Large scale manufacturing processes &; equipments for Tablets

This presentation gives general ideas about tablet formulation on large scale and gives information about modern Pharma equipments for Tablets manufacturing.

2. Contents
1. Introduction.
2. Primary goals of tablet manufacturing process.
3. Factors that influence the choice of manufacturing process used
during tablet formulation.
4.Personnel requirements during manufacture of pharmaceutical
tablets.
5.Tablet Manufacturing Equipment/ Machines.
6.Steps Involved In Tablet Formulation/ Procedure for Manufacturing
Tablets.
7.Some large scale tablet manufacturing equipments in details.
8. Tablets defects/ special problem in compressing tablet process

3. Introduction
Tablets may be defined as the solid unit dosage form of
medicament or medicaments with suitable excipients and
prepared either by molding or by compression. It
comprises a mixture of active substances and excipients,
Pharmaceutical tablets are solid, flat, or biconvex dishes, unit dosage
form, prepared by compressing a drugs or a mixture of drugs, with or
without diluents. It is most popular dosage form and 70% of the total
medicines are dispensed in the form of tablets

4. The design and manufacture of pharmaceutical tablets is a complex multi-stage
process whereby formulation scientists ensure that the correct amount of drug
substance in the right form is delivered at the appropriate time, at the proper
rate and in the desired location with its chemical integrity protected to that
point. Most drug substances do not possess the required properties which give
satisfactory flow from the hopper to the die cavity of tablet presses. As a result,
they are subjected to pre-treatment either alone or in combination with suitable
excipients to form free-flowing granules that lend themselves to tabletting.
Tablets are commonly manufactured by wet granulation, dry granulation or
direct compression. These methods may be considered to consist of a series of
steps (unit processes) – weighing, milling, mixing, granulation, drying,
compaction, (frequently) coating and packaging. Regardless of the method used
the unit processes – weighing, milling and mixing, are the same; subsequent
steps differ.

5. Primary goals for tablet manufacturing process
▪To formulate tablets that are strong and hard to withstand mechanical shock
encountered during manufacturing, packing, shipping, dispensing and use.
▪To formulate tablets that are uniform in weight and in drug content.
▪To formulate tablets that are bioavailable according to indication requirements.
▪To formulate tablets that are chemically and physically stable over a long period
of time.
▪To formulate tablets that have elegant product identity which is free
from any tablet defects.

6. Factors that influence the choice of manufacturing
process used during tablet formulation
▪Compression properties of the Active Pharmaceutical Ingredient (API)/
drug substance.
▪Physical and chemical stability of the API during the manufacturing
process.
▪Particle size of the formulation ingredients.
▪Availability of the necessary processing equipment.
▪Cost of the manufacturing/formulation process

7. Personnel requirements during manufacture of
pharmaceutical tablets
▪Production pharmacists/ supervisors
▪Manufacturing chemist
▪Analytical chemist
▪Quality assurance manager
▪Machine operators
▪Mechanics

8. Tablet Manufacturing Equipment/ Machines
Common equipment used in pharmaceutical tablet manufacturing
include:
1. Size reduction equipment/ communition equipment e.g., hammer
mill, vibration mill, roller mill, pin mill, fluidized energy mill,
end-runner mill, edge-runner mill, cutter mill and ball mill.
2.Weighing balance/ balances e.g., bulk weighing balance (weighs in
kilogram), electronic weighing balance (weighs in grams and
milligrams).

9. 3.Mixing equipment e.g., pneumatic mixers (air-mix mixer or air-driven
mixer), diffusion/ tumbling mixers (e.g., V-blender, double cone blender,
cubic mixer, drum blender), convective mixers (e.g., ribbon blenders,
orbiting screw mixers, horizontal high-intensity blenders, planetary
blenders, diffusion mixer with intensifier bar/agitator, Forberg blenders,
horizontal double arm mixers, vertical high-intensity mixer).

4.Granulators e.g., rotating shape granulators, mechanical agitator
granulators (e.g., ribbon or paddle blender, sigma blade mixer, planetary
mixer, orbiting screw mixers), high-shear granulator, fluidized bed
granulator, dry granulator etc.

5.Dying equipment e.g., spray dryer, rotary dryer, fluidized bed dryer etc.

6.Tabletting machine – single punch tablet press and multi-station/ rotary
tablet press (e.g., High-speed rotary tablet machines and multi-layer rotary
tablet machines).

10. 7. Quality control equipment e.g., disintegration equipment (Manesty
single unit disintegrating apparatus or Erweka multiple unit
disintegrating apparatus), USP Dissolution Tester, Tablet Hardness
Tester, Tablet Thickness Tester, Tablet Friability Testers etc.

8.Coating and polishing machines for coated tablets e.g., standard
coating pan, perforated pan, fluidized bed/ Air suspension coating
system etc.

9.Packaging machines e.g., blister packaging machines, strip packing
machine, aluminium foil packaging machine, etc.

Tablet Manufacturing Equipment continues to improve in both
production speed and uniformity of the tablets compressed.

11. Steps Involved In Tablet Formulation/ Procedure for
Manufacturing Tablets
1Dispensing: Each ingredient in the tablet formula is weighed and
accurately dispensed as per dose. This is one of the critical steps in
any type of formulation process and should be done under technical
supervision.
2.Sizing: Formulation ingredients must be in finely divided form,
otherwise, size reduction should be carried out for better flow
property and easy mixing.

12. 3.Powder blending: Powders are mixed using a suitable blender to
obtain a uniform and homogeneous powder mix. The drug
substance and excipients are mixed in geometric dilution.

4.Granulation: Here small powder particles are gathered together
into layers, and permanent aggregates to render them into
free-flowing states.

5.Drying and dry screening: Screened wet granules need to be
dried for a particular time period in tray dry or fluid bed dryer at
controlled temperature not exceeding 550C. Dried granules are
screened through the appropriate mesh screen.

13. 6.Tablet compression: This step involves the compression of granules
into a flat or convex, round, oblong, or unique shaped, scored or
unscored tablets; engraved with an identifying symbol and/ or code
number using tablet press.

7.Coating: Tablets and granules are coated if there is need to mask
the unpleasant taste/odour of some drug substance or to increase
the aesthetic appeal of uncoated tablets as well as to modify the
release or control the release of drug substance from tablets. This is
achieved by enclosing or covering the core tablet or granules with
coating solutions.

14. Large scale manufacturing equipments / Machines

15. Double cone blender

16. The Double Cone Blender is an efficient and versatile
machine tor mixing dry powder and granules
homogeneously. All the contact parts made out of
stainless steel of required grade by customer. Two third
of the volume of the Cone Blender is filled to ensure
proper mixing. It can be used for Pharmaceutical, Food,
Chemical and Cosmetic products etc.

?????? Salient Features
▪ The conical shape at both ends enables uniform mixing and
easy discharge.
▪All contact parts are made out of stainless 304 or 316 quality
material, as required by customer.

17. ▪Maximum care has been taken to ensure safe operation of the unit.
▪Manual rotating facility with hand wheel for inching. The same
will be provided with ss cover & limit switch. ( In 200 Kgs. & above
model
▪Two nos. of safety road will be provided at back side. (One LH side
&one RH side ) Suitable size of butter fly valve at one end of the
cone provided for material discharge & hole with openable cover
provided at other end of the cone for material charging & cleaning.
▪One shaft with 04 nos. of fixed buffels with mirror polished provided
inside the cone.

18. V- Blender or Twin shell blender

19. ▪It is V shaped and made up of stainless steel or transparent plastic.

▪Material is loaded through shell hatches and emptying is normally done
through
and apex port.

▪The material is loaded approximately 50-60% of the total volume.
▪Small models - 20 kg ,rotate at 35rpm
▪Large models -1 ton, rotate at 15rpm

▪As the blender rotates, the material undergoes tumbling motion.

▪When V is inverted, the material splits into two portions. This process
of dividing and recombining continuously yields ordered mixing by
mechanical
means.

20. Ribbon Blender
?????? Principle:
Mechanism of mixing is shear. Shear is
transferred by moving blades. High shear rates
are effective in breaking lumps and aggregates.
Convective mixing also occurs as the powder bed
is lifted and allowed to cascade to the bottom of
the container. An equilibrium state of mixing can
be achieved.

21. ?????? Construction:

▪Consists of horizontal cylindrical trough usually open at the top. It is fitted with
two helical blades, which are mounted on the same shaft through the long axis of
the trough.
▪Blades have both right and left hand twists.
▪Blades are connected to fixed speed drive.
▪It can be loaded by top loading and emptying
is done through bottom port.

??????Uses:
▪Used for mixing of finely divided solids, wet solid mass, and
plastic solids.
▪Uniform size and density materials can be easily mixed.
▪Used for solid- solid and liquid - solid mixing.

22. Planetary Mixer
?????? Principle:
Mechanism of mixing is shear. Shear is
applied between moving blade and stationary
wall. Mixing arm moves around its own axis and
around the central axis so that it reaches every
spot of the vessel. The plates in the blades are
sloped so that powder makes an upward
movement to achieve tumbling action also.

23. ?????? Construction:

▪Consists of vertical cylinder shell which can be removed.
▪The blade is mounted from the top of the bowl.
▪Mixing shaft is driven by planetary gear and it is normally built with variable
speed drive.
??????Uses
▪Break down agglomerates rapidly.
▪Low speeds are used for dry blending and fast for wet
granulation.
??????Advantages
▪Speed of rotation can be varied at will.
▪More useful for wet granulation process.
??????Disadvantages.
▪Mechanical heat is buildup within the powder mix.
▪It requires high power
▪It has limited size and is usefl for batch work only.

24. Rotocube blender

25. ?????? Process:

The shape of Roto Cube blender, process larger volume in less space
compared to similar blender like "V" and double cone blender.
It can perform homogenously dry mixing of free flowing powders,
granules requiring low shearing force, mixing and blending of partícies
with rapid intermixing of particles irrespective of varying specific
gravities.
The material is loaded into the blender drum.
The roto cube blender tumbles the material in the container and spread
out.
The mixing is achieved in 5 to 30 minutes
with better homogeneity depending on type of material.

26. Sigma blade mixer
PRINCIPLE
The mechanism of mixing is shearing.
The inter meshing of sigma shaped blades
creates high shear and kneading actions.

27. ?????? CONSTRUCTION AND WORKING :

▪It consists of double tough shaped stationary bowl.
▪Two sigma shaped blades are fitted horizontally in each tough of the bowl.
▪These blades are connected to a fixed speed drive.
▪Mixer is loaded from top and unloaded by tilting the entire bowl.
▪The blades move at different speeds, one about twice than the other, which
allows movement of powder from sides to centers.
▪The material also moves top to downwards and gets sheared between the
blades and the wall of the
tough resu lting cascading action.
▪Perforated blades can be used to break lumps and
aggregates which creates high shear forces.
▪The final stage of mix represents an equilibrium
state.

28. ?????? Uses of sigma blade mixer

▪Used in the wet granulation process in the manufacture of tablets. pill
masses and ointments,
▪It is primarily used for liquid - solid mixing although it can
be used for solid - solid mixing.

??????Advantages of sigma blade mixer
▪Sigma blade mixer creates a minimum dead space during mixing
▪It has close tolerances between the blades and the sidewalls as
well as bottom of the mixer shell

??????Disadvantages of sigma blade mixer
Sigma blade mixer works at a fixed speed.

29. Diosna mixer granulators


▪The machine have a stainless steel mixing
bowl containing three bladed impeller and
auxiliary chopper blade.
▪The main blade rotate about 150-300 rpm
and high speed chopper blade at about
1500-3000 rpm.

30. ▪The high-shear wet granulation process using high
shear granulator can be divided into 5 stages and
they included;
1. Powder mixing
2. Binder addition or addition of granulating liquid.
3. Wetting of powder and nucleation
4. Growth of granules and densification of the powder.
5. Granule attrition and breakage

▪A typical time sequences for the use of Diosna mixer
are as follows:
Mixing: 2 min or less,
Granulating: 8 min or less,
for discharge: one min

31. Gral Mixer processor

32. ▪This is modification of industrial planetary mixer.
▪The principle is based upon the planetary mixer.
▪It contain two mixing devices. Larger three blade
shaft provide mixing motion on powder.
▪Smaller chopper blade used to cut the wet mass into
granules.
▪The main mixing blade rotates at 450-600 rpm in 10
L model.
▪In all models the high speed chopper blade rotates at
1500-3000 rpm.

33. Nauta Mixer processor

34. ▪It is widely used in pharmaceutics for the granulation
purpose.
▪The principle of mixing of powder is based on convicting
mixing mechanism.

?????? Advantages:
▪Complete closed system secures environmental protection.
▪No damage to heat sensitive products.
▪Important savings by combining operations such as mixing,
drying and granulation.

35. Oscillating Granulator

36. ▪The moist mass has been transferred to a granulator,
as oscillating granulator.

▪The rotor bars of the granulator oscillate and force the
moist mass through the sieve screen, the size of which
determines granule size.

▪The mass should be sufficiently moist to form discrete
granules whensieved. If excess liquid is added, string
(filament) of material will be formed and if the mix is too
dry the mass will be sieved as powder and granules will
not be formed.

37. Fluidized bed granulator

38. ▪The powder particles are fluidized in a stream of
air.
▪Granulation fluid is pumped from a reservoir
and sprayed from a nozzle on to the bed of
powders.
▪Heated and filtered air is blown through the bed
of unmixed powders to fluidize the particles and
mix the powders.
▪The fluid causes the primary powder particles to
adhere when the droplets and powders collide.

39. ▪Sufficient liquid is sprayed to produce granules of
the required size, at which point the spray is
turned off but the fluidizing air continued.
▪The wet granules are then dried in the heated
fluidizing air stream.

?????? Advantages
It reduces product loss.
It improves worker safety.
??????Disadvantages
time consuming.
Difficulty of assuring reproducibility

40. Single Pot Processor

41. ▪A high-shear-mixer-granulator-dryer, combining
the steps of mixing, granulation and drying in oral
solid dosage form production

▪Thus, single pot processing (SPP) is the
production of pharmaceutical granules using a
wet granulation process in which dry mixing,
liquid addition, wet granulation, drying and sizing
of the granules is done in one machine.

?????? Applications _ Wet granulation., Vacuum drying,
Hot melt granulation., coating, Effervescent products,
In oncology drugs formulation etc.

42. Chilsonater (Roller Compactor)
▪Chilsonator machine used for dry granulation.
▪Formation of dry granules requires dry powder densification and for
agglomeration.
?????? Construction and Working
▪Feeding system
▪A size reduction unit
▪Fixed roller compactor
▪Variable gap roller

44. Advantages
▪It is used in granulating thermo labile drugs.
▪Moisture sensitive drugs like Aspirin, vitamins are granulated by dry granulation.
▪Those drug do not compress well after wet granulation.

45. Topo vacuum granulator
▪It was developed in Austria for the preparation of granules and coated
particles under high vacuum.
, ▪The material placed in chamber which must be dust free suction. Then
compartment is loaded by vacuum, granulating fluid or addition products.
▪Under vacuum granulation force are increased greatly increase to produce
the necessary compaction. Resulted agglomerated particles dried under
vacuum in chamber.
▪Advantage is low requirement of-granulating fluid

46. Tablets defects/ special problem in compressing
tablet process
▪Weight variation (granule size and size distribution)
▪Poor mixing ▪Double Impression
▪Poor flow. ▪Punch variation
▪Capping and lamination. ▪Presence of hair
▪Picking of tablets. ▪Black spot/stain
▪Chipping and splitting. ▪Low hardness/hardness variation
▪Sticking. ▪Motting