixers
b) V Mixers
c) Double Cone/H type
d) Y Mixers
5. Agitator Mixers
a) The Ribbon Blender
b) Helical Flight Mixer
c) Monastery Blender
d) Paddle Mixer
e) Granulating Mixer
f) Trough Mixer
FLUID MIXERS / LIQUID MIXERS
1. BATCH MIXERS
a. Shaker Mixer
b. Impellers
i. Propeller Mixer
ii. Turbine Mixer
­ Pitched Blade Turbine
­ Curved Blade Turbine
­ Disk Style Turbine
iii. Paddle Mixer
­ Simple Paddle
­ Gate Paddle
­ Anchor Paddle
­ Helix Paddle
c. Air Jets
d. Fluid Jets
2. CONTINUOUS MIXERS
a. Baffled Pipe Mixers
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61. GM Hamad

b. Mixing Chamber
c. Continuous Mixing Tank
SEMI-SOLID MIXERS
1. Agitator Mixers / Kneaders
2. Shear Mixers / Mulling Mixers
3. Ultrasonifiers
POWDER MIXING
INTRODUCTION
• Powder mixing is a process in which two or more than two solid
substances are mixed in a mixer by continuous movement of particles.
• It is a neutral type mixing and is one of the most common operations
employed in pharmaceutical industries for the preparation of different
types of formulations e.g. powders, capsules.
FACTORS AFFECTING POWDER MIXING
1. MIXING FACTORS
• Powder mixing operation is quite different from that of liquid. Following
factors must be considered:
A. VOLUME
• Sufficient space should be provided during mixing for dilation of the bed
overfilling of the mixer reduces the efficiency of mixing. The mixer
should not be full to the brim.
B. MIXING MECHANISM
• The mixer selected for mixing must apply suitable shear forces and
convective movement so that the whole of the material passes through
the mixing area.
C. DURATION OF MIXING
• Mixing of powders must be done for optimum time for any particular
situation.
D. HANDLING OF MIXED POWDERS
• After mixing the powders, they should be handled in such a way that the
separation of ingredients in minimized.
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• Sometimes vibration caused by subsequent manipulation, transport,
handling or use is likely to cause segregation.
2. PHYSICAL PROPERTIES / FACTORS
A. MATERIAL DENSITY
• If the density of mixing ingredients is different, the denser material will
sink through the lighter one forming a layer at the bottom resulting in
improper mixing.
B. PARTICLE SIZE
• Variation in particle size can lead to segregation since smaller particles
can fall through the voids between the larger particles.
C. PARTICLE SHAPE
• Spherical shape of particle is ideal for mixing the powders and any
deviation from this shape leads to difficulty in mixing. However, once the
mixing has been done, the particles with irregular shapes can interlock
with each other, reducing the chance of segregation.
D. PARTICLE ATTRACTION
• Some particles exert electrostatic charges due to which the particles of
one powder may attract to particles of another powder leading to
aggregation of particles.
E. PROPORTION OF THE MATERIALS TO BE MIXED
• It is easy to mix powders if they are available in equal quantities but it is
difficult to mix small quantities of powders with large quantities of other
ingredients or diluents.
MECHANISM OF POWDER MIXING
• Powder mixing proceeds by a combination of one or more underlying
mechanisms:
1. CONVECTIVE MOVEMENTS OF POWDER BED
• It is caused by an invasion of powder bed that occurs due to the
movement of relatively larger mass of material from one part of powder
bed to another. It is analogous to bulk transport. It is done by means of
blades, paddles and screws.
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2. SHEAR MIXING
• When shear occurs between regions of different composition and
parallel to their interface, it reduces the scale of segregation by thinning
the dissimilar layers.
• Shear occurring in a direction normal to the interface of such layers is
also effective since it too reduces the scale of segregation.
• In addition, large or irregular grains of powder tend to be expelled from
regions of high shear through a mechanism shear induced migration.
3. DIFFUSE MOVEMENTS (DISPERSION)
• The random motion of powder within a particular bed cause them to
change position relative to one another. Such an exchange of position by
single particles results in reduction of the intensity of segregation. Most
efficient mixers operate to induce mixing by all three mechanisms.
Diffusion is rate limiting mechanism for powder mixing.
EQUIPMENTS FOR POWDERS MIXING
1. PESTLE AND MORTAR
• It is the most commonly used equipment for small scale mixing,
especially in compounding prescriptions. In this method, particle size
reduction and mixing is done in a single operation.
2. SPATULA
• This method is relatively insufficient but is used when compaction
produced by pestle and mortar method is undesirable.
3. SIEVES
• Sieves are generally used for breaking the loose aggregates of powders
in pre or post mixing operation so as to increase overall effectiveness of
a blending technique. Sometimes powder may have to be passed a
number of times through the sieve to get a homogenous powder.
4. TUMBLER MIXER (BLENDER)
• These mixers are used for large scale mixing or batch mixing of powders.
The efficiency of tumbling mixer is highly dependent on the speed of
rotation. Rotation that is too slow that does not produce the desired
intense tumbling or cascading motion nor does it generate rapid shear
rates. The rotation that is too rapid tends to produce centrifugal force
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sufficient to hold the powders to the sides and thereby reducing
efficiency. Speed of rotation commonly ranges from 30-100rpm.
• The optimum rate of rotation depends upon:
­ Size and the shape of tumbler
­ Type of material being mixed
• Tumbler mixer consists of a container which is mounted so that it can be
rotated about an axis. The resulting tumbling motion is accentuated by
means of baffles or simply by virtue of shape of container.
• Mostly an eight-angle shaped tumbler is used with baffles on each side.
Granules are twisted, flowing along the angle of baffle and mixed again
by the center short baffle. It can give best mixing result.
PRINCIPLE
• The mixers work on the principle of:
­ Convective movement
­ Shear mixing
WORKING
• In tumbler mixers rotation of vessel imparts movement to the materials
by tilting the powders until the angle of surface exceeds the angle of
repose when the surface layers of particles go into a slide and the
material is tumbled, rolled and folded e.g. in case of Y-cone blender.
• Plain of shear is always changing throughout the mass and the moving
material is constantly re divided and recombined.
CONSTRUCTION
METALLIC CONTAINER
• It consists of metallic vessel of various shapes rotating about its mid-
point on horizontal axis. Depending upon shape of vessel, they could be:
I. Cube mixer
II. V mixer
III. Double cone mixer
IV. Y mixer
MOTOR
• Horizontal axis is rotated with the help of motor.
I. CUBE MIXER
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• It consists of a cube shaped stainless steel drum which is connected to
motor, blades are also attached inside the container to reduce the size.
The cube has an opening in front with screw nuts. It is good for wet
granulation mixing.
II. TWIN SHELL BLENDER V-SHAPED
• This is most popular mixer used in industry. When this is rotated, the
material is collected in the bottom of V, splits into two portions when V
is inverted. This design is quite effective because shear forces are
enhanced. Facilitate asymmetric rotation.
III. H-TYPE MIXERS / DOUBLE CONE MIXER
• It consists of mixing blades which rotates inside the pan with the help of
electric motor. Material is put in the pan and mixed by rotating blades.
Cover of pan is transparent and operation can be viewed.
IV. Y-CONE BLENDER
• It has a shallow drum with conical portion, the smaller end of which
provides discharge opening and longer end has two cylindrical portions
mounted approximately at right angles to each other.
WORKING
• Sliding material is deflected by inclined curved surface as there is
continuously changing angle to achieve the current in both vertical and
horizontal directions which is essential feature of efficient mixing.
• The gentle force is free from attrition it does not breakup crystal shape
and does not result in change of particle size and neither does it
generates heat.
• In case of Y-shaped cone blender, 2-fold force/reaction occurs;
­ Rolling and folding movements
­ Continuous dividing and recombining of powder.
• By its unique geometrical consideration; all internal substances blend
with each other.
ADVANTAGES
• Tumbler mixers are designed for rapid, economical blending of powders,
colors, resins, granules etc.
• It does not change the particle size distribution
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• It has useful application in pharmaceutical food, cosmetics production,
detergents, insecticides and explosive materials
• It does not break up the crystal shape
• It can be used for heat sensitive materials.
DISADVANTAGES
• It cannot perform wet mixing.
• Cube mixer is less efficient than paddle mixer.
5. AGITATOR MIXERS
PRINCIPLE
• The mixing is done by means of mixing screws, paddles or blades. The
high shear forces are setup during the process which break the lumps or
aggregates and produce homogenous mixture.
• They consist of a stationary container, with a horizontal or vertical
agitator moving inside it. The agitator may take the form of blade,
paddles or screws.
• They are used for mixing of wet solids. Also used for sticky or plastic
state.
TYPES
• Well known mixers of this type include:
1. The ribbon blender
2. Helical flight mixer
3. Monastery blender
4. Paddle mixer
5. Granulating mixer
6. Trough mixer
I. RIBBON BLENDER
• It is also known as conventional mixer. It consists of a horizontal
cylindrical tank usually opening at the top and fitted with helical blades.
The blades are mounted on a shaft through the long axis of the tank and
are often of both right- and left-hand twist.
• It is used for dry granules, wet granules, dry powders and semi-solids.
CONSTRUCTION
• TROUGH
­ These are stationary container of welded stainless steel and of
such shapes ass to eliminate the cervices, trough are robust and
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polished from inside and outside so that they may rapidly be
cleaned.
• LID WITH COVER
­ A polished stainless-steel lid is fitted with a safety grind with an
inspection cover.
• RUBBER GASKET
­ Lid seats on the trough with a rubber gasket and held together
with two toggle fasteners.
• AGITATOR
­ Mixer is fitted with a polished stainless-steel paddle type agitator
which is suitable for dry or moistened material. In cases where
mass becomes sticky, special agitator ribbon blender are
recommended.
• AGITATOR SHAFT
­ It passes through the long axis of tank. The shaft entering the
trough is sealed by means of gasket so that dust can be avoided
and lubricant from bearing can effectively be preventing from
reaching and contaminating the mixture. When shaft is rotated,
the material is picked up by the helical blades which are then split
back.
• MOTOR
­ It is fitted with a 3-phase gear motor unit that rotates the shaft.
WORKING
• The material to be mixed is put in the mixer and mixed for optimum
time period. Then the lid lifted by hand for discharge. The lid is fitted
with an electrical limit switch which prevents the agitator being in
motion with the lid raised.
II. HELICAL FLIGHT MIXER
• Powders are lifted by a centrally located vertical screw and allowed to
cascade to the bottom of the tank.
III. TROUGH MIXERS
• These are most commonly in the form of trough in which an arm rotates
and transmits shearing force to particles.
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FACTORS AFFECTING MIXER SELECTION
1. MEASURE OF DEGREE OF MIXING
• In case of powder mixing, mixer selection also depends on quantitative
measure of the degree of mixing. This is generally accomplished by the
arbitrary choice of a statistical function that indicates the uniformity of
composition of the powder bed.
2. TIME AND POWER CONSUMPTION
• Unlike most liquid mixers, solid mixers can be made to produce good
mixtures, when they are operated incorrectly, simply by mixing for a
long period of time. The mixture reaches an equilibrium state of mixing
that is the function of speed of operation of mixer.
• Minimum power is that required to operate the mixer for the time
necessary to reach a satisfactory steady state.
3. PHYSICAL PROPERTIES OF MATERIAL
• Physical properties of material greatly influence the selection of mixers.
4. ECONOMIC CONSIDERATIONS
• Economic considerations should be taken before selecting a mixer.
FLUID MIXING
INTRODUCTION
• Liquid mixing may be divided into two groups:
1. MIXING OF LIQUID AND LIQUID
­ Mixing of two immiscible liquids
­ Mixing of miscible liquids
2. MIXING OF SOLIDS AND LIQUIDS
­ Mixing of liquid and soluble solids
­ Mixing of liquid and insoluble solids
THEORY
• Mixing occurs in two stages:
1. LOCALIZED MIXING
­ In which shear applied to the particles of the liquid.
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2. GENERALIZED / BULK MIXING
­ Sufficient to take all the particles of the materials through the
shearing zone so as to produce a uniform product.
1. MIXING OF LIQUID AND LIQUID
A. MIXING OF TWO MISCIBLE LIQUIDS
• Mixing of two miscible liquids is caused by diffusion. Simple shaking and
stirring is enough but if the liquids are not readily miscible or if they have
very different viscosities then electric stirrer may be used.
B. MIXING OF TWO IMMISCIBLE LIQUIDS
• When two immiscible liquids are mixed together in the presence of an
emulsifying agent, an emulsion is formed. For the production of a stable
emulsion, mixing must be continuous without ceasing because the
components tend to separate out if continuous work is not applied on
them.
2. MIXING OF LIQUIDS AND SOLIDS
A. MIXING OF LIQUIDS AND SOLUBLE SOLIDS
• In this case, soluble solids are dissolved in a suitable liquid by means of
stirring. It is a physical change.
B. MIXING OF LIQUIDS AND INSOLUBLE SOLIDS
• When insoluble solids are mixed with a vehicle, a suspension is produced
which is an unstable system the ingredients of a suspension out when
allow to stand for some time therefore to get a good suspension a
suitable suspending agent should be used.
MECHANISM OF FLUID MIXING
• Fluid mixing involve more than one following mechanisms.
1. BULK TRANSPORT
• The movement of relatively large portion of the material being mixed
from one location of the system to the constitutes bulk transport. This is
usually accomplished by means of paddles, revolving blades or other
devices within the mixer arranged so as to move adjacent volumes of
the liquid in different direction thereby shuffling the system in different
directions.
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2. TURBULENT FLOW
• The phenomenon of turbulent mixing is a direct result of turbulent fluid
flow, which is characterized by a random fluctuation of fluid velocity at
any given point within the system. With turbulence, the fluid has
different instantaneous velocities at different locations at the same
instant of time and such velocity differences within the body of fluid
produce a randomization of fluid molecule, therefore turbulence is an
effective mechanism.
3. LAMINAR MIXING
• When two dissimilar liquids are mixed through laminar flow, the shear
that is generated stretched the interface between them. If the mixer
employed folds the layer back upon themselves, the number of layers
and hence the interfacial area between them increases exponentially
with time. If the mixer employed operates by simply stretching the fluid
layers without any significant folding force, an exceedingly long time is
required for the layers of different fluids to reach molecular dimensions.
4. MOLECULAR DIFFUSION
• The primary mechanism responsible for mixing at molecular level is
diffusion resulting from thermal motion of molecules. The process is
described quantitatively in terms of Fick’s first law of diffusion;
dm
dt
=−DA
dc
dx

• Where,
­ D = diffusion coefficient, A = area of interface, dc/dx =
concentration gradient across the interface.
• The rate of transport of mass (dm/dt) across an interface of area A is
proportional to the concentration gradient (dc/dx) across the interface.
EQUIPMENTS FOR FLUID MIXING
• There are two types of equipment;
A. BATCH MIXING
• When the material to be mixed is limited in volume it is called batch
mixing. It is a feasible method. A system for batch mixing commonly
consists of two primary components:
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­ A tank or other container suitable to hold the material being
mixed.
­ A means of supplying energy to the system so as to bring about
rapid mixing.
• Power may be supplied to the liquid mass by means of:
­ Impellers: propellers, turbines and paddles are employed as
impellers
­ Air jets
­ Fluid jets
B. CONTINUOUS MIXING
• The process of continuous mixing produces an uninterrupted supply of
freshly mixed material and is often desirable when very large volume of
material is to be handled. It can be accomplished in two ways:
­ In a tube or pipe (baffled pipe) through which the material flows
and in which there is a very backflow or recirculation.
­ In a chamber (mixing chamber) in which a considerable amount of
hold up and recirculation occurs.
BATCH MIXERS
1. SHAKER MIXERS
• In these mixers, the material present in the container is agitated either
by an:
­ Oscillatory motion (For small scale mixing) (Lab scale)
­ Rotatory movement (For large scale work) (Industrial scale)
• These have limited use in industries.
2. IMPELLERS
• The distinction between impeller types is often made on the basis of
type of flow pattern they produce, or on the basis of shape and pitch of
blades. There are 3 basic components which produce flow patterns.
I. RADIAL COMPONENTS
• Radial components work in a direction vertical / perpendicular to the
impeller shaft.
II. AXIAL COMPONENTS
• It acts parallel to impeller shaft.
III. TANGENTIAL COMPONENTS
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• It acts in a direction that is a tangent to the circle of rotation round the
impeller shaft.
CLASSIFICATION
I. PROPELLER MIXERS
• Propellers characteristically produce axial flow parallel to their axis of
rotation. Propellers are most effective when they can be run at high
speed in liquids of relatively low viscosity. Not used foe liquids whose
viscosity is greater than 50poise or 500 centi-poise.
• Propellers are effective of mixing viscous liquids e.g. glycerin and castor
oil.
CONSTRUCTION
• The agitator consists of a shaft to which many blades are attached
(usually three blades). The size of agitator is small as compared to the
size of container. The propeller rotates at a very high speed which is
8000rpm.
• The propeller pitch is defined as the distance of axial movement per
revolution. If no slippage occurs, usually the pitch is approximately equal
to the propeller diameter. The blades of the propeller do not have
constant pitch throughout the length sometimes high speed of propeller
may lead to undesirable vortex formation and entrapment of air.
(aeration)
• This problem can be avoided by:
­ Attaching propeller shaft off set from the center.
­ Mounting the propeller shaft from the side of vessel.
­ Using push, pull propellers. In this two propellers of opposite pitch
are attached on the same shaft so that their rotatory effects are in
the opposite directions and cancel each other.
­ Using baffles; which are generally vertical strings attached to the
side of vessel.
­ Using vessel of shape other than a cylinder.
­ It may be mounted at an angle.
USES
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• They are useful in the preparation of suspensions of solids in liquid (if
solid contents are less than 10%)
DISADVANTAGES
• They are not used for liquids having viscosities more than 5000
centipoise.
• Not have constant pitch throughout the length.
• It is not useful when considerable shear is needed e.g. emulsification
II. TURBINE MIXER
• Turbine may produce radial or tangential flow or combination of these.
Majorly radial movement because of more shear.
CONSTRUCTION
• Turbine mixer uses a circular disk impeller to which many short (straight
or curved) vertical blades are attached. Most turbine impellers have flat
blades. Turbines having tilted blades produce an axial discharge quite
similar to that of propellers.
• The turbine impeller is rotated at a lower speed than propeller and the
ratio of the impeller and container diameter is low. It rotates at a speed
of 50-200rpm. Turbine impellers give rise to greater shear forces which
can be further increased by diffusion ring so that the discharged liquids
must pass through perforations.
TYPES OF TURBINE MIXERS
• Pitched blade turbine
• Curved blade turbine
• Disk blade turbine
USES
• Turbines can be operated satisfactorily in fluids 1000 times more viscous
than fluids in which propellers of comparable size can be used.
• Useful in the preparation of emulsions.
• Useful if solid contents are up to 60%.
III. PADDLE MIXERS
• Paddle produce tangential flow. Since circulation is primarily tangential,
the concentration gradient in the axial and radial directions may persist
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even after prolonged operation. These mixers are effective in mixing
viscous liquids or semisolids which tend to sling to the surface.
• One of the promising hybrids of paddle mixer is dispersion. It has coaxial
blades one for macro mixing and other for micro mixing. Counter
rotation of macro-micro mixing element with variable speed is useful for
mixing extremely viscous materials, materials with high solid content, for
emulsification and homogenization. The equipment generates maximum
shear without vortex formation and minimal air entrapment.
CONSTRUCTION
• It uses an agitator consisting usually of flat blades attached to a vertical
shaft and rotating at a low speed of 50rpm or less. Paddles for more
viscous liquids generally have a number of blades often shaped to fit
closely to the surface of vessel, avoiding “deep-spots” and deposited
solids.
• Diameter of shaft is 50-80% of the diameter of mixing. Width of blade is
1/6th to 1/10th of its length.
• It is suitable for mixing thus liquids having viscosities of 1000 centipoise.
Gate paddles can be used for viscous liquids.
• The blades have a large surface area in relation to the container in which
they are employed; an aperture that permits them to pass close to the
tank wall.
TYPES OF PADDLE MIXERS
• Simple paddle
• Gate paddle
• Anchor paddle
• Helix paddle
DISADVANTAGES
• They are ineffective in suspending heavy solids because of absence of
axial flow.
IV. PLANETARY MOTION MIXERS
• Impart planetary mixing action that rotates on its own axis but also
travels in a circular path round the mixing vessel. The diameter of
agitator is not more than half to 2/3 of the diameter of vessel.
• The double rotation of element and its offset position reduces the dead
zone and avoids vortex formation.
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USES
• It is used for more viscous liquid mixing
3. AIR JETS
CONSTRUCTION AND WORKING
• In this apparatus air or any other gas is passed through a liquid at
surface level. The air bubbles rise and as a result, fluid at the bottom of
container is also forced to rise. Thus, may be better accomplished by
using tube. Hence mixing of different sections of liquids occurs. The
intense turbulence generated by jet produces intimate mixing.
USES
• Air jets are used for low viscosity, non-foaming, non-volatile and non-
reactive liquids.
4. FLUID JETS
• These are somewhat similar to sir jets but instead of air one of the
mixing component is pumped into other at high pressure. Thus, mixing is
achieved.
WORKING
• When liquids are to be pumped into a tank for mixing, the power
required for pumping often can be used to accomplish the mixing
operation, either partially or completely. In such a cases liquids are
pumped through nozzles arranged to permit good circulation of material
through the tank.
• Behave like propellers. Generate turbulent flow axially.
USES
• These are used for liquid/liquid mixing.
CONTINUOUS MIXERS
• Following are the examples of continuous mixing devices.
1. BAFFLED PIPE MIXERS
• It induces turbulence in fluid. However, recirculation is desirable when
overall fluctuations occur in the material fed to the mixer. In this, mixing
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takes place mainly through mass transport in directions normal to that
of primary flow. Mixing in such system requires the careful control of
feed rate of raw materials if the mixture of uniform composition is to be
obtained.
2. MIXING CHAMBER WITH INDUCED RECIRCULATION
• It also induces the turbulence in fluids. However, recirculation is
desirable when overall fluctuations occur in the material fed to the
mixer. Since these fluctuations cannot be eliminated by simple
transverse mixing in a pipe.
3. CONTINUOUS MIXING TANK WITH VERTICAL SIDE WALL BAFFLES
• It consists of two zones one is above and second is below the impeller.
Net effect of such a device is similar to that obtained by the operation of
two tanks.
SEMI-SOLID MIXING
INTRODUCTION
• The process of missing solids in viscous fluids to achieve semi-solid
consistency as that of paste or dough is called semisolid mixing.
• Semi-solids: As the percentage of solid is increased or if highly viscous
fluids are employed, the solid-liquid system takes the consistency of a
paste or dough.
THEORY
• In mixing an insoluble solid with a liquid, a number of stages can be
observed as the liquid content is increased.
­ Pellet and powder state
­ Pellet state (when small amount of liquid is added powder balls up
and form pellet)
­ Plastic state (mixture become homogenous)
­ Sticky state (paste like material due to continuous incorporation
of liquid)
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­ Liquid state (decreased consistency, and increased rate of
homogenization)
EQUIPMENT FOR SEMI-SOLID MIXING
• Mixers for semi-solids may be divided into three main groups.
1. AGITATOR MIXER/ KNEADERS
• The agitator arms are designed to give a pulling and kneading force and
the shape and movement is such that material is cleaned from all sides
and all corners of the mixing vessel.
PRINCIPLE
• Kneaders operate by pushing masses of all materials past each other and
by squeezing and deforming them at the same time. Such mixers usually
have counter rotating blades or heavy arms that work the plastic mass.
Shear forces are generated by the high viscosity of mass and are
effective in disaggregation as well as distribution of solids in the fluid
vehicle.
SIGMA ARM MIXERS
• The shape of mixer blades resemble sigma “σ”. They are commonly used
for handling semisolids of plastic consistency.
CONSTRUCTION AND WORKING
• The two blades rotate towards each other and operate in a mixing vessel
which has a double trough shape, each blade fitting into a trough. The
two blades rotates at a different speeds, one usually about twice the
speed of other, resulting in a lateral pulling of the material and division
into the two troughs, while the blade shape and difference in speed
causes end to end movement.
• As with many other mixers, the vessel is jacketed for heating or cooling
and the blades can be hollow for the same purpose.
• The most common mixers used for handling of semi-solids and plastic
consistency are sigma arm and sigma blade mixers.
USES
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• This form of mixer can handle even the heaviest plastic materials and
products such as pill masses, tablet, granule masses and ointments are
mixed usually.
2. SHEAR MIXERS/ MULLING MIXERS
• Mulling mixers are efficient in desegregation of solids but are typically
insufficient in distributing the particles uniformly through the entire
mass. These devices are suitable for mixing of previously mixed material
of uniform composition but containing aggregates of solids; is suitable
for mixing in these devices. If segregation occurs during milling, a final
remixing may be necessary.
PRINCIPLE
• The basic principle lies in the production of shear forces but the general
overall mixing efficiency is poor.
3. ROLLER MILL/ SHEAR MILL
• It consists of one or more rollers. The three rollers type seems to be
preferred. Rotor rotates at a speed of 3000-15000rpm
CONSTRUCTION AND WORKING
• In operation, rollers composed of a hard abrasion resistant material and
arranged to come into close proximity to each other are rotated at
different rates of speed. Material coming between the rollers is sheared
due to the difference in rate of movement of the two surfaces. The
material passes through from the hopper between rollers and is reduced
in size in the process.
USES
• Preparation of ointments, pastes and other semi-solids preparations.
4. ULTRASONIFIERS
• Limited output
• Very expensive
• Used in laboratory purposes i.e. emulsions and suspensions of high
consistency.
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5. COLLOID MILL
• On the principle of high shear, which normally generate between the
rotor and the stator of mill. Speed of rotor is 3000 to 20,000 rpm.
Initially colloid mill is used for comminution of poorly wetted solid
suspensions and viscous emulsions.
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FILTRATION AND CLARIFICATION
INTRODUCTION
FILTRATION
• Filtration may be defined as the separation of solid from a fluid by
means of a porous medium that retains the solid but allows the fluid to
pass.
• It leads to optically transparent liquid free from insoluble solids, colloidal
hazes or insoluble liquid.
CLARIFICATION
• This term is used when the solids present in the liquid is very small
(<1%), and filtrate is required product.
DIFFERENT TERMS
FEED OR SLURRY
• The suspension of solids and liquid to be filtered is called as feed or
slurry.
FILTER MEDIUM
• Porous medium through which slurry is forced to pass.
FILTER CAKE
• The solid collected on the filter medium is called as filter cake.
FILTRATE
• The clear liquid which passes through the filter is called filtrate.
CAKE FILTRATION
• When solids collected on the filter medium is the desired product then
the process is known as cake filtration.
FACTORS AFFECTING FILTRATION
• Filtration is affected by the characteristics of the slurry, including:
1. The properties of the liquid, such as density, viscosity, and
corrosiveness.
2. The properties of solid, for example, particle shape, particle size,
particle size distribution, and rigidity or compressibility of solid.
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3. The proportion of solids in the slurry.
4. Whether the objective is to collect the solid, the liquid, or both.
5. Whether the solids have to be washed free from the liquid or a
solute.
RATE OF FILTRATION
• All other things being equal, the object of the operation is to filter the
slurry as quickly as possible.
• The factors affecting rate of filtration is known as Darcy’s law and may
be expressed as:
d
v
d
t
=?????? ??????
??????
????????????

­ Where, V = volume of filtrate, t = time of filtration, K = constant
for the filter medium and filter cake, A = area of filter medium, P =
pressure drop across the filter medium and filter cake, u =
viscosity of the filtrate and l = thickness of cake.
FACTORS AFFECTING RATE OF FILTRATION
I. PERMEABILITY COEFFICIENT
• The constant (K) represents the resistance of both the filter
medium and the filter cake. As the thickness of the cake increase,
the rate of filtration will decrease. Also, the surface area of the
particles. the porosity of the cake, and rigidity or compressibility
of the particles could affect the permeability of the cake.
II. AREA OF FILTER MEDIUM
• The total volume of filtrate flowing from the filter will be
proportional to the area of the filter. The area can be increased by
using larger filters. In the rotary drum filter, the continuous
removal of the filter cake will give an infinite area for filtration.
III. PRESSURE DROP
• The rate of filtration is proportional to the pressure difference
across both the filter medium and filter cake.
• The pressure drop can be achieved in a number of ways:
GRAVITY
­ A pressure difference could be obtained by maintaining a
head of slurry above the filter medium. The pressure
developed will depend on the density of the slurry.
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VACUUM
­ The pressure below the filter medium may be reduced
below atmospheric pressure by connecting the filtrate
receiver to a vacuum pump and creating a pressure
difference across the filter.
PRESSURE
­ The simplest method being to pump the slurry into the filter
under pressure.
CENTRIFUGAL FORCE
­ The gravitational force could be replaced by centrifugal
force in particle separation.
IV. VISCOSITY OF FILTRATE
• It would be expecting that an increase in the viscosity of the
filtrate will increase the resistance of flow, so that the rate of
filtration is inversely proportional to the viscosity of the fluid.
• This problem can be overcome by two methods:
a. The rate of filtration may be increased by raising the
temperature of the liquid, which lowers its viscosity.
However, it is not practicable if thermolabile materials are
involved or if the filtrate is volatile.
b. Dilution is another alternative, but the rate must be
doubled.
V. THICKNESS OF FILTER CAKE
• The rate of flow of the filtrate through the filter cake is inversely
proportional to thickness of the cake. Preliminary decantation
may be useful to decrease the amount of the solids.
FILTER MEDIA
• The surface upon which solids are deposited in a filter is called the
“Filter medium”
• Properties of ideal filter medium:
1. It must be capable of delivering a clear filtrate at a suitable
production rate.
2. It must withstand the mechanical stresses without rupturing or
being compressed.
3. No chemical or physical interactions with the components of the
filtrate should occur.
4. It must retain the solids without plugging at the start of filtration.
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5. Sterile filtration imposes a special requirement since the pore size
must not exceed the dimension of bacteria or spores.
CLASSIFICATION OF FILTER MEDIA
I. WOVEN FILTERS
• These include:
a. Wire screening.
b. Fabrics of cotton, wool and nylon.
• Wire screening e.g. stainless steel is durable, resistance to
plugging and easily cleaned.
• Cotton is a common filter, however, Nylon is superior for
pharmaceutical use, since it is unaffected by mold, fungus or
bacteria and has negligible absorption properties.
II. NON- WOVEN FILTERS
• Filter paper is a common filter medium since it offers controlled
porosity, limited absorption characteristic, and low cost.
III. MEMBRANE FILTERS
• These are basic tools for micro-filtration, useful in the preparation
of sterile solutions. These filters are made by casting of various
esters of cellulose, or from nylon, Teflon, polyvinyl chloride. The
filter is a thin membrane with millions of pores per square
centimeter of filter surface.
IV. POROUS PLATES
• These include perforated metal or rubber plates, natural porous
materials such as stone, porcelain or ceramics, and sintered glass.
FACTORS AFFECTING IN THE SELECTION OF FILTER MEDIA
• While selecting the filter media the following factors must be taken into
considerations
­ Size of the particles to be filtered.
­ Amount of the liquid to be filtered.
­ Nature of the product to be filtered i.e. a solution suspension or a
viscous preparation.
­ Purpose of filtration i.e. only to get clear preparation or to get a
clear sterile preparation.
FILTER AID
• Usually, the resistance to flow due to the filter medium itself is very low
but will increase as a layer of solids builds up, blocking the pores of the
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medium and forming a solid cake.
• The objective of the filter aid is to prevent the medium from becoming
blocked and to form an open, porous cake, so reducing the resistance to
flow of the filtrate. The particles must be inert, insoluble,
incompressible, and irregular shaped.
­ If too little filter aid is used, the resistant offend by the filter cake
is greater than if no filter aid is used, because of added thickness
to the cake.
­ If high amounts of filter aids arc added, the filter aid merely adds
to the thickness of the cake without providing additional cake
porosity.
­ At low concentration of filter aid, the flow rate is slow because of
low permeability.
­ As the filter aid concentration increases, the flow rate increases
and peaks off. Beyond this point the flow rate decreases as the
filter aid concentration is increased.
• Filter aids may be used in either or both two ways:
1. PRE- COATING TECHNIQUE: By forming a pre-coat over the filter
medium by filtering a suspension of the filter aid.
2. BODY- MIX TECHNIQUE: A small proportion of the filter aid (0.1-
0.5 %) is added to the slurry to be filtered. This slurry is
recirculated through the filter until a clear filtrate is obtained,
filtration then proceeds to completion.
• The following filter aids may be used:
­ Diatomite (Kieselguhr), obtained from natural siliceous deposits.
­ Perlite, it is an aluminum silicate.
­ Cellulose and Asbestos.
INDUSTRIAL FILTERS
Four groups may be listed:
1. Gravity filters
2. Vacuum filters
3. Pressure filters
4. Centrifugal filters
1. GRAVITY FILTERS
• Employing thick granular beds are widely used in water filtration e.g.
Sand Filter.
• This device is composed of two chambers, the upper chamber, and the
lower chamber. The upper chamber is the part where you pour in your
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contaminated water, and the lower chamber will then be the finish line
where your contaminated water is now turned into filtered water.
• The Gravity Water Filter is perfect because of its convenience, and it
does no longer require plumbing or electricity for it to function.
WORKING
• The upper chamber of the gravity water filter
contains an element that takes care of the
filtering process of your contaminated water.
Basically, that element is composed of
microscopic pores that disable the
contaminants and other pollutants to pass
through it, which leaves only the water to be
able to pass through that microporous element
going to the lower chamber. Now, you had your filtered water
which is ready and made safe for drinking.
ADVANTAGES
• The gravity water filtration system is effective and efficient. It is
simple and very functional.
• There are various sizes to choose from, depending on your needs.
• It requires less maintenance. It only needs filter replacement once
or twice each year, depending on the suggestion of the
manufacturer.
• The system does not need electricity.
DISADVANTAGES
• The parts of the gravity water filter can be costly especially for
those who are in tight budget.
• Limited filtration capacity.
• Some gravity filter takes time to clean the water, while others can
do the cleaning really quick.
TYPES OF GRAVITY WATER FILTERS
a. Ceramic Gravity Water Filter.
b. Stainless Steel Gravity Water Filter.
c. Gravity Bag Water Filter.
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2. VACUUM FILTERS
• Vacuum filters operate practically at higher pressure differentials
than gravity filters.
• Rotary vacuum filter and the leaf filter are most extensively used.
I. THE LEAF FILTER
• The leaf filter is consisting of a frame enclosing a drainage
screen or grooved plate, the whole unit being covered with
filter cloth.
• The outlet for the filtrate connects to the inside of the frame,
the general arrangement is shown in the Fig. which represents
a vertical section through the leaf. The frame may be circular,
square or rectangular shapes.
OPERATION
­ The leaf filter is immersed in the slurry and a receiver and
a vacuum system connected to the filtrate outlet.
ADVANTAGES
i. The slurry can be filtered from any vessel.
ii. The cake can be washed simply by immersing the filter in a
vessel of Water.
iii. Removal of the cake is facilitated by the use of reverse air flow.
Fig. Filter leaf
iv. The filter can be modified by employing a suitable number of
unites.
v. The leaf filter is most satisfactory if the solids content of the slurry
is not too high, 5 % being a suitable maximum.
vi. Labor costs for operating the filter are comparatively moderate.

• An alternative method is to enclose the filter leaf in a special vessel into
which the slurry is pumped under pressure. A number of leaves are
connected to a common outlet, to provide a large area for filtration e.g.
Sweetland filter.
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II. ROTARY VACUUM FILTER (ROTARY FILTER)
• In large –scale operation, continuous
operation is sometimes desirable, and it may be
necessary to filter slurries containing a high
proportion of solids.
• The rotary filter is continuous in operation and has a
system for removing the cake that is formed, so, it is
suitable for use with concentrated slurries.
• It is a metal cylinder mounted horizontally, the curved surface being a
perforated plate, supporting a filter cloth. Internally, it is divided into
several sectors and a separate connection is made between each sector
and a special rotary valve.
OPERATION
• The drum is immersed to the required depth in the slurry, which is
agitated to prevent settling of the solids, and vacuum is applied to
those sectors of the drum which is submerged.
• A cake of the desired thickness is produced by adjusting the speed
of rotation of the drum. Each sector is immersed in turn in the
slurry and the cake is then washed and partially dried by means of
a current of air.
• Finally, pressure is applied under the cloth to aid the removal of
the cake.
• Removal of the washed and partially dried cake is affected by
means of a doctor knife.
RESIDUAL CAKE
• The suspended solids deposits on the filter drum as a cake and as
rotation continues, vacuum holds the cake at the drum surface. This is
followed by washing and further drainage in drying zone.
• As the cake moves towards the discharge point, it may be scraped from
drum or it may be supported by strings until it breaks free under
gravitational forces (cake removal zone).
• The cake discharge may be done through a scraper, belt, roll or a string.
Scraper discharge mechanisms will suit cake that could be scraped
readily.
­ Roller discharge mechanisms are better for thixotropic cakes.
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­ A string discharge filter is useful in the manufacturing of
antibiotics when removal of cake of mould mycelia is necessary.
SUMMARY OF THE PROCESS
• The drum is dipped into the slurry and vacuum applied to the
outlet, which is connected to the filtrate receiver. When the cake
has formed, the cake drained or partially dried by vacuum.
• The drum is sprayed with water to wash the cake. Retaining the
vacuum connection drains the cake and produces partial dryness
then, removed by a doctor knife.
• When the solids of the slurry are too much that the filter cloth
becomes blocked with the particles, a pre-coat filter may be used.
A pre-coat of filter aid is deposited on the drum prior to the
filtration process.
ADVANTAGES
• The rotary filter is automatic and is continuous in operation, so
that the labor costs are very low.
• The filter has a large capacity, so it is suitable for the filtration of
highly concentrated solutions.
• Variation of the speed of rotation enables the cake thickness to be
controlled.
• Pre-coat of filter aid could be used to accelerate the filtration rate.
DISADVANTAGES
• The rotary filter is a complex piece of equipment, with many
moving parts and is very expensive.
• In addition to the filter itself, some accessories are connected, e.g.
a vacuum pump, vacuum receivers, slurry pumps and agitators are
required.
• The cake tends to crack due to the air drawn through by the
vacuum system, so that washing and drying are not efficient.
• Being a vacuum filter, the pressure difference is limited to 1 bar
and hot filtrates may boil.
• It is suitable only for straight- forward slurries
USES
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• The rotary filter for continuous operation on large quantities of
slurry.
• Suitable for slurry contains considerable amounts of solids in the
range 15-30%.
• Examples of pharmaceutical application include the collection of
calcium carbonate, magnesium carbonate, and starch, and the
separation of the mycelium from the fermentation liquor in the
manufacture of antibiotics.
3. PRESSURE FILTERS
• Due to the formation of cakes of low permeability, many types of
slurry require higher pressure difference for effective filtration
than can be applied by vacuum techniques.
• Pressure filters are used for such operations.
• However, high operational pressures, may prohibit continuous
operation because of the difficulty of discharging the cake whilst
the filter is under pressure.
• Examples are the
­ Sweetland filter
­ Plate and frame filter press.

PLATE AND FRAME FILTER PRESS
• This press is made up of two units,
known respectively as plates and
frames, with a filter medium, usually
filter cloth, between the two.
• The frame is open, with an inlet for
the slurry, while the plate has
grooved surface to support the filter
cloth, and with an outlet for the filtrate.
OPERATION
• The slurry enters the frame from the feed channel.
• The filtrate passes through the filter medium on to the surface of the
plate while the solids form a filter cake in the frame.
• The filtrate then drained down the surface of the plate, between the
projections on the surface and escapes from the outlet.
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• Filtration is continued until the frame is filled with filter cake, when the
process is stopped, the frame emptied, and the cycle re-started.
• Channels for the slurry inlet and the filtrate outlet can be arranged by
fitting eyes to the plates and frames. This has the advantages that the
filtrate from each plate can be seen and, in the event of a broken cloth,
the faulty plate can be isolated, and the filtration continued with one
plate less.
• The thickness of the cake can be varied by using frames of different
thickness and, in general, there will be an optimum thickness of filter
cake for any slurry, depending on the solids content of the slurry and
the resistance of the filter cake.
• As filtration proceeds, the resistance of the cake increases, and the
filtration rate will decrease. At a certain point it will be preferable in
terms of the overall output of the process, to stop and empty the press
rather than to continue filtration at a very low flow rate.
• Plates and frames may be made in various metals to provide resistance
to corrosion or prevent metallic contamination of the product. Non-
metals e.g. plastics is lighter, also varieties of wood are satisfactory
materials of construction.
• Plates and frames may be of considerable size, of about 1m square.
ADVANTAGES
• Construction is very simple, and a wide variety of materials can be
used.
• It provides a large filtering area in a relatively small floor space.
• It is versatile, the capacity being variable according to the
thickness of the frames and the number used.
• The construction permits the use of considerable pressure
difference.
• Efficient washing of the cake is possible.
• Operation and maintenance are straight forward, because there
no moving parts, filter cloths are easily renewable and, because all
joints are external, any leaks are visible and do not contaminate
the filtrate.
DISADVANTAGES
• It is a batch filter, so it is a time consuming.
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• The filter press is an expensive filter, the emptying time, the labor
involved, and the wear and tear on the cloths resulting in high
costs.
• Operation is critical, as the frames should be full, otherwise
washing is inefficient and the cake is difficult to remove.
• The filter press is used for slurries containing less about 5 % solids
• In view of the high labor costs, it is most suitable for expensive
materials. e.g. the removal of precipitated proteins from insulin
liquors.
4. CENTRIFUGAL FILTERS
• A centrifuge consists of a basket in which mixture of solid and
liquid, or mixture of two liquids is rotated at high speed so that it
is separated into its constituents by the action of centrifugal force.
TYPES OF BASKETS
I. Imperforated, in which the liquid is removed through a
skimming tube, while the solid particles, sediment to the
wall.
In pharmacy, the centrifuge is commonly used for drying
crystals and for separating emulsions into their constituent
liquids.
II. Perforated basket, in which the liquid passes out through
the holes.
1. THE PERFORATED BASKET CENTRIFUGE
• A vessel about 1m. in diameter and its outer wall is perforated. It
is mounted on a vertical shaft by means it can be rotated at a high
speed. An outer casing with an outlet collects the liquid thrown
out from the basket.
• The drive motor may be below the centrifuge and it is called
under-driven,
• Other form is over-driven.
ADVANTAGES OF A CENTRIFUGE
• It is very compact, occupying very little floor space.
• It is capable of handling slurries with high proportions of
solids.
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• The final product has generally, a very low moisture content
if compared to a filter cake of a similar material.
DISADVANTAGES
• Batch process
• It involves a considerable labor cost, making the process
expensive.
2. THE PUSHER-TYPE CENTRIFUGE
• This type of centrifuge is used for the separation of suspensions
and is fitted with a perforated basket.
OPERATION
• The feed is introduced through a centrally located conical funnel, and
the cake is formed in the space between the flange and the vertical base
of the basket.
• A reciprocating pusher disc moves the formed cake along the surface of
the basket freeing the surface for further cake deposition.
• The pusher makes one stroke forward and backward, until a further
layer of solids is built up when a second stroke follows, and so on. The
filtrate passes through the holes of the basket and is collected by
suitable piping.
• In a second stage, a washing spray is admitted by a perforated head.
• In a third stage, drainage, and partial drying of the cake takes place after
which the dry solid may be automatically collected.
ADVANTAGES
• Continuously operated apparatus. thus, reducing the cost of operation
DISADVANTAGES
• The pusher piston mechanism adds to the initial costs of the centrifuge.

3. THE TUBULAR CENTRIFUGE (SUPERCENTRIFUGE)
PRINCIPLE OF OPERATION
• High centrifugal effects can be obtained by using a centrifuge of small
diameter rotated at a high speed.
USES
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• It can separate solids of small particle size from liquids.
• It can be used to separate immiscible liquids from one another. e.g. the
two components of emulsion.
• It can be used for filtration of very diluted suspensions i.e. solutions
containing very low concentration of solids.
ADVANTAGES
• Due to the very high centrifugal speed (15.000- 60,000), It can be used
for clarification of much diluted solutions due to the accelerated
gravitational force.
• On separation of two immiscible liquids, the centrifugal force will form
two layers, with the heavier liquid adjacent the wall.

4. THE DISC- BOWL CENTRIFUGE
EQUIPMENT SELECTION
• Ideally the equipment chosen should allow a fast filtration rate to
minimize production costs, be cheap to buy and run, be easily cleaned
and resistant to corrosion, and be capable of filtering large volumes of
products.
• There are a number of products – related factors that should be
considered when selecting a filter for a particulate process.
• These include:
i. The chemical nature of the product. Interactions with the filter
medium may lead to leaching of the filter components,
degradation or swelling of the filter medium or adsorption of
components of the filtered product on the filter. All of these may
influence the efficiency of the filtration process or the quality of
the filtered product.
ii. The volume to be filtered and the filtration rate required.
iii. The operating pressure needed. This is governing the filtration
rate.
iv. The amount of material to be removed. Prefilters (decantation)
may be required or filter where the cake can be continuously
removed.
v. The degree of filtration required. This affect the chosen pore size
of membrane filters or the filter grade to be used.
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vi. If sterility is required, then the equipment should itself be capable
of being sterilized and must ensure that contamination does not
occur after the product has passed the filter.
vii. The product viscosity and filtration temperature. A high product
viscosity may require elevated pressure to be used.

META FILTERS
• It consists of grooved drainage rod on which a
series of metal rings made from stainless steel
are packed.
• The rings are of 22mm diameter, 15mm internal
diameter and 0.8mm in thickness.
• Rings are tightened on the draining rod with a
nut and it form a trapped channel of 250µm-
25µm.
• Unit is placed in vessel containing the slurry to
be filtered.
• When the vacuum is created the liquid passes
through the pack into the drainage rod and
ultimately to the receiver.
ADVANTAGES
• The filters may be fitted with the steam jacket for the filtration of very
viscous liquid such as syrups or oily substances.
• useful for clarification of parenteral solutions.
• Used as strainers for coarse particles.
• For fine particles first filter aid i.e. kieselguhr or charcoal is first
deposited on rings and then filtration carried out.
FILTRATION OF VOLATILE LIQUIDS
• Volatile and inflammable liquids cannot be filtered through ordinary
method.
• Because these materials can be lost through evaporation and liable to
explode.
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• Therefore, for filtration of these liquids, the funnel must be covered, and
receiver must be closed, and provision must be made for the air to
escape from the receiver.
SEDIMENTATION AND DECANTATION
• The simplest method to separate the solid from its soluble impurities.
• Method consist of allowing the slurry to stand in a suitable vessel until
the solids either settle at the bottom or rise to the top of the liquid.
• The process of removing the clear liquid from the top is called
“Decantation” and setting of solids at the bottom is known as
“sedimentation.”
• These methods are used for washing the precipitates and magmas.
STRAINING
• In this method slurry to be filtered is poured on the muslin cloth or a
porous substance which will allow the liquid to pass but will retain the
solids over it.
• It is a general method for separating the solid impurities from liquid.
• Apparatus used is consist of strainer medium and a support or frame.
• The strainer medium is usually colorless cloth materials.
• The strainer medium must be washed before use.
APPLICATION OF SOLID/LIQUID FILTRATION
1. Improvement of the appearance of solutions, mouth washes, etc.
2. Removal of potential irritants, e.g. from eye drop preparations or
solutions applied to mucous membranes.
3. Recovery of desired solid material from suspension or slurry, e.g. to
obtain drug after crystallization process.
4. Certain operations, such as the extraction of vegetable drugs with a
solvent, may yield a turbid product with a small quantity fine suspended
colloidal matter; this can be removed by filtration.
5. Detection of microorganisms present in liquids; this can be achieved by
analyzing a suitable filter on which the bacteria are retained. This
method can also be used to assess the efficiency of preservatives.
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EVAPORATION
INTRODUCTION
• It simply means vaporization from the surface of liquid. Thus, no boiling
occurs and the rate of evaporation depends upon the diffusion of vapors
through the boundary layer above the liquid. In practice, however, this
would be too slow, so the liquid is boiled causing vapors to be liberated
in the form of bubbles from the bulk of liquid. So practical definition of
evaporation is:
“Removal of liquid from a solution withdrawing the vapor a concentrated
liquid residue behind.”
• This means that heat will be necessary to provide the latent heat of
vaporization and in general, the rate of evaporation is controlled by rate
of heat transfer. Evaporators are designed to give maximum heat
transfer to the liquid.
FACTORS AFFECTING EVAPORATION
1. TEMPERATURE
• As part from the significance of temperature as a factor that affects the
rate of evaporation, its effects on the drug constituents is of great
importance, the thermolability of many medicinal principles during
evaporation, temperature that will cause the least possible
decomposition must be use.
• Many glycosides and alkaloids and some others like hormones, enzymes
and antibiotics are even more heat sensitive substances and may require
special treatment if decomposition is to be avoided during evaporation.
• Malt extract is prepared by evaporation under reduced pressure to avoid
loose of enzymes, and for some antibiotics the only possible method is
freeze drying.
2. TEMPERATURE AND TIME OF EVAPORATION
• Exposure to relatively high temperature for a short period of time may
be less destructive for active principles then a lower temperature with
exposure for a longer period.
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3. TEMPERATURE AND MOISTURE CONTENT
• Some drugs constituents decompose more readily in the presence of
moisture especially at in raised temperature. Since many break down
reactions are examples of hydrolysis and other require water as a
medium in which to act. This explains why evaporation to a
concentrated condition may be carried out at a low controlled
temperature in some cases, although the final drying can be performed
at higher temperature when little moisture remains, belladonna extract
is an example of this type.
4. TYPE OF PRODUCT REQUIRED
• The type of product required will often decide which method and
apparatus should be employed for evaporation. Evaporating pans or
stills will produce liquid or dry products, but film evaporators will yield
only liquid products.
• Hence if a dry product id required a choice must be made between a
method that will form suitable products directly and in which pre
liminary concentration is carried out, with the process completed by
another method.
5. SURFACE AREA
• Greater the surface area greater will be the evaporation.
6. AGITATION
• During evaporation, the upper layer have the tendency to form a layer
(scum) which decreases the evaporation. It is necessary to agitate or stir
the solution. This will prevent the decomposition of material at bottom
due to high heat. It will also prevent the settling of solids at the bottom.
7. ATMOSPHERIC AQUEOUS VAPOR PRESSURE
• If the moisture content in the air is high the rate of evaporation will be
slow but if it is less, then the rate of evaporation will be fast. Therefore,
the rate of evaporation can be increased by free circulation of warm air
in the evaporating pan.
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8. ATMOSPHERIC PRESSURE
• If we reduce the atmospheric pressure on the liquid the rate of
evaporation will be doubled. Due to the reason evaporation is done
under reduced pressure.
9. ECONOMIC FACTOR
• Fuel
• Economy of labor
• Floor area
• Material
EVAPORATORS
• The equipment used in the evaporation may be classified conventionally
according to the form of movements, as this is very important in heat
transfer and can be divided into 3 groups:
1. Natural circulation evaporators
▪ Evaporating pans
▪ Evaporating stills
▪ Short tube evaporators
2. Forced circulation evaporators
3. Film evaporators
▪ Long tube evaporators
▪ Falling film evaporators
▪ Rotary film evaporators
SMALL SCALE METHODS
• Small quantity liquids evaporated in porcelain or glass dish. Direct
heating by bunsen burner or electric hot plate. Direct heating may
decompose substance. So, water bath is most suitable when liquid
heated up to 100℃.
• Sand bath/oil bath containing liquid or soft paraffin used when 300℃
temperature required.
• Glycerin bath attain temperature up to 150℃.
LARGE SCALE METHODS
• Liquid extracts containing water as menstruum are evaporated in open
pans.
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NATURAL CIRCULATION EVAPORATORS
1. EVAPORATING PANS
• The simplest form of natural circulation
evaporation is the evaporating pans. The apparatus
consists of a hemispherical or shallower pan
constructed from a suitable material such as
copper or stainless steel and surrounded by steam
jacket.
• The hemispherical shape gives the best surface/ volume ratio for heating
and the largest area for disengagement of vapors. The pan may have
mounting, permitting it to be titled to remove the product, but the
shallow form makes this arrangement unstable.
ADVANTAGES
• It is simple and cheap to construct.
• It is easy to use, clean and maintain.
• Stirring of evaporating liquid can be done easily.
DISADVANTAGES
• Having only natural circulation the overall co-efficient of heat transfer
will be poor and solids are likely to deposit on the surface leading to
decomposition of the product and further deterioration in heat transfer.
• Also, many products give rise to foaming when boiled under conditions
of natural convection.
• All the liquor is heated all the time, which maybe unsatisfactory with
thermolabile material.
• The heating surface is limited and decreases as the size of pan increase.
2. EVAPORATING STILLS
CONSTRUCTION
• This type of evaporator is known commonly as
still, since it is essentially a vessel made from
copper or stains less steel similar to the
evaporating pan, with a cover that connects it to
a condenser, so that the solvent is condensed
and collected in a receiver. Typical construction is
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often, a quick release system of clamps which allows the cover to be
removing easily or excess to the interior of the vessel for cleaning and
removal of product.
ADVANTAGES
• Like the evaporating pan it is quite simple to construct and easy to clean
and maintain.
• The vapor is condensed, which speeds evaporation, reduces
inconvenience and allows the equipment to be use solvents other than
water e.g. ethanol.
• Receiver and vacuum pump be fitted to the condenser, permitting
operation under reduced pressure and hence at lower temperature.
• Can be used for aqueous and other organic solvents.
DISADVANTAGES
• Natural convection only
• All the liquor is heated all the time
• Heating surface is limited
• Deterioration of product
3. SHORT TUBE EVAPORATORS
• As the size of the evaporators increase heating by
means of an external steam jacket becomes
inadequate. The short tube evaporators as the
name implies use steam heated tubes instead of
surrounding the vessel by steam jacket.
OPERATION
• The lower portion of evaporator consists of nest of tube with liquor
inside and steam outside. These tubes are 1-2m in length and 40-80mm
in diameter with the tubes up to 1000 in number.
• This part of evaporator is known as calandria. The level of liquor is
maintained slightly above the top of the tube. The surface above this
being left for the disengagement of vapor from the boiling liquor during
operation liquor inn the tube is heated and began to boil.
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• When mixture of liquid and vapor will shoot up the tube in a similar
manner in that of liquid i.e. allowed to boil too vigorously in test tube.
This setup a circulation with boiling liquor of the calandria and returning
down the larger central down tank.
ADVANTAGES
• Use of tubular calandria increases the heated area.
• Vigorous circulation reduces boundary layer and keep solids in
suspension so increases the rate of heat transfer.
• Resultant co-efficient of heat transfer is 3-5 times greater than those
found in evaporation pans.
• Like still evaporators a condenser and receiver can be attach.
DISADVANTAGES
• Since the evaporation is filled to a point above the calandria, a
considerable amount of liquor is heated for a long time.
• The effect of continuous heating can be reduced to some extent by
removing strong liquid slowly from the outlet at the bottom of vessel.
• The plant is much more complicated.
• The heat of liquor increases the pressure at the bottom of the vessel.
• This type of equipment will be more useful for the large-scale
production.
FORCED CIRCULATION EVAPORATOR
• These are natural circulation evaporators with some added forms of
mechanical agitation. In fact, it is the simplest form of evaporator pan in
which the contents are agitated by the stirring rod. Alternatively, a
mechanically operated propeller or paddle agitator can be used into an
evaporator pan or still or into down tank of short tube evaporator.
• As the liquid is circulated by means of the pump it could be under
pressure in the tube. The boiling point elevated but no boiling take
place. As the liquor leaves the tube and enter the body of evaporator a
pressure will form super-heated liquor. Compared with natural
circulation type, evaporator with forced circulation has the advantage
that liquid movement improves heat transfer. The equipment is
particularly suitable for operation under reduced pressure.
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FILM EVAPORATOR
• Film evaporator has the name indicated spread the material as a film
over the heated surface. It is important that the basic difference
between 2 groups (circulation and film) greatly influence the rate of heat
transfer and suitability of the method of particular purpose.
1. LONG TUBE EVAPORATORS
• In this type of evaporator, the heating unit consists of
steam jacketed tubes which may have tube of 50mm
in diameter and about 7m in length. The liquid to be
evaporated is introduced into the bottom of the
tube, the film of liquid form on the wall of the tube
and rises up the tube. It also called as climbing film
evaporator.
PRINCIPLE OF CLIMBING FILM EVAPORATOR
• Cold and pre heated liquor is introduced into the tube. Heat is transfer
to the liquid from the wall and boiling begins. Increasing in vigor
eventually the sufficient vapor has been formed or smaller bubble to
unit a larger bubble and trapping a slug of liquid above the bubble. As
more vapor is form the slug of liquid is blown up the tube.
• The tube is filled with vapor while the liquid is spread as film over the
wall. The film of liquid continue to vaporize rapidly, the vapor escaping
up to the tube and because of friction between vapor and liquid the film
also drag up to the tube. Getting the rate of vaporization, the vapor
travels from 6-7m/sec.
ADVANTAGES
• The very high film velocity reduces boundary layer to a minimum during
improved heat transfer. Because of increase efficiency of heat transfer a
small temperature is sufficient with less damage of thermolabile
material.
• The long narrow tube provides large area for heat transfer.
• The time of contact between the liquor and heating surface is short.
Despite the short heating time the evaporation rate is high.
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• Since the film formation gives a large surface area in relation to a
volume of liquid.
• The mixture of liquids and vapor enter the separator at high velocity
which improve the separation, efficiency and makes the method suitable
especially that makes foam.
DISADVANTAGES
• It is expensive to manufacture and difficult to clean.
• From operational point of view heat rate is critical.
• If too high heat the liquor may be concentrated whereas if too low the
film cannot be maintained and dry patch may form on the tube wall.
2. FALLING FILM EVAPORATOR
• An alternate form of long tube evaporator is the
falling film evaporator, which resembles the
climbing form but is inverted as shown in fig. So
that the feed liquor inters over a weir at the top of
the tubes and the concentrate and the vapors
leave from the bottom. The special advantage of
this arrangement is that; the movement of liquid
film is assisted by gravity, enabling more viscous liquids to be handled. In
some cases, climbing and falling films units are combined so that the
weak liquor is concentrated partially in the climbing film unit and the
evaporation completed as the liquor returns down the falling film unit.
The method is used where a high percentage evaporation is required
and where the concentrated liquor is viscous. It can be useful also where
the plant is located on one floor since the product is returned to same
level as the starting point.
• Where space is important and a small versatile film
evaporator is required to serve a similar purpose to
a steam pan, the Horizontal Film Evaporator can be
useful. The arrangement is illustrated in figure
where it will be seen that it is in fact a climbing film
evaporator that has been “folded up” and
occupies, therefore, a very small space, needing
little hand room. Since most forms have only one
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tube, and the U-tube bends can be removed easily, it can be used safely
with small batches of different materials.
3. WIPED/ROTARY FILM EVAPORATOR
• It consists of single short tube of wide diameter or
narrow cylindrical vessels 1-2m in length. The vessel is
surrounded by steam heated jacket through the vessel
is a bladed rotor, with clearance of the order of 1mm
between the tips of the rotor blade and walls of the
vessels. The liquor is introduced at the top of the
vessels and is spread as a film over the heated walls by
the action of rotor. Evaporation occurs as the liquid
passes down the wall, vapor is taken off to a condenser and the
concentrated liquor withdrawn at the bottom of the vessel. It is a single
tube form evaporator in which the film is formed and agitated
mechanically. It is useful for viscous liquid.
IMPROVEMENT OF EFFICIENCY OF EVAPORATORS
• Each part by weight of water vaporized in an evaporator will require an
equal weight of steam. In practice more is required because of deviation
in specification of heat and to allow for heat loss. Modification in normal
method will allow efficiency to be increased.
1. MULTIPLE EFFECT EVAPORATION
• The single effect evaporator use steam to
supply heat to the liquor and provide latent
heat of vaporization. This vapor is then
taken off to a condenser, where latent heat
is given up to cooling water which goes up
to waste. In the simplest case of multiple
effect evaporation 2 evaporators are
connected together with piping arranged so that the calandria of 1
st

effect is heated by steam.
• The vapors from the 1
st
effect are used to heat the calandria of 2
nd

effect. In other words, the calandria of 2
nd
effect is used as a condenser
for the 1
st
effect. So that the latent heat of vaporization is used to
evaporate further quality of the liquor instead of going to waste. The
102

105. GM Hamad

vapor from 2
nd
effect is taken to condenser. Any number of evaporators
can be connected in this way with increasing economy but there are
some limitations.
2. VAPOR RECOMPRESSION
• When vapor recompression is used on an evaporator,
some of the vapor from the process is returned to the
calandria to provide heat to vaporize more of the
liquid. Since the pressure will need to be increased to
provide the necessary temperature gradient, the
vapor is compressed by mean of pump or by injection
of certain amount of high-pressure heat. The use of compressor is more
useful in situation where the power is cheapest then heat. The use of
vapor recompression allows as economy in heat to be made.
ADVANTAGES
• Evaporation can be carried out at low temperature where the earliest
effect of multiple effect system may have to operate at high
temperature for thermolabile products.
• Only 1 evaporator is used which reduces the cost of equipment.
EVAPORATION UNDER REDUCED PRESSURE
• The application of this system is based on the principle that vapor
pressure exerted by the liquid depends upon the temperature. The
liquid boil when the vapor pressure is equal to atmospheric pressure. If
the pressure in an evaporator is reduced below the atmospheric
pressure and aqueous liquid will boil at temperature less than 100oC.
ADVANTAGES
• Evaporation occurs at lower temperature so less risk of damaging heat
to sensitive materials.
• A lower operating temperature gives higher temperature gradient
without need for excessive steam pressure.
• The lower the operating temperature the lower will be the steam
pressure.
DISADVANTAGES
103

106. GM Hamad

• It is possible for flow to change from turbulence to stream-line.
• There is 2-fold increases in the viscosity of water.
• Boundary layer thickness will increase the difficulties in heat transfer
and risk of overheat.
VAPOR CONDENSATION
• All evaporators except evaporating pans use condenser for removing
vapor. In principle a condenser in identical to evaporators with reversed
objective. Evaporator’s uses vapor (steam) to heat liquid. Condenser
uses liquid to cool vapor.
1. INDIRECT/SURFACE CONDENSER
• In this type where no direct contact between
coolants and vapors, the vapors are
condensed to a cool surface on large scale
multi-tubular condensers are used.
Generally, the vapors being inside the tube
and cooling water outside which can be
reversed. These condensers operate by
counter current flow i.e. the water and vapor
move in opposite direction. The condensed liquid as it leave the
condenser is cooled by entering cool water while the water leaves
immediately after meeting the entering vapors. The water caries away
as much heat as possible.
2. DIRECT CONTACT/JET CONDENSER
• The vapor and cooling water are brought into direct
contact. As procedure comparable with the use of live
stream for heating since the water and vapor mixed. It is
applicable only to condenser for evaporation handling
aqueous liquid.
• Different types of equipment are available but exact form
of causes vapor to enter where it is brought in contact with
jets of water. Condensate of vapor lowers the pressure so
assist the reduced pressure operation of evaporation. But
the vacuum pump can be connected to the top of vessel.
104

107. GM Hamad

To prevent water being drawn into the vacuum, pump, the barometric
legs.
• This is simply a pipe of greater length then water barometer. It is about
10 or 11 meter dipping into reservoir. The vacuum pump unable to lift
the water to the height of condensing vessel. This length of pipe may
seem inconvenient but it is very cheap and located alongside the
evaporator without difficulty especially in long tube evaporator.
• In general, surface condenser use for organic solvent in all cases and for
smaller installation for dealing with aqueous liquid. Jet condensers are
used with large evaporators to condense water vapor only.
APPLICATIONS OF EVAPORATION
• One of the most important processes in manufacturing of
pharmaceuticals.
• Used in the preparation of liquid extracts, soft extracts and dry extracts
and in concentration of drug plasma and serum.
• Also used in manufacturing of drugs containing antibiotics, enzymes,
hormones and many other substances.
DIFFERENCE BETWEEN DRYING AND EVAPORATION

Drying Evaporation
Left over product is solid always Left over product is semi-solid or liquid
Drying is the removal of liquid from
a solid/semi-solid/liquid to produce
solid product by thermal energy
input causing phase change i.e.
solid mixture into vapors by
sublimation.
Evaporation is Removal of liquid from a
solution withdrawing the vapor a
concentrated liquid residue behind.

105

108. GM Hamad

COMPRESSION AND COMPACTION
COMPRESSION
• Compression means reduction of bulk volume of material as a result of
the removal of gaseous phase (air) by applied pressure.
EXAMPLE
• In tableting machine, pressure exerted by upper punch and lower punch
to the powder to make tablet.
CONSOLIDATION
• Consolidation is an increase in mechanical strength of material resulting
from particle-Particle interactions.
• Interactions include:
COLD WELDING
• The free surface energies of closely related particles result in strong
attractive forces when the particles approach each other under force,
the process is called cold welding.
FUSION WELDING
• The local rise in temp due to increased frictional forces between
particles result in melting of the particles that cause bonding between
them and process is called fusion welding.
FACTORS EFFECTING
• Chemical nature of materials
• Presence of surface contaminants
• The inter surface distances
• Extent of available surface
COMPACTION
• The compression and consolidation of a two phase (solid + gas) system
due to an applied force, resulting in the formation of a compact but
porous mass of definite geometry.
• Compaction = compression + consolidation of two phases (solid-gas) on
application of force.
106

109. GM Hamad

POWDER
INTRODUCTION
• Solid dosage form of medicaments which are meant for internal and
external use. Available in amorphous or crystalline form. Drugs are
prepared in different forms and shape but many of them are prepared
by using one way or other.
POWDER FLOW PROPERTIES
• Pharmaceutical powders may be classified as free flowing or non-free
flowing (cohesive).
• Flow properties are significantly affected by changes in:
­ Particle size, shape, electrostatic charges and adsorbed moisture
which may arise from processing or formulation.
• Powder flow should be determined for improvement of pharmaceutical
formulation and consequence of processing.
FLOW RATE
• It Is the ratio of mass of the substance to time taken by it to flow”
(mass/time)
• The flow rate of powder is important consideration in tableting and
other pharmaceutical processes.
• Good flow rate will allow efficient movement within the machines and
give good results.
FACTORS AFFECTING POWDER FLOWABILITY
I. PARTICLE SIZE
• Frictional + cohesive forces increase as size is decreased resulting in
decreased flowability.
II. DENSITY AND POROSITY
• Increase density leads to freely flowing powder, decreased porosity
leads to freely flowing powder.
III. PARTICLE SHAPE
• Increase in roughness decreases flowability.
IV. PARTICLE SIZE DISTRIBUTION
• Increase in amount of fine powder because of compression so that
spaces between the granules can be encamped by the fine powders.
107

110. GM Hamad

V. MOISTURE CONTENT
• Increase in moisture content leads to decrease flowability.
FLOW RATE DETERMINATION
• By measuring weight of powder passed through an orifice per time
g/sec)
• Variety of orifice size (⅛ to ½ inches) should be made.
• Greater standard deviation between flow rate measurements, greater is
weight variation in Products. (Not more than two tablet)
PARTICLE SIZE ANALYSIS (ACCORDING TO USP)
• Powders may be course to very fine powders.
• Size analysis is done by sieving method in specified time.
COARSE POWDER
• Particles pass through No. 20 sieve and not more than 60% through No.
40 sieve.
MODERATELY COARSE POWDER
• Particles pass through No. 40 sieve and not more than 60% through No.
60 sieve.
FINE POWDER
• Particles pass through No. 80 sieve. No limit as to greater fitness.
VERY FINE POWDER
• Particles pass through No. 120 sieve. No limit as to greater fitness.
METHODS FOR DETERMINATION OF PARTICLE SIZE
BY WEIGHT
• Sieve method
• Light scattering
• Sedimentation
BY VOLUME
• Electronic sensing zone
• Light scattering
• Optical microscope
1. SIEVING
• Sieve Analysis is performed using a nest or stack of sieves where each
lower sieve has a smaller aperture size than that of the sieve above it.
• Sieving size range: 5μm – 360mm.
• Sieving may be performed wet or dry, by machine or by hand, for a fixed
time or until powder passes through the sieve at a constant low rate.
108

111. GM Hamad

2. MICROSCOPY
• In this method, small sample size is mounted on the stage of microscope
and the particle size is measured using the micrometer joined to it.
• Microscopy size range: 0.2 – 100 Micrometer.
3. SEDIMENTATION
• Determined by measuring setting velocity of particles through liquid
medium in gravitational or centrifugal environment. It can be calculated
by Stokes law using Andreasen pipette.
4. LIGHT ENERGY DIFFRACTION
• Disperse particles in liquid/gas, sensing zone determines light reduction.
5. LASER HOLOGRAPHY
• Pulsed laser is fired through an aerosolized particle spray and
photographed in 3 dimensions with holographic camera.
INHERENT PROPERTIES OF POWDERS
SOLID AIR INTERFACES
• Atoms or ions located at the surface of any solid particle are exposed to
a different distribution of intramolecular and intermolecular bonding
forces than those within the particle.
• They may be envisaged as unsatisfied attractive molecular forces
extending out some small distance beyond the solid surface. This
condition gives rise to what is called the free surface energy of the solid,
which plays a major role in the interaction between particles, and
between a particle and its environment.
• Many important phenomena such as adsorption, cohesion and adhesion,
rate of solution, and crystallization are manifestations of this
fundamental property of all solids.
COHESION AND ADHESION
• Because of these unsatisfied bonding forces at the surface of particles,
those that approach each other closely enough are inherently attracted
and tend to stick to one another. This attraction between like particles is
called cohesion.
• In addition, when they approach other types of particles or solid
surfaces, they are attracted to them, leading to what is termed
adhesion.
109

112. GM Hamad

SIGNIFICANCE OF ATTRACTION
• These attractions give rise to an intrinsic property of all bulk powdered
solids:
­ They resist differential movement of their constituent particles
when subjected to external forces.
• This phenomenon has an important influence on several operations,
such as flow from hoppers or feeders, relative motion in mixers, and
compression to produce granules or tablets.
FACTORS EFFECTING RESISTANCE
• The overall resistance to relative movement of particles may be
markedly affected by two other factors.
­ First, many powders of pharmaceutical interest readily develop
electrostatic forces, especially when subjected to internal friction,
although particle contact and separation are the only prerequisite.
The charge developed de-pends on the particular material
involved and the type of motion produced in it. Usually,
electrostatic forces are relatively small, but may be significant
because they act over a greater distance than the molecular
forces.
­ The second factor, namely the presence of an adsorbed layer of
moisture on the particles. However, these films of moisture can
form liquid bridges, which hold the particles together by surface
tension effects and by a negative capillary pressure.
ANGLE OF REPOSE
• Relatively simple technique to determine flowability of powder.
• Qualitative assessment of cohesive and frictional forces under levels of
external loading, applied in powder mixing, in tablet dye or capsule shell
filling.
• Can be determined by allowing powder to flow through funnel making
heap and then determining height and diameter of heap.
• “Maximum angle obtained between a freely standing surface of powder
heap and horizontal surface or plane”
FORMULA
????????????&#3627408475;θ=
2h
D

110

113. GM Hamad

• Where,
­ h = heap height of powder cone
­ D = powder bed diameter
Angle of repose Flow property of powder
<25 Excellent
25-30 Good
30-40 Passable
>40 Poor

DETERMINATION OF ANGLE OF REPOSE
• CONE METHOD
• A close funnel is fully filled with powder and then inverted on a plain
surface and lifted, then from this “h” and ”D” is measured and calculated
by following equation:
????????????&#3627408475;θ=
2h
D

• FIXED FUNNEL METHOD
• Take a paper with known width and length. Calculate area by length x
width. Adjust funnel on stand and put that paper under funnel.
• Allow 100g powder to flow through funnel. Now, calculate height of
heap and encircle the heap and cut paper.
• Now, find grammage:
Grammage=
Weight of paper (??????)
Area of paper (m
2
)

• Gram per unit area is necessary for label and cost effectiveness. Now,
determine area of cut circular paper by:
Area of cut paper=
Weight of circular paper
Grammage

• Then, calculate
Area=πr
2

r=√
Area of cut paper
π

• Then, determine θ by:
111

114. GM Hamad

Tanθ=
h
r

θ=Tan
−1
h
r

• ROTATING/REVOVING CYLINDER METHOD
• The material is placed within a cylinder with at least one
transparent face. The cylinder Is half filled with the test
powder. The cylinder is rotated at a fixed speed and the
observer watches the material moving within the
rotating cylinder. The granular material will assume a
certain angle as it flows within the rotating cylinder and the angle at
which it begins to cascade is noted.
• TILTING BOX METHOD
• This method is appropriate for fine grained, non-
cohesive materials, with individual particle size less than
10mm. The material is placed within a box with a
transparent side to observe the granular test material. It
should initially be levelled and parallel to the base of the
box. The box is slowly tilted at a rate of approximately 3 degrees/
second. Tilting is stopped when the material begins to slide in bulk,
and the angle of tilt is measured.
FACTORS AFFECTING ANGLE OF REPOSE
• Angle of repose is affected by different coefficients of friction between
different substances.
• The size of the particles is a factor. Other factors being equal, fine
grained material will form a shallower pile with a smaller angle of repose
than coarse grains.
• Moisture affects the angle of repose.
• The method by which the angle of repose is measured can also affect
the measurement.
MASS VOLUME RELATIONSHIP
Mass of a bulk powder sample can be determined with great accuracy,
measurement of the volume is more complicated.
Three types of air spaces/voids present in powders
I. OPEN INTRA-PARTICULATE VOIDS
112

115. GM Hamad

• Those within a single particle but open to the external environment.
II. CLOSED INTRA-PARTICULATE VOIDS
• Those within a single particle but closed to the external environment.
III. INTER-PARTICULATE VOIDS
• The air spaces be-tween individual particles.
Three interpretations of "powder volume" may be proposed:
I. THE TRUE VOLUME (VT)
• The total volume of the solid particles, which excludes all spaces greater
than molecular dimensions, and which has a characteristic value for each
material.
II. THE GRANULAR VOLUME (Vg)
• The cumulative volume occupied by the particles, including all intra-
particulate (but not inter-particulate) voids.
III. THE BULK VOLUME (Vb)
• The total volume occupied by the entire powder mass under the
particular packing achieved during the measurement.
METHODS TO MEASURE
I. HELIUM PYCNOMETER METHOD
• Provides nearest approach to true volume.
• Within a system containing helium, change in pressure caused by finite
change in volume is the measure of total volume.
II. LIQUID DISPLACEMENT METHOD
• To measure granular volume Vg.
DENSITY
• The ratio of mass (weight) to volume is known as the density of the
material.
TYPES
• Three different densities for powdered solids based on following ratios
are defined:
I. TRUE DENSITY
• It is obtained by dividing mass by true volume of sample
M
V
t
=??????
?????? the true density
II. GRANULAR DENSITY
113

116. GM Hamad

• It is obtained by dividing mass by granular volume.
M
V
g
=??????
?????? the granular density
III. BULK DENSITY
• It is obtained by dividing mass by bulk volume of sample.
M
V
b
=??????
&#3627408463; the bulk density
RELATIVE DENSITY
• Comparing the density of sample under specific conditions to true
density (sometimes called theoretical density)
??????
??????????????????&#3627408462;???????????????????????? =
??????
(&#3627408454;??????&#3627408474;??????&#3627408473;&#3627408466;)
??????
(&#3627408455;&#3627408479;&#3627408482;&#3627408466; &#3627408465;&#3627408466;&#3627408475;&#3627408480;??????&#3627408481;??????)

• During compression process, relative density reaches to maximum of
unity (1) as all air spaces are eliminated.
METHOD OF MEASUREMENT
BY PYCNOMETER
• Wash pycnometer with water and rinse with acetone and air dry it.
• Calibrate pycnometer and weigh it.
• Fill pycnometer with given samples one by one.
• Then subtract mass of pycnometer from total mass so mass of sample is
calculated.
• Now, calculate density by formula:
????????????&#3627408475;&#3627408480;??????&#3627408481;??????=
????????????&#3627408480;&#3627408480;
??????&#3627408476;&#3627408473;&#3627408482;&#3627408474;??????

GRANULES
GRANULATION
• It is a process in which primary powder particles are made to adhere to
form larger, multi-particles entities called granules. It is the process of
collecting particles together by creating bonds between them. Bonds are
formed by compression or by using a binding agent.
114

117. GM Hamad

NEED OF GRANULES
TO AVOID POWDER SEGREGATION
• Segregation may result in weight variation that is why granules are
used to avoid weight variations.
IMPROVE FLOW PROPERTIES OF MIXTURE
• Many powders because of small size, irregular shape or surface
characteristics give poor flow but granules improve the flow properties
of mixture.
IMPROVE COMPACTION CHARACTERISTICS OF MIXTURE
• Some powders are difficult to compact so binders are added but
granules have good flowability and produce strong tablets.
REDUCE HAZARDS OF TOXIC DUST POWDERS
• Hazards of toxic dust powders may arise when handling powders.
• By making granules vibrations are decreased hence stable machinery
and no friability.
REDUCE HAZARDS OF HYGROSCOPIC POWDERS
• On storage, powders may adhere and form cake.
• Granulation may reduce this by absorbing moisture and yet retain their
flowability because of size that is why granules are convenient for
storage.
GRANULATION METHODS
• Granulation methods can be divided into following types:
1. Dry methods (dry granulation/slugging) - no liquid is used.
2. Wet methods (wet granulation) - use a liquid in the process, binders are
added in solution/suspension form.
3. Direct compression
GRANULATION ADDITIVES
DILUTENTS
• To increase bulk, to give unit dose shape, pharmaceutically elegant.
DISINTEGERATING AGENT
• To break granules and tablet form before compaction and before
granulation.
115

118. GM Hamad

ADHESIVES
• They may also be added in form of dry powders, particularly if dry
granulation is employed. These ingredients will be mixed before
granulation.
1. DRY GRANULATION
• The dry granulation process is used to form granules without using a
liquid solution because the product to be granulated may be sensitive to
moisture and heat. Forming granules without moisture requires
compacting and densifying the powders. In this process the primary
powder particles are aggregated under high pressure.
STEPS IN DRY GRANULATION
I. Compaction of powder
II. Milling
III. Screening
METHOD
• The blend of powders are forced into the dies of a large capacity
tablet press and is compacted by means of flat faced pinches, the
compacted masses are called slugs, the process known as slugging.
• They are then broken into suitable size granules by passing through
an oscillating granulator or sieve no 10, 20 etc.
• The resultant granules are mixed with lubricants and other necessary
additives. Then they are compressed into finished tablets in rotatory
machine.
• There are two main processes:
I. SLUGGING
• Slugs range in diameter from 1 inch for the more easily slugged material
to ¾ inch for materials that are more difficult to compress and require
more pressure per unit area to yield satisfactory compacts.
II. ROLLER COMPACTOR
• The powder is squeezed between two rollers to produce sheet of
material (roller compactor or chilsonator). In both cases these
intermediate products are broken using a suitable milling and sieving
technique to produce granular material, which is usually sieved to
separate the desired size fraction. On large scale, compression
granulation can be performed in specially designed machines.
116

119. GM Hamad

­ Chilsonator compactor ­ Hutt's compactor
ADVANTAGES OF DRY GRANULATION
• Avoid heat-temperature combinations that might cause degradation of
products.
• Best suited for drugs, sensitive to moisture.
2. WET GRANULATION
• Wet granulation involves the massing (passing through sieve) of dry
primary powder particles using a granulating fluid. The fluid contain a
solvent which may be volatile so that it can be removed by drying and be
non-toxic. Typical liquids includes water, ethanol and isopropanol, either
alone or in combination. The granulation liquid may be used alone or
more usually, as a solvent containing a dissolved adhesive (binding
agent) which is used to ensure particle adhesion once granules are dry.
• In the traditional wet granulation method, the wet mass is forced
through a sieve to produce wet granules which are then dried. A
subsequent screening stage breaks agglomerates of granules and
removes the fine material, which can then be recycled.
EQUIPMENT USED FOR WET GRANULATION
• High speed mixer granulator
• Shear granulators
• Fluidized bed granulators
• Spray drier granulators
• Spheronizers/palletizers
• Rotor granulators
SHEAR GRANULATORS
• Powder mixing in separate operation using suitable mixing equipment.
Planetary mixer is used for wet massing of powder with some
formulations such as those containing 2 or 3 ingredients in equal
quantities, it is suitable to mix powder in planetary mixer.
• Mixed powders are used. Moist mass is transferred to granulator on
oscillating granulator. Rotor bars of granulator oscillate and force moist
mass through sieve screen, size of which determines granule size.
• Mass should be sufficiently moist to form discrete granules when sieved.
If excess liquid is added, string (filament) of material will be formed and
117

120. GM Hamad

if mixture is too dry, mass will be sieved as powder and granules will not
be formed.
• Granules can be collected on trays and transferred to drying oven.
Afterwards dry sieving of granules is performed.
HIGH SPEED MIXER-GRANULATOR
• The machines have a stainless-steel mixing bowl containing a main
impeller, which revolves in the horizontal plane, and an auxiliary
chopper (breaker blade) which revolves either in the vertical or the
horizontal plane. The mixer utilize a bowl.
• A high-speed mixer blade revolves around the bottom of the bowl. The
impeller assembly fit over a shaft at the bottom of the mixing bowl. The
impeller assembly is specially constructed to discharge the material from
getting under it. The mixer also contains a high-speed chopper blade
which functions as lump or agglomerate breaker.
FLUID BED DRYER
• Fluidized-bed granulators have a similar design and operation to
fluidized-bed driers. The powder particles are fluidized in a stream of air,
but in addition granulation fluid is sprayed from a nozzle to the bed of
powder.
• Granulating fluid is heated and filtered air is blown or sucked through
the bed of unmixed powder to fluidize the particles and mix the powder;
fluidization is actually a very efficient mixing process. pumped from a
reservoir through a spray nozzle positioned over the bed of particles.
The fluid causes the primary powder particles to adhere when the
droplets and powders collide.
3. DIRECT COMPRESSION
• The materials which are available in crystalline form and have free
flowing and binding characteristics can be compressed directly. But
majority of drugs cannot be compressed easily in this way because
sometimes they produce tablets which may not disintegrate. To
overcome this difficulty, directly compressible vehicles such as
anhydrous lactose, compressible sugars are used and then compressed.
Drugs which can be directly compressed are NaCl, NaBr, Na Salicylate.
• This method has an advantage of low labor costs and fewer processing
steps.
118

121. GM Hamad

EFFECT OF GRANULATION METHOD ON GRANULE STRUCTURE
Method Effect
Dry granulation/slugging Simple drug by compaction
Wet granulation Wet massing
Fluidized bed granulation Greater porosity covered by film of binding agent
Spray drying granulation
Composed of an outer shell and an inner core
(API) of particles
TABLETS
TECHNOLOGY OF MAKING TABLETS
DEFINITION
• Tablets are solid unit dosage forms consisting of active ingredients
and stable pharmaceutical excipients.
• They may vary in size, shape, weight, hardness, thickness,
disintegration and dissolution. They may be classified according to
method of manufacturing as compressed tablet or molded Tablets.
ADVANTAGES (PRODUCTION ASPECT)
• Large scale production at low cost.
• Earlier and cheapest to package and shipment.
• High stability and user approach.
DISADVANTAGES
• Some drugs resist compression into dense compact.
• Drugs with poor wetting, slow dissolution, intermediate to large dosage,
may be difficult or impossible to formulate and manufacture as tablet
that provides adequate or full drug bioavailability.
• Bitter taste, drugs with an objectionable odor or sensitive to oxygen or
moisture.
TYPES OF TABLETS
• Mainly the tablets are classified into two classes:
­ Compressed tablets
­ Molded tablets
COMPRESSED TABLETS
119

122. GM Hamad

• The compressed tablets are usually prepared on large scale production
methods.
­ Oral tablets
­ Chewable tablets
­ Buccal/Sublingual tablets
­ Lozenge tablets
­ Effervescent tablets
­ Implants
­ Vaginal tablets (Inserts)
­ Enteric coated tablets
­ Sustained action tablets
­ Sugar coated tablets
­ Film coated tablets
­ Press coated tablets
MOLDED TABLETS
• The molded tablets are prepared extemporaneously on a small scale.
­ Hypodermic tablets
­ Dispensing tablets
TABLET EXCIPIENTS
• Compressed tablets usually contain number of pharmaceutical adjuncts
known as excipients in addition to medicinal substances.
• Use of appropriate excipient is important in development of optimum
tablets. Excipients determine bulk of final product in dosage form such
as tablet, capsule etc. Speed of disintegration, rate of dissolution,
release of drug, protection against moisture, stability during storage
depends upon excipients used.
• Excipients should have no bioactivity, no reaction with drug substance,
no effect on function of other excipients, no support of microbial growth
in product.
DILUENTS
• It increases volume of formulation to prepare tablet of desired size.
• Widely used fillers are lactose, dextrose, microcrystalline cellulose,
starch, pre gelatinized starch, powdered sucrose and Calcium
phosphate.
• Diluent is selected based on various factors such as experience of
manufacturer in preparation of other tablets, its cost, compatibility with
other formulation ingredients.
• Example: In preparation of tablets or capsules of tetracycline antibiotics,
a calcium salt should not be used.
BINDERS
120

123. GM Hamad

• Promote adhesion of particles of formulation i.e. adhesion of granules
in tablets preparation and maintains integrity of final tablet.
• Commonly used binding agent are starch, gelatin sugar (sucrose,
glucose, dextrose, lactose)
LUBRICANT
• Capable of reducing or preventing friction.
• Improve flow of granules in hopper to die cavity.
• Prevent sticking of tablet formulation.
• Reduce friction between tablet and die wall.
• Gives shine to finished tablets.
DISINTEGRATING AGENTS
• Breaking of Tablet into smaller particles.
INPROCESS QUALITY CONTROL TESTS
• Friability
• Hardness
FRIABILITY
• Friability is the tendency of tablet to crumble.
• Friction and shock are the forces that cause tablets to
chip, crack or break. Friability test is performed to
evaluate ability of tablets withstand abrasion in packing,
handling and transportation.
• It is measured by Roche Friabilator.
PRINCIPLE
• The drum moves at speed of 25rpm and it is rotated for 4 mins or 100
revolutions, which induces self-abrasion of tablets and at the same time
tablets undergo shock as they fall 6inches on each turn.
PROCEDURE
• Dedust 6 tablets and weigh them
• Place the tablets in drum and rotate at 25rpm for 4 mins
• Remove the tablets from drum, dedust them and weigh accurately
• Calculate weight loss by applying formula:
Starch in dry form –
disintegrating agent
Starch in paste form –
disintegrating + binder
121

124. GM Hamad

% weight loss=
Initial weight − Final weight
&#3627408444;&#3627408475;??????&#3627408481;????????????&#3627408473; ????????????????????????ℎ&#3627408481;
⨯100
COMPRESSION OF TABLETS
• Compression is the reduction in bulk volume of a material as a result of
displacement of gaseous phase.
STAGES OF COMPRESSION
• In pharmaceutical tableting an appropriate volume of granules in a die
cavity is compressed b/w an upper and lower punch to consolidate the
material into a single solid matrix, which is subsequently ejected from
the die cavity as an intact tablet.
• The subsequent events that occur in the process are:
1) Transitional repacking
2) Deformation at the
point of contact
3) Fragmentation
4) Bonding
5) Decompression
6) Ejection
1. TRANSITIONAL REPACKING / PARTICLES REARRANGEMENT
• Under the pressure of upper punch, the particles rearrange in a
closely packed arrangement like tapped density.
2. DEFORMATION AT POINT OF CONTACT
• When stress is applied deformation occurs.
• On removal of stress:
­ Original state regain – elastic deformation
­ Original state lost – plastic deformation
3. FRAGMENTATION
• Once they reach the elastic limit, the particles either fracture or
deform.
4. BONDING
• By further pressure, particles contact area will increase along with
mobility which provides bond formation.
5. DECOMPRESSION
• As applied force is removed, compression ends and decompression
results accompanied by elastic recovery.
6. EJECTION
• The tablet is subjected to a new set of stresses, which is augmented
by forces necessary to eject the tablet from the die. Tablets must be
mechanically strong enough to accommodate these stresses
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otherwise structural failure will occur.
• Three stages of force is are necessary to eject a finished tablet:
­ Peak force required to initiate ejection.
­ Small force required to push tablet up to die wall.
­ Decline force as tablet emerge from die.
FORCES INVOLVED IN COMPRESSION
1. DIE WALL FRICTIONAL FORCE
• Die wall frictional force results from material being pressed against
the die wall. This friction may be reduced by addition of lubricants
and smaller height to weight ratio in tablets.
• Force applied to the upper punch:
F
a=F
b+F
d
­ Where, Fa = force of upper punch, Fd = axial frictional force, Fb =
force of lower punch
• Therefore, mean compaction force:
F
m=
F
a+F
b
2

• Geometric mean force:
F
g=√F
a.F
b
• Force applied by upper punch diminishes exponentially at increasing
depth:
F
b=F
a.e
k.H/D

­ Where, k = experimentally determined material constant that
includes a term for average die wall frictional components, H =
height of tablet, D = diameter of tablet.
2. RADIAL FORCE
• When the material is confined in the die and not free to expand in
horizontal direction. On application of force in vertical direction, a
radial force develops perpendicular to die wall surface.
3. EJECTION FORCES
• Peak force
• Small force
• Decline force
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HECKEL PLOTS
• The hackle analysis is powerful method for determining the volume
reduction mechanism under the compression force.
EXPLANATION
• The hackle equation is based on the assumption that powder
compression follows 1
st
order kinetics with the inter-particulate pores
as the reactants and densification of the powder as product.
Log
I
E
=&#3627408472;??????&#3627408477;+k
r
­ Where, ky = material dependent constant and is inversely
proportional to its yield strength.
Ky=
1
3S

­ Kr = related to repacking stage and hence Eo.
• The above relationships may be established by simply measuring the
applied compression force F and movements of punches during a
compression cycle and translating this data into values of P (applied
pressure) and E (porosity).
• For cylindrical tablet, P is given by:
P=
4??????
π.D
2

­ Here, P = applied pressure, F = applied compressional force, D =
tablet diameter.
• Similarly, values of E can be calculated for any stage from:
E=100[1−
4W
??????
??????.π.??????
2
.&#3627408443;
]
­ Where, W = weight of tableting mass, ρt = true density, H =
thickness of tablet.
CLASSIFICATION
• Hersey & Rees and York & Pilpel classified powders into 3 types A, B and
C according to heckel plot.
• Classification is based upon hackel plot and compaction behavior of
material.
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1. TYPE A
• A graph plotted between log E
-1
(Y-axis) and
compressional force (X-axis)
• For type A materials, this gives a linear relationship at
start and until plastic deformation occurs.
• Example: NaCl is such type of material and they are
called soft materials.
2. TYPE B
• Initially graph gives curved region and then become
linear.
• This indicate brittle materials that are fragmenting in
early stage of compression.
• Example: Lactose and they are called hard materials.
3. TYPE C
• For such materials there is an initial steep linear region that become
superimposed and flatten out after force is increased.
APPLICATION OF HECKEL PLOT
• Used to check lubricant efficacy.
• For interpretation of consolidation mechanisms.
• Duberg and Nystom distinguish between plastic and elastic deformation
characteristics of a material.
MACHINES USED FOR TABLET COMPRESSION
• Following are the machines used for tablet compression:
­ Single punch machines
­ Multi punch machines
­ Rotary punch machines
­ High speed rotary tablet machines
­ Multilayer rotary tablet machines
1. SINGLE PUNCH MACHINE
• One set of dye and punches are available. One tablet at one time is
compressed. Used to prepare small quantities of tablets. Hand operated
or power operated (60-90 tabs/min)
CONSTRUCTION AND WORKING
• Two components are present:
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128. GM Hamad

I. Core component (without which tablets cannot be prepared)
II. Auxiliary component (For Efficiency)
• Made up of high-quality stainless steel with heavy base therefore
minimum vibration is present so granules do not separate from
powders.
• Horizontally placed dies are held firmly by means of screws. Vertical
shaft holds lower punch and it can be filled with specific amount of
granules.
• Capacity and ejection regulating screws are fitted. Upper punch is
attached to vertical shaft and strikes downward forcefully on lower
punch hence compression is done.
• Single punch machines are used for small scale compression of tablets.
Hopper shoe is responsible for granules to be filled. Driving wheel is
attached to shaft (maybe hand driver or motor driven)
• Core components:
­ Dies ­ Punches
• Auxiliary components:
­ Hopper
­ Weight and pressure adjuster
­ Hardness and ejector adjuster
BASIC MECHANICAL PROCESS OF TABLETING WITH SINGLE PUNCH
I. Filling material in hopper to die.
II. Scraping away excessive granules then making space for upper punch.
III. Forming tablet by compression.
IV. Punching up tablet to stage surface.
V. Putting away the tablet to make space for next filling.
2. MULTIPLE PUNCH MACHINE
• Construction and working similar to single punch machine.
• No. of dies 2-12 and same no. of upper and lower punch and they work
at same time during one cycle of punching.
ADVANTAGES
• Pressure can be adjusted
• Many small size tablets can be made at a time.
DISADVANTAGES
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• Weight variation.
3. ROTARY TABLET PRESS
CONSTRUCTION AND WORKING
• They are fitted with as many as 70 dies and can produce 10000 tabs/min
• The dies and punches are present on a rotating head which passes them
in sequence through filling, compression and ejection phases at much
faster speed so output is increased.
CIRCULAR ROTATING HEAD
• The Circular rotating head consists of 3 parts:
I. Upper part which carries upper punches
II. Central part which carries dies
III. Lower part which carries lower punches
• All these parts are arranged in circle round the rotating head.
HOPPER
• A large hopper is present that feeds the granules to central part and fills
the dies on continuous rotating head.
WORKING
• As the hopper fills the dies, upper and lower punches gradually
compress the granules and tablets are formed and at the same time
lower punch move the formed tablets and a picker remove the tablets
continuously and collect them into collecting chamber.
ADVANTAGE
• Large scale production.
DISADVANTAGE
• Cannot produce multiple layer tablet.
4. HIGH SPEED ROTARY PRESS
• It Is similar to simple rotary press but have high speed.
• Increase production 16k-25k (10k-16k in Pakistan).
5. MULTIPLE LAYER ROTARY PRESS
• Tablets having 2 or more layers can be formed.
• Incompatible drugs can be produced.
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• Sustained action preparations can be prepared.
• Separating two layers with an inert material is possible.
TABLET MANUFACTURING DEFECTS
• There are three main categories:
PROBLEMS DUE TO TABLET CHARACTERISTICS AND DEFECTS
• Lamination
• Broken tablet
• Lipping
• Capping
• Sticking
PROBLEMS DUE TO COATING CONDITIONS / EQUIPMENT
• Logo in-filling
• Twinning
• Peeling
• Hats
• Flakes
• Picking
• Chipping
• Orange peel roughness
OTHER
• Problems due to coating suspension
• Spots / Specks
• Tablet Printing issue
1. LAMINATION
DEFINITION
• Separation of tablet into two or more distinct layers.
These problems are apparent immediately after
compression may occur in hours or often days later.
CAUSE
• Lack of homogeneity in granulate, poor level of binder in formulation
• Wear of punches
• Pre-compression level
CORRECTIVE/PREVENTATIVE ACTIONS
• Target value of moisture content on granulate
• Optimal compression force to be set up at start of compression
• Pre compression adsorbent.
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2. LOGO IN-FILLING
DEFINITION
• The coating fills in the logo of the tablets. The embossed logo /
code is not fully readable.
CAUSE
• In-filling of logo with spray-dried coating material (atomization air
pressure too high, drying air temperature too high, viscosity of the
coating suspension too high)
• Erosion of tablet surface around logo.
CORRECTIVE/PREVENTATIVE ACTIONS
• Avoid spray drying
• Corrective: Accounting, 100% visual inspection on belt.
3. TWINNING
DEFINITION
• Two tablets (or more) that stick together.
CAUSE
• High contact surface between tablets
• Spray rate too high, pan speed too low – over wetting
• In sugar coating (manual process), this defect is usual and happens on
the front of the pan.
CORRECTIVE/PREVENTATIVE ACTIONS
• Decrease coating flow rate, increase pan speed
• Change shape of tablets (radius)
• Corrective: Accounting, 100% visual inspection on belt, use of packaging
feeding lanes
• For sugar coating process, the defect is fixed manually.
4. CAPPING
DEFINITION
• Upper or lower surface of the tablet is missing.
CAUSE
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• Compression process (granulate quality, wear of punch, punch sticking,
operating parameters, etc.)
• Bad setting of ejection finger (for Major)
CORRECTIVE/PREVENTATIVE ACTIONS
• Work on compression process (granulate humidity target, set up of
ejection gate)
• Corrective: Accounting, 100% visual inspection on belt.
5. BROKEN TABLET
DEFINITION
• Piece of tablet is missing.
CAUSE
• Compression process, low hardness (uncoated broken tablet)
• Defect raised following significant mechanical strength (ex: mechanical
valve on bottom of tablet container)
CORRECTIVE/PREVENTATIVE ACTIONS
• Work on compression process (increase hardness) or equipment design
depending on root cause.
Corrective: Accounting, 100% visual inspection on belt.
6. HATS
DEFINITION
• Loss of shape due to excess of coating material or piece
of coated tablet coated on another tablet.
CAUSE
• Tablets brittle due to compression stage that break
• Mechanical strength during sugar coating stage
• Release of piece of pan coating
CORRECTIVE/PREVENTATIVE ACTIONS
• Improve mechanical strength of core
• Supervision of exhaust air temperature of the coating pan
• Corrective: Accounting, 100% visual inspection on belt.
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7. PEELING
DEFINITION
• Torn or cracked sugar coating
CAUSE
• Refer to Arcalion study
• Lack of robustness of the sugar coating
CORRECTIVE/PREVENTATIVE ACTIONS
• Optimization of the coating suspension formula (implementation of talc
directly into the suspension)
• Corrective: Accounting, 100% visual inspection on belt.
8. STICKING
DEFINITION
• Small in-print on the surface of the tablet.
CAUSE
• Compression process, punch sticking (material from the tablet stuck to
the punch after compression)
• Granulate humidity issue.
CORRECTIVE/PREVENTATIVE ACTIONS
• Clean active part of the punches with alcohol, target granulate humidity.
• Corrective: punch cleaning, punch replacement Accounting, 100% visual
inspection on belt.
9. CHIPPING
DEFINITION
• Little to very faint piece of tablet missing.
CAUSE
• Worn tablet punches, low tablet hardness / friability
• Abrasion due to mechanical strength, everywhere possible during the
process (feeding chute, press ejection finger, excessive coating pan
speed, etc.)
CORRECTIVE/PREVENTATIVE ACTIONS
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• Investigation of abrasion mechanism and location.
• Replace worn punch, set up ejection finger, reduce pan speed, increase
spray rate at start of coating stage.
• Corrective: Accounting, 100% visual inspection on belt.
10. SPOTS / SPECKS
DEFINITION
• Particles, black spots, colored spots, oily marks.
CAUSE
• If spot with regular edge: particle or black spot
• If spot with irregular edge: likely to be lubricant.
CORRECTIVE/PREVENTATIVE ACTIONS
• Investigation to find the source of contaminant.
• Corrective: Accounting, 100% visual inspection on belt.
11. LIPPING
DEFINITION
• Raised tablet edge.
CAUSE
• Compression, wear of punch, punch damaged.
CORRECTIVE/PREVENTATIVE ACTIONS
• Preventative maintenance
• Corrective: Polishing of the concerned punches / punch replacement
Accounting, 100% visual inspection on belt.
12. COATING SPANGLES
DEFINITION
• Little pieces of coating material in the air, forming a mist
in the pan can stick on tablets.
CAUSE
• Clogging of exhaust air filter
• Bad setting of guns.
CORRECTIVE/PREVENTATIVE ACTIONS
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• Preventative: maintenance, blow back of the exhaust air filter
• Corrective: Accounting, 100% visual inspection on belt.
13. FLAKES
DEFINITION
• Pieces of coating material. Formed on the wall and can be
released on tablets.
CAUSE
• Over spray
• Bad setting / damaging of spray guns
• Lack of cleaning of the coating pan (refer to cleaning validation).
CORRECTIVE/PREVENTATIVE ACTIONS
• Reduce spray rate
• Preventative maintenance on spray guns
• Corrective: 100% inspection with use of automatic sifting machine.
14. PICKING
DEFINITION
• Small holes in the coating surface due to unsticking.
CAUSE
• Spray rate too high during coating stage, over wetting
• Inadequate drying conditions, pan speed too low.
CORRECTIVE/PREVENTATIVE ACTIONS
• Check spray guns (spray pattern), reduce spray rate, improve drying
conditions, increase pan speed
• Corrective: Accounting, 100% visual inspection on belt.
15. ORANGE PEEL ROUGHNESS
DEFINITION
• Tablet with rough, irregular, unsmooth surface.
CAUSE
• Viscosity of coating suspension too high
• Poor atomization of coating suspension.
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• Humidity level too high in the pan.
CORRECTIVE/PREVENTATIVE ACTIONS
• Reduce solid content of suspension
• Increase atomization air pressure, check exhaust air filter
• Corrective: Accounting, 100% visual inspection on belt.
TABLET COATING
INTRODUCTION
• Tablet coating is a process of application of an edible paint to the surface
of a pharmaceutical dosage form to impart certain characteristics.
• Coating may be simple or complex. Simple coating consists of thin film of
varnish applied to make tablets dust free and reduce any bitter taste.
Complex coating consists of inner and outer shell enclosing different
types of drugs which may be incompatible or required to release at
specific time.
CHARACTERISTICS
• Elegant product
• Improve stability
• Masking Unpleasant taste
• Improved aesthetic quality
• Modifying drug release characteristics.
COATING PROCESS
• Liquid is sprayed to the tablet
• Air flow is maintained for temperature control during process
• Pressure of chamber is maintained little lower than outside to provide
isolated process.
COATING EQUIPMENT
• They include:
­ A rotating coating pan
­ Warm air supply
­ Spray gun
­ Source of spray
­ Tablet bed
­ Exhaust
TYPES OF TABLET COATING
1. SUGAR COATING
• Coating sugar based (sucrose) formulations on tablets, the water
evaporates and leaves sugar coating on the tablet. It should be done on
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137. GM Hamad

convex sided and round edged tablets. It gives shiny and colored
appearance.
• The tablet core should be strong, not easily broken and having high
friability values to do sugar coating.
STEPS FOR SUGAR COATING PROCESS
I. SEALING (WATERPROOFING)
• It is the first process. It is done to waterproof the tablet to prevent it
from disintegration due to aqueous nature of sugar coating.
• It protect the tablet from disintegration. Various coats can be done to
make tablet extended release. Coating materials used are
pharmaceutical shellac or synthetic polymers like CAP.
II. SUB COATING
• A sub coating of Sugar and acacia is done on the tablets until they are
sticky to each other and pan, then anti adherents are added e.g. talc,
starch etc. to prevent sticking.
III. SMOOTHING
• After sub coating, the surface is rough so it is smothered to facilitate
coloring process. It is done with sucrose syrup coating.
IV. COLORING
• Water soluble dyes or insoluble pigments maybe used.
• Sucrose + coloring material solution is sprayed several times and at the
end only color is sprayed.
V. POLISHING
• To achieve shinny and glossy surface, it is polished with waxes (bees wax
etc.). After it, tablets are allowed to rotate and volatile materials to
evaporate.
VI. PRINTING
• Logo, code, strength etc. are printed with help of edible inks.
DISADVANTAGES OF SUGAR COATING
• Increase in size
• Difficult for small scale process
• Longer process and increase cost.
2. FILM COATING
• Made up of Polymer (Cellulose), Plasticizer, Solvents (Water,
polyethylene glycol, alcohol) and colorants.
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• No need of smoothing or water proofing.
ADVANTAGES
• Economical
• Taste masking
• Easily swallowed
• Mechanical integrity (color, shine)
• Easier process and less time required.
DISADVANTAGES
• Organic solvents may cause allergy, pollution, toxic environment.
3. COMPRESSION COATING
• It involves compressing another core outside the inner core of tablet by
means of specially designed processes.
• The process involves preliminary compression of the core, which is then
transferred to a large die already containing some coating material.
After centralizing the core, further coating material is added and the
whole compressed to form the compression coated tablets.
• There are two types of machines available for the preparation of press
coated tablets:
­ Core previously prepared on other machines
­ Compression of core and coat in one continuous cycle.
4. ENTERIC COATING
• It is done to save the tablet from acidic effects of stomach and this coat
dissolves in alkaline environment of intestines.
• It is done on tablets that cause irritation in stomach.
PROCESS
I. SUB COATING
• Done for water proofing of internal core from outer coatings with PVP
etc.
II. ENTERIC COATING
• Other than sub coating materials, other materials can be used to insure
enteric coating of the tablet.
• This may be done by surfactants, plasticizers, solubilizing agents etc.
III. COLOR COATING
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139. GM Hamad

• 3% color coating solids (water soluble dyes, water insoluble pigments)
are coated.
IV. POLISHING
• The previous coatings make rough appearance so the tablet is coated
with waxes to make glossy surface.
5. OTHER TYPES OF COATING
I. DIP COATING
• Tablet is dipped in coating material and then dried.
II. GELATIN COATING
• Gelatin coated tablets are called gel caps.
III. ELECTROSTATIC COATING
• Ionic coating is done.
CAPSULES
INTRODUCTION
• A Pharmaceutical solid unit dosage form containing unit doses of drugs,
enclosed in a soluble shell of gelatin and starch, intended to be
swallowed orally.
ADVANTAGES
• Neat and elegant in appearance
• More stable and longer shelf life
• Capsules are easy to handle and carry
• They are made from gelatin and hence they are inert
• Capsules release the medicaments as and when desired in GI tract
• Tasteless shell to mask the unpleasant taste/odor of the drug
• The contents may be removed from the gelatin shell and employed as a
pre-measured medicinal powder, the capsule shell being used to contain
a dose of the medicinal substance. Example: Theo dur Sprinkle
• Commonly embossed or imprinted on their surface the manufacturer’s
name and product code readily identified
• The ready solubility of gelatin at gastric pH provides rapid release of
medication in the stomach
• Packaged and shipped by manufacturers at lower cost less breakage
than liquid forms.
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DISADVANTAGES
• Capsules are not suitable for liquids that dissolve gelatin, such as
aqueous or hydro alcoholic solutions
• The concentrated solutions which require previous dilution are
unsuitable for capsules because if administered as such lead to irritation
into stomach
• Not useful for efflorescent or deliquescent materials. Efflorescent cause
capsules to soften and deliquescent may dry the capsule shell to
brittleness.
TYPES
• Capsules are of two main types:
­ Hard gelatin capsules
­ Soft gelatin capsules
1. HARD GELATIN CAPSULES
• Also called as dry filled capsules. These are used for administration of
solid medicaments. The capsule shell is prepared from gelatin. It consists
of two parts i.e. body and cap. The powdered material is filled into the
cylindrical body of the capsules and then the cap is placed over it.
SHAPES OF HARD GELATIN CAPSULES
• They are of different shapes:
­ Snap fit
­ Coni snap
­ Coni snap supro
­ Standard
SIZES OF HARD GELATIN CAPSULES
• Hard gelatin capsules for human use are available in 8 different sizes:
▪ 000 – 1000mg
▪ 00 – 650mg
▪ 0 – 520mg
▪ 1 – 320mg
▪ 2 – 260mg
▪ 3 – 195mg
▪ 4 – 160mg
▪ 5 – 90mg
MANUFACTURING OF HARD GELATIN CAPSULES
I. GELATIN MELTING SYSTEM
• Gelatin and demineralized hot water are mixed to form gelatin solution.
This solution is prepared under vacuum in gelatin melting system. This
solution is than transferred to stainless steel feed tank.
II. ADDITIVES
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141. GM Hamad

• Dyes, opacifants, preservatives and water are added in feed tank.
III. DIPPING
• The resultant mixture is fed to hopper called dip pan/pot. The sets of
molds are then dipped in mixture at 22℃ to form the capsule of desired
shape.
IV. SPINNING
• The molds are slowly withdrawn from mixture and spinned to form a
film of uniform thickness.
V. DRYING
• The pin bars (mold shaped) are passed through dry kilns and dried by
hot air blow.
VI. CUTTING AND JOINING
• The dried films removed from molds are cut and 2 parts are joined
together to make a capsule.
VII. OUTPUT
• Machine output is 1 million capsules per day.
VIII. ASSEMBLING
• Capsules are assembled, sorted and visually inspected on specially
designed Inspection Stations. Perfect capsules are imprinted with the
logo.
PRINCIPLES OF CAPSULE FILLING
• Diluents, protective sorbents, lubricants are filled in capsules by
following principles i.e. directly or indirectly.
I. AUGAR FILLING
• Empty capsules are placed in rectifying unit. Rectifier descends the
capsules such that caps are turned up and bodies down. From rectifying
unit these are placed one by one in filling ring kept on rotating mode.
• The lower ring is rotated with a suitable speed and the hopper
containing powdered drug is held over this ring. The auger drives the
drug into bodies.
II. DOSATOR SYSTEM
• In this system, dosing assembly is tube/cylinder with an inside moveable
piston forming a chamber and an open end at bottom. Assembly lowers
the open end into the bed of the powder to form a plug.
• Plug can be further consolidated by a compression force with piston. The
assembly is raised and positioned over the capsule body. Lowering of
piston ejects plug into capsule body.
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III. TAMPING PISTON AND DOSING DISK
• These piston tamps alter the shape of powder by compressing the
powder to form slugs. These plugs are transferred into the empty
capsule bodies with the application of slight pressure. Finally, the bodies
are ejected from the machine.
IV. VACUUM FILL PRINCIPLE
• It consists of an open-ended cylinder. The upper end of this is fitted with
a piston. The open end is placed in bulk powder. Vacuum is applied and
the piston is moved upward by sucking the predetermined amount of
powder which results in filling of the cylinder. The cylinder is positioned
above the capsule body and by applying slight pressure powder is filled
in body.
V. VIBRATORY FILL PRINCIPLE
• The feed is placed in the feed hopper and the capsule bodies are passed
under it. A perforated resin plate is placed in the feed hopper. Due the
vibrations of the resin plate, the powder flows freely through the pores
into bodies.
FILLING OF HARD GELATIN CAPSULES
• There are usually three types of machines for filling capsules
­ Hand operated filling machine
­ Semi-automated filling machine
­ Fully automated filling machine
I. HAND OPERATED FILLING MACHINE
• Used for small scale operation and quick dispensing.
CONSTRUCTION
• A hand operated hard gelatin capsule filling machine consists of the
following:
­ A capsule loading tray and powder bed with
200 to 300 holes.
­ A powder tray and pin plate having 200 to 300
plus corresponding to the no. of holes in the
bed and capsule loading tray.
­ A leveler, handle and plate fitted with rubber
top.
• All parts of the machine are made up of stainless-steel. This machine is
very simple to operate. It can be easily disintegrated and reassembled.
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143. GM Hamad

WORKING
• The empty capsules are filled into the loading tray which is then placed
over the bed. By operating the handle, the bodies of capsule are un-
locked and caps are separated in the loading tray itself which is then
removed by operating the lever.
• The weighed amount of the drug to be filled in the capsule is placed in
the powder tray already kept in position over the bed. Spread the
powder with the help of powder spreader so as to fill the bodies of
capsule uniformly. Collect excess of powder on the platform of the
powder tray.
• Lower the pin plate and move it downward so as to place the powder in
the bodies. Remove the powder tray and place the caps holding tray in
position. Press the caps with help of plate and rubber top and operate
the lever to lock the cap and body of the capsule.
• Remove the loading tray and collect the filled capsule in a tray. With 200
holes machine about 5000 capsules can be filled per hour and with 300
holes machine 7500 capsules can be filled/hr.
II. SEMI-AUTOMATIC CAPSULE FILLING MACHINE
• Parke-Davis Capsule Filling Machine. Each of these machine requires an
individual operator and may achieve a daily output of 2lac capsules.
WORKING
• Placement of the loading rings on the first turntable below the capsule
shell hopper and rectifier unit. Rectification of the empty shells with the
aid of the vacuum system. Manual separation of the loading rings. This
removes the caps from the bodies. The upper ring is kept aside.
Placement of the lower ring containing the bodies on the second
turntable under the powder hopper.
• Filling of the capsule bodies by discharging the powder from hopper. The
turntable is rotated to sequentially fill all the bodies placed in the lower
ring. The two parts of the ring are set together. The bodies and caps are
now ready to be closed.
• The holing rings are placed on the pin plate and closed on the front side
with the closing plate. By pneumatic pressure, the pins are used to push
the bodies inside the caps to lock the capsules.
• The closing plate on the front side is released and the pins used again to
push the filled and joined capsules out of the holes. The ejected capsules
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144. GM Hamad

are delivered through the collecting tube into a container.
III. FULLY AUTOMATED FILLING MACHINE
• Different types of this machine are Farmatic. Macofar, Osaka, Zanasi
and perry.
CONSTRUCTION
• Generally, an automated capsule filling machine may have or must have
the following Parts:
­ Empty capsule hopper and rectifier
­ Cleaning station
­ Bulk powder stopper
­ Capsule closing and ejection station
­ Cap holder removal station
­ Powder dosing head
­ Cap holder replacing station
WORKING
• Capsules are fed from the storage hopper through individual tubes and
rectified into individual two-piece side holders on a continuous station.
Capsules are separated within the two-piece holder by applying vacuum
to the lower portion. which pulls the body into it while the cap is
retained in the upper holder.
• As the chain and retaining blocks progress through the cycle, the cap
containing upper holder is moved aside to recess at the outer end of the
conveying holder, exposing the lower holder containing the body. The
powder is continuously mixed within the powder hopper and is
maintained at a constant level prior to discharge.
• The body carrying units now are carried under a series of 12 volumetric
dosing nozzles, each of which picks up the product from the rotating
container, first compressing and then ejecting the powder into capsule
bodies. The cap container is repositioned over the block and closing is
accomplished by upper and lower closing pins.
• Each station is equipped with a safety device that automatically stops
the machine in the event of an irregularity. Capsule carrying holders are
cleaned by air prior to being returned to the rectifier station.
APPLICATIONS OF HARD GELATIN CAPSULES
• Granules can also be delivered by hard gelatin capsules
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• Pastes and oils can also be filled in hard gelatin capsules
• Thixotropic substances can be added to prevent leakage from hard
gelatin capsules.
• Incompatible drugs can also be supplied.
• Hard gelatin capsule is also used as an inhaler when punctured and
inhaled into lungs along with breath.
2. SOFT GELATIN CAPSULES
• These capsules are prepared from soft, globular and thick gelatin to
which glycerin and polyhydric alcohol such as sorbitol is added to
provide it an elegant appearance.
SHAPES OF SOFT GELATIN CAPSULES
• They are of different shapes:
­ Spherical
­ Round
­ Oval
­ Tube shaped
SIZES OF SOFT GELATIN CAPSULES
• Size of soft gelatin capsule varies from 0.1ml – 30ml capacity.
MANUFACTURING AND FILLING OF SOFT GELATIN CAPSULES
• The manufacturing of shell and filling of medicament take place
simultaneously for soft gelatin capsules.
I. PLATE PROCESS
• Place the gelatin sheet over a die plate containing numerous die
pockets. Application of vacuum to draw the sheet in to the die pockets.
Fill the pockets with liquid or paste.
• Place another gelatin sheet over the filled pockets, and Sandwich under
a die press where the capsules are formed and cut out.
II. ROTARY DIE PROCESS
• In this process, two continuous sheets of gelatin are supplied to two die
rolls of the machine which has a no. of matching dies at the same speed
and in opposite direction.
• As the gelatin sheet comes in between the rollers, the material to be
filled in it is injected through the metering device. The pressure exerted
by the material forces the gelatin sheet to go in cavities of die roll to
form two halves of the capsule and fill them. The heat and pressure
exerted by the die rolls seals and cut out the capsules.
• The rotary die machine can produce 25,000 – 30,000 capsules/hr.
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III. RECIPROCATING DIE PROCESS
• It is similar to rotary process in which ribbons of gelatin are formed and
used and used to encapsulate the fill but it differs in actual encapsulating
process. The gelatin ribbons are fed between asset of vertical dies that
continuously open and close to form rows of pockets in gelatin ribbons.
• These pockets are filled with medication and are sealed, shaped and cut
out of film as they progress through the machinery.
• As the capsules cut from the ribbons, they fall into refrigerated tanks
which prevents the capsules from adhering to one another and from
getting dull.
IV. ACCOGEL MACHINE
• Another means of producing soft gelatin encapsulation is the use of
accogel machine and process. The accogel machine uses a system rotary
die. The machine is available to entire pharmaceutical industry used in
many countries of the world.
• It is extremely versatile not only producing capsules with drug powder
but also encapsulating liquid and combination of liquid and powders.
APPLICATIONS OF SOFT GELATIN CAPSULES
• The capsules are suitable to seal the medication within capsule.
• These are easy to swallow and elegant in appearance.
• Vitamin E, digoxin and demeclocycline HCl are dispensed in soft gelatin
capsules.
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SAFETY METHODS IN PHARMACEUTICAL
INDUSTRY
INTRODUCTION
• Safety in simple terms means freedom from the occurrence of risk or
injury or loss.
• Industrial safety refers to reduction from the risk of injury or loss and
danger to persons, property from the industrial hazards.
• Hazard is a term associated with a substance that is likely to cause injury
to a personnel in a given environment or situation.
• Industrial hazard may be defined as any condition produced by
industries that may cause injury or death to personnel or loss of product
or property.
• Toxic corrosive chemicals, fire explosions and personnel falling into
accident are major health and safety hazards encountered in the
operations of chemical and pharmaceutical industries.
• Identification of hazards and employing protective measures to control
the hazards are important to protect the people from their
consequences.
OBJECTIVES OF INDUSTRIAL SAFETY
• Understand the harmful effects of industrial hazards
• Define the relationship between hazard and risk
• Explore the routes of exposure to industrial hazards
• Shed lights on type of toxicity by industrial hazards
• Know the most toxic environmental hazardous substances.
• For evaluation of safety aspects, following steps are narrated:
­ Source of hazard
­ Type of hazard
­ Control procedure
­ Contingency plan
INDUSTRIAL HAZARD V/S RISK
• Hazard is the potential of a substance to cause damage.
• Toxicity is the hazard of a substance which can cause poisoning.
• Risk is a measure of the probability that harm will occur under defined
conditions of exposure to a chemical.
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??????=?????? (??????⨯&#3627408440;)=(??????⨯&#3627408439;⨯??????)
• Where,
­ R = risk, f = function, H = hazard, E = exposure, D = dose, t = time.
• Thus, chemicals which pose only a small hazard but to which there is
frequent or excessive exposure may pose as much risk as chemicals
which have a high degree of hazard but to which only limited exposure
occurs.
• Reducing risk is based on reducing exposure.
ACCIDENT
• “An accident is an unplanned and uncontrolled event which causes or is
likely to cause an injury”.
• It is something which is un-expected, un-predictable or un-intended or
not desired.
• An accident may be caused from a result of some unsafe activity, act,
working condition etc.
TYPES / CATEGORIES OF HAZARDS
1. Fire hazards
2. Mechanical hazards
3. Chemical hazards
4. Dust explosions
5. Gas hazards
6. Electrical hazards
7. Biological hazards
1. FIRE HAZARDS
• Three elements must be present to start fire:
­ Oxygen
­ Heat
­ Fuel
• If anyone of compound Is removed the fire will not start/extinguish. In
almost all conditions, oxygen and heat must present. It Is essential to
ensure that the third component heat Is never sufficient
to start a fire.
CAUSES
• Smoking in the factory
• Defective heating equipment,
• Electrical equipment & wiring.
• Explosive gas leakage.
• Inadequate protection of electric motors
• Sparking of electric wires.
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CLASSIFICATION OF FIRES
• Most fires that occur will fall into one or more of the following
categories:
CLASS A
• Fires involving ordinary combustible materials, such as
Paper, wood, and textile fibers.
• A cooling, blanketing, or wetting extinguishing agent is
needed.
CLASS B
• Fires involving flammable liquids such as gasoline, thinners, oil-
based paints and greases.
• Extinguishers for this type of fire include:
­ Carbon dioxide
­ Dry chemical
­ Halogenated agent types.
CLASS C
• Flammable gases under pressure including liquefied gases. E.g.
Propane, butane, ethane.
• Dry chemical extinguisher may be used to extinguish fire.
CLASS D
• Fires involving combustible metals such as magnesium, sodium,
potassium, titanium, and aluminum.
• Special dry powder extinguishing agents are required for this class
of fire and must be tailored to the specific hazardous metal.
CLASS E
• Fires involving energized electrical equipment.
• Where a non-conducting gaseous clean agent or smothering
agent is needed. The most common type of extinguisher for this
class is a carbon dioxide extinguisher.
CLASS F
• Fires involving commercial cooking appliances with vegetable oils,
animal oils or fats at high temperatures.
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• A wet potassium acetate, low pH-based agent is used for
this class of fire.
• When the agent reacts with the hot grease, it forms a layer
of foam on the surface of the fat. This soap-like blanket of
foam acts as an insulator between the hot grease and the
atmosphere, helping to prevent flammable vapors from
escaping and reducing the chance for flame reignition.
FIRE EXTINGUISHERS
• Fire extinguishers include:
­ Water and water-based extinguishers
­ Foam extinguishers
­ Dry chemical extinguishers
­ Carbon dioxide extinguishers
­ Halon extinguishers.
DETECTION OF FIRE HAZARDS
• Many automatic fire detection systems are used today in industry.
• Some include:
­ Thermal expansion detectors
­ Heat sensitive insulation
­ Ionization or radiation sensors
­ Ultraviolet or I.R detectors
• These sound an alarm through which fire flames are detected.
SAFETY MEASURES TO PREVENT FIRE HAZARDS
• Fire generates heat which can cause injury to people. Fire can also cause
explosions and generate smokes and toxic gases. An explosion may give
rise to blast waves which can cause damage to humans and buildings.
STRUCTURAL FEATURES AND EXITS
• Building of factory should be sufficiently fire resistant or extinguishing
water lines are present. Fire resistant construction will ensure that
structural parts do not readily burn. Break glass are provided to start the
flow of water in case of emergency.
EXITS
• No part of building should be far from exit. Each floor should have 2 exits
sufficiently quite protective against flame and smoke and well
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segregated from each other.
• Wooden or spiral stairs and ladders should not be present at exits.
• Exit should be kept un-obstructed. Outside stairways and fire escapes
should not lead to Interior country yard or building corridors.
FIRE EXTINGUISH FACTORS
• Buckets of water and sand
• Sprinkled system
• Portable fire extinguisher
• Most of factories have pipe water supply, hoses, hydrants
FIRE GUARDS
• The practice of fitting guards are mainly concerned, which compliance
with law. It was considered nuisance to labors. Guards were
unsatisfactory for one or more reasons.
• There were unreliable and hamper the work, so they needed much
attention. Guards for power transmission equipment as motors did not
give the problems, but for wood/metal works, where the faces, eyes are
covered with goggles and masks, it hampers the work and often was not
used for efficient work. As soon as supervisor left, the workers remove
the guard, putting off gloves, masks. For clean operation in
pharmaceutical Industry are the common example of non-compliance
with protective equipment.
BUILT IN GUARDS
• The most effective way of protecting machine is to make built in guards
as integral part of machine. Built In guards are much cheaper and more
effective than guards added to machine after it has been delivered.
2. MECHANICAL HAZARDS
• These are associated with power-driven machine, whether automated or
manually operated by steam, hydraulic and/or electric power.
• Mechanical hazards are exacerbated by the large number and different
designs of equipment, crowded work-place conditions and different
interaction between workers and equipment.
• Injuries like cutting, tearing, shearing, puncturing and crushing may
occur with moving machinery.
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CAUSES
• Accidents usually take place by the combination of unsafe condition and
carelessness.
• Most of industrial accidents are due to:
­ Faulty inspection
­ Inability of employee
­ Poor discipline
­ Lack of concentration
­ Unsafe practice
­ Mental and physical unfitness for job
­ Faulty equipment or improper working condition
­ Improper training regarding the safety aspects.
SAFETY MEASURES TO PREVENT MECHANICAL HAZARDS
• Mechanical hazards can be reduced by the application of appropriate
safeguards.
• Inspection, adjustment, repair and calibration of safeguards should be
carried out regularly.
• Risk control must be applied to hazards for reducing injuries and harms.
A. SEPARATION
• Separation is a simple and effective machinery and equipment risk
control.
• Separation may be achieved by distance, barrier or time.
­ Distance separation means a person cannot reach the hazard due
to distance.
­ Barrier separation means an effective barrier or guard denies
access and control ejection of parts, products and waste.
­ Time separation means at the time of access the machinery or
equipment Is disabled.
B. GUARDING
• A guard can perform several functions. It can deny bodily access
containing ejected parts.
• IF access Is generally not required, a permanently fixed barrier Is
preferred option.
• Where access to hazard is infrequent, the installation of a fitted guard
that can be removed by use of tool may be an acceptable control.
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• Adjustable guarding Incorporates moveable sections or panels of guard
and allows for material or parts to be fed into the guarded area while
still preventing bodily contact.
• Tunnel guards provide a tunnel aperture or chute in which material can
be inserted into the machinery and equipment, but due to restrictive
design and depth of opening fingers, hands, arm or entire person is
prevented from introducing into danger area.
• Interlock guarding occurs when the act of moving the guard (opening,
sliding or removing) to allow access stops the action of hazardous
mechanism.
C. OTHER MECHANICAL HAZARD RISK CONTROL OPTIONS
I. SIMULTANEOUS TWO-HANDED OPERATION
• Where a machine has only one operator, the use of simultaneous two-
handed operation buttons can serve as a risk control. This ensures that
operation of hazardous mechanism cannot occur until both hands are
clear of danger area.
• The two buttons must be pushed at the same time and are located at a
distance from each other that prevents simultaneous operation by one
hand.
II. PRESENCE SENSING SYSTEMS
• If physically, guards are not reasonable, practicable then a presence
sensing system can be used where people enter areas shared by moving
production equipment.
• Presence sensing system detects when the person is in the identified
danger area and stops or reduce the power/speed of mechanism at the
time of entry to provide safe access.
3. CHEMICAL HAZARDS
• Some chemicals have the potential to cause fires and explosions and
other serious accidents.
• Chemical exposure may cause or contribute to many serious health
effects such as heart diseases, central nervous system damage, kidney
and lung damage, cancer, burns and rashes.
• Chemicals may be found in solid, liquid, aerosol or gas and vapor form.
• The degree of danger varies according to the form of the chemical and
the factors like:
­ Its physical properties
­ Toxicity
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­ The way it is used
­ The environment in which it is encountered.
ROUTES OF ENTRY
• Routes of entry of chemical hazards are following:
­ Inhalation
­ Ingestion
­ Skin
­ Absorption
CLASSIFICATION OF CHEMICAL AGENTS
• Chemical agents can be classified into:
­ Metals: lead, arsenic (As), mercury (Hg), (Cd), nickel (Ni).
­ Aromatic hydrocarbons: benzene, toluene, phenol.
­ Aliphatic hydrocarbons: methyl alcohol
­ Gases:
▪ Simple asphyxiants: N2, CO2
▪ Chemical asphyxiants: CO, H2S, HCN
▪ Irritant gases: Ammonia, SO2, CL2
▪ Systemic poison: CS2
­ Carcinogens: nickel, chromium, cobalt, coal tar etc.
MANAGEMENT OF OVER-EXPOSURE TO CHEMICALS
• Management of over-exposure to chemicals is performed by:
1. REMOVAL FROM EXPOSURE
• Prompt removal of person to exposure site.
• Air respirators and lifelines are mandatory first aid.
2. RESUSCITATION
• Resuscitation means restoration of life of one who is apparently dead
(collapsed or shocked).
• Further supportive care should be provided as with any other medical
emergency.
3. DECONTAMINATION
• A victim whose skin or clothing has been contaminated requires
immediate removal of garments and shoes.
• Vigorous showering with soap and water, including attention to the
fingernails and scalp is advised.
4. SYMPTOMATIC TREATMENT
• Acute symptoms over exposure may require general supportive medical
management regardless of specific agent.
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• Example: control of convulsive seizures, treatment of bronchospasm,
hydrating the patient.
SAFETY MEASURES
• Before starting work with a chemical a “chemical hazard pocket guide”
should be consulted for necessary information about the chemical. It will
give the type of reaction the chemical may produce, its inflammability,
carcinogenicity, prevention and treatment procedures etc.
• No eating, drinking, or smoking where chemicals are used.
• Skin should be covered with protective clothing.
• Clothing should be removed immediately it gets wet or contaminated
with a chemical.
• Eyes or skins should be washed with plenty of water after an accident.
• Face mask may be used in toxic dust or gases.
• Workers working in antibiotic related products must be changed
routinely so that an individual is not exposed to a certain antibiotic for a
long period of time.
• Whenever a dust allergy or respiratory problem precipitates, the worker
should immediately be removed from the work-place and put under
proper healthcare.
• In case of inflammable gas or solvent leakage the exhaust fans should be
started and all the source of fire should be extinguished.
4. DUST EXPLOSION
• Dust explosion is a rapid combustion of a dust cloud. During the process,
heat and reaction products are evolved. The required oxygen for
combustion is mostly supplied by air.
• If iron or stone pieces get into the disintegrator or grinding mill, sparks
are emitted, which may bring about explosion with some easily
combustible materials.
SOURCES OF DUST HAZARDS
• Grinding or milling of drugs, excipients, or herbal products.
• During weighing dusts may float on air.
• During powder mixing dusts may be generated.
• During coating operation dusts are generated.
• During capsule filling and tablet punching operation dusts may be
generated.
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FACTORS IMPACTING A DUST EXPLOSION
I. CHEMICAL PROPERTIES OF THE DUST
• If the dust is not combustible there cannot be an explosion.
II. PARTICLE SIZE
• No matter how combustible the powder, if it is in big lumps it is not
going to cause a dust explosion. Explosion depends on size and surface
area of dust particles. This is because particle size/surface area
influences the speed at which volatiles are extracted from the particle
(or how fast the particle vaporizes) before they burn.
III. MOISTURE CONTENT
• Moisture content of a dust will affect the ability of a dust cloud to be
ignited and its ability to sustain an explosion.
IV. COMBUSTIBLE GAS MIXED WITH DUST CLOUD
• Addition of a fuel gas (or vapor) can lower the ignition energy for a pure
dust cloud massively and raise the maximum explosion pressure.
PREVENTION
I. CONTROLLING IGNITION SOURCES
• Separating ignition sources from areas where explosive atmospheres
may form, reduces the risk of explosion considerably. As with any other
combustion process, heated surfaces, sparks, and static discharges
should be eliminated. Regular inspection, testing, and maintenance of
equipment are vital to their proper operation and the prevention of
fires.
II. COMBUSTIBLE CONCENTRATION REDUCTION
• Process modification, use of dust-control equipment, and good
housekeeping.
III. OXIDANT CONCENTRATION REDUCTION
• Oxidant reduction can be accomplished by adding inert gas to enclosed
processes in order to reduce the oxygen concentration to a level below
that required for ignition to occur.
• This process, commonly referred to as inerting, is frequently used to
protect grinding, mixing, pulverizing, storage, and other enclosed
operations.
IV. MITIGATION/CONTROL
• There are four primary methods of explosion mitigation and control.
They are:
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­ Containment: Equipment can be designed to be pressure resistant
or pressure-shock-resistant. Pressure resistant equipment is
designed and constructed to withstand specific pressures without
deforming or rupturing.
­ Isolation: Isolation is accomplished by separating dust producing
processes from other plant operations.
­ Venting: Vent is an opening in an enclosure through which
materials expand and flow. Pressure venting will generally be
accompanied by the discharge of large quantities of burning dust,
unburnt mixtures, and combustion gases.
­ Suppression: Automatic explosion suppression systems are active,
which are designed to prevent the creation of unacceptably high
pressure by gas or dust explosions. Explosion suppression systems
consist of a sensor system that will detect an incipient explosion
and activate extinguishment devices. When activated, the
extinguishing medium is injected into the enclosure, quenching
the flames.
V. FILTRATION
• Air is sucked through a suitable filter medium (like paper, wool, cotton-
wool and nylon). Filter bags can be attached with machines where dust
is produced.
VI. INERTIAL SEPARATOR
• In cyclone separator the air is circulated at high speed in a spiral manner.
Due to centrifugal force the dust particles are thrown outward and the
particles are collected at the bottom and the clean air comes out
through the top.
VII. ELECTROSTATIC SEPARATOR
• It consists of metal tubes though which a conductor wire is passed.
Several thousand volts of DC current is applied on the metal wire. When
air is passed through the pipes the dust particles becomes charged and
precipitates on the inner wall of the tube and clean air passes out.
Periodically the dust is collected.
5. GAS HAZARDS
TYPES OF GAS HAZARDS
• Three major type of gas hazards:
1. FLAMMABLE
• Risk of fire or explosion.
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• E.g. methane, butane, propane.
2. TOXIC
• Risk of Poisoning
• E.g. Carbon Monoxide, Hydrogen, Chlorine
3. ASPHYXIANT
• Risk of suffocation. E.g. Oxygen deficiency.
• Oxygen can be consumed or displaced by another gas.
GAS SAFETY AT WORK
• The Gas Safety require the following:
­ All gas appliances, pipe work and safety devices must be
maintained in a safe condition and be inspected by a competent
person.
­ When a gas appliance is installed, it must be located in a position
that is easily accessible for use, inspection and maintenance.
6. ELECTRICAL HAZARDS
SOURCES OF ELECTRICAL HAZARDS
• Short circuits
• Spark hazards
• Combustible and explosive materials
• Improper wiring
• Insulation failure.
DETECTION OF ELECTRICAL HAZARDS
• Circuit tester
• Receptacle wiring tester.
PREVENTION OF ELECTRICAL HAZARDS
• Verify circuit voltages
• Periodically inspect insulation
• Use only explosion proof devices and non-sparkling switches in
flammable liquid storage areas
• Ensure all flexible wires and power cables are properly insulated
• Installation of earth trip devices for all electrical equipment
• Worker should avoid working in electric circuits or equipment in wet
clothing or shoes
• Grounding of electrical equipment.
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7. BIOLOGICAL HAZARDS
• These include medical waste or samples of a microorganism, virus or
toxin that can impact human health. It can also include substances
harmful to animals.
DISEASES DUE TO BIOLOGICAL HAZARDS
• Biological hazards cause a lot number of diseases:
I. BRUCELLOSIS
• it usually occurs in dairy farm workers.
• Symptoms: fever, arthritis, and enlarged spleen etc.
II. BYSSINOSIS
• It usually found in textile industries workers due to inhalation of the
cotton fiber, dust over long period of time.
• Symptoms: cough breathlessness, slight fever and bronchitis.
III. BAGASSOSIS
• An interstitial lung disease, is a type of hypersensitivity pneumonitis
attributed to exposure to moldy molasses (bagasse)
IV. INDUSTRIAL DERMATITIS
• It is a skin disease caused by conditions at work. It may be the result of
irritation or allergy.
• Usually it starts with redness and itchiness. Sometimes there may be
swelling, scaling, cracking, blistering and oozing.
PREVENTIVE MEASURES
• Periodic health check up
• Personnel protection
• The manufacturer should also provide:
­ First aid facilities
­ Facility for vaccination
­ Routine sanitation program.
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EMULSIONS
INTRODUCTION
• An emulsion is a dispersion of two immiscible liquids, one of which is
distributed uniformly in the form of fine droplets (the dispersed or
discontinuous phase) throughout the other (the external or continuous
phase).
• Emulsions are normally formed by mixing two immiscible liquids as both
liquids are immiscible into each other that’s why emulsions are
heterogenous dispersion system.
• The immiscible liquids are by convention described as `oil' and 'water',
as invariably one liquid is non-polar (e.g. an oil, wax or lipid) and the
other is polar (e.g. water or aqueous solution).
• Oil-in water (o/w) emulsions contain oil droplets dispersed in water, and
water-in-oil (w/o) emulsions contain water droplets dispersed in oil.

Fig:(a) An oil-in-water emulsion and (b) a water-in-oil emulsion. The shaded
area represents the oil.
MULTIPLE EMULSIONS
• Multiple emulsions can also be formed from oil and water by the re-
emulsification of an existing emulsion to form two dispersed phases.
• For example, multiple emulsions can be described as oil-in-water-in-oil
(o/w/o) emulsions. These are o/w emulsions which are further
dispersed in an oil continuum. Conversely water-in-oil-in-water (w/o/w)
type multiple emulsions can be prepared by further emulsification of a
w/o emulsion in water.

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Fig: A multiple w/o/w emulsion and a o/w/o emulsion. The shaded area
represents the oil.
THERMODYNAMIC STABILITY
• As emulsions are thermodynamically unstable and will attempt to
return to separate oil and water phases (i.e. crack) by coalescence of
dispersed globules unless they are kinetically stabilized by the addition
of emulsifiers.
• This happens because emulsions contain two different phases and both
phases have different physical and chemical properties. In the bulk
phase molecules are attracted to each other equally in all directions such
that no resultant forces are acting on them but upon bringing both
phases come in contact to each other they exhibit forces of attraction at
the boundary between two phases. E.g. Emulsion of water and mineral
oil.
• Thus, molecules situated the interface of both phases experience
interaction forces dissimilar to the molecules in each bulk phase. Due to
this reason, the actual contact area between dissimilar molecules will be
reduced and this is the reason emulsified droplets tend to cream and
coalesce.
• An emulsifier is operationally defined as a stabilizer of the droplet form
(globules) of the internal phase.
• On the basis of their structure, emulsifiers may be described as
molecules comprising both hydrophilic (oleophobic) and hydrophobic
(oleophilic) portions. For this reason, this group of compounds is
frequently called amphiphilic (i.e. water- and oil-loving).
DECISION OF W/O EMULSION OR O/W EMULSION
• The type of emulsion that forms and the droplet size distribution
depends upon number of inter-related factors which includes:
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­ Method of preparation of emulsion
­ Relative volumes of water and oil phases
­ Chemical nature of emulsifying agent
• Generally, it is the dominance of the polar or non-polar characteristics of
the emulsifying agent which plays a major part in the type of emulsion
produced.
• When only oil and water are mixed vigorously in the absence of an
emulsifier, initially droplets of both liquids will be produced and as in
emulsions one liquid/phase exists in the form of droplets for the longer
time surrounded by the other liquid as continuous phase.
• So, here the liquid present in greater amount have probability to form
continuous phase because of its greater number of droplets which have
probability of rapid coalescence and subsequent formulation of
continuous phase and without emulsifier it would be temporary
emulsion. So, in order to produce stable emulsion, we need to add
emulsifier.
• When an oil, water and an emulsifying agent are shaken together, A
number of simultaneous processes have to be considered:
­ Droplet formation
­ Aggregation and coalescence of droplets
­ Interfacial film formation
• In given Figure:
­ (A) If the greater number of charged
molecules or the greater number of
hydrated polymer chains at the
interphase, there will be greater tendency
to reduce oil droplets coalescence and oil
will remain in droplets and in internal
phase while water will be the continuous
phase.
­ (B) If longer hydrocarbon chain length and
greater the number of these molecules
present per unit area of the film, the
greater is tendency for water droplets to
be prevented from coalescence and in
this way water droplets will remain in
droplet form and will be the internal
Fig: (a) o/w emulsion, (b) w/o
emulsion
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phase of the emulsion and oil will be the continuous phase.
• The charged surface-active agents which are highly ionized and possess
strong polar groups, favor O/W emulsions such as sodium and potassium
oleates.
• The emulsifying agents which are little dissociated tend to produce W/O
emulsions such as calcium and magnesium soaps.
• Similarly, nonionic sorbitan esters favor w/o emulsions, while more
hydrophilic polyoxyethylene sorbitan esters produce o/w emulsion.
FORMULATION OF EMULSION
• The Choice of Formulation components will depend on:
­ Emulsion type (o/w, w/o or multiple emulsion)
­ The route of administration
­ Clinical use
­ Cost and Compatibility of Ingredients.
• The Processing conditions are also optimized as they control:
­ Droplet size distributions and Rheological properties.
­ Droplet size of internal phase of emulsion and consistency of
emulsion influence emulsion stability and its therapeutic response
because the smallest the globule size, greater will be the
absorption.
COMPONENTS OF EMULSION
• Aqueous phase
• Oil phase
• Emulsifying agent
• Preservatives
• Antioxidants
• Flavourant for Oral Emulsion
• Fragrance for cosmetic
emulsion
I. OIL PHASE
• Oil may be the medicament itself or may be used as carrier for some
lipid soluble drugs.
CONSIDERATION FOR OIL PHASE
• The desired physical properties of Emulsion
• The miscibility of the oil and aqueous phases
• The solubility of the drug in the oil
• The desired consistency of final emulsion.
FOR ORAL EMULSIONS
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• The selection of oil phase depends upon the purpose or the product. E.g.
Castor oil and mineral oil are used as laxative and fish liver oil and
arachis oil are used as nutritional supplements.
FOR EXTERNAL EMULSIONS
• Oils based on hydrocarbons are widely used. E.g. Liquid paraffin, soft or
hard paraffin. Similarly turpentine oil and various silicone oils are also
used.
FOR PARENTERAL EMULSIONS
• A range of purified vegetable oils have been used over many years in
emulsions for parenteral nutrition and as lipid soluble drug carriers. E.g.
refined fish oils, purified olive and soya oils.
II. EMUISIFYING AGENT
• The choice of emulsifier depends on many factors, these include:
­ Type of emulsion to be prepared
­ Emulsifier toxicity or irritancy
­ Clinical use of emulsion
­ Shelf life of emulsion
­ Cost and availability
III. PRESERVATIVES
• An ideal preservative should:
­ Exhibit a wide spectrum of activity against bacteria and fungi
­ Be free from toxic and irritant activity
­ Be stable to heat and storage
­ Be chemically compatible (e.g. polyoxyethylene nonionic
surfactants and phenolic preservatives are incompatible)
­ Have reasonable cost
­ Have acceptable taste, odor and color.
• Examples: phenoxyethanol, benzoic acid and the p-hydroxybenzoates.
IV. ANTIOXIDANTS
• Antioxidants prevent oxidative deterioration of the oil, emulsifier or the
drug itself during storage.
• The antioxidants commonly used in pharmacy include butylated hydroxy
anisole and butylated hydroxytoluene at concentrations up to 0.2%, and
the alkyl gallates, which are effective at very low concentrations (0.001%
to 0.1%).
• A-Tocopherol is added to some commercial lipid emulsions to prevent
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peroxidation of unsaturated fatty acids.
V. OTHER EXCIPIENTS
• Humectants are often added to dermatological preparations to reduce
evaporation of water from the emulsion during storage and use. E.g.
propylene glycol, glycerol and sorbitol at concentrations up to 5% are
added.
• Other excipients for proper formation of emulsion are flavoring agent
for oral emulsions and fragrances for topical cosmetic emulsions.
FUNCTIONS AND CLASSIFICATION OF EMULSIFYING AGENTS
• Emulsifiers are added to prevent coalescence.
• When two immiscible liquids are mechanically agitated, both phases
initially tend to form droplets. When the agitation is stopped, the
droplets quickly coalesce and the two liquids separate.





FUNCTIONS OF EMULSIFYING AGENTS
• Emulsifiers generally impart stability by the formation of a mechanical or
electrostatic barrier at the droplet interface (an interfacial film) or in the
external phase (a rheological barrier).
• They impart thermodynamic and kinetic stability to emulsion.
RHEOLOGICAL BARRIER
• In many emulsions the external phase is thickened by the emulsifier
which means the emulsifier significantly increases the viscosity of
continuous phase.
• In this way the structured continuous phase forms a rheological barrier
to prevent the movement and close approach of droplets. That is why
they work as rheological barriers to prevent coalescence.
THERMODYNAMIC STABILITY
• As the surfactant emulsifier lowers the interfacial tension between the
oil and water. This facilitates the formation of droplets during
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emulsification and reduces the thermodynamic tendency for
coalescence.
KINETIC STABILITY
• As emulsifier increases the viscosity of emulsion, that is how they
restrict the motion of globules and maintains the dispersion state of
emulsion for extended period of time.
CLASSIFICATION OF EMULSIFYING AGENTS
1. Synthetic or semisynthetic surface-active agents and polymers
• Surface-active agents and polymers
a) Ionic surfactants
▪ Anionic surfactants
▪ Cationic surfactants
b) Nonionic surfactants
c) Fatty amphiphiles
d) Polymeric surfactants
2. Natural macromolecular materials
a) Phospholipids
b) Steroidal emulsifiers
c) Hydrophilic colloids
d) Solid particles
1. SURFACE ACTIVE AGENTS AND POLYMERS
• Surface active agents are those compounds which
have a tendency to accumulate at the boundary
between two phases. Surface active compounds
have two distinct regions in their chemical structure,
a hydrophilic (water-liking) region and a hydrophobic
(water-hating) region.
• The existence of two such regions in a molecule is
referred to as amphipathy and the molecules are consequently often
referred to as Amphipathic molecules.
A. IONIC SURFACTANTS
I. ANIONIC SURFACTANTS
• They dissociate at high pH to form a long chain anion with surface
activity
i. ALKYL SULFATES
• Sodium lauryl sulfate (sodium dodecyl sulfate) is a commonly used
surfactant. Alone, it is a weak emulsifier of the o/w type but forms a
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powerful o/w blend when it is used in conjunction with cetostearyl
alcohol.
ii. MONOVALENT SALTS OF FATTY ACIDS
• Emulsifiers in this group consists mainly of the alkali salts of long-chain
fatty acids and form o/w emulsions. They are generally formed in situ by
the interaction of a fatty acid with appropriate alkali. For example, in
white liniment, ammonium oleate is formed in situ from the reaction
between ammonia solution and oleic acid.
iii. DIVALENT SALTS OF FATTY ACIDS
• Calcium salts of fatty acids containing two hydrocarbon chains form w/o
emulsions because of their limited solubility in water. In zinc cream,
calcium oleate is formed in situ from the interaction between oleic acid
and calcium hydroxide.
II. CATIONIC SURFACTANTS
• They dissociate at low pH to form a long chain surface-active cation.
• Emulsions containing cationic surfactant as emulsifier are unstable at
high pH and in the presence of anionic materials including anionic
surfactants and polymers.
QUATERNARY AMMONIUM COMPOUNDS
• These constitute an important group of cationic emulsifiers in
dermatological preparations because they also have antimicrobial
properties. For example, in cetrimide cream, the mixed emulsifier is
prepared by blending cetrimide (cetyltrimethyl ammonium bromide)
with cetostearyl alcohol to form cationic emulsifying wax.
B. NONIONIC SURFACTANTS
• Most nonionic surfactants are based on:
­ A hydrophobic moiety with 12-18 carbon atoms. The starting
material may be a fatty acid or sorbitan.
­ A hydrophilic moiety composed of an alcohol (-OH) and/or
ethylene oxide groups linked to form long polyoxyethylene chains.
i. POLYOXYETHYLENE GLYCOL ETHERS (MACROGOLS)
• They are used as both o/w emulsifier and w/o emulsifiers. E.g.
cetomacrogol 1000.
ii. SORBITAN ESTERS (SPANS)
• These are hydrophobic and produce w/o emulsions. E.g. Sorbitan
monolaurate (Span 20), Sorbitan Monooleate (Span 80) etc.
iii. POLYOXYETHYLENE SORBITAN ESTERS (POLYSORBATES) (TWEENS)
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• They are more hydrophilic and used to produce o/w emulsions. E.g.
Polyethylene 20 sorbitan monolaurate (Tween20), Polyethylene 20
sorbitan monooleate (Tween 80).
C. FATTY AMPHIPHILES
• Fatty alcohols and fatty acids E.g. Cetyl alcohol and stearic acid used as
auxiliary emulsifiers. Glycerol monoesters E.g. Glyceryl monostearate
and glyceryl monooleate are the most common monoesters used in
dermatological preparations.
D. POLYMERIC SURFACTANTS
• The poloxamers are a series of neutral synthetic polyoxyethylene-
polyoxypropylene block copolymers which are used either alone or as
auxiliary emulsifiers with lecithin in small-volume parenteral injections.
2. NATURAL MACROMOLECULAR MATERIALS
A. PHOSPHOLIPIDS
• E.g. Purified lecithin derived from egg yolk or soya bean oil. They are
used extensively as o/w emulsifiers in parenteral and oral emulsions.
B. HYDROPHILLIC COLLOIDS;POLYSACCHARIDES
• Polysaccharides, including gums, such as acacia and tragacanth and
alginate and cellulose derivatives are hydrophilic colloids used as
emulsifying agents in oral preparations.
C. STEROIDAL EMULSIFIERS
• E.g. Wool fat (lanolin), wool alcohols (lanolin alcohols), beeswax and
cholesterol, used for their emollient properties and as w/o emulsifiers.
D. SOLID PARTICLES
• E.g. Bentonite, aluminum hydroxide, magnesium hydroxide, aluminum
magnesium silicate.
INSTABILITIES OF EMULSION
1. CREAMING
• Creaming is a process which occurs when the dispersed droplets
separate under the influence of gravity to form a layer of more
concentrated emulsion, the cream.
• There is aggregation of globules of the dispersed phase at the top or
bottom of the emulsion, similar to cream on milk.
• Creaming occurs inevitably in any dilute emulsion containing relatively
large droplets if there is a density difference between the oil and water
phases.
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Original emulsion
Original emulsion Flocculation
• Creaming is a reversible process.




REASONS OF CREAMING
• If emulsion contains large droplets of dispersed phase.
• If emulsion is dilute.
• If there is a density difference between the oil and water phases.
TO REDUCE CREAMING
• Small droplet size.
• Increase viscosity of external phase.
Q: When the globules of dispersed phase will rise to surface and when they
sediment to bottom?
Ans: It depends upon density of dispersed phase. If density of dispersed phase
is less than that of continuous phase the droplets of dispersed phase will rise
to the surface of emulsion. For example: More oils are less dense than water.
So, in o/w emulsion where the dispersed phase is oil. So, in this emulsion oil
droplets will rise to the surface to form an upper layer of cream and opposite
occurs in w/o emulsion.
2. FLOCCULATION
• Flocculation is a weak, reversible aggregation of droplets of the internal
phase in the form of clusters.





• Tendency for flocculation can be reduced by the use of a suitable
emulsifier, viscosity enhancer and internal phase volume.
• Flocculation is undesirable because floccules cream more rapidly under
Creaming
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Original emulsion Coalescence
Phase separation/
Cracking
Original emulsion Ostwald ripening
the influence of gravity than individual droplets.
3. COALESCENCE AND CRACKING
• It is irreversible process in which dispersed phase droplets merge to
form larger droplets. The process will continue until the emulsion breaks
(cracks) and there is complete separation of the oil and water phases.





• Absence of coalescence can be achieved by the formation of a thick
interfacial film from macromolecules or from particulate solids.
Q: How the droplets retain the individuality?
Ans: This is because of the charges on the surface of emulsified globule or
presence of mechanical protective barrier at the interface of globules which
prevents their coalescence. So, if the amount of emulsifier is insufficient to
work as proper mechanical or electrical barrier at these individual droplet
interfaces. These droplets can not remain intact and their coalescence will
occur rapidly.
4. OSTWALD RIPENING
• It is an irreversible process which involves the growth of large droplets
at the expense of smaller ones.




• Ostwald ripening can be inhibited by the addition of the surfactant,
which is strongly adsorbed at the o/w interface and does not form
micelles in the continuous phase.
• It can also be inhibited by increasing the viscosity of the emulsion
external phase.
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Original emulsion

Phase inversion
5. PHASE INVERSION
• It is an irreversible process in which an emulsion changes from one type
to another, for example o/w to w/o.




REASONS FOR PHASE INVERSION
• If the amount of disperse phase approaches or exceeds a theoretical
maximum of 74% of the total volume.
• If the emulsifier solubility is changed.
EQUIPMENT FOR EMULSIFICATION
• Various types of equipment are available either in laboratory or in
industries:
1. Mortar and pestle
2. Agitators
3. Mechanical Mixers
4. Colloid Mills
5. Homogenizers
6. Ultrasonic Devices
7. Microfluidizers
SELECTION OF EMULSIFICATION EQUIPMENT
• The selection of emulsification equipment depends on a number of
inter-related factors, including:
­ The oil used
­ The volume of emulsion to be prepared
­ The type of emulsifier used
­ The range of droplet sizes required
­ The flow properties of the emulsion during the emulsification and
cooling processes
­ Phase to volume ratios
­ The desired physical properties of the product.
1. MORTAR AND PESTLE
• On a small scale, as in laboratory or pharmacy, emulsions may be
prepared using a dry porcelain mortar and pestle.
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2. AGITATOR AND MECHANICAL MIXERS
• An emulsion may be stirred by means of various impellers mounted on
shaft which are placed directly into system to be emulsified.
I. SHAKER MIXERS
CONSTRUCTION
• A vessel and an oscillator or rotator.
WORKING
• In these mixer material is placed in the vessel and is agitated by either by
an oscillator or rotary movement. Shaker mixers have limited use in
industries.
II. PROPELLER MIXERS
CONSTRUCTION
• A container
• Shaft
• Propeller and strips
WORKING
• The size of the propeller is very small as compared to container It
rotates at very high speed up to 8000 rpm. Propeller mixers are the most
widely used form for liquid of low viscosity.
• They are not suitable for viscous liquids like glycerin, liquid paraffin etc.
Propeller mixers are suitable for routine laboratory and production
purposes.
III. TURBINE MIXERS
CONSTRUCTION
• A circular disc impeller
• Blades
• Containers
WORKING
• These mixers are rotated at lower speed than propellers and ratio of the
impeller and container diameter is also low. It produces greater shear
forces.
• They are used for special application in the preparation of emulsion of
high or moderate viscosity. If more vigorous agitation is required, they
are used. Used for laboratory and production purposes.
IV. PADDLE MIXERS
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CONSTRUCTION
• Number of paddles
• Vertical shaft
• Flat blade
• Container
WORKING
• A number of paddle mixers having different shapes and sizes depending
on the nature and viscosity of the product are available for use in
industries. The blades have a large surface area in relation to container.
Blades help them to rotate close to the walls of container and effectively
mix the viscous liquids and semi-solids. They rotate at speed of 10 rpm
or less.
3. COLLOID MILLS
PRINCIPLE
• Homogenizer and ultrasonic equipment depend on sudden changes in
pressure to effect dispersion of liquids.
• Colloid mills operate on principle of high shear which is generated
between motor and stator.
CONSTRUCTION
• Hopper
• Shaft
• Conical rotator
• Motor
WORKING
• It consists of conical motor and rotator. The gap between them can be
adjusted from 0.005-0.075 .
• Rotator is connected to high speed motor which can revolve at speed of
3000-20000 rpm.
• Previously grounded material is fed into machine with hopper and it is
thrown outward by centrifugal action. As the material passes through a
narrow gap between rotor and stator, it is size is reduced.
ADVANTAGES
• Products with particle size less than 1um can be obtained.
• Useful for preparing pharmaceutical syrup, emulsion, lotions, ointments
and creams.
• Size reduction is always carried out in presence of liquid.
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DISADVANTAGES
• Not applicable for processing dry material.
• Materials need to be milled previously.
4. HOMOGENIZER
PRINCIPLE
• Homogenizers are based on the principle that large globules in coarse
emulsion are passed, through a small inlet orifice at high pressure is
broken into smaller globules having a greater degree of uniformity and
stability.
• Homogenizers can be built with more than one emulsifier stage and it is
possible to recycle the emulsion and pass it through the homogenizer
more than one time.
• There are different designs of equipment and homogenizer raises
temperature of emulsion so cooling is required.
HAND HOMOGENIZER
CONSTRUCTION
• Hopper
• Handle
• Orifice
• Base
• Strong spring
• Pump (that raises the
pressure of dispersion to 500-
5000psi)
WORKING
• The most commonly used hand homogenizer is on laboratory scale. The
preformed emulsion which is performed by using a pestle and mortar is
placed in hopper.
• The emulsion is then forced to pass through a narrow orifice by up and
downward movement of the handle which reduces size of oil globules.
This size reduction in size increases with speed of pumping.
5. ULTRASONIFIERS
• Ultrasonifiers are used to make emulsions by ultrasonic energy.
CONSTRUCTION
• Inlet and outlet
• Nozzle jet
• Blade
• Pump
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WORKING
• The dispersion is forced through orifice at a modest pressure and is
allowed to impinge upon vibrating blade. The pressure required is in
range of 150-350 psi and can cause the blade to vibrate rapidly and
produce ultrasonic note.
• When system reaches steady state, creational field is generated at
leading edge of the blade and pressure fluctuation of 60 tons psi can be
achieved in equipment.
6. MICRO FLUIDIZERS
• The process subjects the emulsion to an extremely high velocity through
micro-channels into an interaction chamber.
• As a result, droplets are subjected to shear, turbulence, impact and
cavitation.
• Two advantages of this type of equipment are:
­ Lack of contamination in the final product
­ Ease of Production scale up.
7. SILVERSON MIXER EMULSIFIER
CONSTRUCTION
• Emulsifying hand with vessel
• Blades and motor
• Mesh sieve and sieve band
WORKING
• The emulsifying head is adjusted in such a way that it is immersed in the
liquid to be emulsified. The head is rotated at high speed with motor.
• The liquids are sucked through fine mesh into the blade of emulsifying
head where they are subjected vigorous mixing by high speed rotating
blades. The material is then expelled forcefully through sieve hand.
• In this way whole of the liquids to be mixed are made to pass repeatedly
through emulsifying head and large globules are converted to small
globules.
• Various sizes of Silverstone mixers are available and if necessary, the
mixing vessel maybe surrounded by a jacket so that the process can be
carried out at desired temperature.
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8. KENWOOD MIXERS
CONSTRUCTION
• Mixing vessel
• Blades and whisks (coiled wire)
• Container fitted with jacket
WORKING
• It offers very effective mixing and is quite suitable for making small
batches of emulsion. By this machine, the mixing action is effective
because both the beaters and axis on which they are fixed rotates due to
which the whole of the liquid in mixing vessel is affected.
• Different types of beaters and whisks are available with the machine
which can be easily changes by simple locking magnet. Containers may
be fitted with a jacket so that heating or cooling of contents maybe
carried out.
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SUSPENSIONS
INTRODUCTION
• Pharmaceutical suspension is a coarse dispersion in which internal phase
is dispersed uniformly throughout the external phase.
• The internal phase consisting of insoluble solid particles having a specific
range of size which is maintained uniformly throughout the suspending
vehicle with aid of single or combination of suspending agent.
• The external phase (Suspending medium) is generally aqueous in some
instance, may be an organic or oily liquid for non-oral use.
FLOCCULATED SUSPENSIONS
• In flocculated suspension, formed flocks (loose aggregates) will cause
increase in sedimentation rate due to increase in size of sedimenting
particles. Hence, flocculated suspensions are sedimented more rapidly.
Here, the sedimentation depends not only on the size of the flocks but
also on the porosity of flocks.
DEFLOCCULATED SUSPENSIONS
• In deflocculated suspension, individual particles are settling. Rate of
sedimentation is slow, which prevents entrapping of liquid medium
which makes it difficult to re-disperse by agitation. This phenomenon
called “caking” or “claying”. In deflocculated suspension, larger particles
settle fast and smaller particles remain in supernatant liquid so
supernatant appears cloudy.
METHODS OF FORMULATION OF SUSPENSIONS
• The formulation of a suspension depends on whether the suspension, is
flocculated or deflocculated. Three approaches are commonly involved
1. Use of structured vehicle
2. Use of controlled flocculation
3. Combination of both methods.
1. STRUCTURED VEHICLE
• Structured vehicles are also called thickening or suspending agents. They
are aqueous solutions of natural and synthetic gums. These are used to
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increase the viscosity of the suspension. It is applicable only to
deflocculated suspensions e.g. methyl cellulose, sodium carboxy methyl
cellulose, acacia, gelatin and tragacanth. These structured vehicles
entrap the particles and reduces the sedimentation of particles. Thus,
the use of deflocculated particles in a structure vehicle may form solid
hard cake upon lone storage.
• Too high viscosity is not desirable as:
­ It causes difficulty in pouring and administration
­ It may affect drug absorption since they adsorb on the surface of
particle and suppress the dissolution rate.
• Structured vehicle is not useful for parenteral suspension because they
may create problem in syringeability due to high viscosity.
2. CONTROLLED FLOCCULATION
• Controlled flocculation of particles is obtained by adding flocculating
agents, which are:
­ Electrolytes
­ Surfactants
­ Polymers Flocculation
in Structured vehicles.
• Sometimes suspending agents can be added to flocculated suspension to
retard sedimentation. Examples of these agents are:
­ Carboxymethylcellulose (CMG)
­ Carbopol 934
­ Veegum and bentonite.
INGREDIENTS FOR FORMULATION OF SUSPENSIONS
Ingredients Role
Wetting agent
They are added to disperse solids in continuous liquid
phase.
Flocculating agent They are added to floc the drug particles.
Thickness agents They are added to increase the viscosity of suspension.
Buffers and pH
adjusting agents
They are added to stabilize the suspension to a desired
pH range.
Osmotic agents
They are added to adjust osmotic pressure comparable
to biological fluid.
Coloring agents
They are added to impart desired color to suspension
and improve elegance.
Preservatives They are added to prevent microbial growth.
External Liquid
Vehicle
They are added to construct structure of the final
suspension.

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FLOWCHART OF FORMULATION OF SUSPENSION

PREPARATION OF SUSPENSIONS
• Following consideration are important for manufacturing pharmacist.
­ Selection of right material that goes into the manufacture.
­ The step involved and their sequence in the manufacture.
­ Preservation and storage of the product.
SMALL SCALE PREPARATION OF SUSPENSIONS
1. Suspensions are prepared by grinding or levigating the insoluble
materials in the mortar to a smooth paste with a vehicle containing the
wetting agent.
2. Al! soluble ingredients are dissolved in same portion of the vehicle and
added to the smooth paste to gel slurry.
3. The slurry is transferred to a graduated cylinder, the mortar is rinsed
with successive portions of the vehicle.
4. Decide whether the solids are:
­ Suspended in a structured vehicle
­ Flocculated
­ Flocculated and then suspended
Add the vehicle containing the suspending agent or flocculating agent.
5. Make up the dispersion to the final volume. Thus, suspension is
prepared.
Deflocculated
Suspension
Addition of
Structured
Vehicle
Deflocculated
suspension in
external
vehicle
Flocculating
Agents
are added
Flocculated
suspension
Flocculating
Agents
are added
Addition of
external
Vehicle
Flocculated
suspension in
external
vehicle
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INDUSTRIAL SCALE PREPARATION OF SUSPENSIONS
• Three steps:
­ Optimization of Particle size
­ Addition of wetting agent
­ Addition of Suspending agent
• Oral suspension should not feel gritty. Topical suspension should feel
smooth to the touch. Injectables should not produce tissue irritation
­ Very small particles less than 1 um have will have higher solubility
and faster dissolution. Thus, particle size of suspension can
influence the rate of sedimentation, flocculation, solubility,
dissolution rate and ultimately bioavailability.
OPTIMIZATION OF PARTICLE SIZE
• Particle size reduction is accomplished by dry milling prior to
incorporation of dispersed phase into dispersion medium. Milling is the
mechanical process of reducing particle size which may be accomplished
by a number of different machines:
­ Hammer Mill
­ Fluid Energy Mill
­ Ball Mill
I. HAMMER MILL
• This mill grinds the powder by impact. Centrifugally rotating hammers or
blades contact the particles and direct them against a screen typically in
the range of 4 to 325 mesh.
• The particles are forced through screen, which regulates final particle
size. The typical size range of particles in hammer mill is 10 – 50 um.
II. FLUID ENERGY MILL
• Fluid energy or jet mill produce particles under 25 um thorough violent
turbulence in high velocity air. Pulverizing nozzles are attached around
the grinding chamber which inject high speed air into the grinding
chamber.
• The centrifugal air flow accelerates particles and reduces particle size
through particle-particle impaction and friction.
III. BALL MILL
• A ball mill contains umber of steel or ceramic balls. The balls reduce
particle size to 20 to 200 mesh by both attrition and impact.
• A roller mill can also be used to reduce particles to a mesh of 20 to 200.
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ADDITION OF WETTING AGENT/ SUSPENDING AGENT
• On large scale, the fine drug particles are treated with a small portion of
water that contains the wetting agent and allowed to stand for several
hours.
• A wetting agent is a surfactant with an HLB value between 7 and 9.
Surfactant with higher HLB are also recommended such as Polysorbates
and Poloxamers. Used in concentration of 0.05 to 0.5 %.
• At the same time suspending agent is added to the main portion of the
external phase and allowed to stand until complete hydration takes
place. Subsequently, wetted drug particles are added slowly to the
dissolved suspending agent.
• Electrolytes and buffering agents are carefully added. The preservatives,
flavoring agents and coloring agents are added last.
• Finally, the formulation is processed with homogenizers, colloid mill or
ultrasonic device to produce a uniform product.
TESTS FOR SUSPENSION
1. SEDIMENTATION VOLUME DETERMINATION
• The sedimentation volume is simple ratio of the height of sediment to
initial height of initial suspension. The suspension formulation (50 ml)
was poured separately into 100ml measuring cylinders and
sedimentation volume was read after 1, 2, 3 and 7 days, and thereafter
at weekly intervals for 12 weeks. Triplicate results were obtained for
each formulation.
• Sedimentation volume was calculated according to the equation:
F = Vu / Vo
­ Where, F = sedimentation volume, Vu = ultimate height of
sediment and Vo = initial height of total suspension. The larger the
value better is the suspensibility.
2. VISCOSITY MEASUREMENT OF SUSPENSION
• It provides information about the settling behavior, the arrangement of
the vehicle and the particles structural features.
• Brookfield viscometer is used to study the viscosity of the suspension. It
is mounted on heli path stand and using T-bar spindle.
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• T-bar spindle is made to descend slowly into the suspension and the dial
reading on the viscometer is then a measure of the resistance the
spindle meets at various levels.
• This technique also indicates at which level of the suspension the
structure is greater owing to particle agglomeration. The dial reading is
plotted against the number of turns of spindle. The better suspension
shows a lesser number rate of increase of dial readings with spindle
turns, i.e. the curve is horizontal for long period.
3. MEASUREMENT OF ZETA POTENTIAL
• Measurement of Zeta-potential is done by using Micro electrophoresis
apparatus & Zeta Plus (Brookhaven Instruments Corporation, USA).
• It shows the stability of a disperse system.
DETERMINATION OF ZETA POTENTIAL
• The zeta potential of the formulated suspensions was determined using
a Zeta Plus (Brookhaven Instruments Corporation, USA).
• Approximately 1 ml of suspension was transferred into a plastic cuvette
using a pipette and diluted with distilled water.
• The Brookhaven zeta potential software was used for the measurement.
• Parameters set to a temperature 25℃ and refractive index (1.33)
• The zeta potential of the formulation was determined on day 0,7,14,21
and day 28 post formulation.
4. PARTICLE SIZE DETERMINATION OR SUSPENSION
• The stability of suspension depends on particle size of the dispersed
phase. Changes in particle size with reference to time will provide useful
information regarding the stability of a suspension.
• A change in particle size distribution and crystal habit is studied by:
­ Microscopy
­ Coulter counter method
­ Photo-microscopic method
PHOTO MICROSCOPIC TECHNIQUE
• The microscope can be used to estimate and detect changes in particle
size distribution and crystal form. Rapid processing of photo
micrographs is enhanced by attaching Polaroid camera to the piece of
monomolecular microscope. By using these photo-micrographs we can
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determine the changes in physical properties and stability of
suspensions.
5. FREEZE THAW TEST
• Freeze-Thaw test is conducted by placing the sample in a freezer for 18
hours followed by thawing at room temperature for 4 to 6 hours.
• Repeat the Freeze-Thaw cycle for up to 10 times. This test is conducted
to determine the tendency to crystallize or cloud.
6. PH MEASUREMENT
• The measurement and maintenance of pH is also very important step in
the quality control testing of suspensions. Generally, there are 2
different types of methods used in the measurement of pH.
METHODS FOR PH MEASUREMENT
• The simplest and cheapest method is to dip a piece of pH paper into the
sample. The paper is impregnated with chemicals that change color and
the color may be compared to a chart supplied with the paper to give
the pH of the sample. If greater accuracy is required a pH meter should
be used. A typical pH meter consists of a special measuring glass
electrode connected to an electronic meter that measures and displays
the pH reading.
7. VISUAL INSPECTION
• With visual inspection, the ingredients and the final products are
carefully examined for purity and for appearance. Physical appearance
of products for patient adherence and compliance is critical so it should
be:
­ Good looking
­ Elegance in appearance.
8. DISSOLUTION STUDY OF SUSPENSIONS
• The drug release from suspensions is mainly through dissolution.
Suspensions share many physico-chemical characteristics of tablet and
capsules with respect to the process of dissolution.
• As tablets and capsules disintegrate into powder ad form suspensions in
the biological fluids. So, dissolution is carried as follows.
DISSOLUTION TEST: OFFICIAL METHOD (CONVENTIONAL METHOD)
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• It is known as paddle method. The apparatus consists of a cylindrical
1000 ml round bottom flask in a multiple – spindle dissolution drive
apparatus and immersed in a controlled temperature bath maintained.
• Dissolution profile of the 500 mg sample suspension is determined at
37°C in 900 ml of pH 7.2 phosphate buffer using the FDA paddle method
at 25 rpm.
• The paddle should position to extend to exactly 2.5 cm above the flask
bottom. The suspension is to be introduced carefully into the flask at the
bottom using a 10 ml glass syringe with an attachment 19 cm needle.
• Withdraw 5ml of dissolution medium (and replace with an equal volume
of drug free buffer) in a 5 ml glass syringe. Immediately filter through a
0.2 μm membrane and analyze.
9. DETERMINATION OF SURFACE TENSION
• The Wilhelmy Plate Pull method and the Ring Detachment method are
the best suited for determination of interfacial tension.
• Surface tension is a downward force per unit length on the perimeter of
the plate.
10. CONTENT UNIFORMITY TEST
• The requirements are met if result obtained from each of the 10
containers falls within the limits of 85 to 115% of the average limits If
not more than 1 result fall outside the limits of 85 to 115 percent. And if
none of tablets fall outside the limits of 75 to 125 percent of the average
then assay 20 more containers individually. The requirements are met if
result from additional 20 containers fall between 85 to 115 percent.
11. ASSAY OF ACTIVE INGREDIENT
• For assay of active ingredient see individual monograph.
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SEMISOLIDS
DEFINITION
• “Semi solids are topical dosage form containing one or more active
ingredients dissolved or uniformly dispersed in a suitable base and
suitable excipients (emulsifier etc.) that are used for therapeutic,
protective or cosmetic function.”
• They may be applied on skin or used nasally, vaginally or rectally.
PROPERTIES
• Their common property is the ability to cling for suitable time to the
surface on which it is applied.
• Above property is due to their plastic rheologic behavior.
IDEAL SEMI SOLIDS
• Smooth texture
• Elegant in appearance
• Non dehydrating
• Non gritty
• Non greasy and non-non-
staining
• Non hygroscopic Physiological
properties
• Non-irritating
• Do not alter membrane
function
• Miscible with skin secretion
• Easy applicable with efficient
drug release
• High aqueous washibility
SEMI SOLIDS FORMULATIONS
• Ointments
• Pastes
• Creams
• Gels
I. OINTMENTS
• They are generally composed of fluid hydrocarbons generally meshed in
a higher melting solid hydrocarbons.
• Most ointments are based on mineral oils and petroleum.
PREPARATION MECHANISM
• Melting of all components together. Drugs and other components are
added in fluidized state.
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• If the solids to be mixed are insoluble, the system is put through a
milling process (colloid mill, homogenizer or ultrasonic mixer)
II. PASTES
• Pastes are basically ointments but with very high percentage of insoluble
solids
PREPARATION MECHANISM
• They are prepared by incorporating a solid directly into congealed
system by levigating with a portion of base to form paste like mass.
Remainder of base is added until solids are uniformly mixed.
III. CREAMS
• They are semisolid emulsion systems with opaque appearance.
• Their properties depend upon emulsion types (oil in water or water in
oil)
IV. GELS
• Gels are semisolid systems in which a liquid phase is constrained within
a three-dimensional polymer matrix (containing natural or synthetic
gums) in which high degree of physical (sometimes chemical) cross-
linking is present.
• Natural gums used ( tragacanth, pectin etc.)
• Synthetic materials ( methyl-cellulose etc.)
PREPARATION MECHANISM
• They are usually prepared by fusion process.
EQUIPMENT FOR SEMISOLID PREPARATION
• A wide range of machines are available for large-scale production of
ointments and creams. Each of these machines is designed to perform
certain unit operation, such as milling, separation, mixing, emulsification
and deaeration.
I. MILLS
• Milling is performed to reduce the size of actives and other additives
various mills used for this purpose are:
­ Fluid mills
­ Impact mills
­ Cutter mills
­ Compression mills
­ Tumbling mills
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• Mechanism of size reduction
­ Cutting
­ Compression
­ Impact
­ Attrition
II. SEPARATORS
• Separators are employed for separating materials of different size,
shape, and densities. Two types of separators are mostly used for
separation. These are:
­ Centrifugal separators
­ Vibratory shakers
III. MIXERS
• Mixing of the active and other formulation components with the
ointment or cream base is performed using various types of mixers, such
as:
­ Agitator mixers
­ Roller mills
• Mixers with heating provisions are also used to aid in the melting of
bases and mixing of components.
MECHANISM OF MIXING
• Convective mixing
• Shear mixing
• Diffusive mixing
TYPES OF MIXTURES
• Positive mixtures
• Negative mixtures
• Neutral mixtures
IV. EMULSIFIERS
• These emulsifiers are used to disperse the hydrophilic components in
the hydrophobic dispersion phase (e.g. water-in-oil creams) or
oleaginous materials in aqueous dispersion medium (oil-in-water
creams).
• The choice includes:
­ Low shear emulsifiers
­ High shear emulsifiers
­ Roller mill
­ Colloid mill
­ Ultrasonic emulsifier
V. DEAERATION
• Entrapment of air into the final product due to mixing processes is a
common issue in large scale manufacturing of semisolid dosage form.
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Various offline and in line deaeration procedures are adopted to
minimize this issue. Effective deaeration is generally achieved by using
vacuum vessel deaerators.
VI. SHIFTERS, HOLDERS, FILLERS, AND SEALERS
• Various low and high shear shifters are used to transfer materials from
the production vessel to the packaging machines. In the packaging area,
various types of holders, fillers, and sealers are used to complete the
unit operation.
STORAGE OF SEMI SOLIDS
• After semi solid dosage forms are prepared, they have to go through
quality control testing. This process can take time, but during this time,
semi solids are needed to be stored properly, otherwise they will
deteriorate by evaporation of water and other volatile components.
• So, they are stored in Stainless-steel drums and covered by suitable
plastic sheets on surface and covering the drum properly.
PACKAGING OF SEMI SOLIDS
FILLING
• When the QC and QA processes are completed, semi solid preparations
are filled in suitable containers. Most of the filling is due to transfer of
materials into container by gravitational forces but filling can also be
done with help of pumps or tubes.
• There should be proper and regular cleaning of filling equipment to
ensure no contamination and other bad impacts like bubbles during
filling.
CONTAINERS
I. Plastic / Metal tubes
• Plastic tubes made up of PVC etc. or metal tubes made up of stainless
steel are used for packaging of ointments and pastes.
II. Shallow Glass or plastic jars
• Such type of jars are used for packaging of creams and gels.
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STERILE PRODUCTS
INTRODUCTION
• Sterile products are dosage forms of therapeutic agents that are free of
viable microorganisms. Principally, these include parenteral, ophthalmic
and irrigating preparations.
• Formulations are:
­ Ophthalmic
­ Freeze dried products
­ Long acting formulas
­ Suspensions
­ Emulsions
FORMULATION DEVELOPMENT
• The final objective in the development of a sterile product is the
elicitation of a therapeutic effect in a patient. The formulation of a
sterile product involves the combination of one or more ingredients with
a medicinal agent to enhance the convenience, acceptability, or
effectiveness of the product.
1. THERAPEUTIC AGENT
• A therapeutic agent is a chemical compound subject to the physical and
chemical reactions characteristic of the class of compound which it
belongs.
2. VEHICLE OR SOLVENT SYSTEM
AQUEOUS SYSTEMS
• The most frequently employed vehicle for sterile products is water since
it is the vehicle for all-natural body fluids.
I. WATER FOR INJECTION
• Also known as WFI. Clear, colorless, odorless. Pyrogen free. Having ph 5-
7. Dissolved solids 10ppm: Determined by 100ml of water or by
conductivity method.
• It must be used within 24 hours and must be stored at temperature
either 5°C or 60-90°C if to be held for 24 hours.
• Manufactured by reverse osmosis process and distillation
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II. STERILIZED WATER FOR INJECTION
• Single dose container not exceeding 100ml. No bacteriostatic agent.
Hardness not more than 30ppm. Used for dispensing parenteral
solution, for mixing and making of dry powders.
• It should not be placed in container greater than one liter. It is prepared
by filling a volume of WFI in final container and then sterilized by moist
heat.
III. BACTERIOSTATIC WATER
• Bacteriostatic water for injection unlike water for injection must be
sterile. Bacteriostatic agents are present i.e. benzyl alcohol or mixture of
methyl propyl hydroxyl benzoate
• As it contains bacteriostatic agents, therefore not more than 5ml is used
to avoid the toxicity of substance. It must not be placed in container
larger than 30ml
IV. RINGER'S INJECTION
• The Ringer's injection USP is a sterile solution of sodium chloride,
potassium chloride and calcium chloride in water for injection. The three
agents in the ringer’s solutions are present in the concentration similar
to that found in physiological fluids.
NON-AQUEOUS AND MIXED SOLVENTS
• In the formulation of sterile pharmaceutical products, it is sometimes
necessary to eliminate water entirely or in part from the vehicle,
primarily because of solubility factors or hydrolytic reactions.
• It must not be irritating, toxic, or sensitizing, and it must not exert an
adverse effect on the ingredients of the formulation.
• Solvents that are miscible with water, and that are usually used in
combination with water as the vehicle, include dioxolanes,
dimethylacetamide, N-(β-hydroxyediyl), lactamide, butylene glycol,
polyethylene glycol 400 and 600, propylene glycol, glycerin, and ethyl
alcohol.
• Water-immiscible solvents include fixed oils, ediyl oleate, isopropyl
myristate, and benzyl benzoate. The most frequently used non-aqueous
solvents are polyediylene glycol, propylene glycol, and fixed oils.
OILS
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• These are used when the use of water is contraindicated, like:
­ When the medicament is insoluble or slightly soluble in water i.e.
steroids and hormones are not soluble in water but soluble in
peanut, corn oil
­ To increase the stability of preparation
­ To prolong the duration of action of drug
• Whenever non-aqueous vehicles are used in the injection preparation,
they must be administered by IM route.
AQUEOUS NON-AQUEOUS AND MIXED VEHICLES
• Water-miscible solvents we widely used to enhance solubility and to
serve as stabilizers. The most common solvents include glycerin, ethyl
alcohol, propylene glycol and polyethylene glycol 300.
3. ADDED SUBSTANCES
• Substances added to a product to enhance its stability are essential for
almost every product.
• Such substances include
­ Solubilizers
­ Anti-oxidants
­ Chelating agents
­ Buffers
­ Tonicity contributors
­ Antibacterial agents
­ Antifungal agents
­ Hydrolysis inhibitors
­ Antifoaming agents
• Added substances should possess following properties:
­ They must be non-toxic in the quantity administered to the
patient.
­ They should not interfere with the therapeutic efficacy or with the
assay of API.
­ The must also present and active when needed throughout the
useful life of the product.
I. ANTIBACTERIAL PRESERVATIVES
• Antibacterial agents in the bacteriostatic concentration must be included
in the formulation of products packaged in the formulations of product
packaged in multiple-dose vials and are often included in formulations to
be sterilized by marginal processes or made by aseptic manipulation.
• Most commonly used antibacterial agents are:
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­ Benzyl alcohol 0.5-10.0%
­ Methyl paraben 0.01-0.18%
­ Propyl paraben 0.005-0.035%
II. ANTIOXIDANTS
• Antioxidants, included in many formulations to protect a therapeutic
agent susceptible to oxidation, particularly under the accelerated
conditions of thermal sterilization, may function in at least two ways. i.e.
­ By being preferentially oxidized (reducing agents), and thereby
gradually used up.
­ By blocking an oxidative chain reaction in which they are not
usually consumed.
• Antioxidants (reducing agents)
­ Ascorbic acid 0.02-0.1%
• Antioxidants (Blocking agents)
­ Butylated hydroxytoluene (BHT) 0.005-0.02%
• Antioxidants (Synergists)
­ Citric acid 0.005-0.01%
III. BUFFERS
• Buffers are added to maintain the required pH for many products, as
change in pH may cause significant alterations in the rate of degradative
reactions.
• Ideal pH for parenteral products is 7.4. A pH greater than 9 may cause
tissue necrosis while pH 3 cause pain and damage to tissues. Acetates,
citrates and phosphates are the principal buffer systems used.
IV. TONICITY CONTRIBUTORS
• Compounds contributing to the isotonicity of a product reduce the pain
of injection in areas with nerve endings. Various agents are used in
sterile products to adjust tonicity.
• Simple electrolytes such as sodium chloride or other sodium salts and
non-electrolytes such as glycerin and lactose are most commonly used
for this purpose. Tonicity adjusters are usually the last ingredients added
to the formulation after other ingredients in the formulation are
established and the osmolality of the formulation measured.
V. SOLUBILIZING AGENTS
• These are used to increase solubility of insoluble or poorly soluble drugs
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in water. The solubilizing agents usually used are alcohol (1-50%),
glycerin (1-50%), polyethylene glycol (1-50%), propylene glycol (1-50%)
and lecithin (0.5-2%). Surfactants are also used as solubilizing agents.
• Wetting, suspending and emulsifying agents. These are used to reduce
interfacial tension thus preventing lump formation, also act as ant
foaming agents.
­ Wetting agents—tween 80 and sorbitan trioleate
­ Suspending agents—gelatin, acacia, methyl cellulose
­ Emulsifying agent—lecithin, gelatin
VI. SURFACTANTS
• A surfactant is a surface-active agent that is used to disperse water
soluble drug as a colloidal dispersions. These are utilized for wetting of
dry solids to prevent crystal growth in a suspension and to enhance
syringeability.
EXAMPLES
• Polyoxyethylene sorbitan mono oleate (0.5%)
• Sorbitan mono oleate (0.05-0.25%)
VII. CHEATING AGENTS
• Chelating agents may be added to bind, in non-ionizable form, trace
amounts of heavy metals, which if free, would catalyze degradative
changes.
• The chelating agent most commonly used is the trisodium or calcium
disodium salt of ethylenediamine tetra acetic acid in a concentration of
about 0.05% (w/v).
VIII. PROTEIN STABILIZERS
• A number of ingredients have been shown to stabilize proteins, both in
the dry and solution state. Serum albumin competes with therapeutic
proteins for binding sites in glass and ether surfaces and minimizes the
loss of the protein caused by surf ace binding.
• Primary examples include polyhydric alcohols (sorbitol, glycerol,
polyethylene glycol); amino acids (glycine, lysine, glutamine); non-
reducing sugars (trehalose, sucrose); and polymers such as dextran,
polyvinylpyrrolidone, and methyl-cellulose.
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PRODUCTION
• The production process includes all of the steps from the accumulation
and combining of the ingredients of the formula to the endosing of the
product in the individual container for distribution.
I. FACILITIES
• The facilities for the manufacture of sterile products should be designed
for control of cleanliness appropriate for each step. Near-perfect
cleanliness must be achieved in the aseptic filling rooms.
CLASSES OF CLEAN AREA
INTRODUCTION
• A clean environment designed to reduce the contamination of processes
and materials.
• According to FS209E;
­ "The room in which concentration of airborne particles is
controlled to specified limits."
CLASS A
• The particle count should not exceed a total of 3000 particles per m
3
of a
size of 0.5um or greater. The greatest particle present in any sample
shall not exceed 5um.
CLASS B
• The particle count shall not exceed a total of 300,000 particles/m
3
of a
size 0.5um or greater. 2000 particles/m
3
of a size 5μ or greater: 30
particles/m
3
of a size 10μ or greater.
CLASS C
• The particles count shall not exceed a total of 1,000,000 particles/m
3
of
a size 1μ or greater: 20,000 particles/m
3
of a size of 5μ or greater: 4000
particles/m
3
of size 10μ or greater: 300 particles/m
3
of a size 25μ or
greater.
CLASS D
• The particle count shall not exceed a total of 200,000 particles/m
3
of size
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5μ or greater: 40,000 particles/m
3
of size 10μ or greater: 4000
particles/m
3
of size 25μ or greater.
CLASSIFICATION OF CLEAN ROOM
• Clean rooms are classified by how clean the air is:
­ ISO SYSTEM
­ USFDA GUIDELINES
­ EUC GUIDELINES
­ WHO GUIDELINES
I. ISO SYSTEM
• There are nine classes of cleanroom in ISO but only ISO5 to ISO8 for 0.5
um and 5um are applicable in pharmaceuticals.
ISO
classification
number (N)
Maximum concentration limits (particles/m
3
of air) for
particles equal to and larger than the considered sizes
0.1μm 0.2μm 0.3μm 0.5μm 1μm 5μm
ISO Class 1 10 2
ISO Class 2 100 24 10 4
ISO Class 3 1000 237 102 35 8
ISO Class 4 10000 2370 1020 352 83
ISO Class 5 100000 23700 10200 3520 832 29
ISO Class 6 1000000 237000 102000 35200 8320 293
ISO Class 7 352000 83200 2930
ISO Class 8 3520000 832000 29300
ISO Class 9 35200000 8320000 293000

II. USFDA GUIDELINES
• Class 100-100,000 rooms are used in pharmaceutical industry. The
number of particles equal to or greater than 0.5mm is measured in one
cubic foot of air, and this count is used to classify the cleanroom.
III. EUC GUIDELINES
• These are classified in two conditions:
­ At rest ­ Operational
• Grade A: Local zone for high risk operations, filling zone ampules and
vials, making aseptic connection.
• Grade B: Aseptic preparation and filling.
• Grade C and D: Carries critical stages in manufacture of sterile products.
IV. WHO GUIDELINES
• Classification of Air and Microorganism as per WHO guidelines
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GRADE
Maximum particles/m
3
Maximum number of
viable micro-organism per
m
3

0.5-5μm >5μm
A 3500 None Less than 1
B 3500 None 5
C 350000 2000 100
D 3500000 20000 500

HEATING, VENTILATION, AND AIR CONDITIONING (HVAC) SYSTEM
• HVAC systems are milestones of building mechanical systems designed
to achieve the environmental requirements of the comfort of occupants
and a process. HVAC systems can be classified into central and local
systems according to multiple zones, location, and distribution.
• Central HVAC systems locate away from buildings in a central
equipment room and deliver the conditioned air by a delivery ductwork
system. Central HVAC systems contain all-air, air-water, all-water
systems.
• Local HVAC systems can be located inside a conditioned zone or
adjacent to it and no requirement for ductwork. Local systems include
local heating, local air-conditioning, local ventilation, and split systems.
• Primary HVAC equipment includes heating equipment, ventilation
equipment, and cooling or air-conditioning equipment.
UNI DIRECTIONAL FLOW
II. ENVIRONMENTAL CONTROL
• Effective environmental control, both physical and biologic, is essential,
but the level achievable is related to the characteristics of the facility.
The standards of environmental control vary, depending on the area
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involved (clean-up, pack-aging, compounding, or filling) and the type of
product being prepared.
I. TRAFFIC CONTROL
• A carefully designed arrangement to control and minimize traffic,
particularly in and out of the aseptic areas, is essential. Access by
personnel to the aseptic corridor and aseptic compounding and filling
rooms is only through an airlock. Pass through openings and double-
ended sterilizers are provided to permit controlled passage of supplies
from no aseptic to aseptic areas.
• Once they have entered the aseptic area, they should not be permitted
to move in and out of the area.
II. HIGH EFFICIENCY PARTICULATE AIR (HEPA)
• The air then passes through the most efficient cleaning device, HEPA
filters having an efficiency of at least 99.97% in removing particles of
0.3μm and larger. HEPA-filters remove larger particles inertial impaction,
medium-sized particles by direct intercept and the small particles by
Brownian diffusion. Air exits from the filter face at the rate of 0.45 m/s.
• In practice 25-35 air changes per hour are common. They are composed
of filter glass asbestos medium. These are treated with DOP (diocetide
phthalate) smoke and their efficiency depends upon complete absence
of leaks in the filter and along ceiling surfaces between filter and frame.
HEM filters have greater life. It is life ranges from 1 year - 10 years
depending upon conditions and use.
III. AIRLOCKS
• Means an enclosed space with two or more doors, which is interposed
between two or rooms of differing classes of cleanliness for the purpose
of controlling the airflow these rooms when they need to be entered
and an airlock is designed for and used by either people or goods.
• Airlock can be custom designed for your application. They can he
adapted to accept various filtration and lighting units. Wall can be
constructed from a variety of materials, from soft, clear vinyl's to color
and anti-static vinyl's, as well as rigid ABS and clear Lexan sheets,
screens and even aluminum panels
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APPLICATIONS OF AIRLOCK IN INDUSTRIES
• Medical device and pharmaceutical manufacturing -Use Airlock for
process isolation to prevent cross contamination and control humidity
and temperature. Airlock can be adapted for Class 100,000 down to class
10 clean rooms with positive or negative pressure.
• Hazardous materials - Set up area isolation for emergency toxic waste
cleanup and hazardous material handling.
• Food preparation and processing - Airlock adapts to virtually any
configuration, including assembly lines and packaging. Airlock walls and
anodized aluminum frames wash down quickly and easily.
• Semi-conductor manufacturing - from mini-environments to large, self-
contained clean rooms, airlock can provide a room of any size and
classification.
• Industrial and manufacturing - Use Airlock to create machinery
enclosures, isolate welding operations, laser procedures, contain paint
operations and construct sound booths.
IV. HOUSEKEEPING
• All-equipment and surrounding work area must be cleaned thoroughly
at the end of the working day. No contaminating residues from the
concluded process may remain.
V. SURFACE DISINFECTION
• After thorough cleaning, all surfaces should be disinfected, at least in the
aseptic areas. An effective liquid disinfectant should be sprayed or wiped
on all surfaces.
VI. AIR CONTROL
• In any area occupied by personnel, the air must be exchanged at
frequent intervals. Fresh outside or recycled air must first be filtered to
remove gross particulate matter. A spun glass, cloth, or shredded
polyethylene filter may be used for this preliminary cleaning operation.
• Blowers should be installed in the air ventilation system upstream to the
filters so that all dirt-producing devices are ahead of the filters.
• The clean, aseptic air is distributed in such a manner that it flows into
the maximum-security rooms at the greater volume flow rate, thereby
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producing a positive pressure in these areas. This prevents unclean air
from rushing into the aseptic area through cracks, temporarily opened
doors, or other openings.
A. LAMINAR FLOW ENVIRONMENT
• It provides a total sweep of a confined area because the entire body of
air moves with uniform velocity along parallel lines, originating through
a HEPA-filter occupying one entire side of the confined area. Therefore,
it bathes the total wen with very clean air, sweeping away contaminants.
• A unidirectional air flow sweeps contaminants towards exhaust system
and is achieved when the air throw system and the exhaust system are
installed oppositely.
• The airway direction may be arranged as horizontal or vertical and may
involve a limited area such as a work bench or an entire room. The
effective air velocity is considered to be 100±20 ft/min.
ADVANTAGE OF LAMINAR AIR FLOW
• Class-100 clean room is achieved by the technique laminar air flow.
• Contaminants are controlled because laminar airflow sweeps away the
contaminants.
HORIZONTAL LAMINAR FLOW
• In horizontal open-air system, the room air comes through cleanable air
prefilters situated at the base of the units. Blowers draw the air in
pressure that behind the bench HEPA-filter which forms the back wall of
working station. Air is discharged through the duct quietly, uniformly
and essentially the bacteria free air from the HEPA-filter flows
horizontally across the bulk area at 100 ft/min velocity and sweep away
all the contamination from the working area.
VERTICAL LAMINAR FLOW
• HEPA-filter is mounted horizontally to form the ceiling of work-station.
In this system, the work-space is perforated. Pre-filter air is flowing
through HEPA-filter in vertically downward direction at a velocity of 100
ft/min, thus cleaning the area continuously with clean air. When this
operation is required, temperature and humidity is also controlled.
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Vertical Laminar Flow Horizontal Laminar Flow
Particles travel shorter distance,
from ceiling to floor.
Particles travel longer distance,
throughout the room.
Variation at different location is
negligible
Air becomes more and more
contaminated as it travels
throughout the room.
Requires less space Provides more floor space
Used in injectable section. Used in tableting section
Expensive Less expensive
Difficult maintenance and cleaning Easy maintenance and cleaning.
More air is required Constant volume is required.
Settling of panicle is minimum Settling of particle is maximum
Less air velocity i.e. 50-75 ft/min is
requited
Greater air velocity i.e. 100 ft/min is
required

B. ENVIRONMENTAL MONITORING METHODS
• Following construction of a clean room, it must be tested to ensure that
it is providing the required quality of environment. These verification
tests are performed and are similar to the tests used to monitor the
clean room subsequently. The monitoring tests ensure that the clean
room continues to provide satisfactory operation.
METHODS
• Air Quality
• Air Movement
• Air Velocity
• Airborne particulate and
microbial contamination
• Microbial Monitoring
A. AIR QUALITY
• The air supplied to the clean room must not contribute to particulate or
microbial contamination within the room. The HEPA-filters for inlet air
must be tested to ensure that both the filter fabric and the filter seals
are not leaking.
B. AIR MOVEMENT
• Adequate ventilation throughout the clean room can be determined by
air movement tests. These are carried out at time of clean room
validation.
C. AIR VELOCITY
• The velocity of air at several points in a critical clean room area should
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be determined. This is done both at validation at the clean room and at
timed intervals.
D. AIRBORNE PARTICULATE AND MICROBIAL CONTAMINATION
• The particle count and the microbial bio-burden of the clean room
provide the basis of air classification system for grading a clean room.
The points for sampling and the number of samples taken at each
position are determined by the size and the class of the clean room.
E. MICROBIAL MONITORING
• Sampling for microbial contamination is necessary when people are
present in the clean room during production. Monitoring of the
microbial contamination during production will ensure that the use of
clean room clothing by the operators. Air sampling is carried out by
volumetric sampling or by the use of settle plates.
VII. PERSONNELL
THE TRAINING
• The people who produce sterile products are usually non-professional
persons, supervised by those with professional training. To be effective
operators, they must be inherently neat, orderly, reliable, and alert, and
have good manual dexterity.
• All employees should be in good health and should be subjected to
periodic physical examinations. They should understand their
responsibility to report the developing symptoms of a head cold, sore
throat, or other infectious diseases so that they can be assigned to a
less—critical area until they have fully recovered.
FOLLOW SOPS
• Personnel entering the aseptic areas should be required to follow a
definite preparatory procedure. This should include removing at least
outside street clothing, scrubbing the hands and arms thoroughly with a
disinfectant soap, and donning the prescribed uniform.
UNIFORMS
• The attire worn by personnel in the aseptic areas usually consists of
sterile coveralls, hoods, face masks, and shoe covers. Sterile rubber
gloves also may be required.
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CONTAINERS
1. PLASTIC CONTAINERS
• The principal ingredient of the various plastic material used for
containers is the thermoplastic polymer i.e. polyethylene low density,
polypropylene, polyvinylchloride, polycarbonate and polystyrene etc.
ADDED SUBSTANCES IN PLASTICS
• Although most of the plastic materials used in the medical field have a
relatively low amount of added ingredients, some contain a substantial
amount of:
­ Plasticizers
­ Fillers
­ Antistatic agents
­ Antioxidants
TOXICITY WITH PLASTIC CONTAINERS
• Tissue toxicity can occur from certain polymers, but additives are a more
common cause. Reactivity due to sorption (absorption and/or
adsorption) has been found to occur most frequently with the polyamide
polymers, but additives leached from any of the plastic materials may
interact with ingredients of the product.
AUTOCLAVING
• All of the polymeric materials except low-density polyethylene and poly-
styrene can be autoclaved if they have been formulated with a low
amount of plasticizers, although most of them soften at autoclaving
temperatures and care must be exercised to avoid fusing adjacent
surfaces or otherwise deforming them.
TOXICITY TESTING
• The USP has provided test procedures for evaluating the toxicity of
plastic materials. Essentially the tests consist of three phases:
­ Implanting small pieces of the plastic material intramuscularly in
rabbits.
­ Injecting eluates using sodium chloride injection, with and without
alcohol, intravenously in mice, and injecting eluates using
polyethylene glycol 400 and sesame oil intraperitoneally in mice.
­ Injecting all four eluates subcutaneously in rabbits.
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• The reaction from the test samples must not be significantly greater
than nonreactive control samples.
2. GLASS CONTAINERS
• Glass is still the preferred material for containers for Injectable products.
The two general types of glass are soda-lime and borosilicate. TYPE 1
(borosilicate glass) is preferred for most sterile products.
TYPE I: BOROSILICATE GLASS
• It is least reactive and highly resistant glass. It is more chemically inert
than soda lime glass. A substantial amount of alkali or earth cations are
replaced by boric oxide.
• This type of glass has higher ingredient like aluminum and zinc and
higher processing costs and is therefore used primarily for more
sensitive pharmaceuticals such as parenteral or blood products e.g.
Ampoules and vials.
• Although the glass is considered to be a virtually inert material and is
used to contain strong acids and alkalis as well as all types of solvents, it
has a definite and measurable chemical reaction with some substances,
notably water.
CHEMICAL RESISTANCE
• The USP provides the Powdered Glass and the Water Attack tests for
evaluating chemical resistance of glass. The test results are measures of
the amours of alkaline constituents leached from the glass by purified
water under controlled elevated temperature conditions.
• The Powdered Glass test is per formed on ground, sized glass particles.
Water Attack test is performed on whole containers. The conditions of
the test must be rigidly controlled to obtain reproducible since the
quantity of alkaline constituents leached is small.
PHYSICAL CHARACTERISTICS
• Ultraviolet rays can be completely filtered out by the use of amber glass.
• If the product contains ingredients subject to iron catalyzed chemical
reactions, amber glass cannot be used. The product must then be
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protected from ultraviolet rays by means of an opaque carton
surrounding a flint (colorless) glass container.
• In addition to other physical characteristics, glass containers should have
sufficient physical strength to withstand the high-pressure differentials
that develop during autoclaving and the abuse that occurs during
processing, shipping, and storage.
• A low coefficient of thermal expansion to withstand the thermal shocks
that occur during washing and sterilization procedures.
3. Rubber Closures
• Rubber closures are used to seal the openings of cartridges, vials, and
bottles, providing a material soft and elastic enough to permit entry and
withdrawal of a hypodermic needle without loss of the integrity of the
sealed container.
COMPOSITION AND REACTIVITY
• Rubber closures are compounded of several ingredients, principally,
­ Natural rubber (latex) and/ or a synthetic polymer. A vulcanizing
agent, usually sulfur. An accelerator, one of several active organic
compounds such as 2-mercaptoben-zothlazole.
­ An activator, usually zinc oxide. Fillers, such as carbon black or
limestone and a variety of other ingredients such as antioxidants
and lubricants.
• These ingredients are combined by kneading them into a homogeneous
plastic mass on a roller mill.
PHYSICAL CHARACTERISTICS
• Several properties of rubber closures are significant, particularly
elasticity, hardness, and porosity.
• Rubber closures must be sufficiently elastic to provide a snug fit
between the closure and the neck and lip of the glass container.
• They must also spring back to close the hole made by the needle
immediately after withdrawal.
• Although porous, they should not permit the easy transfer of water
vapor and gases in either direction.
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PROCESSING
1. WATER FOR INJECTION
PROPERTIES
• Clear, colorless, odorless. Pyrogen free. Having ph 5-7. Dissolved solids
10ppm.
• Determined by 100ml of water or by conductivity method
• It must be used within 24 hours and must be stored at temperature
either 50°C or 60.90°C if to be held for 24 hours.
• It should not contain more than 1mg/100ml of total solids and may not
contain added substances.
A. PREPARATION
• Water for injection (WFI) is usually prepared by;
­ Distillation in a still specifically designed to produce the high-
quality water required.
­ Reverse osmosis, however, is the process that is now approved by
USP.
PREPARATION THROUGH DISTILLATION
• WFI is prepared by distillation of deionized water. The source of WFI is
the tap water which contains the microorganism, dissolved organic and
inorganic substances, gases and suspended materials. The water is
pretreated for chemical softening, filtered, deionized and pH is adjusted.
Mineral ions and inorganic substances are removed by distillation.
• Membrane and depth filters are used to remove organic materials. The
resultant purified water from the pretreatment is a feed for distillation
system to produce WFI. Distillation is accomplished in stills made of
stainless steel or chemically inert glass. In addition to conventional stills,
vapor compression stills and multiple effect stills are also frequently
used. Both these utilizes heated feed water and steam to conserve
energy consumption. These are capable of producing high purity water
at rates of 50-1000 or more gallons/hr. A still is equipped with;
­ An evaporator
­ A condenser
­ A collecting system
• The feed water is heated at atmospheric pressure in a horizontal
evaporator to produce stream. The condenser, attached vertically has
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angled baffles at the base to facilitates the entry of steam and prevent
entry of water droplets in condenser. The distillate is usually free of
microbial contamination.
PREPARATION THROUGH REVERSE OSMOSIS
• A reverse osmosis system functions by applying pressure (usually 200 to
400 psi) to raw water sufficient to force the permeation of water
through a semipermeable membrane in the opposite direction to natural
osmosis. The membranes most commonly used are composed of
cellulose esters or polyamides (nylon) and are effective in retaining all
macromolecules and 85% or more of small ions such as Na
+
and Cl
-
. Since
pyrogens are macromolecules, they should be retained as well as such
viable particles as microorganisms.
B. STORAGE
• A closed system is desirable with air exchange through a filter. It must be
used within 24 hours and must be stored at temperature either 5˚C or
60-90˚C if to be held for 24 hours.
C. DISTRIBUTION
• From storage tank to the point of use, may be direct withdrawal from
the tank or through pipes in large plants.
2. CLEANING EQUIPMENT AND CONTAINERS
• For manufacturing of any type of dosage form, it is the basic step to
clean and wash containers, closures and equipment. Debris is removed
by vigorous treatment with hot detergent.
• After cleaning, the equipment should be rinsed several times with final
rinse with water for injection.
• For ampules with a markedly constricted opening that makes water
drainage incomplete, the final treatment is usually a blast of clean air to
blow out remaining water.
• A new method for large tanks, pipelines, and associated equipment that
can be isolated and contained within a process unit has been developed
and identified as a CIP (Clean in Place) system. Cleaning is accomplished
primarily with high-pressure rinsing treatments delivered automatically
within the equipment. This is usually followed by steam sanitization
through the same system.
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• For glass or metal equipment small enough to be transported by hand,
machine washing is possible.
CLEANING RUBBER AND PLASTIC COMPONENTS
• Rubber closures are usually washed by mechanical agitation in a tank of
hot detergent solution (such as 0.5% sodium pyrophosphate) followed
by a series of thorough water, the final rinse being WFI.
OVEN STERILIZATION OF CONTAINERS
• Sometimes, the closures are subjected to an autoclave cycle as a part of
the cleaning process. Such treatment aids in loosening surface debris
and also leaches from the closure some of the extractives, thus reducing
the subsequent contamination of the product.
3. COLLECTION OF MATERIAL
• It consists of collection of suitable vehicles, additive etc.
A. VEHICLE
• Aqueous vehicle—Normal saline, ringer solution
• Water miscible vehicle—ethyl alcohol/ propylene glycol
• Water immiscible vehicle—fixed oil, benzyl benzoate
B. ADDED SUBSTANCES
• Solubilizing agents & stabilizers
• Buffers & preservatives etc.
4. COMPOUNDING THE PRODUCT
• The product should be compounded under clean environmental
conditions. Aseptic conditions usually are not required since it may not
be possible or feasible to sterilize some of the ingredients or the
equipment, e.g. large tanks. Whenever possible, however, equipment
and ingredients should be sterile to reduce the microbial load.
5. FILTRATION
• The solution formed as a result of compounding is subjected to filtration
to remove all the foreign particles, if necessary, the solution is also
passed through a suitable filter to make it sterilized.
• For this purpose, following types of filters are used:
­ Seltz filters ­ Sintered glass fillers
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6. FILLING
• A liquid may be subdivided from a bulk container to individual dose
containers.
FILLING OF LIQUIDS
• Sterile solutions of relatively low potency dispensed in large volume do
not normally require the precision of filling that is required for smell
volumes of potent injectable. Therefore, bottles of solutions are usually
filled by gravity, Pressure or Vacuum Fillings Devices.
A. GRAVITY FILLINGS
• It is relatively slow but is accomplished in a simple manner. The liquid
reservoir is positioned above the filling line with a loose connection from
the reservoir to shut-off device at the filling line. The shut-off device is
usually hand-operated & the bottles are filled to graduations on the
bottles.
B. THE PRESSURE PUMP FILTER
• Often is operated semi-automatically and differs from gravity filter
principally in that the liquid is under pressure.
C. VACUUM FILLING
• A vacuum is produced in a bottle when a nozzle gasket makes a seal
against the lip of bottle to be filled. The vacuum draws the liquid from
the reservoir, through a delivery tube into the bottle.
FILLING OF SOLIDS
• Sterile solids such as antibiotics are more difficult to subdivide
accurately and precisely into individual dose containers than liquid. The
rate of flow of solids materials tends to be slow and irregular if finely
powdered.
A. AUGER FILLING
• One type of machine for delivering measured quantities of free-flowing
material employs an auger in the stem of the funnel shaped hopper. The
size and rotation of the auger can be adjusted to deliver a regulated
volume of granular material from the funnel stem into the container.
B. OTHER FILLING MACHINE
• In another filling machine an adjustable cavity in the rim of the filling
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wheel is fitted by vacuum as the wheel passes under the hopper. The
contents are held by vacuum until the cavity is inverted over the
container, when a jet of sterile air discharges the dry solids.
7. SEALING
• Containers should be sealed in the aseptic area immediately adjacent to
the filling machine. In addition to retaining the contents of a sterile
product, sealing of containers assures the user that it has not been
opened. It is obvious that a sterile container that has been opened can
no longer be considered to be sterile. Therefore, tamper proof sealing is
essential.
A. SEALING AMPULE
• Ampules may be closed by melting a portion of the glass of the neck to
form either bead-seals (tip-seals) or pull-seals.
i. TIP-SEALS
• It is made by melting sufficient glass at the tip of the ampule neck to
form a bead of glass and close the opening.
ii. PULL-SEALS
• It is made by heating the neck of a rotating ampules below the tip, then
pulling the tip away to form a small, twisted capillary just prior to being
melted closed.
B. SEALING BOTTLES, CARTRIDGES, AND VIALS
• Rubber closures must fit the opening of the container snugly enough to
produce a seal, but not so snugly that it is difficult to position there in or
on the container. They may be inserted by hand, using sterile forceps.
• Aluminum caps are used to hold rubber closures in place.
­ Single caps may have a permanent center hole or a center hole
that is torn away at the time of use to expose the rubber closure.
­ Double aluminum caps usually have an inner cap with a
permanent center hole, which in use is exposed when the entire
outer cap is torn off.
­ The triple aluminum caps are used for large bottles with rubber
closures having permanent holes for attachment to administration
sets.
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8. STERILIZATION OF PRODUCT
• A product must be sterilized by the most reliable method possible. With
respect to sterilization, the Nitrite manufacturing is of two types
­ Terminal sterilization method
­ Aseptic preparations
TERMINAL STERILIZATION METHOD
• Production followed by terminal sterilization is the placing of the
product in its final container, sealing and terminal sterilization using dry
heat, moist heat or irradiation sterilization.
ASEPTIC PREPARATIONS
• It involves aseptic filling of pre-sterilized product in sterile container and
sealing. This method requires high quality environment.
FREEZE DRYING
• Freeze drying (lyophilization) is a drying process applicable to the
manufacture of certain pharmaceuticals and biological that are
thermolabile or otherwise unstable in aqueous solution for prolonged
storage periods, but that are stable in the dry state.
AUTOCLAVING
• At temperature of 115℃ or at 121℃ for 20 min.
HOT-AIR OVENS
• At temperature of 160℃ for 2 hours, 170℃ for one hour, e.g., oily
injectables are sterilized by this method. For more details see the
sterilization portion.
9. PACKAGING
• It is essential that packaging should provide strong protection for the
product) against physical damage from shipping, handling and storage as
well as protecting light sensitive material from UV radiations. The
preparations should be packed in plastic or glass containers
• Further packaging requirements for injections are given by the USP
essentially as follows:
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­ The volume of an injection in single-dose containers should
provide the amount specified for administration at one time and
in no case is more than one liter.
­ Preparations intended for intraspinal, intracisternal, or peridural
administration should be packaged only in single-dose containers
because of the sensitivity of nerve tissue to irritation from added
substances such as antibacterial agents.
­ Normally, no multiple dose containers shall contain a volume of
injection more than is sufficient to permit the withdrawal of 30ml,
because larger volumes would provide for the withdrawal of more
doses, thereby increasing the potential for contamination.
10. LABELING
• The labeling of an injection must provide the physician or other user
with all of the information needed to ensure the safe and proper use of
product. The U.S.P says that label must state the following imp aspects
of the preparation:
­ Name of preparation
­ %age content of drug
of a liquid preparation
­ Amount of API
­ Volume of liquid to be
added to prepare
Injection
­ Name of vehicle
­ Route of administration
­ Proportions of each
constituent
­ Storage conditions
­ Expiration date
­ Name of manufacturer
QUALITY CONTROL TESTING
1. PYROGEN TESTING
• Pyrogens are products of the growth of micro-organisms especially
molds, bacteria (in particular gram negative), viruses and fungi.
• Pyrogens can be removed by either of the following ways:
­ Distillation
­ Reverse osmosis
­ Heating at 180℃ for 3 to 4 hours
­ Adsorption method
METHODS
• Two Methods are used officially
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­ LAL (limulus amebocyte lysate) test. Also, known as the in vitro
testing.
­ Biological Test. Also, known as the in vivo testing.
I. LAL TEST
• Innovation in pyrogen testing is the use of an in-vitro limules amebocyte
lysate (LAL) test. The test is capable of detecting the more potent
endotoxin pyrogens.
SOURCE OF LYSATE
• An extract from the blood cells of horseshoe crab, limules Polyphemus
contains and enzyme system called as limules amebocyte lysate (LAL)
which reacts with pyrogens, so that an assay mixture increases the
viscosity and opacity until and opaque gel is formed.
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• The tests accomplishes within 15 to 60 minutes, depending upon
concentration of pyrogen after mixing. The concentrated pyrogen makes
the gel more turbid and thicker.
LAL PREPARATION
• LAL is prepared by bleeding healthy mature specimens by heart
puncture. The amebocytes are carefully concentrated, washed, and
lysed by osmotic effects.
PROCEDURE
• The pH of the sample if specified is adjusted. Mix equal parts of (0.05 –
0.2 ml) of test solution and LAL standardized reagent in thoroughly
cleans dried and heat sterilized glass test tube (10 x 75 mm).
• The mixture is incubated immediately at 36 – 38℃ for one hour in assay
tube. The assay tube must remain undisturbed completely, as agitation
may irreversibly destroy the gel leading to fast negative results.
• The test tube is observed after the specified time and is examined for
the formation of the opaque gel which represents a positive test end
point. The test is performed using a commercial LAL test kit. This kit
contains a lyophilized LAL and Escherichia coli endotoxin and pure water
as standards and these later two and used to check the sensitivity of the
test.
• Table below outlines the criteria for interpreting limulus test result.
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LAL
tube
Test sample/Control Result
1 Negative control (pyrogen free saline) Should be negative
2 Positive control (pyrogen) Should be positive
3 Positive internal control (test contain with
endotoxins)
Should be positive
4 Test sample May be positive/negative

II. BIOLOGICAL TEST (THE IN VIVO RABBIT TEST)
• It is an official test. It is known as biological test/the in vivo rabbit test.
• The test consist of measuring the rise in body temperature evoked in
rabbits by the IV injection of a sterile solution of the substance to be
examined. It employs rabbit as test animal.
• The in vivo test involves the following steps:
i. Selection and Rejection of animals
ii. Materials used:
iii. Preliminary Test
iv. Main Test
v. Interpretation of results.
I. SELECTION AND REJECTION OF ANIMAL
SELECTION OF ANIMAL
• Rabbit should be healthy and adult of either sex. Weight of each rabbit
should not be less than 1.5 kg. Should be given normal/balanced diet
without any medicines in particular antibiotics.
REJECTION/EXCLUSION OF THE ANIMAL
• If used for negative Pyrogens test and the period passed was less than
03 days. If used for positive Pyrogens test and the period passed was less
than 03 weeks.
II. MATERIAL USED
• Thermometer or electrical device
• Glass ware, syringes and needles
• Retaining boxes.
III. PRELIMINARY TEST
• One to three days before testing the product, the animals are selected
as discussed below:
­ The animals have not been used for the last two weeks.
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­ They are injected 10 ml per kg of body weight of normal saline
free of Pyrogens.
­ Temperature of test laboratory should not vary more than 3°C
than the building quarter of the rabbit. The animal should be
transferred at least 18 hours before the test start.
­ Withhold food over-night and through-out the test. Withhold
water during the test.
­ Temperature of each animal should be recorded at least 90
minutes before the test and continued for 03 hours after injection
of the solution.
­ Any animal showing temperature variation greater than 0.6°C,
should not be included in pyrogens testing.
IV. MAIN TEST
• Carry out the test using a group of 3 rabbits. Maximum 4 groups
of rabbits can be used.
• Following steps are taken to perform main test:
i. Preparation and Injection of the sample.
▪ Warm the liquid to be examined to 38.5°. Inject I.V.
(intravenous) into rabbit by the marginal ear vein slowly.
The injection period should not exceed 04 minutes (B.P.) or
10 minutes (U.S.P.).
▪ The temperature of each rabbit is noted at 1, 2 and 3 hours
subsequent to the injection of sample. The difference
between the initial and final temperature is noted. Any
increase in the temperature is taken to be the response of
the sample injected.
ii. Determination of initial and maximum temperature
▪ The “initial temperature” for each rabbit is the mean of two
temperature readings recorded for that rabbit at an
interval of 30 minutes in the 40 minutes immediately
preceding the injection of material to be examined.
▪ The “maximum temperature” is the highest temperature
recorded for that rabbit in the 03 hours after the injection.
▪ Note the temperature of each rabbit at intervals of not
more than 30 minutes beginning at least 90 minutes before
the injection of the product to be examined and continuing
3 hours after the injection. The difference between the
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maximum temperature and the initial temperature of each
rabbit is taken o be its response.
V. INTERPRETATION OF RESULTS
• The material under examination meets the requirements for
apyrogenicity if no rabbit shows an individual rise in temperature of
0.6℃ or more above respective control temperature OR The sum of the
temperature rise of 3 rabbits does not exceed 1.4℃.
2. STERILITY TESTING
SELECTION OF CULTURE MEDIA
• Various culture media with methods of preparation are given in B.P. and
U.S.P. which should be chosen.
• Any other medium should give equal or more growth of micro-organisms
like Aerobic, Anaerobic or Fungi.
TESTS FOR MEDIA
I. STERILITY
• Prior to testing it is checked the media prepared is sterilized or not.
PROCEDURE
• Incubate the portions of the media for 14 days.
• Incubation of media for Bacteria at 30℃– 35℃
• Incubation of media for Fungi at 20℃ – 25℃
• Observe the microbial growth.
RESULT
• If there is no growth of microbes, media is sterilized and ready for
testing.
II. GROWTH PROMOTION TEST OF AEROBES, ANAEROBES AND FUNGI
• The growth promotion test is performed to check whether the media
prepared is good for the microbial growth or not. Test each batch of
ready-prepared medium and each batch of medium prepared either
from dehydrated medium or from the ingredients.
PROCEDURE
• Inoculation of the medium with 100 viable micro-organisms of each of
the following micro-organisms.
­ An aerobe ------ (Staphylococcus aureus)
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­ Spore forming aerobe --- (Bacillus subtilis)
­ An anaerobe ----- (Clostridium sporogenes)
­ A Fungus ----- (Candida albicans)
• Incubation Temperature:
­ For Bacteria: 30℃ to 35℃
­ For Fungus: 20℃ to 25℃
• Incubation Period.
­ Incubation period should not be less than 07 days.
RESULT
• If early and copious growth occurs, the medium contains required
nutritive properties and is suitable.
METHODS OF STERLITY TESTING
• Two methods/techniques of sterility testing are:
­ Membrane Filtration
­ Direct Inoculation
I. MEMBRANE FILTRATION
• The method is preferably used for:
­ Filterable aqueous preparations
­ Alcoholic or oily preparations
­ Preparations miscible with or soluble in aqueous or oily solvents
that do not have antimicrobial activity.
• Membrane filters of esters or mixture of cellulose are recommended for
alcoholic or oily preparations.
• The apparatus is designed so that the solution to be examined can be
introduced and filtered under aseptic conditions.
DIFFERENT DOSAGE FORMS/PREPARATIONS ARE TREATED BEFORE
MEMBRANE FILTRATION
A. AQUEOUS SOLUTION
• Membrane is moistened with sterile diluent like 0.1% w/v neutral
solution of meat or casein peptone.
• Volume of the preparation should be according to the specifications.
Dilute the volume of the preparation to about 100 ml with diluent
and filter immediately.
• If preparation has antimicrobial activity, washing is done by three
portions of diluents each of 100 ml.
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• Transfer the whole membrane to the culture medium or cut it
aseptically into two equal parts and transfer one half to each of two
suitable media. Incubate the media for not less than 14 days.
• Alternatively, transfer the medium onto the membrane in the
apparatus. Incubate the media for not less than 14 days.
B. SOLUBLE SOLIDS
• Specified quantity dissolved in 0.1% w/v neutral solution of meat or
casein peptone (sterile).
• After filtration, perform the test as for aqueous solution.
C. OILS AND OILY SOLUTION
• Low viscosity oils/oily preparations filtered through dry membrane
directly. Viscous preparations are diluted with isopropyl myristate
having no antimicrobial activity.
• After penetration, the oil into membrane, filtrations is facilitated by
pressure or suction. Washing with diluents (sterile neutral meat
solution, 0.1% w/v or casein peptone) containing 0.1 % w/v (4-
tertoctylphenoxy) polyethoxy ethanol or 0.1 % w/v polysorbate 80.
• Complete test as in the case of aqueous solutions.
D. OINTMENTS AND CREAMS
• Ointments in fatty bases or W/O emulsion diluted by heating (40℃ or
up to 45℃) and add diluent (Isopropyl myristate). Filter rapidly.
• Test as for oily preparations.
II. DIRECT INOCULATION
• Dilution of the dosage forms. Liquids are to be diluted 10 folds. Solids
are to be diluted 100 folds. To eliminate antimicrobial activity of the
preparation, larger volume is required for dilution. Either concentrated
medium is to be added to the preparation or preparations are added to
the medium.
OILY LIQUIDS
• Use media to which have been added a suitable emulsifying agent at a
concentration shown to be appropriate in the method suitability of the
test, for example, polysorbate 80 at a concentration of 10 g/l.
OINTMENTS AND CREAMS
• Prepare by diluting to about 1 in 10 by emulsifying with the chosen
emulsifying agent in a suitable sterile diluent such as peptone (1 g/l) TS1.
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Transfer the diluted product to a medium not containing an emulsifying
agent.
• Incubate the inoculated media for not less than 14 days. Observe the
cultures several times during the incubation period. Shake cultures
containing oily products gently each day.
OBSERVATION AND INTERPRETATION OF RESULTS
• At intervals during the incubation period and at its conclusion examine
the media for macroscopic evidence of microbial growth.
­ If no evidence of microbial growth is found, the product to be
examined complies with the test for sterility.
­ If evidence of microbial growth is found, the product, in this case
preserve the culture and repeat the whole procedure, if again a
culture is formed, compare it with the first growth. If it matches
then the product to be examined does not comply with the test
for sterility.
• Conventional microbiological methods are generally satisfactory for
identification of microorganisms recovered from a sterility test. While,
routine microbiological method can demonstrate that 2 isolates are not
identical these methods may not be sufficiently sensitive or reliable
enough to provide unequivocal evidence that two isolates are from the
same source.
3. CLARITY (PARTICULATE) TESTING
• The test is very important particularly when injections are given I.V.
(intravenously) as the contents of such injections are entering into blood
directly. After administration, the contents are also circulating through
lungs. Bronchioles and other parts of respiratory system may be
obstructed by the presence of high number as well as larger particles.
• Clarity is checked by either of the two ways:
­ Visual inspection
­ Electronic particulate counting
I. VISUAL INSPECTION
• Officially, the test is performed visually by looking at all the unit packed
injectable i.e. each and every filled ampoule and vial are checked visually
for the presence of particle against the required background, means
colored material is checked against white and white or colorless packed
material against black back ground. Injectable with particle is rejected.
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II. ELECTRONIC PARTICULATE COUNTING
• Now a days, particulate matter is also checked by camera eye. Three
cameras are placed in series and specimen to be checked is spun in front
of each camera. The specimen having particle is identified by any of the
camera and rejected automatically. However, care must be taken that
during spinning process, bubble formation must not occur otherwise,
the cameras may identify it as particle.
4. LEAKERS TEST
• Leakage test is employed to test the package integrity. Package reflects
ability of a container to keep the product in and to keep potential
contamination out. It is because leakage occurs when discontinuity exist
in the wall of a package that can allow the passage of gas under pressure
or concentration differential existing across the wall.
• Leakage is checked by following ways:
I. VISUAL INSPECTION
• It is the easiest leak test method to perform, but the method is the least
sensitive. To increase the sensitivity of the method the visual inspection
of the sample container may be coupled with the application of vacuum
to make leakage more readily observable.
• This method is easy and inexpensive. However, method is insensitive,
operator dependent and qualitative. Sometimes the method is used in
combination with pressure and/ or temperature cycling to accelerate
leakage to improve sensitivity of the test.
II. BUBBLE TEST
• The test package is submerged in liquid. A differential positive pressure
of Psi is applied inside container for 15 minutes. The container is
observed for bubbles. Sometimes, surfactant added liquid is used for
immersion of test package. Any leakage is evident after the application
of differential pressure as the generation of foaming in immersed liquid.
III. DYE TEST
• The test container is immersed in dye bath. Vacuum and pressure is
applied for some time. The container is removed from dye bath, washed
and is then inspected for the presence of dye either visually or by means
of UV spectroscopy.
• The dye used may be of blue, green or yellowish green color. The dye
test can be optimized by use of a surfactant of a low viscosity fluid in the
dye solution to increase the capillary migration through the pores.
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IV. VACUUM IONIZATION TEST
• It is a useful test for testing the leakage in the vials and bottles sealed
under vacuum or for outline testing of the lyophilized products. High
voltage and high frequency field are applied to vials which causes
residual gas if present to glow. Glow intensity is the function of
headspace vacuum level. The blue glow is the indicative of vacuum while
the purple glow is the indicative of no vacuum.
STERILIZATION
• Sterilization is the Process designed to produce a sterile state. It is an
essential concept in the production of sterile pharmaceutical products
like ophthalmic and parenteral.
• Sterile is “free from viable microbes” it is an absolute term
STERILE STATE
• Sterile state is absolute condition of total destruction or elimination of
all living microbes.
ASEPTIC
• The term aseptic indicates a controlled process or condition in which the
level of microbial contamination is reduced to the degree that microbes
can be excluded from a product during processing.
MICROBIAL DEATH KINETICS AND TERMINOLOGY
D-VALUE
• The D-value is the time (for heat or chemical exposure) or dose (for
radiation) required for the microbial population to decline by one
decimal point (a 90%, or one logarithmic unit).
Z-VALUE
• The number of degrees for 1 log reduction in D-value.
F-VALUE
• The equivalent time at temperature T delivered to a unit of product
calculated using a specified value of z.
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METHODS OF STERILIZATION
• Methods of sterilization have been divided into following three
categories:
­ Physical sterilization
­ Chemical sterilization
­ Mechanical sterilization
PHYSICAL STERILIZATION METHOD
• These are further divided into following categories.
­ Dry Heat Sterilization
­ Moist Heat Sterilization
­ Sterilization by Radiations
I. DRY HEAT STERILIZATION
• Substances which are destroyed by moist heat or steam may be
sterilized by dry heat. Dry heat can be used to sterilize items, but as the
heat takes much longer to be transferred to the organism, both the time
and the temperature must usually be increased, unless forced
ventilation of the hot air is used.
• Dry heat sterilization is done at highest temperature 170°C for 4 hours,
this would be in addition to lag time.
LAG TIME
• It is the time taken to acquire the desire temperature of the whole
system. Lag time depends upon:
­ Size of containers
­ Size of the autoclave
­ Arrangement in autoclave
­ Substance Sterilized
• It is applied to fixed oils, liquid paraffin, petrolatum, propylene glycol
and powders. It is also applied to sterilize glass ware, many surgical
instruments and surgical catgut.
MECHANISM
• During the dry sterilization, both the microorganism and their spores are
killed by oxidation, since it is less effective than moist heat, higher
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temperature and longer periods of time is required. Exposure at 160
degree for one hour is required for dry heat sterilization.
METHODS
i. HOT AIR OVEN
• The ovens used to achieve hot air sterilization are of two types, natural
convection and forced convection.
ii. NATURAL CONVECTION OVEN
• Circulation within natural convection ovens depends upon the currents
produced by the rise of hot air and fall of cool air. This circulation can be
easily blocked with containers, resulting in poor heat distribution
efficiency.
iii. FORCED CONVECTION OVEN
• It provides a blower to circulate the heated air around the objects in the
chamber.
iv. FLAMING
• It is the simplest form of dry heat sterilization in which the material to
be sterilized is kept in the hot part of the Bunsen burner flame for few
seconds and the process is repeated several times.
v. INCINERATION
• Incineration will also burn any organism to ash. It is used to sanitize
medical and other biohazardous waste before it is discarded with
nonhazardous waste.
APPLICATIONS
• Glassware like syringes, petri dishes, flasks, test tubes
• Surgical instruments like scalps, forceps
• Chemicals like liquid paraffin, oils, fats, glycerol
• Certain ingredients that are used for sterile pharmaceutical preparations
are made sterile by this method.
II. MOIST HEAT STERILIZATION
INTRODUCTION
• Moist heat sterilization is a procedure in which heated, high-pressure
steam is used to sterilize an object.
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MODE OF ACTION/PRINCIPLE OF MOIST HEAT STERILIZATION
• Moist heat destroys microorganisms by the irreversible denaturation of
enzymes and structural proteins.
• The temperature at which denaturation occurs varies inversely with the
amount of water present. Sterilization in saturated steam thus requires
precise control of time, temperature and pressure.
• Pressure serves as a means to obtain the high temperatures necessary to
quickly kill microorganisms. Specific temperatures must be obtained to
ensure the microbicidal activity. Minimum sterilization time should be
measured from the moment when all the materials to be sterilized have
reached the required temperature throughout.
METHODS
i. AUTOCLAVE
• It is an apparatus used for sterilization by steam under pressure.
• Autoclave commonly use steam heated to 121-134°C to achieve sterility,
a holding time of at least 15-20 minutes at 121°C or 3 minutes at 134°C
is required. After sterilization, autoclaved liquids must be cooled slowly
to avoid boiling over when the pressure is test autoclave treatment will
inactivate all fungi, bacteria, viruses and also bacterial spores which can
be quite resistant.
ii. HEATING WITH A BACTERICIDE
• In this method, a bactericide is added to the solution or suspension to be
sterilized which is then sealed. The sealed containers are then heated at
100°C for 30 minutes, in water bath. Commonly used bactericide
includes benzalkonium chloride and chlorocresol.
III. RADIATION STERILIZATION
INTRODUCTION
• Sterilization by radiation is also known as COLD sterilization because no
heat is used in this method. The microorganisms are very susceptible are
very susceptible to lethal effects of radiations.
• Killing of microorganisms with the help of radiations is known as
radiation sterilization.
MECHANISM
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• By radiations, alternation of chemicals takes place present in
microorganism with the formation of new compounds which destroy the
microbes. The vital structure of cells such as nucleoproteins is destroyed
by radiations which kill the microbes.
TYPES
• It has the following types
­ Non-Ionizing
­ Ionizing
i. NON-IONIZING RADIATION STERILIZATION
• Ultraviolet Sterilization/Non-Ionizing Sterilization aid in reduction of
contamination in the air and on the surfaces.
• Can penetrate clean air and pure water well. Increase salt content or
suspended matter reduces the degree of penetration.
• Principal effect on cellular nucleic acid
• Steps include UV light is passed. Energy is liberated. Absorbed energy
cause highly energized state. Alter the reactivity. Excitation or alteration
of reactivity. Organism unable to reproduce and start dying.
• Applications and uses: For germicidal effect on surfaces. For penetrating
effect on clean air and water. Frequently installed in rooms, air ducts
and large equipment. Water supplies have been sterilized.
ii. IONIZING RADIATION STERILIZATION
• Ionizing radiation are high energy radiations emitted from radioactive
isotopes such as cobalt-60 (caesium-137) or produced by mechanical
acceleration of electrons to very high velocities and energies.




A. GAMMA RAYS
• The source of gamma rays is radioactive isotopes such as cobalt-60.
Energy potential of 10MeV or higher may produce by radioactive
material.
Types of ionization radiation
Gamma rays Beta rays
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B. BETA RAYS/CATHODE RAYS
• Beta rays are produced by mechanical acceleration of electrons to very
high velocity.
APPLICATIONS
• A number of vitamins, antibiotics and hormones in the dry form has
been successfully sterilized by radiation.
• The use of radiation is increasing in the frequency and extent as the
experience is gained, particularly for the sterilization of plastic medical
devices.
CHEMICAL STERILIZATION
I. GASS STERILIZATION
INTRODUCTION
• Chemically reactive gasses are used to kill all viable forms of microbes.
• Ethylene oxide and formaldehyde possess broad spectrum biocidal
activity. Found application in sterilization of reusable surgical
instruments and medical diagnostic equipment.
PRINCIPLE
• Alkalization of essential metabolites of microbes, affecting reproductive.
• Alkalization occurs by replacing hydrogen on sulfhydryl, amino, carboxyl,
hydroxyl-groups with a hydroxyediyl radical.
ALKYLATING GASES
• Ethylene oxide
• Beta propiolactone
• Glutaraldehyde
• Formaldehyde
• Propylene oxide
i. ETHYLENE OXIDE
• Cyclic ether, reactivity is because of Oxygen Bridge. Alone, highly
flammable when mixed with air explosive, so admixed with CO2 or
Freons.
• High penetrability through plastic, paper board, powder. Chemically
inert towards most solid materials.
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• An ethylene oxide sterilizer consists of a leak-proof and explosion-proof
steel chamber. Material is placed in a room or chamber and exposed to
RH of up to 98% for 60 mints or more. It is then placed in the chamber,
previously heated to about 55 centigrade, and an initial vacuum of
approximately 27 in, Hg is drawn. The EtO is then introduced along with
moisture, to achieve a relative humidity of 50 to 60%, to pressure
required to give desired conc. of gas, which is maintained, following
exposure period of 6 to 24 hours, gas is exhausted, vacuum of approx.25
in.Hg is drawn.
II. BETA-PROPIOLACTONE
• Concentration 2 to 4 mg/l, temp. > 24 Celsius, humidity at least 70%,
exposure period at least 2 hrs., poor penetrability so for sterilization of
surfaces in large spaces.
III. GLUTARALDEHYDE
• In solution form, for surgical instruments.
OXIDIZING GASES
• Oxidizing agents act by oxidizing the cell membrane of microorganisms,
which results in a loss of structure and leads to cell lysis and death.
• Hydrogen Peroxide
• Ozone
• Chlorine Dioxide
• Peracetic acid
i. HYDROGEN PEROXIDE
• Effective against spores at a range of temperature. Hydrogen peroxide is
used to sterilize heat or temperature-sensitive articles. Greatest action
when used at near-saturation levels on clean dry surface.
ii. OZONE
• It is used in industrial settings to sterilize water and air, as well as a
disinfectant for surfaces. Ozone is a very efficient sterilant because of its
strong oxidizing properties capable of destroying a wide range of
pathogens including prions.
iii. CHLORINE DIOXIDE
• It has sporicidal activity. Applications are limited due to its effect on
materials (uncoated Al foil, copper, polycarbonate and polyurethane.
iv. PERACETIC ACID
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• 0.2% is a recognized sterilant by the FDA. Vaporized from is used to
sterilize isolators. Long contact time is needed though. Can cause
corrosion of metals and rubber. Low penetrating power.
II. FILTRATION
DEFINITION
• Filtration is defined as a process in which particles are separated from a
liquid by passing the liquid through a permeable material. The
permeable medium is a porous material that separates particles from
the liquid passing through it and is known as a filter.
• Almost all of those currently in use with parenteral solutions are
membrane type, that is tissue thin material removing particles primarily
by sieving.
MEMBRANE FILTERS
• Membrane filters are usually composed of plastic polymers including
cellulose acetate and nitrate, nylon, polyvinyl chloride, polycarbonate,
poly-sulfone and Teflon.
• Membrane filters function primarily by sieving, or by screening particles
from a solution or gas, thus retaining them on the filter surface.
• Membrane filters also function in some instances by electrostatic
attraction. This would apply particularly to the filtration of dry gases, in
which electrostatic charges tend to increase because of the frictional
effect of the flowing gas.
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PACKAGING
INTRODUCTION
• Pharmaceutical packaging is the means of providing protection,
presentation, identification, information, and especially enabling
accurate dosing and compliance.
– Spoons, cups for oral dose measurement and delivery.
– Dropper tubes for eye/ear/oral delivery of drops.
– Applicators (e.g. pessaries)
– Dispensing devices, actuators, pre-filled syringes.
– Dose counting and calendar devices.
OBJECTIVES
• Physical protection
• Barrier protection
• Containment or
agglomeration
• Security
• Convenience
• Portion control
PACKAGING TYPES
1. Primary packaging
2. Secondary packaging
3. Tertiary packaging
1. PRIMARY PACKAGING
• Primary packaging is the material that first envelops the product
and holds it. This usually is the smallest unit of distribution or use
and is the package which is in direct contact with the contents.
• For example: Unit packs
• Different type of primary packaging includes:
– Ampules
– Vials
– Containers
– Dosing dropper
– Closures
– Syringe
– Strip package
– Blister packaging
2. SECONDARY PACKAGING
• Secondary packaging is outside the primary packaging – perhaps
used to group primary packages together.
– Paper and boards
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– Cartons
– Corrugated fibers
– Box manufacture
3. TERTIARY PACKAGING
• Tertiary packaging is used for bulk handling, warehouse storage
and transport shipping. The most common form is a palletized unit
load that packs tightly into containers.
TYPES OF PHARMACEUTICAL PACKAGING MATERIALS
• Materials Use for Packaging are
– Polycrystalline (metals)
– Polymerization products (Plastic, glass, rubber)
– Paper and board.
GLASS TRANSITION OF POLYMERIZATION PRODUCTS
• Tg is the temperature below which hard rigid and brittle solids (glassy
state)
• Glasses are super cooled liquids of high viscosity (1013 Poise)
• It is a brittle transparent material based on the network of oxygen and
silicon items.
CHARACTERISTICS OF PACKAGING MATERIALS
• They must protect the preparation from environmental conditions.
• They must not be reactive with the product.
• They must not impart to the product tastes or odors.
• They must be nontoxic.
• They must be FDA approved.
• They must meet applicable tamper-resistance requirements.
• They must be adaptable to commonly employed high speed packaging
equipment.
SELECTION OF PACKAGING MATERIALS
1. On the facilities available, for example, pressurized dispenser requires
special filling equipment.
2. On the ultimate use of product. The product may be used by skilled
person in hospital or may need to be suitable for use in the home by a
patient.
3. On the physical form of the product. For example, solid, semi-solid,
liquids or gaseous dosage form.
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4. On the route of administration. For example, oral, parenteral, external,
etc.
5. On the stability of the material. For example, moisture, oxygen, carbon
dioxide, light, trace metals, temperature or pressure or fluctuation of
these may have a deleterious effect on the product.
6. On the contents. The product may react with the package such as the
release of alkali from the glass or the corrosion of the metals and in turn
the product is affected.
7. On the cost of the product. Expensive products usually justify expensive
packaging.
FACTORS AFFECTING SELECTION OF PACKAGING MATERIALS
• Mechanical factors
– These include Shock, Compression, Puncture and Vibration.
• Environmental factors
– These include Temperature, Pressure, Moisture, Gases, Light,
Infestation and Contamination
CONTAINERS
• Container is one in which the product is placed.
• A pharmaceutical container is defined as a device that holds the drugs
and is or may be in direct contact with the preparation.
IDEAL REQUIREMENTS OF CONTAINERS
• Must be neutral towards the material which is stored in it.
• Must not interact with the substance which it holds.
• Help in maintaining the stability of the product.
• Withstand wear and tear during normal handling.
• Dose can be drawn from it conveniently.
• Able to withstand changes in pressure and temperature.
• Must be non-toxic.
• Can be labelled easily.
• Pharmaceutically elegant appearance.
TYPES OF CONTAINER
• Well-closed containers
• Single dose containers
• Multi dose containers
• Light-resistant containers
• Air-tight containers
• Aerosol containers
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MATERIALS USED FOR MAKING CONTAINERS
1. Glass
2. Plastic
3. Metal
4. Paper and board
1. GLASS
INTRODUCTION
• They are transparent and available in various shapes and sizes.
• They can withstand the variation in temperature and pressure during
sterilization.
• They are economical and easily available.
• They can protect the photosensitive medicaments from light during their
storage.
• They are neutral after proper treatment and impermeable to
atmospheric gases and moisture.
• They have good protection power and do not deteriorate with age.
• They can be easily labelled and sealed hermetically or by removable
closures.
MANUFACTURING OF GLASS
COMPOSITION
• Glass is composed of sand, soda ash, limestone and cullet.
• Silicon, aluminum, boron, sodium, potassium, calcium, magnesium, zinc
and barium are generally used in the preparation of glass.
• The sand is almost pure silica, the soda ash is sodium carbonate, and the
limestone is calcium carbonate.
• Cullet is a broken glass that is mixed with the batch and acts as a fusion
agent for the entire mixture.
• The composition of glass varies and is usually adjusted for specific
purposes.
• The most common cations found in pharmaceutical glassware are
sodium, calcium, magnesium, zinc and potassium.
MODIFIERS
• Monovalent metals
• Divalent metals
• Trivalent metals
GIVING SHAPES TO THE CONTAINERS
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• Blowing
• Drawing
• Casting
• Pressing
COLORED GLASS
• Glass containers for drugs are generally available in clean flint or amber
color.
• The amber coloration results from the addition of iron oxide to the glass.
• For decorative purposes, special colors such as blue, emerald green and
red may be obtained from the glass manufacturer.
• Colored glasses are effective in protecting the content from the effect of
sunlight by screening them.
TYPES OF GLASS
• Type 1: Neutral or Borosilicate glass
– For injectable and laboratory apparatus
• Type 2: Treated Soda lime glass
– For alkali sensitive products, infusion fluids blood and plasma
• Type 3: Regular Soda lime glass
• Type 4: General Purpose Soda lime glass
TYPE I: BOROSILICATE GLASS
• It is least reactive.
• A substantial amount of alkali or earth cations are replaced by boric
oxide.
• This type of glass has higher ingredient like aluminium and zinc and
higher processing costs and is therefore used primarily for more
sensitive pharmaceuticals such as parenteral or blood products e.g.
Ampoules and vials.
TYPE II: TREATED SODA LIME GLASS
• When a glass is stored for several months in damp atmosphere or with
extreme temperature variations, the wetting of surface results in salts
being dissolved out of glass in the form of fine crystals. This is called
‘BLOOMING OR WEATHERING’. At this stage, these salts can be washed
off with water or acid.
• Commercial soda lime glass is de alkalized or treated to remove surface
alkali to prevent the weathering of empty bottles. This treatment is
known as ‘SULPHUR TREATMENT’.
• SULPHUR TREATMENT involves treating the glass surface with sulfur
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dioxide or ammonium sulfate.
• It also has a high chemical resistance but not as much as type I.
• It is cheaper than type I glass, however, and is acceptable for most
products and aqueous pharmaceuticals with a pH greater than 7.
TYPE III: REGULAR SODA LIME GLASS
• Types III and Type IV glass have similar compositions and distinguished
from each other by their hydrolytic resistance.
• Containers are untreated and made of commercial soda-lime glass of
average or better than average chemical resistance.
• Suitable for non-aqueous parenteral and non-parenteral products.
TYPE IV: NP- GENERAL PURPOSE SODA LIME GLASS
• These have lowest hydrolytic resistance, which can sometimes be seen
as a surface bloom if the glass is stored in damp conditions for prolonged
periods, and is suitable for solid products, some liquids and semi- solids,
but not for parenteral.
ADVANTAGES OF GLASS
• Versatile and attractive.
• Superior protective qualities
• Can be molded into many shapes, sizes and colors of container.
• It is hygienic and suitable for sterilization, it has excellent barrier
properties, it is relatively non-reactive, it can accept a variety of closures,
and glass containers can be used on high speed packaging.
• It can be colored to protect light sensitive materials.
• It can be reused.
• They are neutral after proper treatment.
DISADVANTAGES OF GLASS
• It is fragile
• It is heavy
• It is harder to dispose
• It is expensive
ADDITIVES OF GLASS
• Mn/Fe for amber color
• Co/Cu for blue color
• Pb to improve clarity
• Alumina- to increase hardness and durability.
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2. PLASTIC
INTRODUCTION
• Plastic packaging systems define a set of packaging materials that are
composed wholly or in substantial portion of plastic materials which
contain or is intended to contain pharmaceutical formulations.
• They are very commonly used as packaging materials for most types of
pharmaceutical dosage forms due to the several advantages they
possess over glass containers.
TYPES OF PLASTIC
• THERMOPLASTIC TYPE: - Tg very low
– This type of plastic gets softened to a viscous fluid on heating and
hardens again on cooling.
• THERMOSETTING TYPE: - Tg very high, crosslinked plastics
– This type of plastic does not gets softened to a viscous fluid on
heating and hardens again on cooling.
COMPOSITION OF PLASTIC
• Plastics are synthetic polymers of high molecular weight.
• Plastic containers for pharmaceutical product are primarily made from
the following polymers:
– polyethylene
– polypropylene
– polyvinyl chloride
– polystyrene and to lesser extent, polyethylene methacrylate and
amino formaldehyde.
PRODUCTION OF PLASTICS
• Synthesis (polymerization)
• Compounding (excipient)
• Molding (fabricated into shape)
– Compression
– Injection
– Extrusion
ADDITIVES IN PLASTIC CONTAINERS
• Stabilizers - to prevent degradation of polymer chain (octyl tin in PVC)
• Antioxidant (retard oxidation)
• Plasticizer - to achieve softness and flexibility (Camphor, castor oil)
• Pigment - for decorative purposes
• Fillers (asbestos, mica)
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ADVANTAGE OF PLASTIC
• Light in weight.
• Poor conductor of heat.
• Sufficient mechanical strength.
• Transported easily.
• Unbreakable.
• Good protection power.
• Resistance to inorganic chemicals.
DISADVANTAGE OF PLASTIC
• Permeable to water vapor and atmospheric gases.
• Cannot withstand heat without softening or distorting.
• Absorb chemical substance, Such, preservatives for solution.
• They are relatively expensive.
EVALUATION OF PLASTIC
• Plastic can be evaluated by the following tests
– Leakage test
– Collapsibility test
– Clarity of aqueous extract
– Water vapor permeability test
DRUG PLASTIC INTERACTIONS
• Toxicity
• Permeability
• Leaching
• Sorption
• Chemical reactivity
• Modification
USES AND PROBLEMS
• LEACHING: A process in which plastic material get dissolved by the
action of liquid dosage form.
• SORPTION: A process by which one substance becomes attached to
another.
• PERMEATION: It is penetration of liquid or gas into the solid.
• CHEMICAL REACTION: Plastic may react with the dosage form i.e. liquid
or semi solid.
3. METALS
• The metals commonly used are aluminum, tin plated steel, stainless
steel, tin and lead.
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ADVANTAGE OF METALS
• They are sturdy
• They are impermeable to light, moisture, gas
• They are light in weight as compared to glass containers.
• Labels can be printed directly on to their surface.
DISADVANTAGE OF METALS
• They are expensive.
• They may shed metal particles into pharmaceutical products.
• They are not generally used for extemporaneous dispensing.
• They react with certain chemicals of drug.
METAL CONTAINERS
• Collapsible tubes
• Metal containers for tablets and capsules
• Metal foil
COLLAPSIBLE TUBES METAL
• The collapsible metal tube is an attractive container that permits
controlled amounts to be dispensed easily, with good reclosure, and
adequate protection of the product.
• It is light in weight and unbreakable and lends itself to high speed
automatic filling operations.
• Most commonly used are tin, aluminum and lead.
o TIN
– Tin containers are preferred for food, pharmaceuticals and
any product for which purity is considered.
– Tin is the most chemically inert of all collapsible metal
tubes.
o ALUMINIUM
– Aluminum tubes offer significant savings in product shipping
costs because of their light weight.
– They are attractive in nature
o LEAD
– Lead has the lowest cost of all tube metals and is widely
used for non-food products such as adhesives, inks. paints
and lubricants.
– Lead should never be used alone for anything taken
internally because of the risk lead poison.
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– With internal linings, lead tubes are used for products such
as chloride toothpaste.
4. PAPER AND BOARD
• Both are composed of cellulose obtained by the mechanical or
semi chemical treatment of visit able fibers dried from various
sources like wood, hemp, cotton, etc. in some case waste and
regenerated paper is used.
RUBBER (ELASTOMERS)
• Closure in multiple dose vials (insertion of needle and resealing when
needle is withdrawn)
• Natural rubber (latex of rubber tree)
• Synthetic rubber
– Styrene butadiene
– Nitrile rubber
– Silicon rubber
SPECIFICATION FOR RUBBER AS PACKAGING MATERIAL
• Force required to penetrate the closure
• Limitation of fragments detached
• Reseal property
• Permeability to oxygen and water.
VULCANIZATION PROCESS
• Vulcanization is a chemical process in which the rubber is heated with
Sulphur accelerator and activator at 140–160°C.
• The process involves the formation of cross-links between long rubber
molecules so as to achieve improved elasticity, resilience, tensile
strength, viscosity, hardness and weather resistance.
CLOSURES
• Closures are the devices by means of which containers can be opened
and closed.
• It prevents loss of material by spilling or volatilization.
• It avoids contamination of the product from dirt, micro-organism or
insects.
• It prevents deterioration of the product from the effect of the
environment such as moisture, oxygen or carbon dioxide.
TYPE OF CLOSURE
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Crown cap Threaded Screw Cap
Lug Cap Roll on closures


















MATERIALS USED FOR CLOSURE
• Cork
• Glass
• Plastic
• Metal
• Rubber
EVALUATION OF CLOSURES
• Sterilization test
• Fragmentation test
• Self sealibility test
COMMONLY USED PACKAGES IN PHARMA INDUSTRY
• Jars
• Bottles
• Collapsible tubes
• Sachet
• Ampoules
• Vials
• Blisters
• Strips
UNIT PACKS
• Unit packs in which individual dosage are separated from each other are
popular for many types of dosage form.
• It is done through strip packaging.
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BLISTER PACKAGING
• Blister packaging is a type of pre-formed plastic packaging used for small
consumer goods.
• The two primary components of a blister packs are the cavity made from
either plastic or aluminum and the lidding made from paper, plastic or
aluminum.
• The cavity contains the product and the lidding seals the product in the
package.
ADVANTAGES OF BLISTER PACKAGING
• Product integrity
• Product protection
• Temper resistance
• Reduced possibility of
accidental misuse
• Patient compliance









POLYVINYL CHLORIDE (PVC)
• Very clear, stiff material
• Excellent thermoformability
• Low permeability
• Low cost
• Good chemical resistance
• Thickness of about 10-15mm
POLYVINYLIDENE CHLORIDE (COATED PVC)
• PVDC is the most common coating in blister
packaging because it can reduce the gas and
moisture permeability of PVC blister packages
• Coated PVC films have thickness of 8-10mm
• Coating is applied on one side and usually faces the product
Blister
Packaging
Thermo
foaming
Transparent amber
Cold
foaming
Alu-Alu
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• Excellent oxygen and moisture barrier properties as compared to normal
PVC.
POLYSTYRENE
• It is perfectly compatible with the thermoforming
• Its high-water vapor permeability makes it unsuitable as a
blister material for pharmaceutical purpose
ALUMINIUM BLISTER FOIL
• Used in cold foaming technique
• Alu-Alu packaging
• Good barrier to moisture, vapor and gases
• 20-25µm thick
PACKAGING LINE
• In pharmaceutical industry packaging is a coordinated process
• All process starting from primary packaging till tertiary packaging done
in a series of process coordinated/ mounted on a single machine
• These machines are called as packaging line.



DEFECTS IN PHARMACEUTICAL PACKAGING
• Lack of heat seal – incomplete heat seal
• De-laminations channel voids and contaminations
• Inclusions of product or foreign materials in the seal area
• Misplaced lids/tops/closures or crimp seals
• Invisible defects/leaks Holes or crack defects in empty vials/ampoules
QUALITY CONTROL OF PACKAGING
• Powdered Glass Test (As per USP):
– Water Attack at 121°C
• Testing of Plastic Container for toxicity
• Leakage test for Plastic Containers
– Water Vapor Permeability
• Test for Plastic Containers for Injectable
• Collapsibility Test for Plastic Containers
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