Pharmaceutical Technology Complete Notes

Pharmaceutical Technology, Final Proff, Doctor of Pharmacy, PharmD

1. Ghulam Murtaza Hamad
Doctor of Pharmacy, Final Professional
Punjab University College of Pharmacy, Lahore, Pakistan
Session 2016-21

2. GM Hamad

Table of Contents
01
Principles of Pharmaceutical Formulation and Dosage Form
Design
01
02 Advanced Granulation Technology 43
03 Polymers used in Drug Delivery Systems 65
04 Novel Drug Delivery System (NDS) 75
05 Novel GIT Drug Delivery System (DDS) 101
06 Drug Carrier System 135
07 Targeted Drug Delivery System 147
08 Pharmaceutical Biotechnology 151
09 Past Papers 188
10 References 193

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PRINCIPLES OF PHARMACEUTICAL
FORMULATION AND DOSAGE FORM
DESIGN
PHARMACEUTICAL TECHNOLOGY
“Pharmaceutical technology is application of scientific knowledge or
technology to pharmacy, pharmacology, and the pharmaceutical industry”
NEED OF DOSAGE FORM
 Use of some potent drugs from bulk material precludes expectations
that patient safely obtains appropriate dose of drugs.
 Most drugs given in very small quantities that cannot be weighed on
anything but a sensitive electronic balance.
 For some drugs to be used in minute quantities (0.05mg), they are
formulated in tablets or capsules form with fillers or diluents to make
them palatable.
 To protect dosage form or drug substances from destructive influences
of atmospheric oxygen or humidity (coated tablets, sealed ampoules)
 To protect dosage form or drug substances from destructive influences
of gastric acid after oral administration (enteric coated tablets).
 To conceal the bitter, salty or offensive taste or odor of drug substances
(capsules, coated tablets, flavored syrups).
 To formulate liquid preparations of substances that are either insoluble
or unstable in desired vehicles (suspensions).
 To prepare rate controlled drug actions (various controlled release
tablets, capsules and suspensions).
 To provide optimal drug action for topical administration site (Creams,
transdermal patches, ophthalmic, ear and nasal preparations).
 To provide for insertions of drugs in one of body orifices (rectal and
vaginal suppositories).
 To formulate drugs for placement directly in blood stream or body
tissues (injections).
 To provide for optimal drug action through inhalational therapy
(inhalants and inhalation aerosols).
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PREFORMULATION STUDIES
INTRODUCTION
 The meaning of “pre-formulation” literally refers to the steps to be
undertaken before formulation proper dosage form. Prior to the
development of dosage forms, it is essential that certain fundamental
physical and chemical properties of potential drug molecules and other
derived properties of drug powder are determined.
 Determination of these properties for the drug substance and the drug
product decides subsequent events and approaches in formulation
development and by this the formulator may confirm that there are no
significant barriers to the compounds development.
 Thus pre-formulation can be described as:
“The process of optimizing the delivery of drug, through the determination of
physico-chemical properties of the new compound, and thus affording for the
development of an efficacious, stable, and safe dosage form”
 So, the overall objective of pre-formulation studies is to generate
information useful to the formulator in developing stable and
bioavailable dosage forms that can be mass produced.
PREFORMULATION PARAMETERS
A) PHYSICAL CHARACTERISTICS
1. Organoleptic properties
2. Bulk characteristics
a. Solid state
characteristics
b. Flow properties
c. Densities
d. Compressibility
e. Crystalline
f. Polymorphism
g. Hygroscopicity
3. Solubility analysis
a. Ionization constant
(Pka)
b. Partition co-efficient
c. Solubilization
d. Thermal effect
e. Common ion effect
f. Dissolution
4. Stability analysis
a. Solution-state stability
b. Solid-state stability
c. Drug-excipients compatibility
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B) CHEMICAL CHARACTERISTICS
1. Hydrolysis
2. Oxidation
3. Photolysis
4. Racemization
5. Polymerization
6. Isomerization
PHYSICAL CHARACTERISTICS
1. ORGANOLEPTIC PROPERTIES
 Organoleptic properties includes:
­ Description of the drug substance.
­ The color, odor and taste of the new drug must be recorded using
descriptive terminology.
TERMINOLOGY TO DESCRIBE ORGANOLEPTIC PROPERTIES OF
PHARMACEUTICAL POWDERS
COLOR TASTE ODOR
Off-white
Cream yellow
Tan
Shiny
Acidic
Bitter
Bland
Sweet
Tasteless
Pungent
Sulfurous
Fruity
Aromatic
Odorless

 Unpleasant color, odor, taste can be modified by appropriate methods
and the modified forms must be screened for their influence on stability
and bioavailability of the active drug.
2. BULK CHARACTERISTICS
A) SOLID STATE CHARACTERISTICS
 Powders are masses of solid particles or granules surrounded by air (or
other fluid) and it is the solid plus fluid combination that significantly
affects the bulk properties of the powder.
 Physical characteristics of the particles, such as size, shape, angularity,
size variability and hardness affect flow properties.
 External factors such as humidity, conveying environment, vibration and
aeration causes the problem.
PARTICLE SIZE AND SIZE DISTRIBUTION
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 Various chemical and physical properties of drug substances are affected
by their particle size distribution and shapes. The effect is not only on
the physical properties of solid drugs but also in some instances on their
biopharmaceutical behavior.
 For example, the bioavailability of griseofulvin and phenacetin is directly
related to the particle size distributions of these drug.
B) POWDER FLOW PROPERTIES
 The flow properties of powders are critical for an efficient tableting
operation. A good flow of the powder or granulation to be compressed
is necessary to assure efficient mixing and acceptable weight uniformity
for the compressed tablets.
 If a drug is identified at the pre-formulation stage to be "poorly
flowable,” the problem can be solved by selecting appropriate
excipients. In some cases, drug powders may have to be pre-compressed
or granulated to improve their flow properties.
 Some of these methods are angle of repose, flow through an orifice,
compressibility index, shear cell, etc.
ANGLE OF REPOSE
 The maximum angle which is formed between the surface of pile of
powder and horizontal surface is called the angle of repose.
 For most pharmaceutical powders, the angle-of repose values range
from 25 to 45°, with lower values indicating better flow characteristics.
??????????????????θ =
ℎ
??????

 Where,
­ h = height of heap of pile
­ r = radius of base of pile
C) DENSITIES
 The ratio of mass to volume is known as density.
TYPES OF DENSITY
i. Bulk density: It is obtained by measuring the volume of known mass of
powder that passed through the screen.
ii. Tapped density: It is obtained by mechanically tapping the measuring
cylinder containing powder.
iii. True density: It is actual density of the solid material without voids.
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iv. Granule density: Granule density may affect compressibility, tablet
porosity, disintegration, dissolution.
D) COMPRESSIBILITY

"Compressibility" of a powder can be defined as the ability to decrease
in volume under pressure and "Compactibility” as the ability of the
powdered material to be compressed into a tablet of specified tensile
strength.

It can be used to predict the flow properties based on density
measurement.
????????????????????????
?
?????? ??????????????????????????????=
?????????????????? ?????????????????????????????????????????? − ???????????????????????? ??????????????????????????????????????????
?????????????????? ??????????????????????????????????????????
?????? 100
E) CRYSTALLINITY
PHASE

Phase, in thermodynamics, chemically and physically uniform or
homogeneous quantity of matter that can be separated mechanically
from a nonhomogeneous mixture and that may consist of a single
substance or of a mixture of substances.

The three fundamental phases of matter are solid, liquid, and gas
(vapor), but others are considered to exist, including crystalline, colloid,
glassy, amorphous, and plasma phases. When a phase in one form is
altered to another form, a phase change is said to have occurred.
PHASE DIAGRAM

A phase diagram is common way to
represent the various phases of a
substance and the conditions under
which each phase exists.

A phase diagram is a plot of pressure
(P or ln P) vs temperature (T).

Lines on the diagram represent
conditions (T, P) under which a phase
change is at equilibrium. That is, at a
point on a line, it is possible for two (or
three) phases to coexist at equilibrium.

In other regions of the plot, only one phase exists at equilibrium.
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SOLIDS
 Solids are again classified in to two types:
­ Crystalline
­ Non-Crystalline (amorphous)
CRYSTALLINE SOLID
 A crystal or crystalline solid is a solid material, whose constituent atoms,
molecules, or ions are arranged in an orderly repeating pattern
extending in all three spatial dimensions. So a crystal is characterized by
regular arrangement of atoms or molecules.
 Examples:
­ Non-Metallic Crystals: Ice, Carbon, Diamond, NaCl, KCl etc.
­ Metallic Crystals: Copper, Silver, Aluminum, Tungsten, Magnesium
etc.
AMORPHOUS SOLID
 Amorphous (Non-crystalline) Solid is composed of randomly orientated
atoms, ions, or molecules that do not form defined patterns or lattice
structures.
 Amorphous materials have order only within a few atomic or molecular
dimensions.
 Examples:
­ Amorphous silicon, plastics, and glasses.
CRYSTAL PROPERTIES
 Zero entropy i.e. Highly ordered structure, Molecules/ atoms/ Ions are
orderly arranged in three dimensions
 Crystals have sharp melting points
 They have long range positional order
 Crystals are anisotropic (Properties change depending on the direction)
 It has symmetry, translation symmetry.
THE RELATION BETWEEN A CRYSTAL AND STRUCTURE AND ITS DIFFRACTION
PATTERN
OBVIOUS PROPERTIES
 Geometry: Regular arrangement of spots corresponding to directions of
beams of X-rays.
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 Symmetry: In positions and spots,
 Intensities: Wide variation with no apparent pattern except symmetry.
CRYSTAL STRUCTURE DIFFRACTION PATTERN
Unit cell geometry (lattice
parameters)
Diffraction geometry (directions,
positions)
Crystal symmetry (space group) Diffraction symmetry (Laue class)
Unit cell contents (atom positions) Intensities (amplitudes and phases)

TRANSLATION SYMMETRY IN CRYSTALLINE SOLIDS
 The characteristic property of the crystalline solid state is its high degree
of internal order: molecules (or atoms, or ions) are arranged in a regular
way in effectively infinite 3D repeat pattern, like 3D wallpaper
(theoretically, zero entropy). This repetition is translation symmetry. It is
always present in crystalline solids.
 Other kinds of symmetry (rotation, reflection, inversion, improper
rotation) may also be present.
 A complete crystal structure can be specified by describing the contents
of one repeat unit, together with the way in which this unit is repeated
by translation symmetry.
SYMMETRY OF INDIVIDUAL MOLECULES, WITH RELEVANCE TO CRYSTALLINE
SOLIDS
SYMMETRY ELEMENT
 A physically identifiable point, line, or plane in a molecule about which
symmetry operations are applied.
SYMMETRY OPERATION
 Each symmetry element provides a number (one or more) of possible
symmetry operations.
 For individual molecules, all symmetry operations can be classified as
one of two types:
­ Proper rotation: Rotation by 360°/n about a rotation axis.
­ Improper rotation: Combination of a rotation about an axis and a
simultaneous reflection in a perpendicular plane through the
center of the molecule.

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THE SEVEN CRYSTAL SYSTEM

CRYSTALIZATION

Crystallization is the (natural or artificial) process by which a solid forms,
where the atoms or molecules are highly organized into a structure
known as a crystal.

Some of the ways by which crystals form are precipitating from a
solution, melting, or more rarely deposition directly from a gas.
STEPS OF CRYSTALIZATION

Crystallization occurs in two major steps:
­ The first is nucleation, the appearance of a crystalline phase from
either a super cooled liquid or a supersaturated solvent.
­ The second step is known as crystal growth, which is the increase
in the size of particles and leads to a crystal state.
NUCLEATION

It is at the stage of nucleation that the atoms or molecules arrange in a
defined and periodic manner that defines the crystal structure.

"Crystal structure" is a special term that refers to the relative
arrangement of the atoms or molecules, not the macroscopic properties
of the crystal (size and shape), although those are a result of the internal
crystal structure.
CRYSTAL GROWTH

Size increase of nuclei, dynamic process occurs in equilibrium.
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 Supersaturation is one of the driving forces of crystallization. Depending
upon the conditions, either nucleation or growth may be predominant
over the other, dictating crystal size (crystal morphology).
F) POLYMORPHISM
POLYMORPHISM
 Many drug substances can exist in more than one crystalline form with
different space lattice arrangements. This property is known as
polymorphism.
 The different crystal forms are called polymorphs.
CO-CRYSTALS
 Supramolecular entities consisting of two or more molecular moieties
held together by weak non-covalent and non-ionic forces (e.g., hydrogen
bonding)
IMPLICATION IN PHARMACEUTICAL DRUG DEVELOPMENTAL PROCESS
 List of properties that differ among various polymorphs:
­ Packing properties
­ Thermodynamic
properties
­ Kinetic properties
­ Surface properties
­ Mechanical properties
­ Spectroscopic
properties
 Packing properties
­ Molar volume, density
­ Hygroscopicity
­ Refractive index
­ Conductive properties
 Thermodynamic Properties
­ Melting, sublimation
temperature
­ Internal energy
(structural energy)
­ Enthalpy
­ Entropy
­ Solubility
­ Heat capacity
­ Free energy, Chemical
potential
 Kinetic properties
­ Dissolution rate
­ Stability
­ Rate of solid state
reaction
 Surface properties
­ Surface free energy
­ Interfacial tension
­ Habit (i.e. shape,
morphology)
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 Mechanical properties
­ Hardness
­ Tensile strength
­ Compactibility,
tableting
­ Handling, flow,
blending
 Spectroscopic properties
­ Electronic transition
­ Vibrational
­ Nuclear spin transitions
POLYMORPH SCREENING
 Polymorph screening involves:
­ Solid raw material → Preparation of saturated solution →
Recrystallization → Use of seed crystal / Nucleation → Crystal
growth → Crystal selection.
TECHNIQUES / METHODS TO IDENTIFY POLYMORPHISM
 Following are the methods / techniques to identify polymorphism:
­ Powder X-ray Diffraction (PXRD)
­ Differential Scanning Calorimetry (DSC)
­ Thermogravimetric Analysis (TGA)
­ Raman Spectrophotometry
­ Nuclear Magnetic Resonance (NMR)technique
­ Fourier-Transform Infrared Spectroscopy (FTIR) technique
METHODS / TECHNIQUES TO IDENTIFY POLYMORPHISM
TECHNIQUES
ANALYSIS
TIME
SAMPLE
(mg)
DESTRUCTIVENESS PREPARATION IDENTIFICATION
PXRD 3–8 min 10–30 X Simple
Difficult to
differentiate the
mixtures, first-
line to analyze
polymorphs
DSC
20–
30 min
2–4 O Simple
Easy to detect
the mixtures
Thermodynamic
relationships
TGA
20–
30 min
∼10 O Simple
Existence of
solvates/hydrates
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Single crystal
X-ray
1–2 day
Single
crystal
O Difficult Definitive tool
FTIR (Pellet)
10–
20 min
3∼
(pellet)
O Difficult
Molecular
interactions
FTIR (ATR)
10–
20 min
10∼ X Simple
No sample
preparation
FTIR (Probe) 3 s 10 ∼ X Simple
On-line
monitoring
FT-Raman ∼20 min 10∼ O Simple
Molecular
interactions, HTS
FT-Raman
(Probe)
3 s 3 ∼ X Simple
On-line
monitoring
HSM
20–
30 min
2–3 X Simple
Visual
observation
NMR 1 h 20–30 O Difficult
Racemate,
Chirality

G) HYGROSCOPISITY
 Many compounds and salts are sensitive to the presence of water vapor
or moisture. When compounds interact with moisture, they retain the
water by bulk or surface adsorption, capillary condensation, chemical
reaction and, in extreme cases, a solution (deliquescence).
 Moisture is also an important factor that can affect the stability of
candidate drugs and their formulations.
 Sorption of water molecules onto a candidate drug (or excipient) can
often induce hydrolysis. In this situation, by sorbing onto the drug-
excipient mixture, the water molecules may ionize either or both of
them and induce a reaction.
3. SOLUBILITY ANALYSIS
 An important Physical-chemical property of a drug substance is
solubility, especially aqueous solubility. A drug must possess some
aqueous solubility for therapeutic efficacy in the physiological PH range
of 1 to 8.
 For a drug to enter into systemic circulation, to exert therapeutic effect,
it must be first in solution form. If solubility of drug substance is less
than desirable, than consideration must be given to increase its
solubility. Poor solubility (< 10mg/ml) may exist incomplete or erratic
absorption over PH rang 1-7 at 37°C.
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 A drug’s solubility is usually determined by equilibrium solubility
method, in which an excess of drug is placed in a solvent and shaken at a
constant temperature over a long time period until equilibrium is
obtained.
1. IONIZATION CONSTANT (pKA)
 Many drugs are either weakly acidic or basic compounds and, in
solution, depending on the pH value, exist as ionized or un-ionized
species. The un- ionized species are more lipid-soluble and hence more
readily absorbed.
 The gastrointestinal absorption of weakly acidic or basic drugs is thus
related to the fraction of the drug in solution that is un- ionized. The
conditions that suppress ionization favor absorption.
 The factors that are important in the absorption of weakly acidic and
basic compounds are the pH at the site of absorption, the ionization
constant, and the lipid solubility of the un- ionized species. These factors
together constitute the widely accepted pH partition theory.
 The relative concentrations of un-ionized and ionized forms of a weakly
acidic or basic drug in a solution at a given pH can be readily calculated
using the Henderson-Hasselbalch equations:
pH = pKa + log
[Un −Ionized form]
[ionized form]
for bases

pH = pKa+ log
[Ionized form]
[Un −ionized form]
for acids
METHODS FOR DETERMINATION OF pKa
 Methods for determination of Pka are:
­ Potentiometric Titration
­ Spectrophotometric Determination
­ Dissolution rate method
­ Liquid-Liquid Partition method
2. PARTITION COEFFICIENT
 The lipophilicity of an organic compound is usually described in terms of
a partition coefficient; log P, which can be defined as the ratio of the
concentration of the unionized compound, at equilibrium, between
organic and aqueous phases:
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????????????????????????=
(un ionized compound) organic
(un ionized compound) aquous

 This ratio is known as the partition coefficient or distribution coefficient
and is essentially independent of concentration of dilute solutions of a
given solute species.
METHODS OF FINDING PARTITION COEFFICIENT
 Methods of finding Partition coefficient are:
­ Shake-flask method
­ Chromatographic method
­ Counter current and filter probe method
­ Micro-electrometric-titration method
3. SOLUBILIZATION
 For drug candidates, with either poor water solubility or insufficient
solubility for projected solution dosage form, pre-formulation study
should include limited experiments to identify possible mechanism for
solubilization.
METHODS / TECHNIQUES FOR ENHANCING SOLUBILITY
A) pH ADJUSTMENT
 Poorly water soluble drugs may be dissolved in water by applying a pH
change. Applicable to both oral and IV products.
 Solubilized excipients that increase environmental pH within a dosage
form, (tablet or capsule), to a range higher than pKa of weakly-acidic
drugs increases the solubility of that drug, those excipients which act as
alkalizing agents may increase the solubility of weakly basic drugs.
 Advantages:
­ Simple to formulate, analyze, produce and fast track.
 Disadvantages:
­ Risk for precipitation, Tolerability and toxicity, less stable, The
selected pH may accelerate hydrolysis.
B) CO-SOLVENCY
 By the addition of a water miscible solvent in which the drug has good
solubility known as co-solvents. Most widely used technique. Can be
administered orally and parenterally.
 Examples:
­ PEG 300, propylene glycol, ethanol, glycerin, DSMO, DMA.
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 The bioavailability may not be increased because the poorly soluble drug
will typically uncontrollably crash out upon dilution into a crystalline or
amorphous precipitate. Hence, dissolution of this precipitate is required
for oral absorption.
 Advantages:
­ Simple and rapid to formulate and produce.
 Disadvantages:
­ The toxicity and tolerability, Uncontrolled precipitation, the
chemical stability of the insoluble drug is worse than in a
crystalline state.
C) PARTICLE SIZE REDUCTION
 Bioavailability intrinsically related to drug particle size; Reduction =
milling techniques, micro-ionization, nanosuspension.
 Not suitable for drugs having a high dose number because it does not
change the saturation solubility of the drug.
 Advantages:
­ Low excipient to drug ratios is required, Formulations are
generally well tolerated, Crystal forms are more stable.
 Disadvantages:
­ Particle agglomeration, Challenges (sterile IV formulations, high
pay load).
D) MICROEMULSION
 For drugs - practically insoluble in water; along with incorporation of
proteins for oral, parenteral, as well as percutaneous / transdermal use.
 Composed of oil, surfactant and cosurfactant and has the ability to form
o/w microemulsion when dispersed in aqueous phase under gentle
agitation.
 Advantages:
­ Pre-concentrates are easy to manufacture, Optimal bioavailability
and reproducibility can be expected.
 Disadvantages:
­ Precipitation, Formulations containing several components
become more challenging to validate.
E) MICELLER SOLUBILIZATION
 Use of surfactants to improve dissolution performance of poorly soluble
drugs.
 Lower surface tension and improve the dissolution of lipophilic drugs in
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aq. Medium, Stabilize drug suspensions.
 When the conc. of surfactants exceeds their critical micelle
concentration (Range of 0.05-0.10%), micelle formation occurs,
entrapping the drugs within the micelles. Results in enhanced solubility
of poorly soluble drugs.
 E.g. Non-ionic surfactants (Polysorbates, castor oil, and mono- and di-
fatty acid esters of low molecular weight polyethylene glycols).
F) COMPLEXATION
 Complexation of drugs with cyclodextrins (6, 7 or 8 dextrose molecules
(α, β, γ-cyclodextrin) bound in a 1,4- configuration to form rings of
various diameters) - enhance aqueous solubility and drug stability.
 Ring has a hydrophilic exterior and lipophilic core in which appropriately
sized organic molecules can form noncovalent inclusion complexes
resulting in increased aqueous solubility and chemical stability.
 Derivatives of β-cyclodextrin with increased water solubility are most
commonly used.
 Limitation:
­ Compounds with very limited solubility to start with, solubility
enhancement can be very limited.
­ The second limitation is the complexes may still result in
precipitation.
G) SUPERCRITICAL FLUID (SCF) PROCESS
 A SCF exists as a single phase above its critical temperature (Tc) and
pressure (Pc), Low operating conditions (temperature and pressure)
make SCFs attractive for pharmaceutical research.
 Intermediate between those of pure liquid and gas. Moreover, the
density, transport properties, and other physical properties vary
considerably with small changes in operating temperature, pressure, or
both around the critical points.
 Examples of supercritical solvents: CO2, nitrous oxide, ethylene,
propylene, propane, n-pentane, ethanol, NH3, H2O.
 Processing:
­ Precipitation with compressed antisolvents process (PCA), Rapid
Expansion of Supercritical Solutions, Gas Antisolvent
Recrystallisation, Solution enhanced Dispersion by Supercritical
Fluid, solution enhanced dispersion by SCF (SEDS), supercritical
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antisolvents processes (SAS) and aerosol supercritical extraction
system (ASES).
H) SOLID DISPERSION
 A poorly soluble drug is dispersed in a highly soluble solid hydrophilic
matrix, which enhances the dissolution of the drug.
 Yield eutectic (non-molecular level mixing) or solid solution (molecular
level mixing) products.
 Methods:
­ Fusion (melt) method and the solvent method.
I) HYDROTROPHY
 Solubilization process whereby addition of a large amount of second
solute results in an increase in the aqueous solubility of another solute.
 Solute consists of alkali metal salts of various organic acids. Several salts
with large anions or cations that are themselves very soluble in water
result in “salting in” of non-electrolytes called “hydrotropic salts” a
phenomenon known as “hydrotropism”.
 Advantages:
­ Superior to other solubilization method because the solvent
character is independent of pH.
­ Only requires mixing the drug with the hydrotrope in water.
­ Does not require chemical modification of hydrophobic drugs, use
of organic solvents, or preparation of emulsion system.
4. THERMAL EFFECT
 Thermal effect is the effect of temperature on the solubility of drug
candidate. This can be determined by measuring heat of solution i.e. HS
??????????????????=
∆????????????
??????
(1)+??????
??????

 Where,
­ dC/dt = dissolution rate
­ S = molar solubility at temp. T (° K)
­ R = gas constant
5. COMMON ION EFFECT
 The common-ion effect refers to the decrease in solubility of an ionic
precipitate by the addition to the solution of a soluble compound with
an ion in common with the precipitate.
 The common ion effect is the phenomenon in which the addition of an
ion common to two solutes causes precipitation or reduces ionization.
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 An example of the common ion effect is when sodium chloride (NaCl) is
added to a solution of HCl and water.
6. DISSOLUTION
 In many instances, dissolution rate in the fluids at the absorption site, is
the rate limiting steps in the absorption process. This is true for the drug
administered orally in the solid dosage forms such as tablet, capsule, and
suspension and IM drugs.
 Dissolution rate can affect the onset, intensity, duration of response and
control overall bioavailability of the drug from dosage form.
INTRINSIC DISSOLUTION
 The dissolution rate of a solid in its own solution is adequately described
by the Noyes-Nernst equation:
????????????/????????????=
???????????? (??????
?− ??????)
ℎ??????

 Where,
­ A = surface area of the dissolving solid
­ D = diffusion coefficient
­ C = solute concentration in the bulk medium
­ h = diffusion layer thickness
­ V = volume of the dissolution medium
­ Cs = solute concentration in the diffusion layer
PARTICULATE DISSOLUTION
 It determines dissolution of drug at different surface area. It is used to
study the influence on dissolution of particle size, surface area and
mixing with excipient. So, if particle size has no influence on dissolution
than other method like addition of surfactant will be considered.
FACTORS AFFECTING DISSOLUTION
 Dissolution is affected by:
­ Particle size
 Dissolution rate of drugs may be increased by decreasing
the drug’s particle size.
­ Solubility
 Dissolution rate of drugs may be increased by increasing its
solubility.
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METHODS FOR DETERMINATION OF DISSOLUTION RATE
 The dissolution rate of chemical compound is determined by two
methods:
­ Constant surface method
­ Particulate dissolution
4. STABILITY STUDIES
 Stability is an extent to which a product retains within specified limits
throughout its period of storage and use (shelf life).
TYPES OF STABILITY
 There are five types of stabilities:
­ Chemical stability
 Each ingredient retains its chemical integrity and labelled
potency within specified limits.
­ Physical stability
 The original physical properties including appearance,
palatability, uniformity, dissolution and suspendibility are
retained.
­ Microbiological stability
 Sterility or resistance to microbial growth is retained
according to specified requirements.
­ Therapeutic stability
 Therapeutic effect is retained, unchanged.
­ Toxicological stability
 No significant increase in toxicity, stability study before
formulation.
STABILITY STUDIES
 Stability studies on different phases:
­ Solid State Stability Studies
 Solid state reactions are much slower and more difficult to
interpret than solution state reactions, due to a reduced no.
of molecular contacts between drug and excipient
molecules and to the occurrence of multiple phase
reactions.
­ Solution State Stability Studies
 It is easier to detect liquid state reactions as compared to
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solid state reactions.
­ Drug-Excipient Compatibility Studies
 In the tablet dosage form the drug is in intimate contact
with one or more excipients; the latter could affect the
stability of the drug.
CHEMICAL CHARACTERISTICS
1. HYDROLYSIS
 It involves nucleophilic attack of labile groups. E.g., lactam, ester, amide,
imide. When the attack is by the solvent other than water, then it is
known as solvolysis.
 It generally follows 2
nd
order kinetics as there are two reacting species,
water and API. In aqueous solution, water is in excess so the reaction is
1
st
order.
PREVENTION OF HYDROLYSIS
 pH adjustment
 Using salts and esters
 Addition of surfactant
 Store with desiccant
 Use of complexing agent
2. OXIDATION
 It is a very common pathway for drug degradation in liquid and solid
formulations.
 Oxidation occurs in two ways
­ Auto- oxidation
 Occurs within compound (solid) molecule O2.
­ Free radical chain process
 Steps involved are initiation, propagation, H2O2
decomposition, termination.
 Functional groups susceptible for oxidation:
­ Alkenes, amines, anisole, toluene, phenol, ethenes.
 Factors involved in oxidation:
­ Oxygen concentration
­ Temperature
­ Hydrogen and OH group
­ Heavy metals
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PREVENTION OF OXIDATION
 Reducing O2 content (boiling water)
 Storage in dark and cool condition
 Adding anti-oxidants.
3. REDUCTION
 Reduction is a relatively more common pathway of drug metabolic
process.
 Hepatic microsomes catalyze diverse reductive chemical reaction and
require NADPH for this purpose.
4. PHOTOLYSIS
 Electrons of drug compound absorb light (artificial or sunlight) and move
to excited state from ground state.
 The drug then decomposes and emit that light and move back to ground
state.
 Photosensitization: Energy is not absorbed by molecule itself but pass to
other atom, this cause cellular damage inducing formation of radicals.
PHOTO DECOMPOSITION PATHWAY
 N-dealkylation
 Dehalogenation
 Dehydrogenation of ca
++
channel blockers
 Decarboxylation in anti-inflammatory drugs
 Oxidation
 Isomerization and cyclization
 Rearrangement
PREVENTION OF PHOTOLYSIS
 Photolysis can be prevented by:
­ Suitable packing
­ Antioxidant
­ Protection of drug from light
­ Avoiding sunbath
­ Photostabilizer
5. POLYMERIZATION
 It is a continuous reaction between molecules. More than one monomer
reacts to form a polymer.
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 E.g. Darkening of glucose solution is attributed to polymerization of
breakdown product [5- (hydroxyl methyl) furfural].
6. RACEMIZATION
 The interconversion from one isomer to another can lead to different
pharmacokinetic properties (ADME) as well as different Pharmacological
and toxicological effect.
 Example
­ L-epinephrine is 15 to 20 times more active than D-form, while
activity of racemic mixture is just one half of the L-form.
 It follows first order kinetics and depends on temperature, solvent,
catalyst and presence or absence of light.

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PRODUCT FORMULATION
INTRODUCTION
 The process in which different chemical substances, drug(s) and
excipients, are combined to fabricate a final medicinal product of a
desired dosage form i.e. syrup, tablet, capsule, injectable liquid or
powder etc. is known as product formulation.
 A dosage form is the physical form of a dose of a drug intended for
administration or consumption. Pill, tablet, or capsule, liquid, aerosol or
inhaler, liquid injection, pure powder or solid crystal etc. The route of
administration for drug delivery is dependent on the dosage form of the
substance in question.
STEPS IN PRODUCT FORMULATION
 Following are the steps in product formulation:
­ Finding the lead compound
­ Pre-clinical evaluations
­ Clinical trials Phase I – III
­ New drug application
­ Post marketing surveillance
ADVANCE FORMULATION APPROACHES
CONVENTIONAL DRUG DELIVERY SYSTEMS
 Usually, the conventional drug delivery systems have different issues.
PHARMACEUTICAL PROBLEMS
PREPARATION WITH THE CONVENTIONAL FORMULATION APPROACHES
 The conventional delivery systems are prepared using the conventional
methods.
UNPALATABILITY
 Unpleasant taste is masked by microencapsulation or coating with
appropriate film forming substances.
GASTRIC IRRITATION AND PAIN
 Several drugs, such as nonsteroidal anti-inflammatory cause gastric
irritation, pain or harmful for gastric tissues. Elimination of the problem
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can decrease pain and harm and enhance safety and patient
acceptability for a dosage from.
INSOLUBILITY
 Drug insolubility shows problem during drug manufacturing and after
administration. New formulation technologies, such as particulate
delivery system, nanoparticles, microspheres, solid dispersion, co-
grinding, etc. enhance drug solubility.
INSTABILITY
 In vitro drug instability and reaching a drug intact to the blood are
important or drug efficacy. Presenting a drug in a particulate delivery
system or specific targeting dosage form improves the vitro or in vivo
stability of drug.
DRUG RELEASE WHICH COULD NOT BE CONTROLLED
 The conventional delivery system are usually the fast or immediate drug
delivery systems and their drug release time or place could not be
controlled.
PHARMACOKINETIC PROBLEMS
POOR DRUG ABSORPTION DUE TO PHYSIOLOGICAL BARRIERS
 Novel drug delivery systems can address the issue of the lower drug
absorption.
POOR DRUG DISTRIBUTION
 The drug distribution may be altered by surface modification or by
targeting an appropriate site in body.
UNRESTRICTED DISTRIBUTION
 Unrestricted drug distribution exposes the normal tissues unnecessarily.
This can be controlled by modifying the release or by targeted drug
delivery system.
IMPERMEABILITY OF DRUG
 An impermeable drug shows lower or erratic bioavailability. This can be
improved using appropriate drug delivery system, such as lipid based
drug delivery.
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RAPID METABOLISM
 Drug metabolism can be modified by presenting drug as a prodrug, or
targeted drug delivery system. Surface modification can lead to
decreased metabolic inactivation.
RAPID CLEARANCE
 Drug elimination can be modified by a concept of prodrug, surface
modification or drug targeting to appropriate site.
SLOW CLEARANCE
 Drug elimination can be modified by a concept of prodrug, surface
modification or drug targeting to appropriate site.
PHARMACODYNAMICS ISSUES
SHORT ACTION
 Some drugs have short duration of action and thus, require frequent
drug administration. Drug release can be modified for their longer stay
in body.
TOXICITY PROBLEMS
 The drug biodistribution related toxicity issue can be engineered using
appropriate novel technologies.
ADVANCE FORMULATIONS
 Advance pharmaceutical formulation is a dosage form which
demonstrates the optimized properties, robust and without the
drawbacks associated with the conventional dosage forms.
 The categories of the advanced formulation technologies are given in
the following:
­ Drug carrier systems (Particulate system)
­ Prodrug
­ Particulates (liposomes, niosomes, nanoparticles)
­ Lipid based
­ Microchip based
­ Biosensor-based delivery system
­ Bioadhesive
­ Antigen-target delivery system
­ Novel GIT delivery systems
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FORMULATION DESIGN AND DEVELOPMENT
 A drug, active pharmaceutical ingredient (API) or active pharmaceutical
moiety (APM) is seldom given as such, rather is given as a formulation or
drug delivery system.
 The pharmaceutical delivery systems are designed and developed to
meet the required specifications and desirabilities. For instance, it must
have efficacy, safety and elegance. Furthermore, it must maintain
stability and other product quality attributes.
 A pharmaceutical formulation contains active pharmaceutical
ingredient(s) and several non-active ingredients, called as excipients.
Each excipient is added in a formulation to impart certain properties in
the formulation.
 A formulation therefore, is prepared according to certain recipe
(formula) where the specific amounts of ingredients are added,
processed and adjusted to obtain the desired properties, characteristics
or specifications in the formulation.
 A product that has the desired characteristics and meets all the
specifications is called an optimized formulation. The pharmaceutical
formulations are attempted to be optimized systems where all the
properties (quality attributes) are adjusted to certain desired values,
may be quantitative (numeric) or qualitative (maximum or minimum).
 The development of a formulation is usually a complicated process.
During the development process, the choice of excipients and their
levels (amounts), as well as the conditions of manufacturing process are
optimized as a result of intensive and time-consuming experimentation
where series of formulations are prepared.
 As the number of ingredients increases the formulation becomes more
and more complex because of the involvement and the possible
interactions of various ingredients which collectively effect the final
formulation.
FORMULATIONS AS SYSTEMS OF FACTORS (INPUTS) AND PROPERTIES
(OUTPUTS)
 Typically, the ingredients interact and consequently, products’
properties depend on and governed by exact ratios of the ingredients.
The processing of the ingredients also affects product properties.
 A formulation can be defined as a system of inputs (factors) and the
outputs (properties of the product). The physical properties of the
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formulation are determined by the physicochemical properties of the
component excipients and the process of manufacturing.
 The formulative ingredients and the processing methods are considered
as an integral part of the products’ formulation.
 These formulation properties can be influenced by changing the
proportions of the excipients and/or by changing the conditions of the
manufacturing process.
FACTORS AFFECTING PRODUCT PROPERTIES (QUALITY ATTRIBUTES)
 Following are the several categories of factors affecting the properties of
a pharmaceutical formulation.
RAW MARTIAL-RELATED (PHYSICOCHEMICAL) FACTORS
 The raw material related factors include the physical and chemical
characteristics and properties of the raw materials which may affect the
properties of the product.
 For example: the crystalline or amorphous nature, solubility, pH, etc. of
the raw materials. Sometimes, the sources of the raw materials also
affect the final properties of the formulation.
MACHINE-RELATED FACTORS
 Material-related factors include the factors related to machines used in
the manufacturing of a certain formulation.
 For example, for tablets the speed of the tablet machine may affect the
properties of the tablets.
PROCESS-RELATED FACTORS
 Process-related factors are the factors related to the process used in the
manufacturing of the product.
 A change in the process may influence the outcome of the final
formulation.
 The variables (factors) of a formulation system are controllable,
uncontrollable and may be known or unknown.
 The uncontrollable factors are the major cause of variability in outputs’
properties.
 The ingredients of a formulation are the causes and affect the resulting
properties (effects) of the formulation. This has led to a theory, called
cause and effect model.
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CAUSE-AND-EFFECT MODEL
 In a “cause-and-effect” model, the transformation of a system
(ingredients) into an output (product) depends on the way the external
factors interact with the internal components of a system.
 Four types of interactions between internal and external factors can be
proposed:
­ Transformation
­ Partial transformation
­ No transformation
­ Unfavorable
transformation
FAVORABLE INTERACTION
 The favorable interaction of the factors leads to a desired output. The
factors in this case are called as the active factors.
 An emulsion, for example with desired stability would be obtained from
an interaction of the polarity of the solvent (internal factor of the
dispersion phase) and the value of hydrophilic-lipophilic balance (HLB) of
the emulsifying agent which is an external factor.
PARTIAL INTERACTION
 A partial interaction transforms input system into output with partially
acceptable profiles or properties.
 An anionic surfactant may not for example turn dispersion into a stable
emulsion due to a partial interaction of polarity of solvent and HLB value
of the emulsifying agent.
NO INTERACTION
 When there is no interaction of the external and internal factors, the
system remains unaltered.
 The factors in this case are the non-factors or non-active factors. One
type of material, sometime cannot transform the inputs into outputs.
UNFAVOURABLE INTERACTION
 When the interaction is unfavorable, the output has unfavorable
features. This type of interaction is also called as the negative
interaction.
FDA guidelines of Industry (2006) and equivalent authorities of several
countries recommend the understanding of the cause-and-effect relationship
to accomplish products of desired quality attributes by the computer aided
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approaches called as design of experiment (DoE), artificial neural network
(ANN). Quality by design (QBD) and the process analytical technique (PAT) are
the components of DoE and ANN.
FORMULATIONS METHODOLOGIES
TRADITIONAL FORMULATION APPROACH
 The traditional or the conventional approach for pharmaceutical
formulation is based on the trial and error, where the focus of
formulation is the adjustment of one individual factor at a time while
fixing all other factors. The adjustment of the individual factor is usually
based on the experience of the formulator.
 Gaining knowledge of the relationships between the factors and
response is not emphasized in the conventional approach. Thus, the
formulations resulting from the traditional approach are also called as
the experience-based formulations.
 The desired properties of formulation are obtained by changing one
factor and holding all others fixed. Some initial experiments with
selected levels of the ingredients based on the experience are carried
out. The succeeding experiments are based on the results obtained after
each experimentation in the direction of increase (or decrease) of the
response (properties).
 In this way a maximum (or minimum) of property is reached. Since in
this approach, the factors for product properties are optimized one by
one, the approach is also called as one factor at a time (OFAT)
approach. This is called as the sequential approach of formulation
development.
 After formulating a product, if it is not the desired one, then the center
of attention is another, but one specified factor. One by one, by
controlling the other factors at a constant level, effort is made to
accomplish a desired product/formulation in OFAT approach.
 With the OFAT approach, optimized output could not be obtained. The
reason for OFAT failure is that the multiple responses (properties) of a
product are related differently to factors. The traditional OFAT approach
has certain other limitations.
LIMITATIONS OF THE TRADITIONAL APPROACH
 In OFAT, the experimental process is unplanned and based on hit and
trial.
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 Approach is less effective since it may improve but never approaches to
the optimal setting of the factors and properties.
 Development is sequential where the factors are adjusted one by one
for each product property.
 OFAT is unable to estimate effect of each factor independent of the
existence of the effect of other factors. Thus, the factor interaction
remains unrevealed.
 This approach cannot obtain the information on two factor interactions,
which may be synergistic or antagonistic.
 OFAT requires larger number of experimentations to obtain information
helpful to make formulation decision
 The product of OFAT is not knowledge-based.
 OFAT is time consuming, laborious and costly.
 The OFAT approach cannot help in achieving a produce with aspirational
or desired quality.
COMPUTER-AIDED FORMULATION
 Computer-aided formulation or artificial intelligence-based formulations
are new approaches and powerful tools for pharmaceutical formulation
which work by using the artificial intelligence and computational
approaches.
 These are coupled with visualization and statistical validation and robust
optimization methods. Currently, design of experiment (DoE) and
artificial neural network (ANN) strategies have found rapidly increasing
applications in optimization against classical OFAT approach. These
approaches require computerized decision support systems that
recognize relationship existing between the factors and the responses.
 Computational approaches can reduce the formulators’ effort by
automatically generating knowledge (of relationships between factors
and responses) directly from data, which are obtained from the planned
experimentation using different settings (levels) of the factors. Thus, the
resulting formulations are called as the knowledge-based formulations.
 The newer approaches allow simultaneous optimization of all properties,
thus are also called as the simultaneous optimization approaches. Such
approaches plan the complete set of experiments, called as
experimental design or matrix beforehand.
 This matrix is generated by the mathematical and statistical algorithms
in DoE by providing a range of the levels of the factors. However, this
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matrix system is not a requirement for the ANN approach.
 The number of experiments is based on the number of factors and
precision in prediction for the optimized levels of the factors. The
experiments are carried out according to the plan (matrix or grid), the
data are entered in a decision support system (software) and the results
are fitted to a mathematical model.
 The response values can be predicted by using a range for the settings of
variables (formulative, process and machine). A wide range of possible
choices (factor settings) is available for a product in a matrix.
ADVANTAGES AND APPLICATIONS OF THE ADVANCED APPROACHES
FORMULATION DESIGN FOR COMPLEX FORMULATIONS
 The complex formulations, which have several properties or several
factors are the major candidates for such approaches.
DEVELOPMENT OF NEW PRODUCTS
 The new products for which much information or experience is not
available can easily be developed using these approaches.
REVEALING OF THE INTERACTION BETWEEN DIFFERENT VARIABLES
 The advanced formulation approaches reveal interactions between the
factors which may be antagonistic or synergistic for a particular
property.
 Information could be obtained by which, a factor may totally be
excluded from the system without compromising on the quality of the
product. This is called as the breakthrough which can only be achieved
with the computer-aided formulation approaches.
ENHANCEMENT OF PRODUCT QUALITY AND PERFORMANCE AT LOW COST
 The advanced approaches require lesser number of experiments for
optimization of a product or process thus require lesser materials and
time for the optimized formulation development.
SHORTER TIME TO MARKET
 Since an optimized product can be developed with lesser time, the
product can be placed in market in a shorter time. This could provide an
edge in the market competition.
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IMPROVED CUSTOMER RESPONSE
 With the improved quality products, the consumers have more
confidence on the product.
IMPROVED COMPETITIVE EDGE
 Lesser time for a research product from bench to bedside, improved
product quality and the improved consumer confidence in the product
leads to the improved competitive edge for a pharmaceutical company
that uses computer-aided approaches.
RECOMMENDED BY FDA/EQUIVALENT REGULATORY AUTHORITIES
 The use of the advanced formulation approaches is recommended by
FDA, equivalent regulatory authorities of several countries and the
standard setting organizations for formulation design, process validation
and developing control plans.
REGULATORY FLEXIBILITY
 The regulatory authorities recommend the use of advanced approaches
because these generate the “design space”.
 Re-working on the factor levels demonstrated within the design space is
not considered as a “change” in product or process, which would not
initiate a regulatory post approval change process.
 Thus, these approaches provide a regulatory flexibility which is a great
incentive for pharmaceutical industry
ROLE IN SCALE-UP AND POST APPROVAL CHANGE (SUPAC)
 The advanced computer-aided approaches provide information which
are helpful for appropriate scale up of the products. Due to the
generation of design space, the post approval changes are also possible
without initiating the investigational new drug (IND) or new drug
application (NDA).
MISCELLANEOUS APPLICATIONS
 Due to the above advantages, the advance formulation approaches have
wide applications in the following field:
­ Formulation design for pharmaceutical products
­ Optimization of pharmaceutical formulation
­ Optimization of pharmaceutical process
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­ Pharmaceutical process validation
­ Industrial scale up
­ Cost reduction
NEED OF THE ADVANCED FORMULATION APPROACHES
 The failure of the traditional approaches to optimize the output has
created the need for the use of advanced formulation approaches.
 Coping with the following is becoming increasingly difficult for the
pharmaceutical formulations by the traditional approaches:
­ Increasing pressure for developing new products quickly to cope
with market competition
­ Products with more stringent quality standards
­ Partial or totally unavailability of historical knowledge for the new
formulations
­ The task of formulation is complex because there is often no
model for detailed understanding of how changes in formulation
ingredients affect product properties. Data generated during
optimization process is huge and difficult to understand.
­ Optimization process is multi-dimensional (some properties are
required to be minimum while others to be maximum).
­ Existence of opportunity to improve the formulation operations
and resulting profitability by streamlining the formulation design
tasks.
­ Formulation requires experimentation which is expensive in terms
of laboratory and staff time and in terms of opportunities missed
through slow response to new customer requirements
­ Use of the advanced formulation approaches has been
recommended by the FDA, regulatory authorities and standards
setting organizations.
­ Recently, the drug regulatory authority of Pakistan (DRAP)
requires QBD data in a document called as the common technical
document (CTD). The CTD has all the required information on a
product and is submitted to DRAP for evaluation for the product
registration.
DESIGN OF EXPERIMENT
 Design of experiment (DoE) is one of the computer-aided approaches
which is carried out systematically, identifies critical variables, reveals
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factor interactions and helps obtain combinations of variables to
accomplish optimum response with lesser number of experiments.
 DoE is statistical approaches using the algorithms, which are based on
the following components:
FACTORIAL ANALYSIS AND THE ANALYSIS OF VARIANCE (ANOVA)
 The factorial analysis and the ANOVA give the information on the
statistically significant factor(s) and their interactions, individually for all
properties included in a study.
PRINCIPLE COMPONENT ANALYSIS (PCA)
 The PCA supplements the findings of the ANOVA and shows the
principle, major and core factors for the individual properties.
POLYNOMIAL REGRESSION
 The regression is used to predict the best combination of the factors to
forecast the best properties.
RESPONSE SURFACE METHODOLOGY (RSM)
 The RSM composes of several mathematical algorithms which help in
the optimization of the properties. In this approach, two factors are
related simultaneously to a given property to show their combined
effect on the property.
 This DoE approach finds the relationship between the factors and
properties statistically.
EXPERIMENTAL STRATEGY FOR FORMULATION DESIGN IN DOE
 Though a general procedure to execute DoE is available, yet this can be
applicable to ANN as well.
 The different phases in the DoE procedure are the discovery,
breakthrough, optimization, and validation (confirmation).
DISCOVERY
 Discovery studies has two components, brain storming and pilot study.
Discovery is the first step in DoE, where all the possible factors which
may affect the formulation are considered.
 Brainstorming on the problem under study is the basic tool which is
carried out in a group of experts. Ishikawa Fishbone diagram is used as a
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team brainstorming tool to evoke ideas for as maximum as possible
factors (causes) which may affect a particular output.

The property/response is placed at the right of a straight line which is
called as spine or backbone.

Categories of the factors are drawn and connected to the backbone
through angled lines in such a way that the illustration resembles a
fishbone. Thus, a fishbone graphically explains all the possible factors of
a particular property.

The factors are classified as the real variables (values of which can be
changed), fixed variable (values which can be changed but deliberately
fixed due to technologic limitations). Uncontrollable factors are beyond
control in an experiment. If the factors are known and their number is
up to 3, then RSM is carried out directly.

When the factors are more than three and their ranges are unknown, a
range finding pilot study is carried out to find the range of factors.
Usually, a wider range of a factor is selected to capture the effect of
change in the amounts (levels) of the factor on the property). However,
usually there is a restriction on the upper limit due to the toxicity or
other pharmaceutical issues.
BREAKTHROUGH STUDIES

Screening studies under breakthrough phase are more statistically-
intensive and planned than pilot study. Screening study helps narrowing
down the large number of factors to a few critical factors.

In screening study, a factor can be studied at 2-levels, lower and higher.
In this simplest study, the number of experimental runs is minimum. Full
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factorial, optimal, Plackett-Burman or Taguchi design use more levels of
a factor and have own advantages or limitations.
 This phase of DoE is called as breakthrough because usually the factors
which are considered theoretically the most important for a property are
revealed to be otherwise.
OPTIMIZATION
 Optimization of the properties is carried out using RSM. Several tools
available under RSM are central composite design, Box Behnken, 3-
fatorial level and optimal design.
 These designs generate different matrix (a planning to perform
experiments) for different levels of factors for RSM. Sometimes an
experiment performed without matrix is analyzed using data’s “history”
for RSM.
VALIDATION
 Under validation, based on the predicted levels of factors given for
predicted optimized properties of a formulation, a real formulation is
manufactured.
 An agreement between the predicted and the real formulation
properties at the suggested factor level is the success. Sometimes, the
output is not achieved according to the prediction. In this case, design
augmentation is employed, which simply may be addition of another
factor level in the previous factor levels or can be replication of whole
design.
 Statistical approach becomes more difficult for more than three or four
inputs since the formulator is tempted to oversimplify the problem in
order to model it.
 Statistics also often requires the assumption of a functional form (for
example, linearity) in order to generate a model and such assumptions
can be inappropriate for complex tasks like formulation.
ARTIFICIAL NEURAL NETWORK
 Alternative to statistical approach, artificial neural network (ANN), a
biologically inspired mathematical construct (algorithm) mimics the
learning of human brain through modeling of and pattern recognition
within data.
 In ANN, the complexity of biological neural architect is highly abstracted
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as enormous processing elements (PEs), analogous to neurons (called
artificial neurons, nodes or units) connected to other PEs, comparable to
synapse through coefficients (weights), similar to signal strength
(threshold) and the outputs representing axons.
BIOLOGICAL NEURONS AND THEIR ANALOGOUS IN ARTIFICIAL NEURAL
NETWORK
BIOLOGICAL NEURONS ARTIFICIAL NEURAL ANALOGOUS
Neuron Processing elements/nodes/units
Synapse Node to node connection
Signal strength (threshold) Weights/coefficients
Axons Outputs
Dendrites Inputs
Learning Training (process of finding cause-
and-effect relationship within a given
data)
Complex functionality Highly abstracted (simplified)
Slow speed Fast speed
Numerous neurons (n=10
9
) Few neurons (n=10
2
– 10
3
)

 Pattern of connectivity among the ANN units is equivalent to a
mammalian neural architect. A typical ANN forms input and output
layers and at least one or more hidden layers.
 ANN works by reducing the error between observed and predicted
outcomes by adjusting the weight. Like biological neural learning, it
acquires knowledge from a learning process responsible for adapting the
connection strength (weight value) to input stimuli.
 Mathematically, it detects the underlying patterns in data that
recognizes the functional relationships between factors and responses
and predicts optimum levels of factors from a limited input data.
 Finding the relationships between the cause-and-effect is called the
training. ANNs are particularly suitable for complex and non-linear
systems for which the conventional approach is more exhausting.
 Use of ANN for optimization does not require any prior knowledge. The
neural network makes no assumptions about the functional form of the
relationships; it simply generates and assesses a range of models to
determine one that best fits the experimental data provided to it. As
such, increasingly, (ANNs) are used to model a complex behavior in
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problems like pharmaceuticals formulation and processing. The models
generated by neural networks allow “what if” possibilities to be
investigated easily. Even lesser number of experimentations is required
in ANN, than that required by DoE.
ASSOCIATED TERMINOLOGY WITH COMPUTER-AIDED FORMULATIONS
QUALITY BY DESIGN
 Quality by design (QBD) is a structured and organized method for
determining relationship between factors affecting a process and the
response(s)/of that process.
 Under QBD, a thorough investigation of the variables associated with
materials, product design, process, etc. is necessary for understanding
effect of factors and their interactions on the outputs by designed set of
experiments to achieve outputs with desired and predefined
specifications.
 QBD helps achievement of certain predicable quality with desired and
predetermined specifications through relating critical material attributes
and critical process parameters to critical quality attributes of drug
product.
 Simply, the QBD provides understandings for process, output (product)
and process control. For QBD the first step is to set the predefined
objectives, standards and specifications.
 The main aim of QBD is to achieve a product according to or as close as
possible to the desired quality attributes. The QBD uses multivariate
experiments to understand product and process to establish a design
space through design of experiment.
 QBD for health products is required by US FDA and the equivalent
authorities of several countries. The real cause-and-effect or the effect
of factors and factor interaction is difficult to understand with the
conventional ‘hit and trial’ approach which is termed as one factor at a
time (OFAT) approach.
 The QBD is achieved by the computer-aided approaches such as design
of experiment (DoE) or DoE-combined with artificial neural network
(ANN).
 QBD is included in the regulatory quality system. In 2000s, QBD was
introduced where the quality is to be achieved by design and is habitual
using 6-sigma process capability, or better.
 Limitations includes the difficulty in accomplishing, and the lack of
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acceptance by Pharmaceutical industry. QBD was introduced under ICH.
ICH guidelines Q8 (on Pharmaceutical Development), Q9 (on Quality Risk
Management), and Q10 (on Pharmaceutical Quality System) assist
manufacturers to implement Quality by Design into manufacturing
operations or process development. QBD relies on the concept of design
space.
PROCESS ANALYTICAL TECHNIQUE
 The process analytical technique (PAT) is the system for designing,
analyzing and controlling manufacturing through timely measurements,
during processing of critical quality and performance attributes of raw
materials and processes with the goal of assuring final product quality.
 Risk assessment of the critical processing variables is also noted for
process under PAT. The critical processing variables or the control points
in the entire process under study are the subtasks of a complex
operation that is used to measure the success or failure of whole
operations.
 The specifications of the chosen critical points are pre-defined to which
the results of measurements during processing are matched to decide
about the proceeding of error-free process.
 PAT for health products is required by US FDA and the equivalent
authorities of several countries. Like QBD, the PAT is accomplished by
the design of experiment (DoE) or DoE-combined with artificial neural
network (ANN). Six sigma (6σ) is related terminology to QBD and PAT.
 Six sigma is the accomplishment of a level of quality of outputs
(products) where the number of defects are not more than 3.4 per
million produced. This is near zero defect in products. This is a level of
quality where 99.9997% of the products are free of defect and thus are
called as products with near zero defects.
 With the help of QBD and PAT employing DoE and ANN, it is now
possible to achieve such products with 6σ quality. FDA and other
equivalent drug regulatory authorities are requiring now the use of all
these approaches to improve the quality of the drugs and medical
devices.
 The innovative pharmaceutical companies are measuring their overall
performance using QBD, PAT and 6σ approaches, which was earlier
based on quality assurance, quality control, current good manufacturing
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practices, and the total quality concept. QBD, PAT and 6σ have emerged
as the new GMP’s concepts for the 21
st
Century.
MULTI-OBJECTIVE OPTIMIZATION
 Closeness of the properties of a product to its pre-set (desired) criteria
for the critical attributes is called optimization. Optimization is achieving
the desired properties of a product.
 The latest computer-aided approaches, such as DoE and ANN optimize
the several properties of a product simultaneously, thus it is also called
as the multi-objective optimization or simultaneous optimization.
 For instance, an optimized tablet formulation is that which is with a high
hardness (crushing strength), low disintegration time, has certain
dissolution profile and is robust towards (small) deviations (errors) in
process conditions, mixture variable settings or in the environment.
 In a robust formulation, despite small variations, the values of the
properties remain at (almost) the same level or deviate with only within
an acceptable range. It is of course desirable to accomplish a product
which maintain exactly the same values of properties (or specifications)
during and after production, storage before use, or during use, but this
may be costly and is not always needed or achievable.
 Usually there are number of criteria which a formulation has to fulfil
which has made the optimization challenging. It is however almost never
possible to fulfil to all the criteria at once. This means that a compromise
must be found between certain criteria. Usually, for non-critical
attributes are compromised if there is a need to undertake such
compromise.
 Many methods are available to search for such a compromise variable
setting. A pharmaceutical formulation usually, is optimized with a
compromise between cost and quality.
 This robustness aspect can also be extended towards environmental
factors like temperature and (more importantly) humidity. It can be
predicted the shelf-life of a formulation under certain conditions is or
what the desired conditions are to keep a product stable during a certain
time on a desired quality level.
 When there is only one response or property, the goal is often to search
for a maximum or a minimum or property response. However, in
practice the optimization is challenging and difficult to accomplish
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because optimization problems usually require simultaneous optimizing
the multiple properties.
 Sometimes, the optimization requires adjusting qualitative parameters,
e.g., setting zero order release. This complexity in simultaneous
optimization is dealt with undertaking a compromise on certain
properties. Usually, it may be necessary to trade off properties during
such experimentation, to sacrifice one characteristic in order to improve
another, e.g., to accept a tablet with lesser hardness in order to achieve
the desired dissolution profile.
 Thus, the primary objective may not be to optimize absolutely but to
compromise effectively and thereby to produce the best formulation
under a given set of restrictions.
 The optimization procedure can be simplified by discarding highly
correlated responses with other responses. Statistical approach called
Principal Component Analysis (PCA) is used to select these key
responses.
 The ANN finds the critical factor by recognizing (“learning”) the pattern
in the data. The above information is used for optimization. Achieving
optimization is difficult as the product must meet specification which are
complex to accomplish.
DESIGN SPACE
 The above computer-aided experimentation generates the “design
space” which according to FDA is the multidimensional combination and
interaction of input variables (factors, e.g., material attributes) and
process parameters that have demonstrated to provide optimum
responses (outputs).
 Design space is a region where specifications are consistently met. Thus,
design space is a graphical optimization plot of multi-factors and
properties under study. Design space provides the allowable operating
boundaries within which, the process factors can vary with little risk of
producing off-grade product.
 Design space is a processing window that provides a high level of
confidence that 99% of the output population meet (or exceed)
specifications. Design space provides assurance of quality. Thus, finding
the design space is the aim of optimization.
 Design space is proposed by the applicant of a new drug (pharmaceutical
industry) to the regulatory authority and is subjected to regulatory
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assessment and approval.
 The future working on the factor levels demonstrated within the design
space is not considered as a “change” in product or process which would
not initiate investigational new drug application (INDA) or a regulatory
post approval change process.
 In such cases, bioavailability/bioequivalence studies are required. Any of
the following conditions is considered as change: Change in
manufacturing site, change in manufacturing method, change in raw
material suppliers, minor modification in formulation and modification
in the product strength.
FACTOR INTERACTION
 Factor interaction happens when the effect of one factor on a property
depends on the level (low or high) of another factor.
 The factors involved in an interaction are taken into consideration for
accomplishing product with properties close to desirability. The
knowledge of factor interaction leads to a breakthrough and
improvement in formulation.
IMPLEMENTATION OF COMPUTER-AIDED APPROACHES IN R&D
 Though, currently the Quality by design is a mandatory part of the
modern pharmaceutical quality, but the major limitation for its adoption
and implementation in the pharmaceutical industry is the lack of its
understanding.
 Pharmaceutical companies traditionally, are tuned to emphasize the
final product and outcome, with a little attention on the science-based
understanding of a process required for an end product.
 The majority of pharmaceutical companies perceive implementation of
QBD as challenging and believe that there is a need for an easy guidance
from regulatory agency for implementation of QBD.
 The following are the challenges, related to industry (1-4) and regulatory
authority (5-10) for QBD implementation.
1. An uncertainty and lack of understanding over investment
requirements for QBD implementation.
2. An internal disconnect between cross functional areas of industry,
such as R&D and manufacturing or quality and regulatory
departments.
3. Lack of knowledge and technology to execute QBD in industry.
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4. Reliance on suppliers and contract manufactures – how QBD could
be adopted by these third parties.
5. Lack of favorable interactions of regulatory agency with industry
does not facilitating QBD adoption.
6. Lack of tangible guidance on QBD from agency for industry.
7. Lack of the regulator’s preparedness to handle the QBD
applications.
8. Inconsistency of treatment of QBD across regulatory authority.
9. The regulatory benefits from QBD approach does not inspire
confidence.
10. A disconnect among international regulatory bodies.
COMPARISON OF COMPUTER AIDED APPROACHES WITH THAT OF THE OFAT
PARAMETER OFAT DOE/QBD/PAT/ANN
Product development Empirical approach
Designed/scientific
approach
Manufacturing process
Fixed manufacturing
process
Adjustable based on design
space
Process control In-process control QBD, PAT tools
Specifications

Based on batch data/history
Based on product
performance
QC strategy
QC by in-process and
finished product testing
QC by risk-based approach
with real time release test
Life cycle management Reactive Preventive
Information regarding
Formulation
Little information
Knowledge-based built into
product and rich in
understanding
Process
Static process allowing no
change
Flexible process allowing
change
Focus Reproducibility
Robustness, reduced
variation, identification of
critical control point
Quality Assured by testing Designed based

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ADVANCED GRANULATION TECHNOLOGY
INTRODUCTION
 Granulation is the process whereby small particles are gathered into
larger, permanent masses in which the original particles can still be
identified.
 Granulation process transforms fine powders into free-flowing, dust-free
granules that are easy to compress.
CHARACTERISTICS OF GRANULES
1. PARTICLE MORPHOLOGY
 Optical microscopy
 Scanning electron microscopy (SEM)
2. PARTICLE SIZE DISTRIBUTION
 Sieve analysis
3. MOISTURE CONTENT IN GRANULES
 Moisture Content Is generally measured using moisture analyzer.
4. GRANULES FLOWABILITY & DENSITY
 Specific volume
 Carr’s index (higher the compressibility, poor the flowability and vice
versa)
 Flow through orifice
 Angle of repose
5. GRANULE STRENGTH
 Granules strength is measured by:
­ CRUSHING TEST
 The force required to crush the granule is recorded when a
plate is moved at a constant strain rate.
 Deflections In the load profile are interpreted as break
points. The strength is recorded in units of mass or force.
­ FRIABILITY TEST
 In this measurement, Friabilator is charged with granules
and rotated.
 The percentage loss of mass represent granule Friability.

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6. SURFACE AREA
 The surface area of a granules affect the dissolution rate of a solid, it
can be measured by:
­ GAS ADSORPTION
 In this method an inert gas (N2) is adsorbed onto the
surface of a solid at low temperature, this gas is then
desorbed at room temperature.
 The volume of gas adsorbed In a monolayer on the solid
is then converted to surface area.
­ AIR PERMEABILITY
 A column packed with granules is subjected to a stream
of air and the pressure drop is measured across the bed.
 Although this method has not been extensively used on
granulations but it has been applied to compressed
tablets.
7. ELECTROSTATIC CHARGE
 Static Charge on granule surfaces can cause significant problems In
powder handling. It can be measured by:
­ The powder is allowed to flow out of a hopper onto a glass
receptacle, directly beneath this receptacle is a copper disk
that is attached to another copper disk beneath an ionostat.
­ The ionostat records voltage transmitted by the first disk.
­ The improved flow results in the reduction of electrostatic
charge and vice versa.
NEED OF GRANULATION
 To avoid powder segregation.
 To enhance the flow of powder.
 To produce uniform mixtures.
 To produce dust free formulations.
 To ensure content uniformity.
 To improve compaction characteristics of mix.
TYPES OF GRANULATION
 The granulation technique may be widely categorized in to following two
types:

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­ Dry granulation
 Dry granulation uses mechanical compression (slugs) or
compaction (roller compaction) to facilitate the
agglomeration of dry powder particles.
­ Wet granulation
 Wet granulation uses granulation liquid (binder/solvent) to
facilitate the agglomeration of powder.
BROAD CLASSIFICATION OF GRANULATION METHODS
 Broad classification of Granulation methods is given in the following:
GRANULATION TECHNIQUES AND SUBSEQUENT PROCESSING
PROCESS DRYING TECHNIQUE
Wet granulation Low shear mixer
High shear mixer
Fluid bed granulator
Spray dryer
Extrusion / Spheronization
Continuous mixer granulator
Continuous fluid-bed granulator
Tray or fluid-bed dryer
Tray or fluid-bed dryer
Fluid bed granulator / dryer
Spray dryer
Tray or fluid-bed dryer
Fluid bed – Continuous or batch
Fluid bed – Continuous
Dry granulation Direct compression
Slugging

Roller compactor
Blend and process further
Mill slugged tablets / blend /
recompress / process further
Compacts milled / blend / process
further

DRY GRANULATION
 Dry granulation is a process whereby granules are formed without the
aid of any liquid solution.
STEPS
 Compaction of powder
 Milling
 Screening
METHODS
1. SLUGGING
 Large tablets or slugs are produced in heavy duty tablet press.
2. ROLLER COMPACTION
 Powder is squeezed between two rollers to produce sheet of material.
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EQUIPMENTS
 Equipment for dry granulation comprises of two parts:
­ Machine for compressing dry powder to form compacts. E.g.
Chilsonator
­ Mill for breaking these intermediates to granules. E.g. Hammer
mill
ADVANTAGES
 Drug dose is too high (so, to minimize excipient)
 Heat sensitive drug (as no drying step is involved like wet granulation)
 Ideal for moisture sensitive drug e.g. Aspirin , vitamins (as no water is
involved)
DISADVANTAGE
 Capping and Lamination are frequent.
WET GRANULATION
 Involves wet massing of API and excipients and with granulation liquid
with or without a binder (natural or synthetic).
 The granulation liquid must be volatile so that it can be removed by
drying and be non-toxic.
 Natural binders include starch, pre-gelatinized starch, Acacia, other
gums
 Synthetic binders include PVP, MC, HPMC, maltodextrin etc.
STEPS
 Mixing of drug and excipients
 Mixing of binder solution with powder mixture to form wet mass
 Coarse screening of wet mass using a suitable sieve
 Drying of moist granules
 Screening of dry granules through a suitable sieve
STAGES
 Pendular
 Funicular
 Capillary
 Droplet

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METHODS
 Single pot granulation
 High shear mixture granulation
 Fluid bed granulation
 Extrusion- Spheronization
ADVANCED / INNOVATION IN WET GRANULATION
STEAM GRANULATION
 Water steam is used as binder instead of water as granulation liquid.
MOISTURE-ACTIVATED DRY GRANULATION OR MOIST GRANULATION
 Uses very little water to activate a binder and initiate agglomeration.
THERMAL ADHESION GRANULATION
 Utilizes addition of a small amount of granulation liquid and heat for
agglomeration.
MELT GRANULATION
 The agglomeration of powder particles occurs using meltable binders,
which melts at relatively low temperature (50–90 °C)
FREEZE GRANULATION
 Involves spraying droplets of a liquid slurry into liquid nitrogen followed
by drying of the frozen droplets.
FOAMED BINDER OR FOAM GRANULATION
 Involves the addition of liquid/aqueous binder as foam.
REVERSE WET GRANULATION
 Involves the immersion of the dry powder formulation into the binder
liquid followed by controlled breakage to form granules.
MELT GRANULATION
INTRODUCTION
 Melt Granulation or Melt palletization are agglomeration processes with
the concept of utilizing a molten liquid as a binder.

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AGGLOMERATION, GRANULES AND PELLETS
 Agglomeration is the Process of conversion of fine solid particles into
larger entities, it is achieved by agitation of fine particles with molten
liquid using:
­ Tumbling bed
­ Fluid-bed granulator
­ High shear mixer
GRANULES PALLETS
Granules are irregularly shaped
agglomerates of particles having size
distribution between the range of
0.1-2 mm.
Pellets are spherical agglomerates of
particles with size distribution with
the range of 0.5-2mm.

MECHANISM OF MELT AGGLOMERATION
 Similar to wet agglomeration except the formation and growth process
of melt agglomerates.
 Agglomeration occurs in three stages:
1. Wetting and nucleation
­ Nuclei and small agglomerates of loose and porous
structure are formed after wetting of primary particles
2. Consolidation and growth
­ Disappearance of fines resulting in coalescence of wetted
primary particles with formed nuclei and growth
3. Attrition and breakage
­ Fragmentation of agglomerates in the dry and wet state.
REQUIREMENTS OF MELT GRANULATION
 Binder: 10-30% w/w with respect to solid particles
­ Hydrophilic: polyethylene glycol, poloxamers.
 Used to prepare immediate release dosages.
­ Hydrophobic: Fatty acids, Fatty alcohol, Waxes and Glycerides.
 Used for prolonged release dosages.
­ Melting temperature of binding liquid should be within 50-100°C.
 Fine Solids Particles: Either in the form of solid or molten liquid.
­ Melting temperature of fine particles should be 20°C higher than
maximum processing temperature.

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ADVANTAGES
 Immediate and prolonged release agglomerates can be prepared using a
one step process.
 Processing of water sensitive materials such as:
­ Effervescent excipients
­ Hygroscopic Drugs
 Low cost process as organic solvent, flame proof facilities, and solvent
recovery equipment are not required.
 Shortens processing time as drying doesn’t require.
DISADVANTAGES
 Not suitable for heat labile material
 Growth process of melt agglomerates are highly sensitive to
formulation, processing and equipment variables.
CONTINUOUS GRANULATION
ROLLER COMPACTION TECHNOLOGY
INTRODUCTION
 Roller compaction is a method of powder compaction of dry powders
into a solid mass known as the ribbon. This process is achieved by
feeding powder through a set of directly opposed, counter-rotating
rollers.
WORKING
 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.
ADVANTAGES
 To improve powder flow properties for dosage filling and compression
processes.
 To eliminate wet granulation induced degradants and to improve
product stability.
 To prevent active product ingredient from segregating.
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FLUIDIZED BED GRANULATION
INTRODUCTION
 FBG Produce granules by spraying a binder solution onto fluidized
powder bed.
STEPS IN FBG PROCESS
1. Fluidization
­ Conversion of static solid particles to dynamic fluid like state by
means of gas.
2. Spraying
­ Binder solution is sprayed over fluidized particles to form
granules. Binders can be PVP (Polyvinyl pyrrolidine), HPMC.
3. Drying
­ Granules formed are dried by using same gas as used for
fluidization.
TYPES OF FLUID BED
1. Slugging bed
­ Slugging bed has gas bubbles in the entire cross section of product
container converting the bed into layers.
2. Boiling bed
­ Boiling bed has gas bubbles of the same size as the solid particles.
3. Channeling bed
­ In Channeling bed the gas forms channels in the bed.
4. Spouting bed
­ In Spouting bed, gas forms a single opening through which some
particles flow and fall on the outside.
EQUIPMENT FOR FBG
1. AIR HANDLING UNIT
 Consists sections of pre-filtering air, air heating, air dehumidification,
air re-humidification and HEPA filtering.
2. PRODUCT CONTAINER
 It holds the powder feed (filled 35% to 40%)
 Air is introduced from bottom at proper airflow rate for fluidization
3. AIR DISTRIBUTOR PLATE
 A fine screen of 6-325 mesh normally covers air distributor and
retains the product in container.
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4. DISENGAGEMENT AREA
 In this area, larger particles lose momentum and fall back into the
bed.
5. SPRAY NOZZLE
 Spraying is an act of breaking up a liquid into multitude of its
droplets.
 Four types of nozzles are available which are:
1. Pressure nozzle
­ Pressure nozzle fluid under pressure is broken up by its
inherent instability and its impact on the atmosphere ,
on another jet, or on a fixed plate.
2. Rotating nozzle
­ Rotating nozzle (rotary atomizer) fluid is fed at a low
pressure to the center of a rapidly rotating disk, and the
centrifugal force breaks up the fluid.
3. Airless spray nozzle
­ Airless spray nozzle fluid is separated into two streams
that are brought back together at the nozzle orifice,
where upon impingement, they form drops.
4. Gas atomizing nozzle
­ Gas atomizing nozzle (two-fluid nozzle) in which the two-
fluid (binary) nozzle where the binder solution (one fluid)
is atomized by compressed air (second fluid) is the most
commonly used nozzle for fluid bed granulation.
6. PROCESS FILTERS SYSTEM
 A process-air filter system removes the particles from the exhaust air
using bags or cartridges.
 These filter bags can be constructed out of nylon, polyester,
polypropylene, and PTFE lined materials.
7. EXHAUST BLOWER OR FAN
 Once the air leaves the exhaust filters, it travels to the fan.
 The fan is on the outlet side of the system, which keeps the system at
a lower pressure than the surrounding atmosphere.
8. CONTROL SYSTEM
 FBG process can be controlled by pneumatic analog control devices,
or programmable logic controllers (PLCs) or computers.
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9. SOLUTION DELIVERY SYSTEM
 Consist of a low pressure peristaltic pump capable of delivering fluid
at a controlled rate.
 The liquid is transported from the solution vessel through the tubing
and atomized using a two-fluid (binary) nozzle in the fluid bed
processor.
WORKING PRINCIPLE
 If a gas is allowed to flow upward through a bed of solid particles at a
velocity greater than the incipient velocity (the velocity of gas when the
frictional drag on the particles equals the effective weight of the bed)
and less than the entrainment velocity (velocity at which solid particles
are carried over by the gas).
 The solids are buoyed up and becomes partially suspended in gas
stream.
PROCESS VARIABLES
 Factors affecting the fluid bed granulation process can be divided into
three categories:
1. FORMULATION RELATED VARIABLES
 Properties of Primary Material
­ Low particle density, small particle size with narrow range,
spherical shape, no cohesiveness & stickiness are ideal for FBG.
 Low-Dose Drug Content
­ Randomized movement of particles in the fluid bed might cause
segregation of the drug so, uniform distribution is best achieved
by dissolving the drug in the granulating solution.
 Binder
­ Dry binder produces a larger mean granule size whereas, binder in
solution produces less friable and more free-flowing granules,
Diluted binders are preferred because the facilitate finer
atomization.
 Binder Solvent
­ In most instances water is used as the solvent but organic
solvents, due to their rapid vaporization, produce smaller granules
than the aqueous solution.


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2. EQUIPMENT RELATED VARIABLES
 Design
­ Design is optimized to fluidize. granulate and dry the product.
 Air Distributor Plate
­ Perforated plates with 60-325-mesh fine SS screen. provides an
optimum supply of air
 Pressure Drop
­ A properly sized blower. or fan should develop sufficient AP to
fluidize the material.
 Shaker Blow Back Cycle Mechanism
­ To retain entrained particles of a process material. process fibers
are used which arc cleaned during granulation process.
 Other Miscellaneous Factors. i.e. Granulator Bowl Geometry.
Fluidization Velocity etc.
­ Generally, the conical shape of the container and expansion
chamber is preferred.
3. PROCESS RELATED VARIABLES
 Process Inlet Air Temperature
­ Generally, aqueous vehicles require temp b/w 60°C and 100°C
while organic vehicles from 50°C to below room. Higher
temperatures produce rapid evaporation resulting in smaller,
friable granules.
 Atomization Air Pressure
­ Lesser the atomization pressure, larger is the binder droplet size.
 Fluidization Air Velocity And Volume
­ A high airflow causes rapid evaporation, attrition and results in
smaller granules.
 Liquid Spray rate
 Nozzle Position And Number Of Spray Heads
 Product And Exhaust Air Temperature
 Filter Porosity And Cleaning Frequency
 Bowl Capacity.
ADVANTAGES
 One unit system.
 Finer, freely flowing, homogenous granules.
 Less time.
 Uniform drying.
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DISADVANTAGES
 Long resident time.
 Expensive.
 Electrostatic charge develops on granules.
 More granulating liquid used.
 Low density granules are formed.
MECHANICAL WET GRANULATION SYSTEM
INTRODUCTION
 The variety of mechanical granulation system are used one of these is
High throughput granulator - Lo ¨dige Ploughshare Mixers.
PARTS
 The main parts of this granulator are:
­ Horizontal drum and granulation chamber and a horizontally
rotating shaft, equipped with different transporting and blending
elements, the shovels.
WORKING
 Working process involves:
­ The axle part is acts as a feeding section to pre-blend the mixture
and forward it into the granulation section where the blending
elements are carried out by blending sticks.
­ At this point the granulation liquid is added and forwarding of the
material. Consecutively, the material is entering the post-
processing section where the granules are formed to their final
shape and moved to the discharging orifice.
EXTRUSION SPHERONIZATION TECHNIQUE
INTRODUCTION
 Extrusion and Spheronization is a useful technique for the manufacture
of small regularly shaped particles.
 Extrusion is a process that involves forcing a raw material or blend
through a die or orifice under set conditions such as temperature,
pressure, rate of mixing and feed-rate, for the purpose of producing a
stable product of uniform shape and density.
 The extrusion process can be done with the material hot (hot melt
extrusion, HME) or cold (wet massing).
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PROCESS OF EXTRUSION AND SPHERONIZATION
 The active ingredients are mixed with the excipients in a dry form to
create a powder blend
 This powder is then mixed with a liquid binder in a process called Wet
Massing or Granulation
 Extrusion produces a spaghetti-like extrudate, which is then passed into
the Spheronizers to divide it up into spheroids of uniform size and a
spherical shape.
EXTRUSION PROCESS AND EXTRUDER TYPES
 Wet mass is forced through the dies and shaped into small cylindrical
particles with uniform diameter. The extrudate particles breaks at
similar lengths under their own weight.
 Based on their feed mechanism extruders are divided into 3 types:
1. Screw feed extruder (axial and radial)
2. Screen or basket extruder
3. Gravity feed or gear extruder
 The primary extrusion process variables are:
1. The feed rate of the wet mass
2. The diameter of the die
3. The length of the die
4. The water content of the wet mass.
SPHERONIZATION PROCESS
 Machine consists of a rotating friction disk, designed to increase friction
with the product, which spins at high speed at the bottom of cylindrical
bowl.
 During rotation, particles colliding with the wall and being thrown back
to the inside of the plate creates a “rope-like” movement of product
along the bowl wall.
 When particle have obtained the desired spherical shape, discharge
valve of the chamber is opened and the granules are discharged by the
centrifugal force.
HOT MELT EXTRUSION
 It is a process of converting raw material into a product of uniform shape
and density by forcing it through a die under high temperature.
 Polymers for hot-melt extrusion
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­ Polymers with a high solubilization capacity are particularly
suitable because large quantities of drugs can be dissolved.
­ These include:
 Povidone, copovidone and Soluplus® are highly suitable for
hot-melt extrusion.
EXTRUDERS
 Extruders for pharmaceutical use consists of following distinct parts:
­ A conveying system for material transport (The feed hopper and
single or twin screws)
­ Kneading system for material mixing (Temperature-controlled
barrels (heating and / or cooling)
­ A die system for forming the extrudates
­ Downstream axle
­ Airy equipment (cooling, pelletizing and collecting)
WORKING PRINCIPLE
 The feeding section transfers the materials from the feeder/hopper to
the barrel.
 The polymer mixture typically begins to soften in the melting zone.
 The melt moves by circulation in a helical path by means of movement
of single or twin screws.
 At the end of the barrels, the attached die dictates the shape of the
extrudates.
ADVANTAGES
 Optimum flow and shape for coating
 More reproducible packing into small container
 Easy mixing of non-compatible products
 Improve hardness and friability
 HME is used for:
­ Enhancement of the dissolution rate and bioavailability of a drug
­ Taste masking
­ Stabilizing the API
­ Parenteral depots system
 However HME is not applicable for heat labile drugs.
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SINGLE POT PROCESSING GRANULATION TECHNOLOGY
 Single-pot processing was developed to provide the means for mixing,
granulating, drying, and blending pharmaceutical granulations in a single
apparatus.
 Category of processes consists of high and low shear mixer granulator
and outfitting with a variety of drying options.
HIGH SHEAR GRANULATION TECHNOLOGY
INTRODUCTION
 In HSG process, a binder liquid is added to the powder particles in a
closed container with blending tools and a chopper and dense granules
are formed through the liquid and solid bridges.
EQUIPMENT/HIGH-SHEAR GRANULATOR
 High-shear granulators consists of:
­ A mixing bowl
­ A three-bladed impeller (rotates at a speed of 100 to 500 rpm)
­ Auxiliary chopper (break down the wet mass to produce granules.
The rotation speed of the chopper is 1000 to 3000rpm).
 The high-shear granulator could be termed as either vertical or
horizontal, based on the orientation and the position of the impeller.
 The vertical high shear granulator could be either a top driven or bottom
driven unit.
HIGH-SHEAR GRANULATION PROCESS/ WET GRANULATION
 The composition of a powder mixture for granulation generally consists
of an API, a filler, a disintegrant and a binder.
 A high-shear wet-granulation process includes the following steps:
­ Loading all the ingredients into the mixing bowl.
­ Mixing of dry ingredients at high impeller and chopper speeds for
2–5 min.
­ Addition of a liquid binder (either binder solution or solvent) while
impeller and the chopper are running at a low speed.
­ Wet massing with both the impeller and the chopper running at a
high speed.
­ Removal of the resulting wet granules from the granulator bowl
and drying them using fluid-bed or tray drying.
­ Sieving the dried granules.
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APPROACHES FOR HIGH SHEAR GRANULATION
 A commonly used approach in HSG is a two-step process involving:
­ Wet granulation
­ Drying (fluid-bed) and sieving.
 An inherent risk with this approach is exposure to potentially toxic
materials during the transfer of the wet granules from the high-shear
granulator to the fluid bed.
 Therefore, it is needed to be operated under a negative pressure.
Moreover, dehumidifying and heating of a large volume of air is
necessary during drying.
 The alternate approach is to use a one-pot approach. This process is
called moisture-activated dry-granulation process. It consists of two
steps:
­ Wet agglomeration of the powder mixture (by a small amount of
water (1–4%))
­ Moisture absorption stages (MCC and potato starch is then added
to absorb any excessive moisture)
 After mixing with a lubricant, the resulting mixture can then be
compressed directly into tablets.
ADVANTAGES
 The HSWG process offers following advantages over the other
granulation processes:
­ Short processing time
­ Use of less binder solution
­ Granulation of highly cohesive materials containing hydrophilic
polymers, which is not achievable with low-shear granulation
processes
­ Greater densification and production of less friable granules
­ Production of reproducible granules with a uniform particle size
distribution
­ Reduction of process dust, thus minimizing exposure to workers.
DISADVANTAGES
 Production of less compressible granules, compared to low-shear
granulation processes
 Narrow range of operating conditions
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HOT-MELT GRANULATION IN A HIGH-SHEAR GRANULATOR
 HMG utilizes a binder, which is a solid or semisolid at room temperature
and melts at a temperature below the melting point of API (b/w 30 °C
and 100 °C.
 The binder, when heated near its melting point, liquifies or becomes
tacky.
 This tacky and liquified form of binder agglomerates the powder
mixture, which upon cooling forms a solid granulated mass.
 The energy to melt the binder may be derived from heat dissipated from
the circulating hot liquid, such as steam, water, or oil through jacketed
bowl, or heat generated by the friction of high- shear mixing.
LOW SHEAR GRANULATION
INTRODUCTION
 The low-shear granulators generate less shear than granulators such as
extruders or the high-shear mechanical granulators.
PRINCIPLE OF LOW SHEAR GRANULATION
 The granulation mechanisms for wet granulation include wetting and
nucleation, consolidation and growth.
 A binder liquid is fed to the powder particles in a closed container with
blending tools and a chopper. Dense granules are formed through the
liquid and solid bridges that result in attrition and breakage.
EQUIPMENT FOR LOW SHEAR GRANULATION
MECHANICAL AGITATOR GRANULATORS
 The machine classes to be considered under mechanical agitator
granulators are:
­ Ribbon or paddle blender
­ Planetary mixers
­ Orbiting screw mixers
­ Sigma blade mixers.
ROTATING SHAPE GRANULATORS
 These vessel shapes are usually some derivation of a cylinder, with a
double cone and counterparts, the machine shells rotate around an axis
parallel to the ground. The rotation speed is moderate, and generally
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falls into a range of 72.2–106.7 m/min (250–350 ft/min) peripheral
speed.
 The rpm value changes as vessel size grows, laboratory model may
rotate at 25–30rpm, whereas a larger production model may rotate at
4–8rpm.
LOW SHEAR GRANULATION PROCESS
 The composition of a powder mixture for granulation generally consists
of an API, a filler, a disintegrant and a binder.
 A low-shear wet-granulation process includes the following steps:
1. Loading all the ingredients into the mixing bowl
2. Mixing of dry ingredients
3. Addition of a liquid binder
4. Wet massing
5. Removal of the resulting wet granules and drying
6. Sieving the dried granules.
ADVANTAGES
 Low-shear granulator produces more compressible granules when
compared to high-shear granulator.
 It has a range of operating conditions.
 Granulation is achieved within a short time.
DISADVANTAGES
 Granulation process requires more binder solution.
 Pellets obtained by low shear granulation were shown to be less
spherical and more friable than granules elaborated by HSG.
RAPID RELEASE / EFFERVACENT GRANULATION TECHNOLOGY
INTRODUCTION
 Effervescent granules are dry mixture containing sodium bicarbonate,
citric acid and tartaric acid and liberate carbon dioxide when added to
water by the reaction of acid and base.
METHODS FOR PREPERATION
 These are prepared by:
­ Dry or fusion method
­ Wet method
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DRY OR FUSION METHOD
 In this method, water of hydration present in citric acid acts as binder for
powder mixture.
 The citric acid crystals are powdered and then mixed with tartaric acids,
medicament, sodium bicarbonate and sugar of same size ensuring
uniformity of mixture.
 The mixture is stirred in a pan heated to 93 ℃ and 104 ℃, passing
through sieves of a suitable size.
 Then again dry at 54 °C and place in an airtight container.
WET GRANULATION METHOD
 The source of binding is water added to alcohol as moistening agent
forming pliable mass of granulation.
 In this method all of powder may be anhydrous as long as water is added
as moistening agent.
FORMULATION
 Acidic material (Citric acid, Tartaric acid, Ascorbic acid), acid anhydrides
or acidic salts (Sodium dihydrogen phosphate)
 Carbon dioxide sources (Sodium Bicarbonate, Sodium Carbonate,
Potassium Bicarbonate and Potassium Carbonate, Calcium Carbonate
 Binder (PVP-for effervescent formulation) (lactose, mannitol, dextrose
for dry granulation)
 Lubricants combination of calcium and potassium sorbates, micronized
polyethylene glycol with calcium ascorbate or trisodium citrate
 Sweeteners, Coloring Agents, and Flavors.
ADVANTAGES
 Incorporation of large amounts of active ingredients
 No need to swallow tablets/Fizzy formulation
 The product is typically self-mixing and flavorful
 Provide rapid action
 Protection of API from highly acidic environment
DISADVANTAGE
 High dosage
 Hygroscopic in nature.
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CENTRIFUGATION / SPRAY DRYING GRANULATION
INTRODUCTION
 Spray drying is one of the oldest forms of drying and one of the few
technologies available for the conversion of a liquid, slurry, or low
viscosity paste to a dry solid.
 Spay dryers differ from others in those that only fluid materials such as
solutions, slurries and thin pastes.
DESIGN
 All spray dryers consist of following components:
­ 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
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 Sterile solution can be dried
 The dried powder will have uniform particle size and shape
 Powder formed has good flow properties
 Material up to 200 kg per hour can be handled.
DISADVANTAGES
 The equipment is very bulky and costly
 There is a lot of wastage of heat.
PROCESS ANALYTICAL TECHNOLOGY (PAT) & MODELING AND
SIMULATION
PROCESS ANALYTICAL TECHNOLOGY
INTRODUCTION
 PAT is defined as a mechanism to design, analyze, and control
pharmaceutical manufacturing processes through the measurement of
Critical Process Parameters (CPP) which affect Critical Quality Attributes
(CQA).
 The concept actually aims at understanding the processes by defining
their CPPs, and accordingly monitoring them in a timely manner
(preferably in-line or on-line) and thus being more efficient in testing
while at the same time reducing over-processing, enhancing consistency
and minimizing rejects
GOALS OF PAT
 To reduce production cycling time
 To prevent rejection of batches
 To enable real time release
 To increase automation and control
 To improve energy and material use
 To facilitate continuous processing.
TOOLS FOR PAT
 In-line and on-line analytical instruments used to measure those
parameters that have been defined as CPP.
 These include mainly near infrared spectroscopy (NIRS); but also include
biosensors, raman spectroscopy, fiber optics dielectric spectroscopy and
others.
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 Multivariate data acquisition and data analysis tools in advanced
software packages aid in design of experiments, collection of raw data
and statistically analyzing this data in order to determine what
parameters are CPP.
PAT FOR GRANULATION
 In a case study, Real-time measurements using focused beam
reflectance measurement and near-infra red spectroscopy were taken
by inserting in-line probes into the fluidized bed granulator. Non-
intrusive acoustic emission measurements were also performed by
attaching piezoelectric sensors on the external wall of the fluidized bed.
 PAT data comprising chord length distribution and chord count (from
FBRM), absorption spectra (from NIR) and average signal levels and
counts (from AE) were compared with the particle properties measured
using offline samples.
 All three PAT techniques were able to detect the three granulation rate
processes including wetting and nucleation, consolidation and growth,
breakage.
MODELING AND SIMULATION (M&S)
 (M&S) is the use of models (e.g., physical, mathematical, or logical
representation of a system, entity, phenomenon, or process) as a basis
for simulations to develop data utilized for managerial or technical
decision making.
 A model contains key parameters of the physical model in a virtual form,
and conditions are applied that set up the experiment of interest.
 In the simulation computer calculates the results of those conditions on
the mathematical model and outputs in a format that is either machine
or human-readable, depending upon the implementation.

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POLYMERS USED IN DRUG DELIVERY
SYSTEMS
INTRODUCTION
 A polymer is a high molecular weight chemical compound containing a
large number of repeating units called monomers.
 The monomers are linked together by covalent chemical bonds by the
process called polymerization.
CLASSIFICATION OF POLYMERS
1. BASED ON THE NATURE OF MONOMERS
 Homopolymers  Copolymers
2. BASED ON THE ARRANGEMENT OF MONOMERS
 Random copolymers
 Graft copolymers
 Block copolymers
3. BASED ON THE STRUCTURE OF MOLECULE
 Linear
 Branched
 Cross linked
4. BASED ON THE THERMAL RESPONSE AND POLYMER PROPERTY
 Thermoplastics
 Thermosets
 Elastomers
5. BASED ON THE SOURCE
 Natural polymers
 Semisynthetic polymers
 Synthetic polymers
6. BASED ON THE FORM AND USE
 Plastics
 Elastomers
 Fibers
 Liquid resins
7. BASED ON BIO-STABILITY
 Biodegradable polymers
 Non-biodegradable polymers
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HOMOPOLYMERS AND COPOLYMERS
 Polymers are large molecules formed by repeated linking of monomers.
A polymer is a macromolecule formed by sequential addition of smaller
molecules called monomers to each other.
 For example, polyethylene is formed by repeated linkage of ethylene
molecules (monomers).
 Polyethylene is an example of a homopolymer since the fundamental
unit (monomer) is only of one kind, that is, ethylene. Ethylene (CH2
CH2)n, Polyethylene nCH2 CH2.
 In certain other polymers, the fundamental units may be two or more
similar molecules. Such polymers are called copolymers.
(A + B + A + B + A + B )x + y xA + yB
 Examples of copolymers include ethylene vinyl acetate, poly(ethylene-
co-propylene), poly(styreneco- butadiene) and poly(vinylidine chloride-
co-vinyl chloride).
RANDOM COPOLYMERS, GRAFT COPOLYMERS AND BLOCK
COPOLYMERS
 Based on the manner in which the monomers are arranged, copolymers
can be classified as random copolymers, graft copolymers and block
copolymers.
 In random copolymers, there is a random arrangement of the
monomers.
 In graft copolymers, the main polymer chain is made up of one
monomer and the branches are made up of a different monomer.
 Block copolymers contain blocks of monomers of the same type.
LINEAR, BRANCHED AND CROSS-LINKED POLYMERS
 Based on their structure, polymers are classified as linear, branched and
cross-linked.
 Polymers made of only long sequential strands are called linear
polymers. They are characterized by high densities, high tensile
strengths and high melting points. Examples of linear polymers are
polyethylene, nylon and polyesters.
 A branched polymer molecule is composed of a main chain with one or
more substituent side chains or branches. Depending on the nature of
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the branches they can be of different types. They are characterized by
low densities, lower tensile strengths and low melting points. Examples
of branched polymers are amylopectin and glycogen.
 In cross-linked polymers monomeric units are linked together to
constitute a three-dimensional network. They are hard, rigid and brittle.
Examples of cross-linked polymers are Bakelite and melamine
formaldehyde resin.
THERMOPLASTICS, THERMOSETS AND ELASTOMERS
 Thermoplastic polymers can be softened by heating and they return to
their original state when cooled. This softening and solidifying can be
carried out repeatedly. This behavior is possible because their molecules
are held together by relatively weak intermolecular forces. Fabrication
with these polymers requires simultaneous application of heat and
pressure. Most linear and branched polymers with flexible chains are
thermoplastic in nature. The major thermoplastics are produced by
chain polymerization. They are very soft and ductile. Commercially
available thermoplastics include polyvinyl chloride (PVC), polystyrene
and poly(methyl methacrylate) (PMMA).
 A thermoset or thermosetting plastic melts when heated for the first
time but sets irreversibly. It does not soften on subsequent heating and
hence cannot be remolded or reshaped. During heating of thermosets,
strong covalent bonds are formed between the adjacent molecular
chains. These bonds can be severed only by heating to excessive
temperature but is accompanied by polymer degradation. Thermosets
are polymers with a high degree of cross-linking, usually forming a three-
dimensional networked structure. The result is a rigid structure with
restricted movement of the polymer chains. Examples include cross-
linked and network polymers such as vulcanized rubbers, epoxies and
polyester resins.
 Elastomers are rubbery polymers that can be stretched easily, without
the necessity of heating. They can be stretched to several times their
length. On releasing the applied stress, they rapidly return to their
original dimensions. Elastomers have low density of cross-linking. The
polymer chains have limited freedom to move, but they are prevented
from permanently moving in relation to each other.
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NATURAL, SEMISYNTHETIC AND SYNTHETIC POLYMERS
 Natural polymers are those obtained in nature. Examples include
cellulose, starch, proteins and natural rubber. Polysaccharides such as
cellulose, starch and proteins, which control various vital life processes,
are also called as biopolymers.
 Semisynthetic polymers are chemically modified natural polymers. For
example, cellulose, a natural polymer, can be chemically modified into
semisynthetic polymers such as cellulose acetate and cellophane.
Vulcanized rubber is another example of a semisynthetic polymer.
 Synthetic polymers are man-made polymers, artificially prepared in the
laboratory. Examples are polythene, PVC, nylon, polyethylene
terephthalate and Bakelite.
PLASTICS, ELASTOMERS, FIBERS AND LIQUID RESINS
 Plastic is a polymer that is shaped into hard and tough utility material by
the application of heat and pressure. Examples are PVC, polystyrene and
PMMA [Poly(methyl methacrylate)].
 When a polymer is vulcanized into a rubbery product exhibiting good
strength and elongation, it is called an elastomer. Examples are rubber,
synthetic rubber and silicon rubber.
 When a polymer is drawn into a long filament-like material whose length
extends to at least 100 times its diameter, it is known as a fiber.
Examples are nylon and terylene.
 When a polymer is used in the liquid form as an adhesive, potting
compound or sealant, it is called a liquid resin. Examples are polysulfide
sealants and epoxy adhesives.
BIODEGRADABLE AND NONBIODEGRADABLE POLYMERS
 Biodegradable polymers slowly disappear from the site of
administration. Examples are poly(lactic acid) (PLA), poly(glycolic acid)
(PGA), polyanhydrides and poly(ortho esters).
 Nonbiodegradable polymers are inert in the environment of use. These
are eliminated or excreted intact from the site of administration and
serve essentially as rate-limiting barriers to the release of drug from the
device. Examples are poly(ethylene vinyl acetate),
poly(dimethylsiloxane) (PDS), polyurethane, ethyl cellulose and PVC.
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POLYMER CHARACTERIZATION AND TECHNIQUES USED
POLYMER CHARACTERIZATION
 Polymer characterization parameters should be linked to the desirable
properties of the materials such as strength, permeability and molecular
weight distribution.
 Efficient and thorough characterization will advance our understanding
of these materials. The molecular characterization of polymeric material
is a key step in elucidating the relationship between polymer properties,
morphology and chemical structure.
 Polymer characterization can be done to obtain the following
information:
1. Molecular weights
 Distribution
 Molecular weight average
 Polydispersity index
2. Chemical composition
 Repeating units
 Side chains
 Cross-linking groups
 End groups
 Additives (identity, concentration and localization)
3. Stereochemistry and configuration
MOLECULAR WEIGHT DETERMINATION
 Polymer molecular weight is important as it determines many physical
properties. The transition temperatures and the mechanical properties
will be very low if the molecular weight of the polymer is very low, in
order to have any significant commercial applications.
 There are two ways to calculate the average molecular weight:
1. Number Average Molecular Weight
 This parameter influences the polymer properties, such as
the colligative properties, that are sensitive to the number
of molecules present and that are not influenced by the size
of any particle in the mixture.
 Examples are boiling point elevation and freezing point
depression.
2. Weight Average Molecular Weight
 This parameter influences the polymer properties that are
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dependent not just on the number of polymer molecules
but also on the size or weight of each polymer molecule.
 An example is the property of light scattering.
THERMAL ANALYSIS
 Thermal analysis of polymers is important to study the stability and
degradation of polymers. The thermal analytical techniques used in the
characterization of polymers are as follows:
1. Thermogravimetric analysis (TGA)
2. Differential scanning calorimetry (DSC)
3. Dynamic mechanical analysis (DMA)
4. Thermomechanical analysis (TMA)
THERMOGRAVIMETRIC ANALYSIS (TGA)
 Thermogravimetric analysis is a method that provides indication of the
thermal stability and the upper limit of thermal degradation where loss
of sample begins. The method measures only loss of volatile content
from the polymer. The limitation of this method is that it cannot detect
the temperature at which the chain cleavage occurs.
 In this method, the weight of the substance is recorded as a function of
time or temperature in an environment heated or cooled at a controlled
rate. The graphical representation of weight as a function of
temperature is called as thermogram.
DIFFERENTIAL SCANNING CALORIMETRY (DSC)
 Differential scanning calorimetry can be used to measure important
thermoplastic properties. The parameters that can be measured using
DSC are as follows:
1. Glass transition temperature
2. Crystalline melting point
3. Heat of fusion
4. Heat of crystallization
MECHANICAL PROPERTIES
 Mechanical properties are determined by the stress–strain relationship.
Stress—stretching force—is applied to the sample and the strain—
elongation—of the sample is recorded under a given stress. Stress–strain
relation in polymers is time dependent.
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POLYMER SYNTHESIS
 Polymers can be synthesized by addition reactions and condensations
and accordingly are called as addition polymers and condensation
polymers.
ADDITION POLYMERIZATION
 Addition polymerization is a method wherein the monomers are added
one after another to the active site on the growing chain.
 An addition polymer is formed when many monomers bond together via
rearrangement of bonds without the loss of any atom or molecule.
Addition polymers have {–C–C–} linkage along the main chain and no
other atom appears in the main chain.
 Addition polymerization can be of the following types:
1. Free radical polymerization
2. Ionic polymerization
 Cationic polymerization
 Anionic polymerization
1. FREE RADICAL POLYMERIZATION
 This is the most common type of addition polymerization. Free radicals
are mostly generated by the division of a molecule into fragments along
a single bond. In free radical polymerization, the radical attacks one
monomer and the electron migrates to another part of the molecule.
 The newly formed radical attacks another monomer and the process is
repeated. Thus, the active center moves down the chain as
polymerization occurs.
 There are three reactions that take place in addition polymerization,
namely initiation, propagation and termination.
2. IONIC POLYMERIZATION
 Active center is ionic charged instead of free radical. Only monomers
that can sufficiently stabilize positive or negative charge will undergo
ionic polymerization.
 Hence, ionic polymerization is more monomer specific. Most monomers
cannot be polymerized by ionic polymerization. Ionic polymerization also
occurs in three stages, namely initiation, propagation and termination.
 Examples of polymers synthesized by addition polymerization are
polyethylene, polypropylene, PVC and polystyrene.
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CONDENSATION POLYMERIZATION
 In condensation polymerization or step growth polymerization,
polymeric materials are synthesized from small molecules called
monomers with more than two reactive sites on the monomer. Small
molecules such as water or methanol are released as by-products.
 Condensation polymers are formed from intermolecular reactions
between bifunctional or polyfunctional monomer molecules with the
elimination of a small by-product molecule.
 The condensation reactions are characterized by the following features:
1. Repeat unit often not same as monomer structure
2. Release of small molecules such as H2O and HCl
3. Gradual growth of molecular weight
4. Relatively slow reaction
 Examples of polymers synthesized by condensation method are
polyamides, polyesters and polyethers.
CROSS-LINKING OF POLYMERS
 Polymer materials in the lower molecular weight range can be
crosslinked to obtain satisfactory mechanical properties. Polymers can
be cross-linked in different ways:
1. Covalent cross-linking
2. Ionic bonds
3. Physical cross-linking (through Van der Waals, hydrogen bonds or
other interactions)
 Cross-linking of polymers can be achieved using radiations (ultraviolet
rays, x-rays or g -rays) or by chemical crosslinking.
BIO DEGRADATION OF POLYMERS
 Bio degradation is the chemical changes that alter the molecular weight
or solubility of the polymers.
 Bio erosion may refer to as physical process that result in weight loss of
a polymer device.
 The possibility for a polymer to degrade and to have its degradation by
products assimilated or excreted by living system is designated as Bio
Resorbable.
 The erosion of polymers basically takes place by two methods:-
­ Chemical erosion
­ Physical erosion
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CHEMICAL EROSION
 Bio erosions through chemical mechanisms are explained below:
­ MECHANISM I
 It describes the degradation of water soluble
macromolecules that are cross-linked to form three-
dimensional network.
 Degradation in these systems can occur by:
 Type (1A)- Degradation occur at crosslinks to form
soluble backbone polymeric chains. It provides high
molecular weight, Water soluble fragments.
 Type (1B)- Degradation occur to form water-soluble
fragments. Such type provides low molecular weight,
water soluble oligomers and monomers.
­ MECHANISM II
 Describes the dissolution of water insoluble
macromolecules with side groups that are converted to
water insoluble polymers as a result of ionization,
Protonation or hydrolysis of the groups.
 Molecular weight remains unchanged. Materials showing
this type of erosion include Cellulose acetate derivatives,
 Co-polymers of maleic anhydride.
­ MECHANISM III
 Describes the degradation of insoluble polymers with liable
bonds. It forms low molecular weight, water soluble
molecules.
 Polymers undergoing this type of erosion include Poly(lactic
acids)
 Poly(glycolic acid) and their co-polymers etc.
PHYSICAL EROSION
 The physical erosion mechanisms can be characterized as
heterogeneous or homogeneous.
 Most polymers undergo homogenous erosion that means the hydrolysis
occur at even rate throughout the polymeric matrix.
 In homogenous erosion, there is loss of integrity of the matrix or
polymer. In heterogeneous erosion, also called as Surface Erosion. The
polymer erodes only at the surface and maintains its physical integrity as
it degrades.
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 Highly crystalline polymers tend to undergo heterogeneous erosion.
FACTORS AFFECTING BIODEGRADATION
 Polymer morphology
 pH and ionic strength
 Drug – polymer interaction
 Chemical composition and structure
 Processing methods and conditions
 Presence of chain defects
CHARACTERISTICS FOR IDEAL POLYMER
 Should be inert and compatible with the environment.
 Should be non-toxic.
 Should be easily administered.
 Should be easy and inexpensive to fabricate.
 Should have good mechanical strength.
 Should provide drug attachment and release sites for drug polymer
linkages.
APPLICATIONS IN CONVENTIONAL DOSAGE FORMS
 Tablets
­ As binders
­ To mask unpleasant
taste
­ For enteric coated
tablets
 Liquids
­ Viscosity enhancers ­ For controlling the flow
 Semisolids
­ In the gel preparation ­ In ointments
 In transdermal Patches
APPLICATIONS IN CONTROLLED DRUG DELIVERY
 Reservoir Systems
­ Ocusert System
­ Progestasert System
­ Reservoir Designed Transdermal Patches
 Matrix Systems
 Swelling Controlled Release Systems
 Biodegradable Systems
 Osmotically controlled Drug Delivery.
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NOVEL DRUG DELIVERY SYSTEM
DOSAGE FORM
 A drug is seldom given as such – it is developed into a delivery system,
called as dosage / drug delivery system.
 Aim of developing dosage forms is to:
­ Ease of administration, i.e., no need for measurement of dose
before administration
­ Mask taste and enhance palatability
­ Enhance patient compliance
­ Improve drug stability, etc.
­ To deliver drug concentration within therapeutic window which is
neither toxic nor sub-therapeutic.
TYPES OF DOSAGE FORM
 There are several types of dosage forms:
­ Immediate Release (IR) Dosage Forms
­ Modified Release (MR) Dosage Forms
 Extended Release (ER) Dosage Forms
 Sustained Release (SR) Dosage Forms
 Delayed Release (DR) Dosage Forms
IMMEDIATE RELEASE (IR) DOSAGE FORMS
 Most conventional dosage forms are Immediate release (IR)
formulations – release drug immediately after administration.
 These formulations are rapidly and completely absorbed and provide a
fast onset of action.
 Their tmax is short (early achievement of Cmax). They maintains
concentration within therapeutic window for lesser time.
 IR systems have brief duration of action and require more dose
frequency.
 IR release drugs with release rate (Kr) > absorption rate (Ka), i.e., the drug
release is not rate limiting.
 IR systems show fluctuations in blood (if given repeatedly) concentration
time profiles.
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 In reality, unfluctuated therapeutic concentration is needed to be
prolonged for long term in blood. Prolonging therapeutic conc. of IR.
 Increased dose in IR – not feasible as it causes toxicity. Increased
frequency/repeated administration of IR – Not feasible because of:
­ Compliance and dose missing issues
­ Fluctuations in plasma concentration leading either of sub-
therapeutic concentration or unnecessary side effects.
APPROACHES FOR PROLONGING THERAPEUTIC CONCENTRATIONS
 Altering PK/PD:
­ Modification of drug structure (prodrug)
­ Modification of physiology, e.g., pH change at excretory organ to
inhibit excretion.
­ Employing beneficial drug-drug interactions to modify excretion
(e.g., probenecid inhibits excretion of penicillin), to increase
absorption or to potentiate given drug actions.
­ Design of drug delivery system (as modified dosage forms)
 Prodrug is considered as change in drug, thus initiate IND or NDA.
 Physiology modification or drug-drug interaction may involve
manipulation of body system or unnecessary exposure to other drugs.
Thus, design of drug delivery system as modified dosage forms is more
feasible.
MODIFIED RELEASE (MR) DOSAGE FORMS
 USP defines MR as “the delivery system which provides control over
release, temporal, spatial or both and designed to accomplish
therapeutic or convenience objectives not offered by conventional or
immediate-release forms”.
 A system for sustain drug action at predetermined rate by maintaining a
relatively constant, effective drug level with minimization of side effects.
 Localize drug action by spatial placement of controlled release system
adjacent to or in diseased tissue or organ.
 Target drug to a particular “target” tissue/organ by using carriers.
 Reasons for control release are to:
­ Address problems of conventional DDS
­ Better target the diseased tissues
­ Better therapeutic response with precise spatial and temporal
placement of drug
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EXTENDED RELEASE (ER) DOSAGE FORMS
 Extended release (ER) dosage, a type of modified release dosage form,
allows at least a two-fold reduction in dose frequency or significant
increase in patient compliance or therapeutic performance as compared
to an IR.
 After single dose, ER release drug slowly and, its Ka is slow leading to
delayed onset of action for greater duration of action than IR DDS.
 ER release drug in a planned, predicable and slower-than-normal
manner for a longer period of time.
 Synonyms of ERC are: Controlled release (CR), Prolonged release,
Sustained release/Slow release, Long acting (LA).
 Commercial suffixes are: CR, CD (Controlled delivery), ER, LA, PA
(Programmed/Prolonged delivery), SA (Slow acting), TD (Time delivery),
TR (Time release) XL and XR (Extended release).
SUSTAINED RELEASE (SR) DOSAGE FORMS
 Literatures reports some terminologies differently or as other types of
modified release delivery systems, e.g.,
­ A sustained release DDS contains loading dose + maintenance
dose.
 Loading dose is immediately released to produce quick
onset of action.
 Maintenance dose is released at a controlled rate so that
the plasma concentration remains constant above MEC.
DELAYED RELEASE (DR) DOSAGE FORMS
 Delayed release dosage forms contains one or more immediate release
units into a single dosage form.
­ e.g. repeat action tablet, enteric coated tablet.
REPEAT ACTION DOSAGE FORMS
 Repeat action dosage form contains two doses, one is released
immediately, second dose is released at later time but also immediately.
­ Usually achieved by enteric coating.
­ Developed to avoid the need of taking more than one tablet per
day.
 Targeted release dosage forms releases drug at or near the intended
physiologic site of action.
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ADVANTAGES OF ER
 Improved compliance due to reduced frequency of administration.
 Reduced total amount of drug administration – maximum bioavailibility
with minimum dose.
 Improved safety margins for high-potency drugs and reduced local and
systemic side effects.
 Better control of drug absorption.
 Lesser fluctuations in blood concentration due to maintenance of more
even blood levels.
 Overall increased reliability of therapy.
DISADVANTAGES OF ER
 No allowance of prompt termination of therapy.
 Lesser flexible dose adjustment due to fixed dosage form design (i.e.,
cannot break the tablet).
 Dose adjustment in disease states altering PK of drugs cannot be
accommodated.
 Dose dumping.
 Require costly processes and equipment.
CANDIDATE DRUGS FOR SUSTAINED RELEASE DELIVERY SYSTEM
 Design of a successful sustained release delivery system must fulfill the
following conditions:
PHYSICOCHEMICAL CONSIDERATIONS
 Drug must have good solubility which is also pH independent, e.g.,
pentoxifylline.
 Solubility of 0.1 mg/ml for pH range, 1.2 to 7.8 is good.
 Poorly water-soluble drugs are unsuitable because their dissolution is
rate limited.
 Drugs with pH dependent aqueous solubility (e.g. phenytoin) or drug
soluble in non-aqueous solvents (e.g. steroids) are only suitable for
parenteral controlled DS (e.g. intramuscular depot).
 Partition coefficient (apparent) should be high.
 Smaller drug molecules, i.e., having molecular weight < 600 Daltons are
ideal, < 1000 Daltons are suitable for passive diffusion.
 Larger molecules (e.g. peptides and proteins) are not suitable.
 Drug must remain unionized at absorption site. Hexamethonium,
remains ionized and thus is not suitable.
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 Acidic drugs with pKa 3.0-7.5 and basic drugs with 7-11 show good
absorption so are suitable candidate.
 Drug must be stable in GIT environment otherwise bioavailability will be
less.
PHARMACOKINETIC (PK) CONSIDERATIONS
 Drugs requiring dose  500 mg are candidate since dose in MR dosage
forms is 2-3 times that of IR. (Sulfonamides require larger doses, i.e., > 1
g so are not candidate).
 Drugs administered in very small doses are not suitable because they
have narrow therapeutic index.
 Drugs requiring dose adjustment in clinical or diseased situations are not
candidates (anticoagulants, cardiac glycosides)
 Drugs with release rate without influence of pH and enzymes are good
candidates.
 Drugs with Kr slower than Ka (Kr << Ka) or Ka must be rapid than Kr for
successful delivery system.
 Drug must be uniformly absorbed from GIT.
 Drug absorbed only from a specific part in GIT called as “absorption
window” are unsuitable. E.g., fluorouracil, thiazide diuretics.
 Absolute bioavailability must be > 75%.
 Absorption must not be based on receptors mediation (riboflavin is not a
candidate)
 Dugs with rate limited absorption has lesser efficiency for absorption
thus, are not good candidates. Riboflavin, ferrous salts are not
effectively absorbed.
 Drugs with Ka 0.17/h to 0.23/h are good candidates.
 Drugs with slow Ka are inherently long-acting and it is not necessary to
prepare their ERs.
 Drugs with unpredictable Ka are not good candidates.
 Drugs with larger Ka and Ke are not suitable as they remain in body for
longer time e.g., phenytoin and diazepam.
 GIT transit time of drug is 8-12 h, therefore, a drug must have absorption
half-life 3-4 h, otherwise it passes out from potential absorptive region
before it is completely released.
 Lower Css requires lesser amount of drug (dose)
 Enzyme inducers and substrate for first pass effect are not suitable
because first pass clearance causes lower bioavailability.
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­ Rapidly metabolized drug in liver are not good candidate – they
are better given by parenteral controlled release formulation.
­ Drugs that act by affecting enzyme systems may be longer acting
than indicated by their half-lives because of residual effects.
 Ideally, the drug should have half-life of 3-4 h.
 Drugs with short half-life, <1 h are absorbed and excreted rapidly thus,
require prohibitively large quantity, e.g., Penicillin G, Furosemide.
 Drug with half-life ≥ 8 h are sufficiently sustained even from
conventional dosage from. Diazepam, phenytoin has half-life > 12 h thus,
there is no need for developing their sustained release formulations.
 Ke should neither be very slow nor very fast - drugs with slow Ke are
usually inherently long-acting, and it is not necessary to prepare them in
extended-release forms.
 The Clearance must not be dose dependent.
 Vd must not be larger (drugs with larger Vd require larger dose)
PHARMACODYNAMIC (PD) CHARACTERISTICS
 Drug must have relatively larger therapeutic index.
 Drugs with low therapeutic index, if fail in body, dose dumping may
occur (due to product defect), leading to cumulative action and fatalities
e.g. Digitoxin, phenobarbital.
 MEC must not be larger (drugs with larger MEC require larger dose)
 For some drugs, no clear advantage for developing sustained release
formulation (Graseofulvin)
 Drugs whose pharmacological activity is independent of its plasma
concentration are poor candidate, e.g., reserpine.
 Drug used for treatment of chronic rather than acute conditions are
good candidates.
 Drugs for acute conditions require frequent greater dose adjustment by
physician than that provided by extended-release products.
DESIGN AND FABRICATION OF MRDS – THEORY
 Aim of design of MRDs:
­ To deliver drug concentration within therapeutic window without
fluctuations for an extended period of time.
­ To help accomplish PD aims, i.e., to achieve controlled therapeutic
effect without fluctuations.
 Above aims are accomplished by maximizing drug availability and also
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83. Chapter 4 – Novel Drug Delivery System
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controlling drug availability.

An established procedure for fabrication of MRDS formulations is from
approximation to optimization.
APPROXIMATTION OF MR FORMULATION

MRDs are approximately fabricated based on:
­ Characteristics of drug-blood concentrations of drug in IR after
multiple dosing.
­ Knowledge of C
ss
after IR administration: Shorter dose interval
requires frequent number of doses to get C
ss
which leads to lesser
fluctuations and higher value of C
ss

­ Predicted blood level pattern of MRDS is required to be similar,
for up to 12 h to that after constant rate IV infusion (independent
of drug dose/ concentration (=Zero order)
­ Selection of proper dose and dosage interval is prerequisite to
obtaining a drug level pattern that remains in therapeutic range.
­ Decision of dose: A loading dose along with maintenance dose is
added if onset of action is required within short time dose is
added.
­ Selection of dose interval

: as an approximation,

is kept equal to
t
1/2

­ When

= t
1/2
, loading dose is twice of maintenance dose,
according to equation: D
P
= D
Q
k1−e
?4.:=7/r
-/.
o
­ Dose should not exceed total dose administered by conventional
dorms during maintenance period.
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84. Chapter 4 – Novel Drug Delivery System
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­ This is because if total dose is released all at once, it should not
result in a blood level exceed the maximum safe level.
OPTIMIZATION OF MR FORMULATIONS

Optimization of MR formulations requires following parameters, called
as Design parameters for MRDS.
­ Loading or immediately available portion of dose (D
P
)
­ Maintenance or slowly available portion of dose D
Q

­ Time for the start of release of D
Q
(T
k
). It is the delay time
between release of D
P
and D
Q

­ Specific rate of release of D
Q

­ Peak time (T
n
) when concentration is maximum after
administration of D
P

­ Total time (h) after administration in which the drug is effectively
absorbed.
­ Average drug level (C
n
) to be maintained constantly for period of
time equal to (h-T
n
) hours

Constant drug level is achievable when Ka=ke, a situation achievable
when drug is released at rate which provides constant drug
concentration at absorption site.

Release rate (Kr) must be controlled and it must be independent of drug
concentration in dosage form over time (Kr follows zero order)

Kr = rate input=rate output=Cl*CT (where CT is target concentration)

Kr < Ka (or Kr is rate limiting or Ka > Kr)

In the above situation, effect of variation in Ka is minimized.

Design assumes that absorption is complete and of first order. Design
and fabrication theory is extended to:
­ Zero-order release approximation
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85. Chapter 4 – Novel Drug Delivery System
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­ First-order release approximation
 Thus, based on above theory, MRDs are developed as with zero order
release that with First order release for absorption
ZERO ORDER RELEASE APPROXIMATION
 Loading dose with zero order releasing maintenance dose, i.e.,
independent of amount of D
Q (remains unchanged during effective
maintenance period).
 Achieved by two types:
­ Simultaneously release of loading and maintenance dose
­ Delayed release of maintenance dose
 Design parameters for an optimized zero-order model are as:
­ Maximum body drug content to be maintained (Am)
­ Zero order rate constant (Kr0)
­ Peak time for loading dose (Tp)
­ Bioavailability factor (F)
­ Fraction of loading dose at peak (f)
­ Maintenance dose
­ Loading dose with delayed release maintenance dose (Tm=Tp)
­ Loading dose with simultaneous release of maintenance dose
(Tm=0)
 Based on estimation of above, a dosage form is fabricated
 Blood level time data is obtained to match with zero order
approximation
 Design based on simultaneous release of DM and DL requires minimum
total dose and are optimum zero order MRDS
FIRST ORDER RELEASE APPROXIMATION
 Rate of release of drug from maintenance portion of dosage form should
ideally be of zero order to maintain a constant concentration at
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absorption site. But mostly current MRDS do not release drug at
constant rate, and thus do not maintain relatively constant
concentration.

Blood levels decrease over time until the next dose is administered
Rate of appearance of drug concentration at absorption site can be
approximated by an exponential or first order process.

Rate of drug release is a function only of the amount of the drug
remaining in dosage form.

Three different designs are considered:
­ Maintenance dose not delayed
­ Maintenance dose is delayed where Tm=Tp
­ Maintenance dose is delayed where Tm>Tp

Equations used to estimate design parameters for optimized first-order
release models for three different designed are to be considered.

Design parameters are as those for zero order but:
­ Replace Kr0 with Kr1
­ Add Crossing time (Ti) - time at which blood level profiles after
administration of separate loading and maintenance doses
intersect

Closest/better approximation to ideal profile is obtained if:
­ Crossing pint is made at least equal to desired maintenance period
(h-Tp) in systems with simultaneous DM release
­ DM is increased and Kr1 is reduced to maintain product of
Kr1XDM for delayed system with Tm=Tp
­ Tm (delay time for release of DM) is increased in systems Tm>Tp

In system with Tm=0 and Tm=Tp, large maintenance dose is required

Drugs requiring larger DL with shorter half life can not be formulated
with above design.

If Tm=0, is least efficient in terms of dose required.
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 Tm>Tp, despite have fluctuation in plasma profile, a reasonably average
level is maintained with a minimum maintenance dose.
 Optimum first order designs are those in which DM is delayed beyond
the peak obtained from the loading dose, i.e., that with Tm>Tp
 If a drug is administered 4 times a day (12 h), DL may be single dose and
DM would be sum of two doses for a maintenance period of 12 h (total
dose is 5 to 10% lesser than 4 time administration of conventional
dosage form)
MULTIPLE DOSING OF MRDS
 To maintain average drug level for duration of therapy with minimal
fluctuation between dosing intervals, MRDS are also given as multiple
dosing.
 If dosing interval =/< total anticipated release time, accumulation occurs
from systems with loading doses.
 Minimum fluctuations results if dosing interval is = h + t1/2
 Accumulation does not occur unless dosing interval is made less than the
effective maintenance time.
IMPLEMENTATION OF DESIGN – APPROACHES FOR MRDS
 Two approaches for MRDs:
­ Modification of physical and or chemical properties drug
­ Modification drug release rate, characteristics of dosage form
 Approaches based on chemical drug modifications are used to change
physicochemical properties of drugs. Possible only for drugs moiety
having appropriate function groups (Acidic or Basic)
 May contain loading doses of unmodified drug with modified portion in
MRDS. Formulation as suspension, capsules or tablets.
 Advantage of approach is that it is independent of dosage form design.
 Approaches for drug modification:
­ Complex formation (also called as chemical bonding)
­ Drug-adsorbate preparation
­ Pro-drug synthesis
1. COMPLEX FORMATION
 Complex formation of basic drugs with tannic acid. Complex with
cationic ion-exchange resin.
 Effective release rate depends on:
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88. Chapter 4 – Novel Drug Delivery System
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­ Rate of dissolution of solid complex into the biological fluid.
­ Rate of dissociation/breakdown of complex in solution.
???????????????????????? ???????????? ??????????????????????????????????????????????????????????????????=??????
? ?????? ?????????????????????????????????????????? ????????????????????????
­ Where Ks is dissolution rate constant (a function of hydrodynamic
state and factor affecting dissolution process).
­ Surface area can be altered by controlling particle size and or
solubility of drug complex through complexing agent
 Dissociation depends upon digestive process (enzymatic/bile salt action),
pH, ionic composition of gastric fluid.
 If ks > rate of dissociation, a zero order release is expected. If rate of
dissociation > ks, dissolution of complex is rate determining thus, release
rate could be adjusted to zero order by changing dissolution rate.
 Here complex reduces solubility of drug.
 Chemical bonding of drug with ion-exchanging resins:
­ Resin is insoluble ionic material in acidic and basic media.
­ Resin contain ionizable groups which can be exchanged for
positively or negatively charged drug molecules and form
insoluble poly salt resinates.
­ Ionizing acidic drug are complexed with anion exchange resins.
­ Ionizing basic drug with cationic exchange resins.
­ Bonding or complexation is achieved by incubating drug with resin
solution or passing drug solution through column containing ion
exchange resin solution.
­ Drug release is by diffusion through the resin particulate
structure.
 In the stomach:
­ Drug resinate + HCl  acidic resin + drug hydrochloride
­ Resin salt + HCl  resin chloride + sodium salt of drug
 In the intestine:
­ Drug resinate + NaCl  sodium resinate + drug hydrochloride
­ Resin salt + NaCl  resin chloride + sodium salt of drug
2. DRUG ABSORBATE
 Drug absorbate is a special complex which is essentially insoluble.
 Drug availability depends only on rate of dissociation (desorbation) and
thus, on:
­ Access of adsorbent surface to water
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89. Chapter 4 – Novel Drug Delivery System
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­ Effective surface area of the adsorbent
 Molecular scale drug complexed with carrier materials that act to retard
release is similar to drug absorbate.
3. PRODRUG
 Prodrugs are inactive drug derivatives that regenerates the parent drug
by enzymatic or non-enzymatic hydrolysis.
 Solubility, Ka, and/or Ke of prodrug should significantly lower than that
of the parent compound.
 Blood drug concentration depends on rate of bio-conversion of prodrug
to parent drug after absorption.
 If solubility of prodrug is reduced or depends on rate of dissociation at
absorption site, then availability is limited by dissolution rate.
 Dissociation rate depends on in-vivo conditions – against the objectives
of sustained release formulation where minimum effect of in vivo
variables is required.
 Prodrug concept requires chemical modification of drug, thus require
approval from the regulatory authorities. Available for limited number of
drugs having appropriate structural characteristics.
DOSAGE FORM APPROACHES FOR DEVELOPMENT
 Embedding drug in matrix
 Drug in barrier (Barrier imposed delivery system)
1. EMBEDDING DRUG IN MATRIX
 Embedding is putting drug as uniform dispersion in a release retardant
material (matrix). Release retardant material is less soluble than drug in
dispersion fluid.
 Embedded drug matrix can be presented as encapsulated particulates,
granulated, compressed into tablets, as beads, seeds, etc.
­ Embedded drug matrix with Network model where drug is
insoluble in retardant material
­ Embedded drug matrix with dispersion model where drug is
soluble in retardant material
TYPES OF MATRIX
 Types of matrix are
­ Slowly eroding matrix
­ Inert plastic matrix
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90. Chapter 4 – Novel Drug Delivery System
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A) SLOWLY ERODING MATRIX
 A portion of drug is mixed with polymer which erode over time followed
by granulation. A portion of drug is granulated for immediate release.
Both portions are mixed.
 Slowly eroding matrix may release drug by bulk or surface erosion.
BULK EROSION
 On exposure of polymer to water, hydrolysis degrades large polymers
into smaller compounds.
 Small compounds diffuse out of matrix through voids caused by swelling.
Loss of small compounds accelerates formation of voids thus exit of
drug.
SURFACE EROSION
 On exposure of polymer to water, hydrolysis degrades large polymers
into smaller compounds.
 These small compound diffuse from interface of polymer. Loss of small
compounds reveals drug trapped within. These polymer do not swell.
 Drug at surface of unit is dissolved for immediate release then drug
particles in more inner part are dissolved and diffused from pores.
B) EMBEDDING DRUG IN PLASTIC, WAX-LIPID MATRIX
 Granulation of drug with a hydrophobic matrix forming polymer.
Compression of granules to form matrix.
 Drug is slowly released from inert plastic matrix by leaching of body
fluids. Drug release is by diffusion.
MATRIX MATERIAL
 Matrix material may be:
­ Hydrophobic and hydrophilic, insoluble or erodible materials (e.g.,
silicone polymers or lipids)
DRUG RELEASE FROM MATRIX
 Drug release is controlled by combination of several physical process
such as:
­ Permeation of matrix by water, leaching (extraction or diffusion)
of drug from matrix.
­ Erosion of matrix material.
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91. Chapter 4 – Novel Drug Delivery System
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 Alternatively, drug may be dissolved in matrix material and is released
by diffusion through matrix material or partitioned between the matrix
and extracting fluid.
 Higuchi model and zero order equations explain release of drug from
matrix system.
HIGUCHI MODEL
 According to Higuchi, release is triggered by penetrating of medium into
matrix, dissolving drug, creating channels through with diffusion take
place. This event then moves towards core of matrix.
 Higuchi model explains that a plot between amount of drug released per
unit surface area (Q) versus √t is linear.
 Higuchi Equation, Q =B
H∈G
i
?
(2A−∈ C
q)tC
-
.
gives factors for release of
drugs from matrix.
 Where,
­ Q is amount of drug release per unit surface after time, t, D is drug
diffusion coefficient in medium, ∈ is porosity of the matrix, Cs is
the solubility of drug in dissolution media,  is tortuosity of matrix
and A is initial loading dose of drug in matrix.
 Low tortuosity (), represents effective diffusion path gives high release.
High porosity (∈) give high release. Both these properties depends on
amount of dispersed drug, physicochemical properties of matrix,
dispersion characteristics of drugs in matrix.
 If drug is freely soluble in dissolution media, then equation, describing
release from a solution is applicable:
Q = 2Al
Dt
πτ
p
5
6

 Release rate is directly proportional to amount of drug dispersed drug
(A) and if drug is insoluble, then to SQR of A.
ZERO ORDER EQUATION
 When a drug dissolved in matrix, both matrix and partition control are
possible.
 If drug has low solubility in solution media, partition control dominates
and the release is of zero order.
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Q =
KDC
qt
h

 Where K is the partition coefficient and is:
K =
C
q
C
?

 Cs is drug solubility in dissolution media, Cp is dissolution in matrix phase
and h is the thickness of diffusion layer.
 Rate of drug release from embedded matrices can be adjusted by
manipulation of the parameters defined by above 3 equations.
 Above equations helps interpretation variables affecting release from
embedded systems:
­ Nature of retardant, drug solubility, added diluents, drug loading,
drug mixtures, drug-matrix interaction.
MATRIX TABLETS
 Direct compression of blends of drug, retardant material, and additives
to form a tablet where a drug is embedded in a matrix core of retardant.
 Alternatively, retardant-drug blends may be granulated prior to
compression. A less complicated approach.
MATERIALS AS RETARDANT IN MATRIX TABLET FORMULATION
 Three types of materials, Insoluble and inert, Insoluble and erodible and
Hydrophilic are used as release retardants.
­ Insoluble, inert
 Polyethylene
 Polyvinylchloride
 Ethylcellulose
­ Insoluble, erodible
 Carnauba wax
 Castor wax
 Triglyceride
­ Hydrophilic
 Methylcellulose
 Sodium alginate
 Drug bioavailability critically depends on drug polymer ratio and can be
modified by inclusion of diluents (e.g., lactose) in place of polymer.

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METHODS FOR DISPERSING DRUG IN RETARDANT BASE
 Three methods are used to disperse drug and additive in retardant base:
­ Solvent evaporation technique, a solution or dispersion of drug
and additive is incorporated in molten wax phase, the solvent is
removed by evaporation.
­ Drug blending technique, where blends of ingredients are slugged
and granulated.
­ Fusion technique, gives more uniform dispersion where drug and
additive are blended into a molten wax matrix at temperature
slightly above melting point for carnauba wax (approximately 9
o
C).
 Material may be spay-congealed, solidified and milled or granulated.
 Zero order release is possible by addition of additive (polyvinyl
pyrrolidone or polyoxyethylene lauryl ethers).
DRUG RELEASE FROM MATRIX TABLET
 Hydrophilic matrix formers represents non-digestible materials that
form gels in situ.
­ Drug release is controlled by penetration of water through gel
layer produced by hydration of polymer and diffusion through
swollen, hydrated matrix, in addition to erosion of gelled layer.
2. IMPOSING BARRIER ON DRUG
 Imposing barrier on drug where a layer of retardant material is applied
between the drug and the elution medium. Barrier may be permeable or
impermeable.
 Membrane-encapsulated solution or suspension (reservoir systems)
Coating, encapsulation and osmotic control systems are examples of
barrier imposed delivery systems.
 Drug release from drugs with barrier results from:
­ Diffusion of drug through barrier
­ Permeation of barrier by moisture, followed by diffusion
­ Erosion of the barrier
­ Rupture of barrier
 Factor affecting release are barrier composition, thickness of barrier,
integrity of barrier.
 Release from impermeable-to-elution medium where drug is available in
reservoir as a solution or suspension.
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 At steady state, release rate is:
R =
SD
kC
qk
1

­ Where S is surface area, Dm is the diffusion coefficient of drug in
the membrane, l is the thickness of the membrane barrier and Csm
is solubility of drug in membrane.
 For membrane encapsulated solution, release is first order. If membrane
diffusion is slower, than dissolution, release is zero order for membrane-
encapsulated suspensions.
 Two forms, a burst release, if membrane is saturated with drug or time
lag, if drug has not penetrated membrane.
 Time lag is also observed where the barrier is permeable to the elution
media and drug is not released until moisture has penetrated barrier,
dissolving drug in reservoir.
 Additional mechanisms involved may be:
­ Timed erosion of barrier
­ Rupture of barrier after penetration of sufficient moisture.
COATING OF DRUG OR DOSAGE FORM
 Covering drug/dosage form with a material that retards penetration of
dispersion fluid.
 Drug release depends on physicochemical nature of the coating
material.
 A method to retard drug release. E.g.
­ Encapsulated slow release granules/beads
­ Osmotic pump tablets

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ENCAPSULATED SLOW RELEASE GRANULES
 Applies barrier principle of controlling drug release which releases drug
by bursting of barrier.
 System is nonpareil seeds prepared with 20/25 mesh sugar-starch
granules which initially are coated with adhesive followed by powdered
drug and then dried. Step is repeated until desired amount of drug is
applied.
 Resultant granules are coated with a mixture of solid hydroxylated lipids
mixed with modified cellulose.
 Thickness of barrier is regulated by number of applied coatings to
accomplish desired release characteristics.
 A unit of this type contains uncoated and color-coated pellet divided
into 3 to 4 groups, which differ in thickness of time-delay coating.
Uncoated pellets provide loading dose and pellets designed to release
drug at 2-3 h, 4-6 h and 6-9 h.
 Releasing drug at overlapping intervals from different pellets results in a
smooth rather than discontinuous release profile. Release depends on
moisture permeation, causing swelling-rupture of coating.
 Release variables include drug per pellet, composition and thickness of
coating, number of pellets included in each group.
PH SENSITIVE BARRIER
 Time release granules/pellets/beads can be coated with pH-sensitive
materials to release drug at different pHs.
 pH of mouth is 7, stomach 1-4, small intestine 5-7 and > 7 in colon. pH
sensitive system may also be designed to exclude release at certain pH,
such as enteric coating system releases drug at pH above 7 and not in
stomach.
GRANULES AS MICRODIALYSIS CELLS
 Drug containing pellets coated, water insoluble and pH-insensitive
ethylcellulose modified addition of suspended NaCl particles or some
other water soluble material (polyethylene glycol).
 Reaching NaCl from film results in formation of a dialytic membrane in-
situ.
 This allows penetration of water, dissolution of drug and diffusion of
drug essentially through intact membrane.
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OSMOTIC-CONTROL DELIVERY SYSTEM
 Osmotic-control delivery system uses osmotic pressure as driving force
to deliver drug as one daily basis. Osmotic pump based delivery system
is composed of a core tablet surrounded by a semipermeable membrane
have a 0.4 mm diameter hole produced by laser beam.
 System is designed such that only a few drops of water are drawn into
tablet each hour. Rate of water inflow depends upon existence of an
osmotic gradient between contents of the bi-layer core and the fluid in
the GI tract.
 Drug delivery is essentially constant as long as osmotic gradient remains
constant. Release can be controlled by changing:
­ Surface area
­ Thickness or composition of membrane
­ Diameter of the drug release orifice
 Limited to delivery of water soluble drugs.
TYPES
 Single chamber osmotic control delivery system
­ Single chamber consisting of semi-permeable membrane, osmotic
delivery orifice and osmotic core containing drug.
 Multi chamber osmotic control delivery system
­ A polymeric expanding compartment (push layer) provides
additional force on drug layer to deliver drug through delivery
orifice at target rate.
COATING TECHNIQUES
 Wet coating
­ Microencapsulation
­ Spray drying
­ Fluid bed coating
­ Extrusion spheronization
­ Thin precision coating
­ Super critical fluid technique
 Dry coating
­ Magnetically assisted impact coating
­ Rotating fluidized bed coating
­ Hybridizer coating
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MICROENCAPSULATION
 Microencapsulation is the application of thin coating/wall material on
the microscopic particle of solid or droplet of liquid or dispersion as
shell. Entrapment involves the suspension of drug molecules within a
polymeric matrix.
 Encapsulation and entrapment systems release the drug from within the
polymer via molecular diffusion:
­ When the polymer absorbs water, it swells in size
­ Swelling created voids throughout the interior polymer
­ Smaller molecule drugs can escape via the voids at a known rate
controlled by molecular diffusion.
 Encapsulation and entrapment systems are based on biodegradable
polymers:
­ When the polymer is exposed to water hydrolysis occurs
­ Hydrolysis degrades the large polymers into smaller biocompatible
compounds
­ Release by bulk erosion process or surface erosion process.
 Materials used for microencapsulation are polyvinyl alcohol,
polyacrylates, ethylcellulose.
 Microencapsulation enables administration dose of a drug as subdivided
into small units that are spread over a large area of the gastrointestinal
tract, which may enhance absorption by diminishing localized drug
concentration.
 A typical encapsulation process usually begins with dissolving the wall
material, say gelatin, in water. Material to be encapsulated is added and
the two-phase mixture thoroughly stirred.
 With material to be encapsulated broken up to the desired particle size,
a solution of a second material, usually acacia, is added. This additive
material concentrates the gelatin into tiny liquid droplets.
ENCAPSULATION – INSTRUMENTATION
 Physical entrapment and encapsulation of drugs within a polymer is
completed via one of five techniques:
1. Wurster processing
2. Coacervation technique
3. Spray drying (or precipitation)
4. Co-extrusion processing
5. Self-assembly delivery systems
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WURSTER PROCESSING
 Wurster process is a coating process applied after a drug core is formed.
 Polymer shell is applied via spraying while the drug cores (liquid or solid)
is suspended and re-circulated in a gas stream.
COACERVATION TECHNIQUE
 STEP 1:
­ Polymer dissolved in an organic solvent/oil
­ Drug dissolved in water
 STEP 2:
­ Two liquids are rapidly mixed
­ Water droplets form within solvent
 STEP 3:
­ Emulsion from step #2 is mixed rapidly with fresh water
­ Oil droplets within fresh water phase. Oil droplets contain
dispersed water/drug phase
­ Oil diffuses into fresh water phase precipitating the polymer and
entrapping drug.
CO-EXTRUSION PROCESSING
 Several co-extrusion processes share one feature – polymer shell is
flowed concentrically around a pipe containing drug formulation.
 Concentric cylinders then breakup into individual packets either driven
by air flow, electrostatic or mechanical vibration.
SELF-ASSEMBLING DELIVERY SYSTEMS
 Based on use of materials/polymers that self-assemble with drugs to
create controlled drug delivery vehicles.
 Self-assembly is typical approach via one of two methods:
­ Using a molecule that has a hydrophilic head and hydrophobic tail
to form a shell.
­ Electrostatic interaction to entrap drug molecules.
FLUID BED COATING
 Involves drying, cooling, agglomeration, granulation and coating.
 A stream of gas is passing upward through the bed of solid particle
which sets up them in motion. Motion may be as waves for improved
processing.
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FLUID BED COATING – INSTRUMENTATION
TOP SPRAY COATING
 Coating liquid is sprayed down onto fluidized particles.
BOTTOM SPRAY COATING
 Product is air-born upwards in presence of fine spray of liquid.
THIN PRECISION COATING
 For fine particles, which are exposed to high velocity jet, 30-60 ft/s by
accelerating stream or air or inert gas with swirl accelerator.
 A fine spray is introduced into bottom of the high velocity air stream
with a speed faster than particles.
MAGNETICALLY ASSISTED IMPACT COATING
 Oscillating magnetic field accelerates and spin large magnetic particles
mixed with host and guest particles promoting collisions between the
particles and with walls of vessels.
 Coating occurs due to powder impaction, a process is called as peening.
ROTATING FLUID BED COATER
 Dry coating is used for relatively larger particles (1-200 micron) called
host with others called as guest particles mechanically.
HYBRIDIZER
 Consists of very high speed rotating rotor (5000-16000 rpm) with 6
blades and powder recirculation circuit, all in a vessel.
 Host and guest particles in vessel are subjected to height impaction and
dispersion and undergo many collisions in a very short time.
MICELLES AND BILAYERS
 Entrapment by micelle or bilayer formation can be obtained using lipids,
surfactants and block copolymers.
OTHER TYPES OF MRDS
 Drug complexes
 Bioadhesive system
 Ion-activated systems
 pH-dependent system
 pH-independent systems
 Colonic release systems
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 Altered density systems (GRDDS)
 Hydrodynamically balanced system/intra-gastric floating tablets.
EVALUATION AND TESTING
IN-VITRO EVALUATION AND TESTING
 In-vitro evaluation
­ Release of drug from dosage from by dissolution testing at
different time intervals using appropriate dissolution test
apparatus.
­ In-vitro stability evaluation.
IN-VITRO DISSOLUTION TESTING
 In vitro dissolution testing is necessary to:
­ Collect data that is required as a guide to formulation during
development stage.
­ Ensure batch to batch uniformity in production.
 Tests developed for purpose of quality control are limited to USP
dissolution testing methods and apparatus.
 Upper and lower limits are specified for drug release in simulated gastric
fluid (pH 1.2) or simulated intestinal fluid (pH 7.2) or other, i.e., at pH in
between gastric and intestinal.
 Measurements are made at specified time intervals appropriate to
specific product. Measurements are compared with specifications.
 USP requirements and FDA guidance for modified-release dosage forms
for drug release from extended-release and delayed-release is as:
Time (hr) Amount dissolved
1.0 Between 15% and 40%
2.0 Between 25% and 60%
4.0 Between 35% and 75%
8.0 Not less than 70%

 Release data must be evaluated for:
­ Fulfillment of aim of development
­ Unit to unit variation (uniformity of dosage units)
­ Dose dumping (maintenance dose is released before time) or
insufficiently
­ Dose that is unavailable (not released in GIT)
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­ Immediate release of loading dose, if present
­ Release of maintenance time within specified time
­ Stability of formulation with respect to drug release
­ Effect of physiological variables on drug release
­ Kinetics or rate of drug release in simulated gastric and intestinal
fluids.
IN-VITRO STABILITY TESTING
 MRDS usually contain special ingredients which may produce stability
problem.
 Stability testing includes storage of formulation under both normal
(shelf) and exaggerated (accelerated) conditions of temperature,
humidity, light etc.
 Physical stability, chemical stability and release profile is checked after a
time interval at each set of conditions.
IN-VIVO EVALUATION AND TESTING
 In-vitro studies are not sufficient to establish efficacy of new
preparation. Validation of sustained release product designs can be
achieved only by in-vivo testing
 In-vivo testing include:
­ Comparative urinary drug excretion patterns
­ Pharmacokinetics, Bioavailability and Bioequivalence
­ Serial radiophotographs (to follow course of dosage form in GI
tract)
­ Pharmacologic effect as a function of time if drug levels cannot be
measured in biological fluids OR clinical trial to establish
effectiveness of drug product
­ Pharmacokinetics/bioavailability and bioequivalence studies.
AIMS OF STUDY
 Aims of study are:
­ New dosage form meets its controlled release claims
­ Finding consistence between individual dosage units
­ Verification of no dose dumping and insufficient drug availability.
­ Confirmation of equivalence of Css drug levels of dosage form
with currently marketed products.
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­ Correlation of PK, BA with the pharmacologic activity or clinical
evidence of therapeutic effectiveness
­ Determination of fraction of drug absorbed (should be ideally 
80% of conventional release dosage form).
­ Influence of food on drug absorption.
PHARMACOKINETIC STUDIES
 Appropriate animal models (e.g, dogs) are used during product
development to tune formulations to desired specifications.
 Carried out using a single dose pharmacokinetics study using a standard
as pure drug in solution or suspension or commercial controlled dosage
forms.
 Comparison is made between blood level profiles after administration of
single unit of sustained release product and total dose administered as
three divided doses at the recommended dosing interval.
 Samples should be taken over a period of 24 hours or three half-life.
Data is analyzed using model independent approach.
 All design parameters given under MRDS Fabrication-Theory are
computed for zero and first order release approximation, depending
upon type of release from dosage form. Sometimes, in-vitro and in-vivo
measurements are used for prediction of in vivo response.
 Two approaches are transformation of in vitro release profiles into
predicted in vivo response using convolution or deconvolution and by
computer simulation.
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NOVEL GIT DRUG DELIVERY SYSTEM
Gastro-retentive drug delivery is an approach to prolong gastric residence time,
thereby targeting site-specific drug release in the upper gastrointestinal tract
(GIT) for local or systemic effects
GIT ANATOMY AND DYNAMICS
 GI: Group of organs joined in a long tube (several sections)
 Mucosal wall: 4 layers (inner mucosa, submucosa, muscularis externa
and serosa)
 Stomach serves the most primarily mixing area and a reservoir that
secretes pepsinogen, gastric lipase, hydrochloric acid, and the intrinsic
factor.
Need for GRDDS
 Oral drug delivery systems generally suffer from mainly two adversities:
a) Short gastric retention time (GRT)
b) Unpredictable short gastric emptying time (GET)
 Which can result in incomplete drug release from the dosage form in the
absorption zone (stomach or upper part of small intestine) leading to
diminished efficacy of administered dose.
 To formulate a site-specific orally administered controlled release
dosage form, it is desirable to achieve a prolong gastric residence time
by the drug delivery. Prolonged GRT in the stomach could be
advantageous for local action e.g. treatment of peptic ulcer, etc.
POTENTIAL DRUG CANDIDATES FOR GRDDS
 Drugs acting locally in the stomach (active in stomach), e.g. Antacids and
drugs for H. Pylori viz., Misoprostol
 Drugs that are primarily absorbed in the stomach, e.g. Amoxicillin
 Drugs that are poorly soluble at alkaline pH, e.g. Furosemide, Diazepam,
Verapamil, etc.
 Drugs with a narrow window of absorption, e.g. Cyclosporine,
Methotrexate, Levodopa, etc.
 Drugs which are absorbed rapidly from the GI tract, e.g. Metronidazole,
tetracycline.
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 Drugs that degrade in the colon, e.g. Ranitidine, Metformin HCl.
DRUGS UNSUITABLE FOR GASTRO-RETENTION
 Drugs that have very limited acid solubility, e.g. phenytoin etc.
 Drugs that suffer instability in the gastric environment, e.g. erythromycin
 Drugs intended for selective release in the colon, e.g. 5-amino salicylic
acid and corticosteroids etc.
PROCESS OF ORAL DRUG DELIVERY SYSTEM
 After oral administration, drug leaves the formulation and dissolves in
the aqueous digestive fluids. It reaches and crosses the GI mucosal
membrane before passing into blood, moving along the GI tract with the
luminal content at a variable speed.
 Once the drug is reached into the blood circulation, processes of drug
metabolism and elimination starts whilst, it is also possible for some
drug degradation or metabolism to occur sooner than the absorption is
completed leading to a decrease in drug efficiency.
FACTORS AFFECTING THE GASTRO-RETENTIVE SYSTEM
INTRINSIC FACTORS
 Physicochemical properties of API
 Intrinsic dissolution rate
 Particle size, PKa, partition coefficient (Lipophilicity & Hydrophilicity)
 Stability, crystalline amorphous nature, hygroscopicity, etc.
 Stability of the drug at various conditions of GIT
EXTRINSIC FACTORS
 Absorption of drug through GIT
­ Nature and surface area of GI mucosa membrane
­ pH and enzyme systems
­ Dissolution media (Volume and composition)
STRATEGIES TO ADDRESS INTRINSIC AND EXTRINSIC FACTORS
 Prolongation of GIT retention (Novel dosage form)
 Gastro retentive and sustained release dosage forms
 Floating drug delivery system
 Effervescent systems
 Mucoadhesive systems
 Hydrogels
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ORAL OSMOTIC PUMPS
INTRODUCTION
 The delivery of an active agent based on osmotic pressure is one of the
most promising drug delivery technologies of Osmotic pumps are
utilized from the drug development stage (e.g., determination of
pharmacokinetic parameters in animals) to modern drug delivery
technologies (e.g., oral controlled-release and implantable systems)
COMPOSITION
 Osmotic pumps possess a core and coatings that are composed of
similar components as for matrix controlled systems.
 The core constitutes the inner structure of the pump and is composed
of:
­ Therapeutic agent
­ Filler or substrate
­ Viscosity modifier
­ Solubilizer
­ Lubricant/glidant
 The coatings are composed of:
­ Membrane polymer(s)
­ Plasticizer(s)
­ A membrane modifier
­ A color/opacifier
MERITS OF ORAL OSMOTIC PUMPS
 Osmotic pumps are well-characterized drug delivery systems to be
administered by different routes (e.g., peroral and subcutaneous). They
are well-characterized and understood systems, and have some
advantages in relationship to other systems:
­ The coating technology is straight forward, in which controlled
drug delivery is due to the water (diffusion species), and the
modification of the rate of water diffusion is more uncomplicated
than for many active agents.
­ These systems are suitable for a wide range of therapeutic agents,
and they typically give a zero-order release profile after an initial
lag.
­ The delivery rate of active(s) is highly predictable and
programmable.
­ Higher release rates can be achieved than with conventional
diffusion-based drug delivery systems.
­ A high degree of in vitro/in vivo correlation can be obtained.
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DEMERITS OF ORAL OSMOTIC PUMPS
 On the other hand, osmotic pumps have some disadvantages. First, the
orifice size is critical and the laser drilling is very important.
 The membrane must be fully controlled and therefore the coating
process must be well controlled, avoiding the risk of film defects, which
could result in dose dumping. Thus, the film droplets or particles must
be induced to coalesce into a film with consistent properties
 On the other hand, the delay in active delivery is affected by a slowly
solubilized coated layer between the active drug core and the outer
semipermeable membrane
 Changing the surface area, thickness, or composition of the membrane
and/or diameter of the drug release hole can lead to alterations in drug
delivery
 In the case of subcutaneous administration, the system needs to be
removed after therapy. However, when the system is administered
through peroral route, it is eliminated in the feces as an insoluble shell
DRUG DELIVERY RATE
 The drug delivery of the active agent from osmotic pumps across the
semipermeable membrane is controlled by water movement.
 Therefore, for one solution-type osmotic pressure-activated system, the
intrinsic rate of active agent delivery is defined by Equation:
??????
??????
=
??????
? ??????
?
ℎ
?
(??????
? ˗ ??????
?)
Where;
 Q/t is the intrinsic rate of drug delivery,
 Pw is the water permeability in the semipermeable membrane,
 Am is the effective surface area of the semipermeable membrane,
 hm is the thickness of the semipermeable membrane, and
 ps − pe is the differential osmotic pressure between the system (with an
osmotic pressure ps) and the environment (with an osmotic pressure pe)
 For a solid-type osmotic pump system, the intrinsic rate of delivery is
defined considering the drug concentration (aqueous solubility of the
active agent) in the solid reservoir (Sd), according to Equation;
??????
??????
=
??????
? ??????
?
ℎ
?
(??????
? ˗ ??????
?)??????
?
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BIO/MUCOADHESIVE SYSTEMS
INTRODUCTION
 Bioadhesion can be defined as the state in which two biological
materials, or a biological and a synthetic material, are maintained
together for a prolonged time period by means of interfacial forces.
 When there is the presence of mucous tissue, the bioadhesion is named
mucoadhesion.
 Mucoadhesive dosage form is designed to increase the residence time of
formulation by interacting with mucus layer covering the mucosal
epithelial surface and mucin molecule.
 Increase in residence time at the site of absorption. It could be
considered as an example of controlled delivery system.
 Most common are:
­ Bucoadhesive systems meant for buccal cavity
­ MDDS has also been developed for Nasal, Rectal and Vaginal
systems
­ Designed for both local and Systemic effect.
DRUG CANDIDATES FOR MDDS
 Hydrophilic high molecular weight such as peptides that cannot be
administered and have poor absorption, then MDDS is best choice.
 Considerable interest in pharmaceutical mucoadhesive with enzyme
inhibitory and then MDDS is best choice.
 Low absorption due to poor solubility.
 Localized action (e.g. dental pain).
TYPES OF MDDS
MUCOADHESIVE TABLETS
 Adhere to surface and retain their structure (swelling parameters) until
complete release of API.
 Release profile (e.g. control release) of API can be managed by the
selection of ingredients.
 Offer localized and systemic effect at variety of absorption sites.
 Disadvantages:
­ May cause discomfort in drinking, eating
­ Lack physical flexibility
­ Poor patient compliance.
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MUCOADHESIVE FILMS
 Attractive dosage form in recent times. Mucoadhesive films may be
preferred over adhesive tablets in terms of flexibility and comfort.
 They can circumvent the relatively short residence time (super
disintegration) of oral gels on the mucosa, which are easily washed away
and removed by saliva.
 In the case of local delivery for oral diseases, the films also help protect
the wound surface, thus helping to reduce pain, and treat the disease
more effectively.
QUALITIES OF AN IDEAL FILM
 An ideal film should be flexible, elastic, and soft, yet adequately strong
to withstand breakage due to stress from mouth movements.
 It must also possess good mucoadhesive strength in order to be retained
in the mouth for the desired duration of action.
 Swelling of film, if it occurs, should not be too extensive in order to
prevent discomfort.
MUCOADHESIVE PATCHES
 Patches are laminates consisting of an impermeable backing layer, a
drug-containing reservoir layer from which the drug is released in a
controlled manner and a mucoadhesive surface for mucosal attachment.
 Patch systems are similar to those used in transdermal drug delivery.
 Two methods used to prepare adhesive patches include:
1) Solvent casting
 In the solvent casting method, the intermediate sheet from
which patches are punched is prepared by casting the
solution of the drug and polymer(s) onto a backing layer
sheet, and subsequently allowing the solvent(s) to
evaporate.
2) Direct milling
 In the direct milling method, formulation constituents are
homogeneously mixed and compressed to the desired
thickness, and patches of predetermined size and shape are
then cut or punched out.
GELS AND OINTMENTS
 Semisolid dosage forms, such as gels and ointments, have the advantage
of easy dispersion throughout the oral mucosa.
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 In situ gel formation: Certain mucoadhesive polymers, for example,
sodium carboxymethylcellulose, Carbopol, hyaluronic acid, and xanthan
gum, undergo a phase change from liquid to semisolid. This change
enhances the viscosity, which results in sustained and controlled release
of drugs
 Hydrogels: A promising dosage form for buccal drug delivery. They are
formed from polymers that are hydrated in an aqueous environment
and physically entrap drug molecules for subsequent slow release by
diffusion or erosion.
MECHANISM OF MUCOADHESION
 Mechanism of mucoadhesion i.e. bioadhesion of polymers or
macromolecules with surface of mucus membrane is has not been
properly understood yet.
 But it is known that the forces of attraction must overcome the forces of
repulsion for successful utilization. For close contact and increased
surface area, the diffusion of the substrate chains have to be promoted
and therefore, the mucoadhesive must properly spread on the
substrate.
 These theories are used together to understand and explain
mucoadhesion:
­ Wetting Theory
­ Mechanical Interlocking Theory
­ Electronic Transfer Theory
­ Adsorption Theory
­ Fracture Theory
­ Diffusion Interpretation Theory
FORMULATION DESIGN / MATERIALS
1) Mucoadhesive agents
­ The polymer hydration and consequently the mucus cohesive
properties that promote mucoadhesion. Swelling should favor
polymer chain flexibility and interpenetration b/w polymer and
mucin chains. Ex-Polyacrylic acid (PAA), Polyvinyl alcohol, Sodium
carboxymethyl cellulose, Sodium alginate, HPMC, HEC, HPC and
many other novel polymers are being developed.
2) Penetration enhancers (EDTA, Chaetocin derivative, menthol etc.)
3) Enzyme inhibitors (prevents enzymatic degradation at site of adhesion)
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4) Gel forming agents (Xanthan gum).
EVALUATION AND CHARACTERIZATION TECHNIQUES
 Mucoadhesion extent and time
 In vitro Release Profile
 Swelling parameters (Swelling index)
 Other routine Quality tests
APPLICATIONS
 The main application of the bioadhesion strategy is to modify the drug
delivery to control the release of the active within a defined period of
time. Thus, in recent years, bioadhesive dosage forms include adhesive
solid drug delivery systems (tablets and patches), adhesive semi-solid
drug delivery systems and adhesive liquid dispersions.
 For example, it is possible to cite:
­ Solid micro- and nanoparticulate systems
­ Microemulsions
­ Colloidal dispersions of bioadhesive polymers
­ Semi-solid systems
­ Liquid crystalline mesophases
­ Hydrogels
 Which can increase the contact time between the preparation and the
mucous membrane after they undergo in situ gelation.
PROBLEMS / DISADVANTAGES
 Drugs, which irritate the oral mucosa, have a bitter or unpleasant taste,
odor; cannot be administered by this route.
 Drugs, which are unstable at buccal pH cannot be administered by this
route.
 Only drugs with small dose requirements can be administered. Limited
dissolution medium.
 Drugs may swallow with saliva and loses the advantages of buccal route.
 Only those drugs, which are absorbed by passive diffusion can be
administered by this route.
 Eating and drinking may become restricted.
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CHEWING GUM DOSAGE FORM FOR BUCCAL DELIVERY
INTRODUCTION
 Medicated chewing gum (MCG) is a novel drug delivery system
containing masticatory gum base with pharmacologically active
ingredient and intended to use for local treatment of mouth diseases or
systemic absorption through oral mucosa.
 MCG is considered as vehicle or a drug delivery system to administer
active principles that can improve health and nutrition.
NEED OF MEDICATED CHEWING GUM
 Ability of chewing gums to release active ingredients into the oral cavity,
steady and rapid action, capability of both systemic and local delivery,
make it appropriate for extensive use in food and pharmaceutical
industries.
DRUG CANDIDATES FOR MCG
 Few drugs are suitable candidates for incorporation into chewing gum
formulations for the intention of their systemic delivery.
OPTIMAL PROPERTIES OF DRUGS

Physicochemical Properties of Drug Patient Related Factors
High Salivary Solubility Non-toxic to oral mucosa and salivary ducts
pH independent solubility Non-carcinogenic
Tasteless
Should not cause tooth decay, oromucosa and
teeth staining
Should not affect salivary flow rate
COMPONENTS OF MEDICATED CHEWING GUM
 Typically CG comprises two parts:
1) Water insoluble chewable gum base portion
2) Water-soluble bulk portion
 Chewing gum comprises of following components:
­ Active components
­ Gum base
­ Elastomers
­ Plasticizers
­ Adjuvants
­ Antioxidants
­ Compression adjuvants
­ Sweeteners
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­ Coloring agent ­ Flavoring agent
1. GUM BASE
 Gum base is an inert and insoluble non-nutritive product used as a
support for the edible and soluble of the chewing gum (sugar, glucose,
poly oils and flavors).
2. ELASTOMERS
 Including natural and synthetic rubbers. The gum base composition may
contain conventional elastomer solvents to aid in softening
the elastomer base component.
 The elastomer solvents may be employed in amounts from 5% to 75%,
by weight of the gum base, and preferably from 45% to 70% by weight
of the gum base.
 Synthetic elastomers such as butadiene, styrene copolymers,
polyisobutylene, isobutylene isoprene copolymers, polyethylene
mixtures, and non-toxic vinyl polymer, such as polyvinyl alcohol are
widely used bases.
3. PLASTICIZERS
 These may be incorporated into the gum base to obtain a variety of
desirable textures and consistency properties.
4. ADJUVANTS
 Calcium carbonate, talc, or other charging agents are used. These are
served as fillers and textural agents.
5. ANTIOXIDANTS
 Butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate and
mixtures thereof may be included as antioxidants.
6. COMPRESSION ADJUTANTS
 Suitable compression adjuvant such as silicon dioxide, magnesium
stearate, calcium stearate and talc can be used in medicated chewing
gum for ease of compression.
7. SWEETENERS
 Water-soluble sweetening agents
 Water-soluble artificial sweeteners
 Dipeptide based sweeteners
 Water-soluble sweeteners
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 Protein based sweeteners
8. COLORING AGENTS
 The coloring agents include pigments, which may be incorporated in
amounts up to about 6% by weight of the gum composition, titanium
dioxide may be incorporated in amounts up to about 2%.
9. FLAVORING AGENTS
 Flavoring agents suitable for use are essential oils and synthetic flavors
such as citrus oils, fruit essences, peppermint oil, spearmint oil, clove oil
wintergreen oil, and anise oil.
10. ACTIVE COMPONENT
 In medicated chewing gum active pharmacological agent may be present
in core or coat or in both.
MANUFACTURING PROCESS
 Different methods employed for the manufacturing of MCG can be
broadly classified into three main classes namely:
­ Conventional/traditional method (Melting)
­ Freezing, grinding, and tableting method
­ Direct compression method
1. CONVENTIONAL/ TRADITIONAL METHOD (FUSION)
 Components of gum base are softened or melted and placed in a kettle
mixer to which sweeteners, syrups, active ingredients and other
excipients are added at a definite time.
 The gum is then sent through a series of rollers that forms into a thin,
wide ribbon. During this process, a light coating of finely powdered sugar
or sugar substitutes is added to keep the gum away from sticking and to
enhance the flavor.
 In a carefully controlled room, the gum is cooled for up to 48 hours. This
allows the gum to set properly. Finally the gum is cut to the desired size
and cooled at a carefully controlled temperature and humidity.
LIMITATIONS
 Elevated temperature used in melting restricts the use of this method
for thermolabile drugs.
 Melting and mixing of highly viscous gum mass makes controlling of
accuracy and uniformity of drug dose difficult.
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 Lack of precise form, shape or weight of dosage form.
 Technology not so easily adaptable to incorporate the stringent
manufacturing conditions required for production of pharmaceutical
products.
 Such a chewing gum composition is difficult to form into chewing gum
tablets because of their moisture content (2-8%). If attempted to grind
and tablet such a composition would jam the grinding machine, stick to
blades, screens adhere to punches and would be difficult to compress.
2. COOLING, GRINDING AND TABLETTING METHOD (THERMOLABILE)
 This method has been developed with an attempt to lower the moisture
content and alleviate the problems mentioned in conventional method.
COOLING AND GRINDING
 The MCG composition (base) is cooled to a temperature at which the
composition is sufficiently brittle and would remain brittle during the
subsequent grinding step without adhesion to the grinding apparatus.
Generally the temperature of the refrigerated mixture is around -15
o
C or
lower.
 The refrigerated composition is then crushed or ground to obtain minute
fragments of finely ground pieces of the composition. Certain additives
can be added to the chewing gum composition to facilitate cooling,
grinding and to achieve desired properties of chewing gum.
 These include use of anti-caking agent (precipitated silicon dioxide) and
grinding agent (alkaline metal phosphate, an alkaline earth metal
phosphate or maltodextrin)
TABLETING
 Once the coolant has been removed from the powder, the powder can
be mixed with other ingredients such as binders, lubricants,
coating agents, sweeteners etc., all of which are compatible with the
components of the chewing gum base in a suitable blender such as
sigma mill or a high shear mixer.
 Alternatively a Fluidized Bed Reactor (FBR) can be used. The use of FBR is
advantageous as it partially rebuilds the powder into granules, as well as
coats the powder particles or granules with a coating agent thereby
minimizing undesirable particle agglomeration.
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 The granules so obtained can be mixed with anti-adherents like talc. The
mixture can be blended in a V type blender, screened and staged for
compression. Compression can be carried out by any conventional
process like punching. It requires equipment other than
conventional tableting equipment and requires careful monitoring of
humidity during the tableting process which is the major limitation.
3. USE OF DIRECT COMPRESSION CHEWING GUM EXCIPIENTS
 The manufacturing process can be accelerated if a directly compressible
chewing gum excipient is available. The limitations of melting and
freezing can be overcome by the use of these.
 Pharmagum is a mixture of polyol(s) and/or sugars with a chewing gum
base. It is available as directly compressible powder, free flowing
powder which can be compacted into a gum tablet using conventional
tablet press thus enabling rapid and low cost development of a gum
delivery system. It is manufactured under CGMP conditions and
complies with Food Chemicals Codex specifications as well as with FDA,
so they can be considered as "Generally regarded as safe" (GRAS).
FACTORS AFFECTING RELEASE OF ACTIVE INGREDIENT
1. CONTACT TIME
 The local or systemic effect is dependent on time of contact of MCG in
oral cavity. In clinical trial, chewing time of 30min was considered close
to ordinary use.
2. PHYSICOCHEMICAL PROPERTIES OF ACTIVE INGREDIENT
 Physicochemical properties of active ingredient plays very important
role in release of drug from MCG. The saliva soluble ingredients will be
immediately released within few minutes, whereas lipid soluble drugs
are released first into the gum base and then released slowly.
3. INTER INDIVIDUAL VARIABILITY
 The chewing frequency and chewing intensity that affect the drug
release from MCG may vary from person to person. In-vitro study
prescribed by European Pharmacopoeia suggests 60 cycles per minute
chewing rate for proper release of active ingredient.
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4. FORMULATION FACTOR
 Composition and amount of gum base affect rate of release of active
ingredient. If lipophilic fraction of gum is increased, the release rate is
decreased.
EVALUATION AND CHARACTERIZATION OF MCGS
OFFICIAL PRODUCT QUALITY TESTS
 The following methods for testing MCGs have been reported in the 8th
edition of the Ph. Eur under chapters 2.9.5, 2.9.6, and 2.9.7 for the
uniformity of mass, content of single-dose preparations, and friability of
uncoated tablet, respectively.
1. UNIFORMITY OF MASS
 Uniformity of mass is generally applied to noncoated medicated chewing
gums. It is performed by measuring the weight of 20 individual pieces of
chewing gum then calculating the percentage of weight deviation of
each chewing gum from the average weight based on Formula .
 In order to comply with the Ph. Eur test limits, not more two chewing
gum units should deviate from the average weight by more than 7.5%
for gums with an average mass ≥ 300 mg and 10% for gums with an
average mass ≤300 mg. When the average mass of chewing gum is equal
to or less than 40 mg, content uniformity test is used.
2. CONTENT UNIFORMITY
 Content uniformity or drug content of chewing gum is determined by
using a suitable analytical method to ensure the consistency of dosage
units of a single-dose preparation. According to the Ph. Eur, there are
three content uniformity (CU) tests (A, B, and C).
 Test A is designed for testing tablets, while tests B and C are intended
for capsules and transdermal patches, receptively.
 MCGs as solid dosage forms should comply with test A CU limits.
 Test A is used for MCGs that contain 2 mg of API or if the API is less than
2% of the total mass of the chewing gum. It is determined by measuring
the API content in ten random chewing gum units. Each gum piece
should have drug content within the 85 and 115% range.
3. FRIABILITY TEST
 To evaluate friability of compressed gums, ten gum units, if a unit mass
is more than 650 mg (or 6.5 g of cumulative weight if a unit mass is less
than 650 mg) are randomly selected and carefully de-dusted prior to
test.
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 Initially, gums are weighted (W initial) and placed in a drum. Then, the
drum is allowed to rotate 100 times at 25 rpm. Gums are then de-dusted
and weighted again (W final). The difference in weight represents the
friability percentage (F%) that can be calculated based on Formula:
???????????????????????????????????????????????????????????? (??????
%)=
??????
??????? − ??????
?????
??????
???????
??????100
 MCGs pass the friability test if the F% is less than 1%
UNOFFICIAL PRODUCT QUALITY TESTS (MECHANICAL PROPERTIES)
 Unlike other dosage forms, MCGs have mastication property. The
pleasant texture of the chewing gum is important to their commercial
success. Currently, official pharmacopeias do not specify a testing
procedure for the estimation of the mastication, mechanical, and
textural properties of chewing gums. A brief overview of the most
pertinent tests is given below:
1. TEXTURE PROFILE ANALYSIS
 Texture profile analysis (TPA) is a valuable tool that has been used to
evaluate the mechanical properties of food products. Mechanical
properties are determined by subjecting a bite size of materials to two
compression cycles (two-bites test) in a reciprocating motion that
simulate the action of jaws where high compression force is used to
imitate the chewing of the teeth.
 This test generates a forced displacement response curve from which
several textural parameters that correlate well with sensory evaluation
can be extracted and adapted to evaluate the chewing gums.
2. PLASTICITY INDEX
 To measure plasticity Index (PI), a molten gum base is transferred to an
aluminum weight pan with specific diameters and depth. After 24hrs of
cooling, indentation experiment is performed with a texture analyzer
fitted with a spherical probe. In this test, the probe is allowed to move at
a fixed speed for a specific distance into the gum base, which will have
the same thickness of the weight pan.
 From the trigonometric calculation of the sphere, the theoretical chord
value (TCV) for a given depth and diameter can be obtained, while the
experimental chord value (ECV) can be measured using a regular Vernier
caliper. PI is calculated based on the ECV to TCV ratio for each sample as
follows in Equation:
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PI =
Expermental chord value after 24 hrs
Theoretical chord value after 24 hrs

 Measurement of PI suggest to study the influence of the softeners or
plasticizers on the polymeric/continuous phase of the gum base.
3. PENETRATION TEST
 This test has been used to understand the deformation behavior of
MCGs that have been made by direct compression or by then
fusion/traditional method. It evaluates the deformation response of a
tested material to a penetrating probe.
4. IN VITRO RELEASE TESTING OF DRUGS
 MCGs Due to their gummy nature, are not suitable to be tested by the
regular dissolution testing machines that are used with conventional
tablets or capsules.
 Various devices have been developed to mimic the chewing process. The
Ph. Eur (8th ed) published general monographs describing two
apparatuses, A and B, for studying the in vitro release of drug substances
from chewing gums. A release test for chewing gum, however, has not
been officially adopted by the USP 40-NF 35, although individual
monographs for nicotine polacrilex gums with product quality tests such
as assay, identification, uniformity of dosage unit, content, and mass are
provided.
MERITS OF MCG
 Does not require water to swallow. Hence can be taken anywhere.
 Advantageous for patients having difficulty in swallowing.
 Excellent for acute medication.
 Counteracts dry mouth, prevents candidiasis and caries.
 Highly acceptable by children.
 Avoids first pass metabolism and thus increases the bioavailability of
drugs.
 Fast onset due to rapid release of active ingredients in buccal cavity and
subsequent absorption in systemic circulation.
 Stomach does not suffer from direct contact with high concentrations of
active principles, thus reducing the risk of intolerance of gastric mucosa.
 Fraction of product reaching the stomach is conveyed by saliva delivered
continuously and regularly. Duration of action is increased.
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 Aspirin, Dimenhydrinate and Caffeine shows faster absorption through
MCG than tablets.
 Stimulates flow of saliva in the mouth.
 Neutralizes plaque acids that form in mouth after eating fermentable
carbohydrates.
 Helps whiten teeth by reducing and preventing stains.
DEMERITS OF MCG
 Risk of over dosage with MCGs compared with chewable tablets or
lozenges that can be consumed in a considerable number and within
much shorter period of time.
 Sorbitol present in MCG formulation may cause flatulence, diarrhea.
 Additives in gum like flavoring agent, Cinnamon can cause Ulcers in oral
cavity and Liquorice cause Hypertension.
 Chlorhexidine oromucosal application is limited to short term use
because of its unpleasant taste and staining properties to teeth and
tongue.
 Chewing gum has been shown to adhere to different degrees to enamel
dentures and fillers.
 Prolonged chewing of gum may result in pain in facial muscles and ear-
ache in children.
APPLICATIONS OF MCGS
1. DENTAL CARIES
 Prevention and cure of oral disease are targets for chewing gum
formulations.
 It can control the release rate of active substances providing a prolonged
local effect.
 It also re-elevates plaque pH which lowers intensity and frequency of
dental caries.
 Fluoride containing gums have been useful in preventing dental caries in
children and in adults with xerostomia.
 Chlorhexidine chewing gum can be used to treat gingivitis, periodontitis,
oral and pharyngeal infections.
 It can also be used for inhibition of plaque growth.
 Chlorhexidine chewing gum offers numerous flexibility in its formulation
as it gives less staining of the teeth and is distributed evenly in the oral
cavity.
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 The bitter taste of chlorhexidine can be masked quite well in a chewing
gum formulation.
2. SYSTEMIC THERAPY
 Pain
­ Chewing gum can be used in treatment of minor pains, headache
and muscular aches.
 Smoking cessation
­ Chewing gum formulation containing nicotine and lobeline have
been clinically tested as aids to smoking cessation.
 Obesity
­ Active substances like chromium, guaran and caffeine are proved
to be efficient intreating obesity. Chromium is claimed to reduce
craving for food due to an improved blood-glucose balance.
­ Caffeine and guaran stimulate lipolysis and have
a thermogenic effect (increased energy expenditure) and reduce
feeling of hunger.
 Other indications
­ Xerostomia, Allergy, Motion sickness, Acidity, Cold and Cough,
Diabetes, Anxiety, etc. are all indications for which chewing gum
as drug delivery system could be beneficial.

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FLOATING DRUG DELIVERY SYSTEM
INTRODUCTION
 GRDDS (for stomach) is a system that remains in stomach for
appropriate time interval irrespective of all physiological obstructions,
releases the active moiety in controlled manner, ultimately metabolizes
in the body with ease and ensures the optimal bioavailability
HIGH DENSITY SYSTEM
 Small sized high density systems that are to be retained in the stomach
body folds near pyloric region are tackled by the sedimentation process.
This approach helps to formulate the dosage forms having density
greater than the density of normal stomach contents (~ 1.004 g/cm
3
).
 These systems are designed by coating of drugs on heavy core or by
mixing those with inert matters like iron powder, zinc oxide, titanium
oxide and barium sulphate. The density increased by these materials is
up to 1.5 – 2.4 g/cm
3
. For significant elongation of gastric residence time
a density closed to 2.5g/cm
3
seems to be necessary.
LOW DENSITY SYSTEM (FLOATING SYSTEMS)
 FDDS is also designated as hydro-dynamically balanced system (HBS).
 The foremost requirements of the FDDS are:
­ It should release contents gradually to serve as a reservoir.
­ It must have specific gravity lesser than that of gastric contents
(1.004 – 1.01 g/cm
3
).
­ It must have to create a cohesive gel barrier.
 The characteristic low density is majorly delivered by the air entrapment
or integration of low density materials like fatty or oily materials or foam
powder.
DRUG CANDIDATES FOR FDDS
 Drugs having narrow absorption window (for example furosemide, L-
DOPA, riboflavin).
 Drugs that act locally in stomach (for example antacids, misoprostol).
 Drugs that are not stable in colonic or intestinal environment (for
example metronidazole, ranitidine HCL, captopril).
 Drugs that effect the colonic microbes (for example clarithromycin,
tetracycline, amoxicillin).
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 Drugs having low solubility at higher pH (for example verapamil,
diazepam)
 Drugs that are majorly absorbed from the stomach.
CLASSIFICATION OF FDDS
 The development of floating systems based on two markedly different
approaches i.e. effervescent and non-effervescent systems which are
totally based on the buoyancy mechanism.
NON EFFERVESCENT SYSTEM
 The mechanism on which the non-effervescent floating system is based
is the swelling of polymer or bio-adhesion of polymer to the mucosal
layer of GIT.
 This dosage system utilize the swellable or gel forming cellulose type of
polysaccharides, hydrocolloids and matrix developing polymers as
polyacrylate, polycarbonate, polystyrene and polymethacrylates.
TYPES OF NON-EFFERVESCENT SYSTEMS
1. SINGLE LAYER FLOATING SYSTEMS
 These are formed by mixing the drug uniformly with the gel forming
hydrocolloid that swells when comes in contact with the gastric fluid and
ultimately helps to maintain specific gravity lesser than 1.
 They are formed by blending the drug with low density materials like
hydroxyl propyl methyl cellulose and cellulose acetate phthalate.
2. BI-LAYER FLOATING TABLET SYSTEMS
 A bi-layer system have two layers. One layer is an immediate release
layer that releases the loading dose through the system and other layer
is sustained release layer that releases the dose after absorbing the
gastric fluid.
 This will form a resistant gel barrier over the surface and retains the
specific gravity lesser than 1 so remains floating in the stomach.
3. HYDRODYNAMIC BALANCE SYSTEMS
 These systems are single unit based dosage forms having one or more
gel developing hydrophilic polymers.
 Most commonly used excipient is Hydroxy propyl methylcellulose,
though other polymers like sodium carboxymethylcellulose, hydroxy
propyl cellulose, hydroxy ethyl cellulose, carrageenan, alginic acid and
agar are also used.
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 The drug is being mixed with the polymer and frequently administered
in gelatin capsule.
 A floating mass is produced after swelling and hydration of the surface
polymers which are released after capsule get dissolved in gastric fluid.
4. MICRO-BALLOONS / HOLLOW MICROSPHERE
 Drug loaded micro-balloons / hollow microspheres in other polymer
were manufactured simply by solvent diffusion or solvent evaporation
technique to extend the GRT of dosage system.
 Calcium alginate, cellulose acetate, Eudragit S, low methoxylate pectin
and agar are commonly used polymers
5. ALGINATE BEADS
 Multi-unit floating systems are established from freeze dried calcium
alginate. Spherical beads with diameter of approximately 2.5mm can be
prepared by adding the solution of sodium alginate into the calcium
chloride aqueous solution, which forms the calcium alginate precipitates
leading to the development of porous system. This can sustain a floating
force for up to 12 hours.
6. MICRO-POROUS COMPARTMENT SYSTEMS
 This technique is based on the mechanism of encapsulation of drug
reservoir in the micro-porous compartment having pores alongside its
top and bottom walls.
 The peripheral walls of the dosage systems were totally sealed to avoid
any direct contact of the undissolved drug with the gastric surface.
 Entrapped air in the floatation chamber of the stomach causes the
delivery systems to float in the gastric fluid.
 Gastric fluid go through the aperture, dissolves the active drug and
causes the continuous transport of the dissolved drug through the
intestine for absorption of the drug.
EFFERVESCENT SYSTEMS
TYPES OF EFFERVESCENT SYSTEMS
1. GAS GENERATING SYSTEMS
 Effervescent systems has a particular use of gas generating agents,
organic acids like tartaric acid and citric acid as well as carbonates like
sodium bicarbonate.
 These are the part of formulation to yield carbon dioxide (CO2) gas
accordingly reducing the density of the dosage system and causing it to
float over the gastric fluid.
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2. VOLATILE LIQUID CONTAINING SYSTEMS

A substitute approach is the fusion of matrix having portion of liquid that
produce the gas that evaporate at the body temperature.

Buoyancy can be accomplished by the gas bubbles generation. This
approach is acceptable for both single as well as multiple unit systems.
In single unit dosage systems like tablets or capsules, effervescent
materials are merged in the hydrophilic polymer bubbles of CO
2
are
entrapped in the swollen matrix. MECHANISM OF FLOATING

FDDS have low bulk density than that of gastric fluids, so such systems
remain floated in stomach without upsetting the rate of gastric emptying
for extended duration of time.

During the stay time of dosage systems, the drug releases gradually at
the anticipated rate from the concerned dosage system. After releasing
the drug, the leftover system is cleared from stomach resulting in the
improved GRT and better control over the variations in the plasma drug
concentration.

In addition to the least gastric content required for achievement of
appropriate floating principle, a floating force “F” is also needed for
dosage system to remain buoyant over the surface of gastric content.
DEVELOPMENT OF FFDS

Single Unit Dosage form

Multiple Unit Dosage form
EVALUATION / IN VITRO CHARACTERIZATION

Conventional QC tests
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­ Weight variation, drug content uniformity etc.
 Drug loading
 Swelling Index (different pH)
 Floating behaviour
­ Floating time
­ Floating rate
 Dissolution studies
 Drug polymer compatibility studies (FTIR, DSC, PXRD etc)
 Surface characterization (in case of micro beads etc. technique SEM)
MERITS OF FDDS
 Floating dosage forms such as tablets or capsules will remains in the
solution for prolonged time even at the alkaline pH of the intestine.
 FDDS are advantageous for drugs meant for local action in the stomach
eg: Antacids.
 FDDS dosage forms are advantageous in case of vigorous intestinal
movement and in diarrhea to keep the drug in floating condition in
stomach to get a relatively better response.
 Acidic substance like aspirin causes irritation on the stomach wall when
come in contact with it hence; FDDS formulations may be useful for the
administration of aspirin and other similar drugs.
 The FDDS are advantageous for drugs absorbed through the stomach eg:
Ferrous salts, Antacids.
DEMERITS OF FDDS
 Floating systems are not feasible for those drugs that have solubility or
stability problems in gastric fluids.
 Drugs such as Nifedipine, which is well absorbed along the entire GI tract
and which undergo significant first-pass metabolism, may not be suitable
candidates for FDDS since the slow gastric emptying may lead to
reduced systemic bioavailability. Also, there are limitations to the
applicability of FDDS for drugs that are irritant to gastric mucosa.
 One of the disadvantages of floating systems is that they require a
sufficiently high level of fluids in the stomach, so that the drug dosages
form float therein and work efficiently.
 These systems also require the presence of food to delay their gastric
emptying.
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APPLICATIONS OF FDDS
 It helps to reduce the dosing frequency and increases compliance in
patient.
 Due to buoyancy, it increases the gastric stay time.
 It improves the bioavailability of many drugs when designed as FDDS.
 It improves the therapeutic effect of the drugs with shorter half-life.
 It helps to deliver the drug system to the specific site.
 It controls the release of drug in a specified manner.
 Such designs can help to avoid the problem of gastric irritation.
 It avoids the dose dumping by formulating the floating units.
 It provides more uniform effects of the drug.
 Lesser use of total dose. It provides the improved safety/efficacy ratio.
 Lesser chances of GIT side effects.
 It is very effective in cases of the drugs which have local actions e.g.,
antacids.

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COLON SPECIFIC DRUG DELIVERY SYSTEM
INTRODUCTION
DEFINITION
Colon drug delivery system refers to targeted delivery of drug into the lower
part of GIT mainly large intestine
TARGETED DRUG DELIVERY SYSTEM
 Targeted drug delivery implies selective and effective localization of drug
into the target at therapeutic concentrations with limited access to non-
target sites.
 A target drug delivery system preferred in drugs having instability, low
solubility and short half-life.
NEED OF CSDDS
 As most of conventional drug delivery systems for treating colon
disorders such as inflammatory bowel disease, infection diseases and
colon cancers are failing as drug does not reach the site of action in
appropriate concentration.
 Thus, an effective and safe therapy of colonic disorders using specific
drug delivery system.
FACTORS TO BE CONSIDERED IN THE DESIGN OF COLON SPECIFIC
DRUG DELIVERY SYSTEM
1. ANATOMY AND PHYSIOLOGY OF THE COLON
 Colon is made up of caecum, ascending colon, hepatic flexure,
descending colon, splenic flexure, transverse colon and sigmoid colon.
 Wall of colon is composed of 4 layers:
­ Serosa: areolar tissue
­ Muscularis externa: fiber
­ Submucosa: connective tissues
­ Mucosa divided into epithelium, lamina propria, muscularis
mucosa.
FUNCTIONS
 Creation of suitable environment of microorganisms
 It acts as storage reservoir of fecal contents
 Expulsion of the contents of the colon at an appropriate time
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 Absorption pf potassium and water from lumen.
2. GASTROINTESTINAL TRANSIT
 Gastric emptying of dosage forms is highly variable and depend primarily
on the whether the subject is fed or fasted.
 The arrival of an oral dosage form at the colon is determined by the rate
of gastric emptying and the small intestine transit time.
 The transit time of dosage form in GIT:
ORGAN TRANSIT TIME (hr)
Stomach <1 (fasting), > (fed)
Small intestine 3-4
Large intestine 20-30

3. pH IN THE COLON
 pH in colon is subjected to both inter and intra subject variation
 On the entry into the colon the pH dropped to 6.4 ,the pH in the mid
colon and the left colon is 6 to 7.6.
4. COLONIC MICROFLORA
 Many compounds taken orally are metabolized by gut bacteria.
 Drug release depends upon enzymes that are derived from microflora
present in colon.
 These enzymes are used to degrade coating/matrices as well as bond
break between an inert carrier and active agent resulting in drug release
from formulation.
 Important metabolic reactions carried out by intestinal bacteria:
hydrolysis, reduction, dihydroxylation, decarboxylation, dehalogenation,
deamination, acetylation, esterification.
DRUG ABSORPTION IN THE COLON
 Drug are absorbed passively by either paracellular or transcellular route.
 Transcellular absorption involves the passage of drugs through cells.
 Paracellular absorption involves the transport of drug through tight
junction between cells.
 The colon may not be the site for drug absorption since the colonic
mucosa lacks well defined villi as found in the small intestine
 The colon become more viscous with progressive causes a reduced
dissolution rate slow diffusion of drug through the mucosa.
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ROLE OF ABSORPTION ENHANCERS
 The permeability of drugs can be modified by the use of chemical
enhancers. These enhancers increase transcellular and paracellular
transport through one the following mechanism:
­ By modified epithelial permeability via denaturing membrane
proteins
­ By reversibly disrupting the integrity of lipid bilayer colon,
examples:
 NSAIDS: Indomethacin
 Bile salts: Glycocholate
CRITERIA FOR SELECTION OF DRUGS FOR CSDDS

CRITERIA PHARMACOLOGICAL CLASS NON-PEPTIDE DRUGS
Drugs used for local effects
in Colon against GIT diseases
Anti-inflammatory drugs
Nifedipine, Oxprenolol,
Metoprolol
Drugs poorly absorbed from
upper GIT
Antihypertensive and
antianginal drugs
Isosorbides, Theophylline,
Ibuprofen
Drugs for colon cancer Antineoplastic drugs Pseudoephedrine
Drugs that degrade in
stomach and small intestine
Peptides and proteins
Brompheniramine, 5-
Flourouracil, Doxorubicin
Drugs that undergo
extensive first pass
metabolism
Nitroglycerin and
corticosteroids
Bleomycin, Nicotine
Drugs for targeting
Antiarthritic and anti-
asthmatic drugs
Prednisolone,
hydrocortisone
APPROACHES TO COLON SPECIFIC DRUG DELIVERY SYSTEM
CONVENTIONAL PHARMACEUTICAL APPROACHES
 pH dependent drug delivery system
 Time dependent drug delivery system
 Bacteria dependent drug delivery system
NOVEL PHARMACEUTICAL APPROACHES
 Pulsincap system
 PORT system
 Osmotic controlled drug delivery
 Pressure dependent delivery
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CONVENTIONAL PHARMACEUTICAL APPROACHES
1. PH DEPENDENT DELIVERY
 In this systems drugs are formulated into solid dosage forms such as
tablets, capsule, and pellets and coated with ph sensitive polymers.
 Widely used polymers are methacrylic resins (eudragits) which is
available in two forms eudragits (L) and eudragits (S).
 Some other polymers are cellulose acetate butyrate, methacrylic acid
copolymer type A and type B, hydroxypropyl methyl cellulose acetate
succinate.
 At present 5-ASA is commercially available as an oral dosage form
coated with eudragits (L).
DISADVANTAGE
 The disadvantage of this technique is the lack of consistency in the
dissolution of the polymer at desired site.
 Depending on the intensity of GI motility, the dissolution of the polymer
can be in the distal portion of the colon or at the end of ileum.
2. TIME DEPENDENT DELIVERY
 Time dependent/controlled release system such as sustained or delayed
release dosage forms are also very promising drug release system.
 Enteric coated time release press coated (ETP) tablets are composed of
three components, a drug containing core tablets (rapid release
function), the press coated swellable hydrophobic polymer layer
(hydroxy propyl cellulose layer (HPC), time release function) and an
enteric coating layer (acid resistance function).
 The tablet does not release the drug in the stomach due to the acid
resistance of the outer enteric coating layer.
 After gastric emptying the enteric coating layer rapidly dissolves and
intestinal fluid begins to slowly erode the press coated polymer layer.
 When the erosion front reaches the core tablet rapid drug release occurs
since the erosion process takes a long time as there is no drug release
period (lag phase) after gastric emptying.
 The duration of the lag phase is controlled either by the weight or
composition of the polymer layer.
3. BACTERIAL DEPENDENT DELIVERY SYSTEM
 The microflora produces a vast number of enzymes like glucuronidase,
xylosides, arabinosidase, galactosidase, nitroreductase , azoreductase,
deaminase and urea dehydroxylase.
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 This system includes:
­ Coating with biodegradable azo polymers
­ Prodrugs
­ Hydrogel
­ Polysaccharides as carriers
1. COATING WITH BIODEGRADABLE AZO POLYMERS
 The azo polymers are having high degree of hydrophilicity were
degraded by colonic bacteria.
 Examples: Divinyl azobenzene and substituted diamino benzene.
 Drugs used are insulin and vasopressin.
2. PRODRUG
 Generally, a prodrug is successful as a colon drug carrier if it is
hydrophilic and bulky to minimize absorption from the upper GIT and is
converted into more lipophilic in colon for absorption.
 Limitation- It is not a very versatile approach as its formulation depends
upon the functional group available on the drug moiety for chemical
linkage,
 A well-known colon specific prodrug sulfasalazine used in ulcerative
colitis and crohn’s disease.
3. HYDROGEL
 The hydrogels contain acidic co-monomers and enzymatically
degradable azo-aromatic cross-links.
 In acidic pH gel has low degree of swelling which protects degradation of
drug stomach enzyme.
 On entering colon ,gels reach the degree of swelling which makes
crosslinks accessible to enzyme.
 Crosslink are degraded and drug is released from disintegrating gels.
4. POLYSACCHARIDES AS CARRIERS
 The polysaccharides are assessed to remain intact in physiological
environment of stomach and small intestine. As they reach colon, they
are acted upon bacterial polysaccharides and results in degradation of
the matrices. e.g., Amylose, Pectin, Chitosan, Dextran, Guar gum, etc.
 These are broken down by the colonic microflora to simple saccharides,
so these fall into the category of “generally regarded as safe” (GRAS)
NOVEL PHARMACEUTICAL APPROACHES
1. PULSINCAP
 It consists of non-disintegrating half capsule body filled with drug
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content sealed at the opened end with the hydrogel plug, which is
covered by water soluble cap. Polymers used for hydrogel plug are
HPMC, PVA etc.
 Upon entering small intestine, enteric coating is dissolved, hydrogel plug
swells and drug content is released after stipulated period of time.
2. PORT SYSTEM
 Drug release mechanism from port system
­ Cap dissolves off, IR (Immediate release) or MR (Modified release)
dose is released.
­ Energy source is activated by controlled permeation of GI fluid.
­ Time released plug is expelled.
­ Pulse or sustained release of 2
nd
dose.
3. OSMOTIC CONTROLLED DRUG DELIVERY SYSTEMS
 Osmotic controlled drug delivery to colon. It can be single osmotic unit
or may incorporate as many as 5-6 units, each 4mm in diameter.
 It can maintain a constant release rate for up to 24hrs in the colon.
4. PRESSURE CONTROLLED DRUG DELIVERY SYSTEMS
 As a result of peristalsis higher pressures are encountered in the colon
than in small intestine.
 Developed pressure controlled colon delivery capsules prepared using
ethyl cellulose which is insoluble in water.
 In such systems drug release occurs following the disintegration of a
water insoluble polymer capsule because of pressure in the lumen of the
colon.
 The thickness of the ethyl cellulose membrane is the most important
factor for the disintegration of the formulation.
 The system also appeared to depend on capsule size and density.
MERITS OF CSDDS
 The site specific delivery of drug to lower part of GIT for localized.
treatment of several colonic disease.
 Prevent drug from degradation.
 Ensure direct treatment at disease site.
 Suitable absorption site for protein binding and peptide drug.
 Used to prolong the drug therapy.
LIMITATIONS / CHALLENGES / DIFFICULTIES OF CSDDS
 Multiple manufacturing steps.
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 Microflora affects the activity of drugs via metabolic degradation of the
drug.
 Bioavailability of drug may be low due to potentially binding of drug in a
non-specific way to dietary residues, intestinal secretions ,mucus or fecal
matter.
 Non bioavailability of an appropriate dissolution testing method to
evaluate the dosage form in vitro.
 Drug should be in solution form before absorption and there for
 Rate limiting step for poor soluble drugs.
 Substantial variation in gastric retention time may affect drug delivery.
 Diseased condition may affect the colonic transit time and drug release
profile.
 Ph level of colon may vary between individuals due to disease state and
temperature of food consumed.

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ION EXCHANGE CONTROLLED DRUG DELIVERY SYSTEM
INTRODUCTION
 One of the attractive methods for modified drug delivery systems is the
use of ion exchange resins (IER) a carriers for such systems.
 Ion Exchange Resins (IER) are insoluble polymers that contain acidic or
basic functional groups and have the ability to exchange counter-ions
within aqueous solutions surrounding them.
 An ion exchange resin is exhibited like small bead with a diameter
between 1-2 mm.
 Ion exchange is a reversible process in which ions of like sign are
exchanged between liquid and solid when in contact with a highly
insoluble body.
STRUCTURE AND CHEMISTRY OF ION EXCHANGE RESIN
 IER are simply insoluble polyelectrolytes that are insoluble polymers
which contain ionizable groups distributed regularly along the polymer
backbone.
 The most common resins used in formulations are:
­ Cross-linked polystyrene
­ Polymethacrylate polymers
 When IER are mixed with a fluid such as water, ions in the fluid can
exchange with the polyelectrolyte’s counterions and be physically
removed from the fluid.
TYPES OF ION-EXCHANGE RESINS
 There are two major classes of ion-exchange polymers:
 Cation IER:
­ Strong acid ­ Weak acid
 Anion IER:
­ Strong basic ­ Weak basic
ROLE OF IER IN CONTROLLED DRUG DELIVERY SYSTEMS
 The major drawback of controlled release is dose dumping, resulting in
increased risk of toxicity.
 The usage of IER during the development of controlled release
formulations plays a significant role because of their drug retarding
properties and prevention of dose dumping.
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 The drug resinates can also be used as a drug reservoir, which has
caused a change of the drug release in hydrophilic polymer
 The use of IER into drug delivery systems have been encouraged because
of their:
­ Physico-chemical
stability
­ Inert nature
­ Uniform size
­ Spherical shape
assisting coating
 The physical and chemical properties of the IER will release the drug
more uniformly than that of simple matrix system.
MECHANISIM AND PRINCIPLE
 Anion exchange resins involve basic functional groups capable of
removing anions from acidic solutions while Cation exchange resins
contain acidic functional group, capable of removing cations from basic
solutions.
 The use of IER to prolong the effect of drug release is based on the
principle that positively or negatively charged pharmaceuticals,
combined with appropriate resins to yield insoluble polysalt resinates.
R-SO3
-
H
+
+ H2N-A ↔ R-SO 3
-
– H3N-A
R-N
+
H3OH
-
+ HOOC-B ↔ R-N
+
H3 –OOC-B + H2O
 Where,
­ H2N-A → Basic drug
­ R-SO3
-
H
+
→ Cation exchanges
­ HOOC-B → Acidic drug
­ R-NH3
+
OH
-
→ Anion exchange resins
 Ion exchange resinates administered orally are likely to spend about two
hours in the stomach in contact with an acidic fluid of pH 1.2, and then
move into the intestine where they will be in contact for several hours
with a fluid of slightly alkaline pH
IN THE STOMACH
R-SO3
-
- H3N
+
-A + HCl ↔ R-SO 3
-
H
+
+ A-N
+
H3Cl
R-N
+
H3-OOC-B + HCl ↔ R-N
+
H3Cl
+
+ B-COOH
IN THE INTESTINE
R-SO3
-
- H3 N-A + NaCl ↔ R-SO 3
-
Na
+
+ A-N + H3Cl
-

R-N
+
H3- OOC-B + NaCl ↔ R-N + H3Cl
-
+ B-COO-Na
+
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IMPORTANT PROPERTIES OF IER
 During the process of developing formulations with IER, some of the
important properties normally considered by researchers include the
following:
­ Particle size and form
­ Porosity and swelling
­ Cross linkage
­ Available capacity
­ Acid base strength
­ Stability
­ Purity and toxicity
APPLICATIONS OF IECDDS
 Taste masking
 Tablet disintegrant
 Drug stabilization
 Powder Processing Aid
 Deliquescence
 Rapid Dissolution
FACTORS AFFECTING FORMULATION AND DRUG RELEASE FROM
COMPLEX
 Cross linking of resin
 Particle size
 pH
 Form of resin
 Size of exchanging ion
 Selectivity of counter-ion
 Mixing time
 Effect of temperature

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DRUG CARRIER SYSTEM
CARRIERS
 Carrier is one of the special molecule or system essentially required for
effective transportation of loaded drug up to the pre-selected sites. They
are engineered vectors, which retain drug inside or onto them either via
encapsulation and/ or via spacer moiety and transport or deliver it into
vicinity of target cell.
 Pharmaceutical carriers:
­ Polymers
­ Microcapsules
­ Microparticles
­ Lipoproteins
­ Liposomes
­ Micelles
LIPOSOMES
INTRODUCTION
 Liposomes are simple microscopic vesicles in which an aqueous volume
is entirely enclosed by membrane of lipid molecule. Various amphiphilic
molecules have been used to form liposomes.
 The drug molecules can either be encapsulated in aqueous space or
intercalated into the lipid bilayers. The extent of location of drug will
depend upon its physico-chemical characteristics and composition of
lipids.
STRUCTURAL COMPONENTS OF LIPOSOMES
 Drug molecules can either be encapsulated in the aqueous space or
intercalated into the bilayer. The exact location of the drug in the
liposome depends upon the physiochemical characteristics of the drug
and the composition of the constituent lipids.
 There are number of components of liposomes however phospholipids
and cholesterol are main components. Phospholipids are the major
structural components of biological membrane, where two types of
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phospholipids exist, phosphodiglycerides and sphingolipids, together
with their hydrolysis products. The most common phospholipids is
phosphotidylcholine (PC) molecules.
CLASSIFICATION OF LIPOSOME
1. BASED ON SIZE
POLYMER SIZE
SUV 20-100 nm
LUV >100 nm
MLV 500-10,000 nm
OLV 0.1-µm
MVV > 1µm

2. BASED ON STRUCTURE
I. CONVENTIONAL LIPOSOMES
 These are simple liposomes made up of simple phospholipids. These are
used to treat problems of phagocytes because of the fact that these are
easily engulfed by phagocytes. Other sites of action of these liposomes
are liver and spleen which are the parts of reticuloendothelial system
(RES).
II. PEGYLATED LIPOSOMES
 Addition of cholesterol leads to improved retention of liposome
contents and prolongation of circulation time.
 However, these relatively improved liposome formulations would still
largely accumulate in the RES and a greater improvement in circulation
half-life appears to be required for cancer targeting.
III. IMMUNOLIPOSOMES
 Liposomes with a specific affinity for an affected organ or tissue are
believed to increase the efficacy of liposomal pharmaceutical agents.
 Immunoglobulins, primarily of the IgG class, and their fragments are the
most promising and widely used targeting moieties for various drugs and
drug carriers, including liposomes.
IV. CATIONIC LIPOSOMES
 Cationic liposomes are structures that are made of positively charged
lipids and are increasingly being researched for use in gene therapy due
to their favorable interactions with negatively charged DNA and cell
membranes.

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V. CELL PENETRATING PEPTIDE (CPP) LIPOSOMES
 Various vector molecules promote the delivery of associated drugs and
drug carriers inside the cells via receptor-mediated endocytosis.
 Some proteins or peptides contain domains of less than 20 amino acids,
termed as Protein Transduction Domains (PTDs) or CPPs, have been used
for intracellular delivery of various cargoes with molecular weights several
times greater than their own.
PREPARATION OF LIPOSOMES
PREPARATION OF MLV
PREPARATION OF LIPOSOME BY HYDRATION METHOD
 When preparing liposomes with mixed lipid composition, the lipids must
first be dissolved and mixed in an organic solvent to assure a
homogeneous mixture of lipids.
 Usually this process is carried out using chloroform or chloroform:
methanol mixtures. Typically lipid solutions are prepared at 10-20mg
lipid/ml organic solvent, although higher concentrations may be used if
the lipid solubility and mixing are acceptable.
 Once the lipids are thoroughly mixed in the organic solvent, the solvent
is removed to yield a lipid film. For small volumes of organic solvent
(<1mL), the solvent may be evaporated using a dry nitrogen or argon
stream in a fume hood. For larger volumes, the organic solvent should
be removed by rotary evaporation yielding a thin lipid film on the sides
of a round bottom flask.
 The lipid film is thoroughly dried to remove residual organic solvent by
placing the vial or flask on a vacuum pump overnight. If the use of
chloroform is objectionable, an alternative is to dissolve the lipid(s) in
tertiary butanol or cyclohexane.
 Hydration of the dry lipid film/cake is accomplished simply by adding an
aqueous medium to the container of dry lipid and agitating (Nitrogen gas
may also be used).
 After addition of the hydrating medium, the lipid suspension should be
maintained above the Tc during the hydration period. Some buffer
system is also added to the aqueous solution which is to be added to dry
lipid cake.
 The drawback of this method is low encapsulation efficiency and the size
distribution is heterogeneous.
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SOLVENT SPHERULE METHOD
 This process involves the dispersing in the aqueous solution the small
spherule of volatile hydrophobic solvent in which lipids had been
dissolved.
 MLVs are prepared when controlled evaporation of organic solvent
occurs in water bath.
PREPARATION OF SUV
SONICATION METHOD
 In this method MLVs are sonicated either a bath types sonicator or a
probe sonicator under an inert atmosphere.
 The main drawback of this method is low internal volume (low
entrapment).
FRENCH PRESSURE CELL METHOD
 The method involves the extrusion of MLV at 20,000 psi at 40
o
C through
a small orifice.
 The method has several advantages over sonication method. The
method is simple, rapid, reproducible and gentle handling of unstable
materials.
PREPARATION OF LUV
SOLVENT INJECTION METHOD
 A solution of lipids dissolved in ether, ether/methanol mixture or
ethanol is added to the aqueous solution of the material to be
encapsulated at 55-65
0
C or under reduced pressure.
 A problem with the use of ethanol is formation of azeotrope with water
which is difficult to treat for evaporation of ethanol.
REVERSE PHASE EVAPORATION METHOD
 First water in oil emulsion is prepared using diethylether or
isopropylether in which lipid is solubilized for the preparation of
emulsion acting as solvent and stabilizer. The liposomes are formed
when solvent is removed under reduced pressure.
 With this method high encapsulation efficiency up to 65% is obtained in
a medium of low ionic concentration for example 0.01 M NaCl.

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FREEZE-THAW METHOD
 SUVs are rapidly frozen and followed by slow thawing. The formation of
LUV is due to the fusion of SUV during the process of freezing and
thawing.
 This kind of fusion is strongly inhibited by increasing the ionic
concentration of the medium.
STABILITY OF LIPOSOMES
PHYSICAL AND CHEMICAL STABILITY
 Cholesterol and phospholipids containing unsaturated fatty acids
undergo oxidation. One solution to this problem is to use phospholipids
which contain saturated fatty acids. The peroxidation of lipids can be
minimized by use of antioxidants such as Vitamin E and butylated
hydroxytoluene (BHT).
 Lecithin undergoes hydrolysis to give lyso-lecithin and other degradation
products. The presence of lyso-lecithin in lipid bilayers greatly enhance
the permeability of liposomes. Therefore, it is important to start with
phospholipids which are free of lysolecithin (also of any phospholipases).
 The formation of ice crystals in liposomes (for example when liposomes
are partially frozen and thawed), the subsequent instability of bilayers
leads to the leakage of entrapped material. When liposomes are
subjected to a freeze thaw cycle and freeze drying in the absence of a
cryoprotectant such as lactose, they lose the entrapped compounds on
reconstitution. It has been shown that liposomes when freeze dried in
the presence of trehalose (a sugar) retained as such as a 100% of their
contents.
 Another way to increase stability of liposomes is to use synthetic
phospholipids which polymerize on exposure to UV light.
 The physical stability of liposomes on storage can be studied by
monitoring the amount of leaked material from liposomes and by the
size of liposomes.
 An increase in physical stability of liposomes can be achieved by
increasing amount of charge on liposomes. An increase in physical
stability against aggregation and fusion can be increase by increasing
surface charge density of liposomes consisting of phosphatidylcholine
and phospholidylserine.
 The presence of divalent metal ions such as Ca
2+
and Mg
2+
causes the
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aggregation of liposomes particularly those with negative charge.
Therefore, aqueous buffer used for the preparation of liposomes should
be free of divalent metal ions. Some workers like to treat water with
EDTA to remove any divalent metal ions present.
PREVENTION FROM CHEMICAL DEGRADATION
 Start with freshly prepared solvents
 Avoid procedure at high temperature
 Manufacture in absence of oxygen
 Deoxygenate aqueous solution with nitrogen
 Store in inert atmospheric conditions
 Use antioxidants
CHARACTERIZATION OF LIPOSOMES
PHYSICAL CHARACTERIZATION
1. SIZE AND SIZE DISTRIBUTION
LIGHT MICROSCOPIC METHOD
 This is used to observe the gross size using oil emersion lens.
FLUORESCENT MICROSCOPIC METHOD
 If one of the cord or chain of phospholipids or both the chains are having
some fluorescent property, then fluorescent microscopy may be used
for analysis of size and size distribution.
 This is also used for the essay of polymeric chain, cell penetrating
peptide (e.g. TAT) and antibody modified.
SCANNING ELECTRON MICROSCOPE
 Scanning electron microscope is also used for this purpose especially in
hydrated solution state.
LASER LIGHT SCATTERING
 This technique is used for 3D imaging.
GEL PERMEATION
 A thin layer chromatography system using agarose beads has been
introduced as a convenient, fast technique for obtaining a rough
estimation of the size distribution of a liposome preparation.

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2. SURFACE CHARGE DENSITY
 Electrophoresis is used for the surface charge density measurement. The
phospholipids are visualized using molybdenum blue reagent.
 Zeta potential is also used for this purpose.
3. PERCENTAGE ENTRAPMENT
 Percentage entrapment describes the percent of the aqueous phase
(and hence the % of the water soluble drug) that becomes entrapped
during the liposomes preparation.
 This is done by using centrifugation and performing TLC of the product
of centrifugation.
% drug entrapment = amount of drug in sediment*100 / total amount of
drug
CHEMICAL CHARACTERIZATION
1. QUALITATIVE AND QUANTITATIVE DETERMINATION OF PHOSPHOLIPIDS
 A method for determination of phospholipids is formation of complex
with ammonium ferrothiocyanate in organic solvent.
 TLC method may also be employed for determining the purity and the
concentration of lipids. If compound is pure it should run as a single spot
in all elution solvents.
2. PHOSPHOLIPIDS HYDROLYSIS
 The major product of lecithin hydrolysis is lysolecithin where one fatty
acid is lost by de-esterification or oxidation.
 Ideally estimation of phospholipids hydrolysis by quantization of
lysolecithin could be carried out by HPLC.
 If this characterization is being done using TLC, then degradation may be
visualized using I2 vapor.
3. CHOLESTEROL ANALYSIS
 Cholesterol is qualitatively analyzed using silica gel based TLC. Iron form
purple color complex with cholesterol, so used as marker for its analysis.
APPLICATION OF LIPOSOMES
 Liposomes are used for the targeted cancer drug delivery using CPP,
aptamers and cationic liposomal preparation.
 Carrier for vaccines in the form immunological adjuvants and carrying
antigen
 For oral drug delivery of steroids (for arthritis) and insulin (for D.M)
 Topical preparation of methotrexate, diclofenac and interferon.
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NIOSOMES
INTRODUCTION
 Niosomes are a novel drug delivery system, in which the medication is
encapsulated in a vesicle composed of a bilayer of non-ionic surface
active agents.
 These are very small, and microscopic in size that lies in the nanometric
scale. Although structurally similar to liposomes, they offer several
advantages over them.
STRUCTURE OF NIOSOMES
 Niosomes are microscopic lamellar structures, which are formed on the
admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol
ether class and cholesterol with subsequent hydration in aqueous
media.
 Niosomes may be unilamellar or multilamellar depending on the method
used to prepare them.
 The hydrophilic ends are exposed on the outside and inside of the
vesicle, while the hydrophobic chains face each other ` within the
bilayer.
 Hence, the vesicle holds hydrophilic drugs within the space enclosed in
the vesicle, while hydrophobic drugs are embedded within the bilayer
itself.
CLASSIFICATION OF NIOSOMES
 The niosomes have been classified as a function of the number of bilayer
or as a function of size. The various types of niosomes are follows.
1. According to the nature of lamellarity
 Multilamellar vesicles (MLV) 1-5μm in size.
 Large unilamellar vesicles (LUV) 0.1 – 1μm in size.
 Small unilamellar vesicles (SUV) 25 – 500 nm in size.
2. According to the size
 Small niosomes (100 nm – 200 nm)
 Large niosomes (800 nm – 900 nm)
 Big niosomes (2 μm – 4 μm)
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PREPERATION OF NISOSOMES
ETHER INJECTION METHOD
 Slow injection of an ether solution of niosomal ingredients into an
aqueous medium at high temperature
 A mixture of surfactant and cholesterol (150 μmol) is dissolved in ether
(20 ml) and injected into an aqueous phase (4 ml) using a 14- gauge
needle syringe
 Temperature of the system is maintained at 60oC during the process
 Niosomes in the form of large unilamellar vesicles (LUV) are formed.
FILM METHOD
 The mixture of surfactant and cholesterol is dissolved in an organic
solvent (e.g. diethyl ether, chloroform, etc.) in a round-bottomed flask
 The organic solvent is removed by low pressure/vacuum at room
temperature
 The resultant dry surfactant film is hydrated by agitation at 50-60
o
C
 Multilamellar vesicles (MLV) are formed.
SONICATION
 The aqueous phase is added into the mixture of surfactant and
cholesterol in a scintillation vial
 Homogenized using a sonic probe
 The resultant vesicles are of small unilamellar (SUV) type niosomes
 The SUV type niosomes are larger than SUV liposomes
 It is possible to obtain SUV niosomes by sonication of MLV type vesicles.
MULTIPLE MEMBRANE EXTRUSION METHOD
 Mixture of surfactant, cholesterol and dicetyl phosphate in chloroform is
made into thin film by evaporation
 The film is hydrated with aqueous drug solution and the resultant
suspension extruded through polycarbonate membranes
 Good method of controlling niosomal size.
REVERSE PHASE EVAPORATION
 Surface-active agents are dissolved in chloroform, and 0.25 volume of
phosphate saline buffer (PBS) is emulsified to get w/o emulsion
 The mixture is sonicated and subsequently chloroform is evaporated
under reduced pressure.
 The surfactant first forms a gel and then hydrates to form niosomal
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Vesicles. The vesicles formed are unilamellar and 0.5μ in diameter.
THE BUBBLE METHOD
 It is novel technique for the one step preparation of liposomes and
niosomes without the use of organic solvents
 The bubbling unit consists of round-bottomed flask with three necks
positioned in water bath to control the temperature
 Water-cooled reflux and thermometer are positioned in the first and
second neck and nitrogen supply through the third neck
 Cholesterol and surfactant are dispersed together in the buffer (pH 7.4)
at 70°C, the dispersion mixed for 15 secs with high shear homogenizer
and immediately afterwards “bubbled” at 70°C using nitrogen gas.
MICRO FLUIDIZATION
 This is a recent technique to prepare small MLVS. A microfluidizer is
used to pump the fluid at a very high pressure through a 5 pm screen
 It is then forced along defined micro channels, which direct two streams
of fluid to collide together at right angles, thereby affecting a very
efficient transfer of energy
 The lipids/surfactants can be introduced into the fluidizer. The fluid
collected can be recycled until spherical vesicles are obtained. Uniform
and small sized vesicles are obtained.
FORMATION OF NIOSOMES FROM PRONIOSOMES
 To create proniosomes, a water soluble carrier such as sorbitol is first
coated with the surfactant. The coating is done by preparing a solution
of the surfactant with cholesterol in a volatile organic solvent, which is
sprayed onto the powder of sorbitol kept in a rotary evaporator.
 The evaporation of the organic solvent yields a thin coat on the sorbitol
particles. The resulting coating is a dry formulation in which a water
soluble particle is coated with a thin film of dry surfactant.
 This preparation is termed Proniosome. The niosomes can be prepared
from the proniosomes by adding the aqueous phase with the drug to the
proniosomes with brief agitation at a temperature greater than the
mean transition phase temperature of the surfactant.
STABILITY OF NISOSOMES
 Vesicles are stabilized based upon formation of following forces:
­ Van der Waals forces among surfactant molecules.
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­ Electrostatic repulsive forces are formed among vesicles upon
addition of charged surfactants to the double layer, enhancing the
stability of the system
 Niosomes in the form of liquid crystal and gel can remain stable at both
room temperature and 4
o
C for 2 months. Recommended temperature of
storage 4
o
C. Ideally niosomes should be stored dry for reconstitution.
 The factors which affect the stability of niosomes:
­ Type of surfactant
­ Nature of encapsulated drug
­ Storage temperature
­ Detergents
­ Use of membrane spanning lipids
­ Inclusion of charged molecule
CHARACTERIZATION OF NIOSOMES
ENTRAPMENT EFFICIENCY
 Depend on the method of preparation. Niosomes prepared by ether
injection method have better entrapment efficiency than those
prepared by the film or sonication.
 Addition of cholesterol to non-ionic surfactants with single- or dialkyl-
chain significantly alters the entrapment efficiency.
 Surfactants of glycerol type lead to reduction in entrapment capacity as
the amount of cholesterol increases.
 Niosomes in the form of liquid crystals possess better entrapment
efficiency than gel type vesicles.
Entrapment efficiency (EF) = (Amount entrapped/ total amount) x 100
 Niosomes, similar to liposomes, assume spherical shape and so their
diameter can be determined using light microscopy, photon correlation
microscopy and freeze fracture electron microscopy.
 Freeze thawing (keeping vesicles suspension at –20°C for 24 hrs and
then heating to ambient temperature) of niosomes increases the vesicle
diameter, which might be attributed to fusion of vesicles during the
cycle.
APPLICATIONS OF NISOSOMES
 Gene delivery
­ Niosomes composed of span 85 and cholesterol can be used for
the topical delivery of pDNA encoding hepatitis B surface antigen.
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 Vaccine delivery
 Anti-cancer drug delivery
 Leishmaniasis treatment
­ Niosomes can be used for targeting of drug in the treatment of
diseases in which the infecting organism resides in the organ of
reticuloendothelial system.
­ In leishmaniasis parasite invades cells of liver and spleen. The
commonly prescribed drugs are Antimonial, which are related to
arsenic, and at high concentration they damages the heart, liver
and kidney.
 Delivery of peptide drugs
­ Insulin and oligo-nucleotide.
 Ophthalmic drug delivery
­ Niosomes contain non-ionic surfactants which are non-antigenic
and non-toxic to the eye.
 Chronic obstructive pulmonary disease (COPD) drug delivery
­ Beclomethasone in niosomes successfully for nebulized drug
delivery system.
 Brain targeted drug delivery system
­ Doxorubicin brain targeted niosomal formulation, functionalizing
with N-palmitoylglucoseamine.
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TARGETED DRUG DELIVERY SYSTEM
DRUG TARGETING
 Targeted drug delivery system is a special form of drug delivery system
where the medicament is selectively targeted or delivered only to its site
of action or absorption and not to the non-target organs or tissues or
cells.
 The drug may be delivered:
­ To the capillary bed of the active sites.
­ To the specific type of cell (or) even an intracellular region.
 Example: Tumor cells but not to normal cells.
­ To a specific organ (or) tissues by complexion with the carrier that
recognizes the target.
REASON FOR DRUG TARGETING
 In the treatment or prevention of diseases
 Pharmaceutical drug instability in conventional dosage form
 Low solubility
 Biopharmaceutical low absorption
 High-protein bounding
 Biological instability
 Pharmacokinetic / pharmacodynamic short half-life
 Large volume of distribution
 Low specificity
 Low therapeutic index.
ADVANTAGES OF TARGETTED DELIVERY
 Drug administration protocols may be simplified.
 Toxicity is reduced by delivering a drug to its target site, thereby
reducing harmful systemic effects.
 Drug can be administered in a smaller dose to produce the desire effect.
 Avoidance of hepatic first pass metabolism.
 Enhancement of the absorption of target molecules such as peptides
and particulates.
 Dose is less compared to conventional drug delivery system.
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DISADVANTAGES OF TARGETTED DRUG DELIVERY
 Rapid clearance of targeted systems.
 Immune reactions against intravenous administered carrier systems.
 Insufficient localization of targeted systems into tumor cells.
 Diffusion and redistribution of released drugs.
 Requires highly sophisticated technology for the formulation.
STRATEGIES OF TARGETTED DRUG DELIVERY
ACTIVE DRUG DELIVERY SYSTEMS
 Active targeting employs a modified drug carrier/drug molecule capable
of recognizing and interacting with a specific cell, tissue or organ in the
body.
 In this approach carrier system bearing drug reaches to specific site on
the basis of modification made on its surface rather than natural uptake
by RES.
 Surface modification technique include:
­ Change in the molecular size,
­ Alteration in surface properties such as coating of surface with a
bioadhesive, nonionic surfactant ).
­ Incorporation of antigen specific antibodies (i.e. monoclonal
antibodies)
­ Attachment of cell receptor-specific ligands (glucose, transferrin,
Folic acid or by albumin protein).
TYPES OF ACTIVE TARGETING
FIRST ORDER TARGETING
 It involves distribution of drug carrier system to capillary bed of target
site or organ. For example lymphatic’s, peritoneal cavity, plural cavity,
cerebral ventricles, etc.
SECOND ORDER TARGETING
 It involves delivery of drug to special cells such as tumor cells or Kupffer
cells in lives.
THIRD ORDER TARGETING
 Third order targeting means intracellular localization of carrier bearing
drug by the process of endocytosis or via receptor based ligand
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mediated entry of drug carrier system, where lysosomal degradation of
drug complex causes release of drug or gene delivery to nucleolus.
OTHER TYPES
 Active Targeting can be further classified into ligand mediated and
physical targeting.
LIGAND MEDIATED TARGETING
 All the drug carrier system can become functional when they are
attached with biologically relevant molecular ligand including antibodies
polypeptides oligosaccharides viral proteins and fusogenic residues.
 These types of engineered carrier selectively make the drug available to
the cell or group of cells generally referred as target. In ligand mediated
active targeting reaction of a ligand to corresponding receptor enhances
the uptake of the entire drug delivery system into the cell.
PHYSICAL TARGETING
 In this type of targeting some characteristics of environment changes
like pH, temperature, light intensity, electric field, ionic strength small
and even specific stimuli like glucose concentration are used to localize
the drug carrier to predetermined site.
 This approach was found exceptional for tumor targeting as well as
cytosolic delivery of entrapped drug or genetic material.
PASSIVE DRUG DELIVERY SYSTEM
 Drug delivery systems which are targeted to systemic circulation are
characterized as Passive targeting (passive delivery systems)
 In this technique drug targeting occurs because of the body’s natural
response to physicochemical characteristics of the drug or drug carrier
system.
 The distribution of the carrier is dictated by local physiological
conditions or by the MPS.
 Passive targeting relies on the natural distribution pattern of the drug-
drug carrier system.
 For example, particles with a diameter of 5um or less are readily
removed from the blood by macrophages of the RES when administered
systemically.
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 This natural defense mechanism of the RES thus provide an opportunity
to target drugs to macrophages.
 Mechanical filtration of particulate carriers larger than 5 to 7um by
capillary blockage has also been exploited to target drugs to the lungs by
venous supply and to other organs through arterial supply.
 Thus by controlling the rate of drug release, can achieve the desired
therapeutic action in the targeted organ.
ADVANCED CARRIERS FOR TARGETING DRUGS
 Microspheres and Microcapsules
 Nanoparticles
 Liposomes
 Niosomes
 Ufasomes
­ These are bilayer structures formed by using single chain
unsaturated fatty acids.
 Virosomes
­ Virosomes are immuno modulating liposomes consisting of
surface glycoprotein of influenza virus.
 Proteosomes
 Cubosomes
­ Cubosomes are liquid crystalline phase forming small cubic
particles suitable for injection.
 Neutrophils
 Lymphocytes
 Artificial cells
 Resealed erythrocytes
 Nano-erythrosomes
 Prodrugs
 Monoclonal antibodies (MABs)
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PHARMACEUTICAL BIOTECHNOLOGY
A. INTRODUCTION TO BIOTECHNOLOGY
BIOTECHNOLOGY
 Any technological application that uses biological systems, living
organisms or derivatives thereof, to make or modify products and
processes for specific use is called as biotechnology.
 Conventional biotechnologies include plant and animal breeding and use
of micro-organisms and enzymes in fermentations and preparation and
preservation of products, as well as in control of pests.
 Advanced biotechnologies relate to the use of recombinant DNA
technology.
GENETICS / GENOMICS
 Genetics and genomics are two terms that are often incorrectly used
interchangeably.
 Genetics is the study of single genes and their role in the way traits or
conditions are passed from one generation to the next.
 Genomics is a term that describes the study of all parts of an organism’s
genes.
GENETICS
 Genetics is a scientific study of the effects that genes — which are units
of heredity — have on an individual. Genes hold information in the
molecule DNA, which is a string of chemicals called bases.
 The order, or sequence, of bases on the string determines the meaning
of a genetic message.
 The message contains instructions for making proteins, which, in turn,
direct cells and functions of the body.
 Humans have thousands of genes that are packaged into 23 pairs of
chromosomes.
GENOMICS
 All of the genes of an organism taken together, plus all of the sequences
and information contained therein, are called the genome.
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 The human genome consists of all of the thousands of genes and the 23
chromosome pairs.
 Genomics includes study of how the genes within the genome interact
with each other and with the individual’s environment.
TECHNOLOGY AND TECHNIQUES
 Technology and techniques used in genetics and genomics include:
­ Proteomics, used in genomics, the large-scale analysis of all of the
proteins in an organism, cell or type of tissue.
­ Pharmacogenetics and pharmacogenomics, studies that combine
pharmacology with analyzing genetic variables in how individuals
respond to certain drugs. While pharmacogenetics deals with
different medication responses caused by variation in a single
gene, pharmacogenomics involves multiple genes.
­ Stem cell therapy, using unspecialized cells with the ability to
develop into specialized body cells. In addition, stem cells can
remain in their unspecialized state and make copies of
themselves.
­ Cloning, a practice that can refer to genes, cells or entire
organisms.
PROTEOMICS
 Branch of biotechnology concerned with applying the techniques of
molecular biology, biochemistry and genetics to analyze the structure,
functions and interactions of proteins produced by genes of a particular
cell, tissue or organisms with organizing the information in databases
and with applications of data.
 Proteomics is the large-scale study of proteomes. A proteome is a set of
proteins produced in an organism, system, or biological context. We may
refer to, for instance, the proteome of a species (for example, Homo
sapiens) or an organ (for example, the liver).
 The proteome is not constant; it differs from cell to cell and changes
over time. To some degree, the proteome reflects the underlying
transcriptome. However, protein activity (often assessed by the reaction
rate of the processes in which the protein is involved) is also modulated
by many factors in addition to the expression level of the relevant gene.
 Proteomics is used to investigate:
­ when and where proteins are expressed; rates of protein
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production, degradation, and steady-state abundance; how
proteins are modified (for example, post-translational
modifications (PTMs) such as phosphorylation); the movement of
proteins between subcellular compartments; the involvement of
proteins in metabolic pathways; how proteins interact with one
another.
­ Proteomics can provide significant biological information for many
biological problems, such as:
­ Which proteins interact with a particular protein of interest (for
example, the tumor suppressor protein p53)?
­ Which proteins are localized to a subcellular compartment (for
example, the mitochondrion)?
­ Which proteins are involved in a biological process (for example,
circadian rhythm)?
BIOMOLECULAR TARGET IDENTIFICATION
 Target identification is process of identifying the direct molecular target
(protein, nucleic acid, or small molecule).
TARGET
 Finding a protein or receptor associated with the disease with which a
potential drug interact is known as the target.
LEAD
 A compound usually a small organic molecule that reveal desired
biological activity on a validated molecule target.
 Lead identification /optimization is the one of most important steps in
drug development. The chemical structure of lead compound is used as
starting point for chemical modification in order to improve potency.
DRUG DISCOVERY PROCESS
 Process starts with the identification of a molecular target and then
Target validation.
 The target validation confirms that interaction with the target produce
the desired change in the behavior of diseased cells.
CHARACTERISTICS OF DRUG TARGET
 The drug target is a biomolecule , normally a protein that could exist in
complex modality.
 The biomolecules have special sites that match other molecule.
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 Drug bind with the protein reversibly.
 Change in the biomolecule/protein structure follow the physiological
response.
 The physiological response play a major role in complex regulation and
have a therapeutic effect.
 Biomolecule’s activity, expression and structure might change over
duration of pathological process.
 These small molecule bind to the biomolecule are drugs.
ROLE OF TARGET IDENTIFICATION
 A good target needs to be efficacious, safe, meet clinical and commercial
needs and above all, be ‘druggable’.
 When a biological molecule elicit a biological response which may be
measured both in vivo/vitro is known to be a druggable target.
 A good target identification increased confidence in the relationship
between target and disease.
APPROACHES TO TARGET IDENTIFICATION
 Direct biochemical method
 Computational inference method
 Genetic interaction method
METHODS OF LEAD IDENTIFICATION
 Random screening
 Nonrandom screening
 Drug metabolism studies
METHODS OF LEAD OPTIMIZATION
 Identification of the active part
 Functional group optimization
 Structure activity relationship studies
 Design of rigid analogs.
PHARMACOGENOMICS
INTRODUCTION
 Pharmacogenomics deals with the influence of genetic variation on drug
response by co-relating gene expression or polymorphism with a drug's
efficacy or toxicity.
 It intends to identify individuals who are either more likely or less likely
to respond to a drug, as well as those who require altered dose of
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certain drugs.
 Pharmacogenetics is often a study of the variations in a targeted gene,
or group of functionally related genes for variability in drug response
 Refers to how variation in one single gene influences the response to a
single drug.
 Pharmacogenomics is the use of genetic information to guide the choice
of drug and dose on an individual basis.
 Broader term, which studies how all of the genes (the genome) can
influence responses to drugs.
THE FOUNDATION OF PHARMACOGENOMICS
MUTATION
 Difference in the DNA code that occurs in less than 1% of population.
 Often associated with rare diseases.
 Cystic fibrosis, sickle cell anemia, Huntington's disease.
POLYMORPHISM
 Difference in the DNA code that occurs in more than 1% of the
population.
 A single polymorphism is less likely to be the main cause of a disease.
 Polymorphisms often have no visible clinical impact
 A single nucleotide polymorphism (SNP) are DNA sequence variation
that occurs when a single nucleotide in the genome sequence is altered.
GOALS OF PHARMACOGENOMICS
PHARMACOKINETIC GOALS
 Absorption
 Distribution
 Metabolism
 Excretion
PHARMACODYNAMIC GOALS
 Receptors
 Ion channels
 Enzymes
 Immune system
EFFECT ON DRUGS
 The cytochrome P-450 mixed-function oxidase (CYP) N-acetyltransferase
(NATI and NAT2) Thiopurine-S-methyltransferase (TPMT)
 Uridine-5 diphosphate glucuronyl transferase-Polymorphisms of UGT1A1
and UGT2B7 play important roles in the phase II metabolism of certain
drugs.
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DRUG CLASSES WHERE PHARMACOGENOMICS TESTING HAS CLINICAL
SIGNIFICANCE
 Anticoagulants
 Antineoplastic drugs
 Antidepressants
 Narcotic analgesics
 Immunosuppressants
ADVANTAGES
 To predict a patient's response to drugs
 To develop 'customized' prescriptions
 To minimize or eliminate adverse events
 To improve efficacy and patient compliance
 To improve rational drug development.
LIMITATIONS
 Many genes are involved in drug action, making the drug target very
difficult
 Insufficient validation of study results
 Identification of small inter-individual variation in everyone's gene is
very difficult
 Expensive
 Ethical issues.
GENE THERAPY
INTRODUCTION
 It is an approach to treat, cure, or ultimately prevent disease by
changing the expression of a person’s genes.
 Gene therapy is introduction of normal genes into cells that contain
defective genes to reconstitute a missing protein product.
 GT is used to correct a deficient phenotype so that sufficient amounts of
a normal gene product are synthesized to improve a genetic disorder.
TYPES
 Gene therapy can be targeted to:
­ Somatic cells
­ Germ cells
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SOMATIC CELLS GENE THERAPY
 Modification of somatic cells by transferring desired gene sequences
into the genome.
 Three categories of somatic cell gene therapy:
1. Ex vivo – cells removed from body, incubated with vector and
gene-engineered cells returned to body.
2. In situ – vector is placed directly into the affected tissues.
3. In vivo – vector injected directly into the blood stream.
GERM CELLS GENE THERAPY
 Somatic cells necessary to ensure that inserted genes are not carried
over to the next generation.
METHODS
1. EX-VIVO GENE THERAPY
 Desired gene is cultured and placed in the cells out of body and then
placed back in the body.
2. IN-VIVO GENE THERAPY
 Desired gene is directly inserted in the body with the help of viral and
non-viral methods.
EXAMPLES OF GENE THERAPY TRIALS
 Severe Combined Immuno-Deficiency (SCID)
 CFTR gene transfer to treat Cystic Fibrosis (CF)
 Advanced Central Nervous System (CNS)
 Malignancy
 Ornithine Transcarbamylase Deficiency
 Hemophilia
 Sickle Cell Disease
OBSTACLES
 Gene delivery and expression
 Short lived
 Immune response
 Viral vectors
 Mutagenic disorders
 Chances of induced diseases
APPLICATIONS
 To replace a missing gene
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 Deliver gene that’s speedup destruction of tumor cells
 Inversion of cancer cell to normal cells
 Vaccines
 Increase healing process.
NUCLEIC ACID THERAPEUTICS
INTRODUCTION
 Numerous gene therapy strategies are under development, some of
which use nucleic acid-based molecules to inhibit gene expression at
either the transcriptional or post- transcriptional level.
 This strategy has potential applications, such as in cardiovascular and
inflammatory disorders, cancer, neurological disorders and infectious
diseases, as well as in organ transplantation.
DNA BASED THERAPEUTICS
1. PLASMIDS
 Plasmids are high molecular weight, double stranded DNA (ds DNA)
constructs containing transgenes, which encode specific proteins.
 On the molecular level, the plasmid DNA molecules can be
considered pro-drugs that upon cellular internalization employ the
DNA transcription and translation apparatus in the cell to
biosynthesize the therapeutic entity, the protein.
 The mechanism of action of plasmid DNA requires that the plasmid
molecules gain access into the nucleus after entering the cytoplasm.
 Nuclear access or lack thereof eventually controls the efficiency of
gene expressions.
 In addition to disease treatment, plasmids can be used as DNA
vaccines for genetic immunization.
2. OLIGONUCLEOTIDES FOR ANTISENSE AND ANTIGENE APPLICATIONS
 Oligonucleotides are short single stranded segments of DNA that
upon internalization can selectively inhibit the expression of a single
protein.
 For antisense applications, oligonucleotides interact and form a
duplex with mRNA and inhibit its translation or processing,
consequently, inhibit protein biosynthesis.
 For antigene applications, oligonucleotides must enter the cell
nucleus, form a triplex with the double stranded genomic DNA. Thus
inhibit the translation as well as transcription process of a protein.
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 For therapeutic purposes, oligonucleotides can be used to selectively
block the expression of proteins that are implicated in diseases.
 APTAMERS
 DNA aptamers are ds nucleic acid segments that can directly interact
with proteins.
 Aptamers interfere with molecular functions of disease- implicated
proteins or those that participate in the transcription or translation
processes.
 Preferred over antibodies in protein inhibition owing to their
specificity, non-immunogenicity and stability of pharmaceutical
formulation
 DNA-ZYMES
 DNAzymes are analogues of ribozymes with greater biological
activity.
 RNA backbone chemistry is replaced by DNA motifs that confer
improved biological stability.
RNA BASED THERAPEUTICS
1. RNA APTAMERS
 RNA aptamers are ss nucleic acid segments that can directly interact
with proteins.
 Recognize their targets on the basis of shape complementarity. Their
binding specificity and affinity for target are extremely high and
similar to MAbs.
2. RNA DECOYS
 RNA decoys are designed to provide alternate, competing binding
sites for proteins that act as translational activators or mRNA-
stabilizing elements.
 Prevent translation or induce instability and ultimately destruction of
mRNA.
3. ANTISENSE RNA
 Antisense drugs (AD) are short stretches of deoxyribonucleotide
analogs that bind to specific complementary areas of mRNA by
Watson-Crick base pairing to block gene expression in a sequence-
specific fashion.
 AD may induce an RNaseH, which cleaves the mRNA at the site
binding or physically block translation or other steps in mRNA
processing and transport to protein biosynthesis.
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4. RIBOZYMES
 Antisense RNA alone is not potent enough to produce complete
inhibition in vivo. Enzymatic moiety can be induced with antisense
oligonucleotide, which will cleave the target RNA once the RNA-RNA
duplex has formed. These enzymatic RNA strands are called
Ribozymes.
5. SMALL INTERFERING RNAS
 RNA interference (RNAi) is a post-transcriptional mechanism of gene
silencing through chromatin remodeling, inhibition of protein
translation, or direct mRNA degradation, which is ubiquitous in
eukaryotic cells.
 SIRNAs can be used for downregulation of disease-causing genes
through RNA interference. Short ds RNA segments with 21-23
nucleotides and are complementary to the mRNA sequence of the
protein whose transcription is to be blocked.
6. MICRO RNA
 Micro RNAs (miRNAs) are a class of naturally occurring small non-
coding RNA molecules with 21-25 nucleotides in length.
 These molecules are partially complimentary to messenger RNA
(mRNA) molecules, and their main function is downregulation of gene
expression via translational repression, mRNA cleavage and
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B. TECHNIQUES USED IN PHARMACEUTICAL BIOTECHNOLOGY
POLYMERASE CHAIN REACTION (PCR)
INTRODUCTION
 A technique used to amplify, or make many copies of, a specific target
region of DNA.
 Polymerase chain reaction (PCR) is a common laboratory technique used
to make many copies (millions or billions) of a particular region of DNA.
 Typically, the goal of PCR is to make enough of the target DNA region
that it can be analyzed or used in some other way. For instance, DNA
amplified by PCR may be sent for sequencing, visualized by gel
electrophoresis, or cloned into a plasmid for further experiments.
 PCR is used in many areas of biology and medicine, including molecular
biology research, medical diagnostics, and even some branches of
ecology.
TAQ POLYMERASE
 Like DNA replication in an organism, PCR requires a DNA polymerase
enzyme that makes new strands of DNA, using existing strands as
templates. The DNA polymerase typically used in PCR is called Taq
polymerase, after the heat-tolerant bacterium from which it was
isolated (Thermus aquaticus).
PCR PRIMERS
 Like other DNA polymerases, Taq polymerase can only make DNA if it's
given a primer, a short sequence of nucleotides that provides a starting
point for DNA synthesis. In a PCR reaction, the experimenter determines
the region of DNA that will be copied, or amplified, by the primers she or
he chooses.
 PCR primers are short pieces of single-stranded DNA, usually around 20
nucleotides in length. Two primers are used in each PCR reaction, and
they are designed so that they flank the target region (region that should
be copied). That is, they are given sequences that will make them bind to
opposite strands of the template DNA, just at the edges of the region to
be copied. The primers bind to the template by complementary base
pairing.
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
When the primers are bound to the template, they can be extended by
the polymerase, and the region that lies between them will get copied.

STEPS OF PCR

The key ingredients of a PCR reaction are Taq polymerase, primers,
template DNA, and nucleotides (DNA building blocks).

The ingredients are assembled in a tube, along with cofactors needed by
the enzyme, and are put through repeated cycles of heating and cooling
that allow DNA to be synthesized.

The basic steps are:
DENATURATION (96°C)

Heat the reaction strongly to separate, or denature, the DNA strands.
This provides single-stranded template for the next step.

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ANNEALING (55 - 65°C)

Cool the reaction so the primers can bind to their complementary
sequences on the single-stranded template DNA.
EXTENSION (72°C)

Raise the reaction temperatures so Taq polymerase extends the primers,
synthesizing new strands of DNA.


This cycle repeats 25 - 35 times in a typical PCR reaction, which generally
takes 2 - 4 hours, depending on the length of the DNA region being
copied. If the reaction is efficient (works well), the target region can go
from just one or a few copies to billions.

That’s because it’s not just the original DNA that’s used as a template
each time. Instead, the new DNA that’s made in one round can serve as
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a template in the next round of DNA synthesis. There are many copies of
the primers and many molecules of Taq polymerase floating around in
the reaction, so the number of DNA molecules can roughly double in
each round of cycling.
USING GEL ELECTROPHORESIS TO VISUALIZE THE RESULTS OF PCR

The results of a PCR reaction are usually visualized (made visible) using
gel electrophoresis. Gel electrophoresis is a technique in which
fragments of DNA are pulled through a gel matrix by an electric current,
and it separates DNA fragments according to size. A standard, or DNA
ladder, is typically included so that the size of the fragments in the PCR
sample can be determined.

DNA fragments of the same length form a "band" on the gel, which can
be seen by eye if the gel is stained with a DNA-binding dye. For example,
a PCR reaction producing a 400 base pair (bp) fragment would look like
this on a gel:


A DNA band contains many, many copies of the target DNA region, not
just one or a few copies. Because DNA is microscopic, lots of copies of it
must be present before we can see it by eye.

This is a big part of why PCR is an important tool: it produces enough
copies of a DNA sequence that we can see or manipulate that region of
DNA.
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APPLICATIONS OF PCR
 Using PCR, a DNA sequence can be amplified millions or billions of times,
producing enough DNA copies to be analyzed using other techniques.
For instance, the DNA may be visualized by gel electrophoresis, sent for
sequencing, or digested with restriction enzymes and cloned into a
plasmid.
 PCR is used in many research labs, and it also has practical applications
in forensics, genetic testing, and diagnostics. For instance, PCR is used to
amplify genes associated with genetic disorders from the DNA of
patients (or from fetal DNA, in the case of prenatal testing). PCR can also
be used to test for a bacterium or DNA virus in a patient's body: if the
pathogen is present, it may be possible to amplify regions of its DNA
from a blood or tissue sample.
DNA SEQUENCING
INTRODUCTION
 The term DNA sequencing refers to sequencing methods for determining
the order of the nucleotide bases - adenine, guanine, cytosine, and
thymine - in a molecule of DNA.
 DNA sequencing involves the determination of the order of DNA bases.
PROCEDURE
 Sequencing an entire genome (all of an organism’s DNA) remains a
complex task.
 It requires breaking the DNA of the genome into many smaller pieces,
sequencing the pieces, and assembling the sequences into a single long
"consensus."
TYPES OF DNA SEQUENCING
 Sanger sequencing
 Illumina’s sequencing
 SMRT (Single molecule real time)
SANGER SEQUENCING
 It is method to find out the nucleotides Sequence of unknown DNA
strand.
 The DNA template is treated with heat so that it becomes single
stranded.
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 A short, single-stranded primer which is radioactively labelled is added
to the end of the DNA template. Add template DNA and primer in 4
Tubes. Now add ddNTPs In tubes in the way that single tube contain one
type of ddNTP.
 Extension is start and band formed of various sizes. The fragments of
DNA are separated by electrophoresis. Overlap these sequences to find
out sequence of Target DNA.
ILLUMINA’S SEQUENCING
 Illumina sequencing is a technique used to determine the series of base
pairs in DNA.
 It involves the following steps:
­ Sample preparation
­ Cluster generation
­ Sequencing
­ Data analysis
SMRT (SINGLE MOLECULE REAL TIME)
 Single-molecule real-time (SMRT) sequencing is a parallelized single
molecule DNA sequencing method.
 Single-molecule real-time sequencing utilizes a zero-mode waveguide
(ZMW). A single DNA polymerase enzyme is affixed at the bottom of a
ZMW with a single molecule of DNA as a template.
 It is useful to look for varieties between different generations and new
reference genome sequence.
APPLICATIONS OF DNA SEQUENCING
 With its study we can understand the function of a specific sequence
and the sequence responsible for any disease.
 With the help of comparative DNA sequence study we can detect any
mutation
 DNA Fingerprints.
 Forensics
­ DNA sequencing has been applied in forensics science to identify
particular individual because every individual has unique
sequence of his/her DNA.
­ It is particularly used to identify the criminals by finding some
proof from the crime scene in the form of hair, nail, skin or blood
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 Agriculture
­ DNA sequencing has played vital role in the field of agriculture.
­ The mapping and sequencing of the whole genome of
microorganisms has allowed the agriculturists to make them
useful for the crops and food plants.
 Medicine
­ In medical research, DNA sequencing can be used to detect the
genes which are associated with some heredity or acquired
diseases.
AFFINITY PROTEIN PURIFICATION
INTRODUCTION
 Affinity chromatography is often described as the most powerful highly
selective method of protein purification available.
 This technique relies on the ability of most proteins to bind specifically
and reversibly to other compounds, often termed ligands.
 A wide variety of ligands may be covalently attached to an inert support
matrix, and subsequently packed into a chromatographic column.
 In such a system, only the protein molecules that selectively bind to the
immobilized ligand will be retained on the column.
 Washing the column with a suitable buffer will flush out all unbound
molecules.
 An appropriate change in buffer composition, such as inclusion of a
competing ligand, will result in desorption of the retained proteins.
NEED OF PROTEIN PURIFICATION
 To identify structure and function of the protein of interest.
 To study protein regulation and protein-protein interactions.
 To produce antibodies.
 Proteins(enzymes) are used in assays.
APPLICATIONS
 Used for isolation and purification of all biological macromolecule.
 Used to purify nucleic acid, antibodies, enzymes. Etc.
 To notice which biological compounds bind to a particular substance.
 To reduce an amount of substance in a mixture.
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C. FUNDAMENTALS OF GENETIC ENGENEERING AND ITS
APPLICATION IN MEDICINE
INTRODUCTION
 Genetic engineering is the process of transferring specific genes from
the chromosome of one organism and transplanting them into the
chromosome of another organism in such a way that they become a
reproductive part of the new organism.
PROCESS
 The process that produces the resulting recombinant DNA involves four
steps:
­ The desired DNA is cleaved from the donating chromosome by the
action of restriction enzymes, which recognize and cut specific
nucleotide segments, leaving a “sticky end” on both ends. The
restriction enzymes also splice the receiving chromosome in a
complementary location, again leaving “sticky ends” to receive the
desired DNA.
­ The desired DNA fragment is inserted into a vector, usually a
plasmid, for transfer to the receiving chromosome. Plasmids are
an ideal vector because they replicate easily inside host bacteria
and readily accept and transfer new genes. Plasmids are circular
DNA molecules found in the cytoplasm of bacteria that bond with
the desired DNA fragment with the help of the joining enzyme,
DNA ligase, to create the resulting recombinant DNA.
­ When the host cell reproduces, the plasmids inside also
reproduce, making multiple clones of their DNA. Because the
plasmid DNA contains the desired as well as unwanted DNA
clones, the entire product is referred to as a gene library. The
desired gene is similar to one book in that library.
­ To recover the desired DNA, the current technology is to screen
unwanted cells from the mixture and then use gel electrophoresis
to separate the remaining genes by movement on an electric grid.
Gel electrophoresis uses a positively charged grid to attract the
negatively charged DNA fragments, thereby separating them by
size, because the smaller ones will migrate the most. Radioactive
or fluorescent probes are added, which attract and bind with the
desired DNA to produce visible bands. Once isolated, the DNA is
available for commercial use.
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APPLICATIONS OF GENETIC ENGINEERING IN MEDICINE
 Genetic engineering has resulted in a series of medical products. The
first two commercially prepared products from recombinant DNA
technology were insulin and human growth hormone, both of which
were cultured in the E. coli bacteria. Since then a plethora of products
have appeared on the market, including the following abbreviated list,
all made in E. coli:
­ Tumor necrosis factor
 Treatment for certain tumor cells
­ Interleukin-2 (IL-2)
 Cancer treatment, immune deficiency, and HIV infection
treatment
­ Pro-urokinase
 Treatment for heart attacks
­ Taxol
 Treatment for ovarian cancer
­ Interferon
 Treatment for cancer and viral infections
 In addition, a number of vaccines are now commercially prepared from
recombinant hosts.

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D. PHARMACEUTICAL RECOMBINANT THERAPEUTIC PROTEINS,
GROWTH FACTORS, HIGH THROUGHPUT SCREENING
PHARMACEUTICAL RECOMBINANT THERAPEUTIC PROTEINS
INTRODUCTION
 Therapeutic proteins are used for the treatment of abnormal health
conditions. Therapeutic proteins are fast-acting and potent medicines
and have proved very successful in the treatment of a wide range of
indications.
 Proteins are capable of performing highly specific and complex
functions, which is impossible for small molecule drugs. The high
specificity of proteins also results in less drug toxicity through
interference with normal body processes.
CLASSIFICATION OF THERAPEUTIC PROTEINS
GROUP 1
 Protein therapeutics with enzymatic or regulatory activity
GROUP 2
 Protein therapeutics with special targeting activity
GROUP 3
 Protein vaccines
GROUP 4
 Protein diagnostics
PROCESS OF DRUG PRODUCTION
 Cell line manufacture medium development
 Bioreactor process development and scale up
 Downstream purification
 Analytical characterization
PRODUCTION SYSTEMS FOR PRODUCTION OF THERAPEUTIC PROTEINS
 Bacterial cells
 Yeast cells
 Plants
 Transgenic animals
 Invitro systems
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RECOMBINANT PROTEINS APPROVED FOR HUMAN USE
 Factor VIII
 Factor IX
 Tissue plasminogen activator
(TPA)
 Insulin
 Human growth hormone
 Erythropoietin
 DNase I
 Interferons (INF)
GROWTH FACTORS
INTRODUCTION
 Orderly development requires extensive coordination and
communication between cells. Much of this is provided by extracellular
proteins (growth factors) that positively and negatively regulate
proliferation, differentiation, migration / pathfinding and survival /
death.
 Via transmembrane receptors that transduce growth factor binding to a
cascade of intracellular signaling events that culminate in both
transcription independent and transcription dependent changes in
target cell behavior.
 A number of growth factor super families have been recognized along
with specific transmembrane receptor.
Growth Factors Effects
Platelet derived growth
factor
Stimulates collagenase, fibronectin and hyaluronic acid
synthesis
Transforming growth
factor
Promotes angiogenesis and collagen production
Vascular endothelial
growth factor
Promotes angiogenesis during tissue hypoxia
Epidermal growth factor Stimulates keratinocytes and fibroblast proliferation
Fibroblast growth factor Promotes angiogenesis, granulation and epithelialization
Interleukins Chemotactic for neutrophils and fibroblasts
Colony stimulating factor Stimulates granulocyte and macrophage proliferation
Keratinocyte growth
factor
Stimulates keratinocyte migration, differentiation and
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SUPERFAMILIES OF GROWTH FACTORS
 There are multiple "superfamilies" of growth factors that contain
multiple subfamilies of proteins, all with related primary sequences.
CLASSICAL GROWTH FACTORS FAMILIES
 EGF - Epidermal Growth Factor
 FGF - Fibroblast Growth Factor
 NGF - Nerve Growth Factor
 TGFβ - Transforming Growth Factor Beta
 INSULIN & IGF'S - Insulin-Like Growth Factors
 PDGF- Platelet Derived Growth Factor.
ADDITIONAL GROWTH FACTOR FAMILIES
 Hedgehog Proteins
 Interleukins
 Netrins
 Ephrin
 Tumor Necrosis A Family (Tnfα's)
HIGH THROUGHPUT SCREENING
INTRODUCTION
 High throughput screening (HIS) is an experimental process or tool that
employs a group of techniques to quickly conduct a very vast number of
chemical, pharmacological, genetic, biological tests to identify
biomolecular pathways or pharmacological actions.
 Very vital to drug design and drug discovery process, vital to general
scientific and medical research.
 Basically helps to identify a compound that can chemically modify a
target. This compound is identified as a hit and may be generated to a
lead.
LEAD GENERATION / HIT TO LEAD
 A Hit is any compound that is confirmed to have binding activity to the
target and appears on High throughput screen. It gives the desired effect
of the HTS experiment and is confirmed on re-testing.
 The Lead is the compound with therapeutic or pharmacological activity
but sub-optimal structure that still requires modification. This is the
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compound selected from a cluster of hits based on certain parameters
like binding and modification capacity, affinity, selectivity, efficacy in cell
tissue assays, freedom of operation or patentability, drug metabolizing
enzyme interaction, serum albumin binding, cytotoxicity and many
others of importance.
 This process is commonly referred as lead generation or hit to lead
(H2L).
 The lead is further optimized and thus can then go through preclinical
and clinical trials and if approved gets marketed.
 The general procedure of HTS involves testing a solution of different
compounds in assay plates called microtiter plates having wells.
 The ligand or protein or embryo of interest is introduced into these wells
containing test solution. They are incubated for a short period of time.
 Analysis is done microscopically or by analytical techniques like
spectrometry. Compounds showing desired effects are hits.
INSTRUMENTATION
MICROTITER PLATES (ASSAY PLATES)
 Plates/containers made of plastic, having spaced wells — up to 384,
1536 or 3456 wells.
 They contain solvents (e.g. DMSO + test compounds), also contain
proteins, cells, etc. to be analyzed.
 Some might be kept empty or contain pure solvents to serve as controls.
DETECTORS
 Diverse spectrometers (fluorescence, mass, NMR, FTIR, etc.),
Chromatography (Gas, Liquid, Ion exchange, etc.) and Microscopy
(Scanning tunnelling microscopy, atomic force microscopy, confocal
microscopy) and Calorimeters.
TECHNIQUES
1. FUNCTIONAL
• Study exactly how the compound interacts with the target.
2. NON FUNCTIONAL
• To find out if the compound interacts with the target or not.
PROCEDURE
• DMSO or any other solvent in microtiter plate wells and label them.
• Add test solution in some, leave others to serve as control.
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• Test should be labelled with fluorophores or dyes. E.g. alamar blue
­ Detect change in fluorescence and view on screen
• Incubate for a period of time
­ Observe microscopically
APPLICATIONS OF HTS
 Selection of compounds from a vast number synthesized by
combinatorial chemistry and other methods.
 For lead generation for the treatment of a disease.
 HTS is an efficient tool in studying biomolecular interactions and
pathways.
 It is highly efficient, fast, accurate and dependable in compound
screening Useful in DNA sequencing.
 Useful in toxicology, to study mechanism of action of various drugs and
toxins.
 Study drug-drug interactions and the effects of drugs on metabolizing
enzymes.
 Useful in cytotoxicity assays and genotoxicity assays.

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E. BIOTECHNOLOGICAL ASPECTS OF PRODUCT DEVELOPMENT
INTRODUCTION
 Biotechnology is the use of biological organisms, systems, or processes
to develop technologies and products to improve the quality of life.
 Biotechnology is used in various fields including agriculture, food
science, and pharmaceuticals.
 Pharmaceutical Biotechnology companies use recombinant DNA
technology, which includes genetic modification of cells, or a
monoclonal antibody for making their biotechnological products.
BIOTECHNOLOGICAL DRUGS
 These drugs are also called biologicals, biotech drugs, biological drugs, or
biopharmaceuticals. True biotech products are manufactured in live
biological systems known as expression systems.
 Biopharmaceuticals are physically very different from small molecule
drugs generally sized at 1 kDa
 Examples of Classes of Protein-based Biotech drugs,
­ Erythropoietin (EPO)
­ Blood factors (Factor VII)
­ Human Growth Hormone: HGH, Somatotropin
­ Cytokines
 Interleukins
 Interferon
ROUTE OF ADMINISTRATION
 The route of administration of a biotech drug is very different from a
traditional drug taken as a pill or capsule, and each drug is developed
with a unique route of administration. These drugs are mainly given
intravenously, subcutaneously or intramuscularly
 There are also biotech drugs given to patients by intrathecal, intra-
articular, and inhalation routes.
 Oral route is less frequent because products would be degraded in the
gastrointestinal tract.
 Most biotech drugs are given in the clinic but for some chronic
indications the trend is to develop subcutaneous versions so that they
can be self-administered at home with an auto injector device. For
example Insulin.
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PROCESS OF DEVELOPMENT OF PROTEIN BIOTECH PRODUCT
 Isolation of gene of interest
 Introduction of gene to expression vector
 Transformation into host cells
 Growth of cells
 Isolation and purification of protein
 Formulation of protein product
ISOLATION OF GENE OF INTEREST
 Genes are pieces of DNA which store information for making specific
proteins that control specific traits. Genes are present in nucleus
chromosomes which code for one polypeptide.
 The double strand of DNA are cut open at specific site i.e. Nucleotide
sequence by special enzymes which are known as Restriction
Endonucleases.
 Ligases are the enzymes used to join pieces of DNA through covalent
bonds.
 Through these enzymes DNA containing genes of interest is cut and
joined with the vector.
DNA RECOMBINATION
 DNA recombination is a process in which the pieces of DNA from
different organisms are artificially mixed to create Recombinant DNA.
 Steps involved in Recombinant DNA technology are:
­ DNA extraction
­ Purification
­ Fragmentation
 Fragmentation of DNA is done by specific 'restriction' enzymes and is
followed by sorting and isolation of fragments containing a particular
gene. This portion of the DNA is then coupled to a carrier molecule
called as PLASMID.
 The hybrid DNA is then introduced into a chosen cell for reproduction
and synthesis.
TRANSFER OF GENE TO EXPRESSION VECTOR
 Different organism may be used to express a target protein, the
expression vector used therefore will have elements specific for use in
the particular organism. The most commonly used organism for protein
expression is the bacterium, Escherichia coli. However not all proteins
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can be successfully expressed in E. coli, and other systems may therefore
be used such as:
­ Yeasts e.g. commonly used for protein expression is Pichia
pastoris
­ Baculovirus
­ Mammalian cell culture
­ Plants
­ Animals.
GROWTH OF CELLS
 After the transfer of rDNA into host of choice, i.e. bacteria, yeast, E.coli
they are cultivated in culture medium.
 For research (small scale):
­ Cell culture flasks
 For productions (large scale):
­ Fermenters and Bioreactors
ISOLATION & PURIFICATION OF PROTEIN
 There is necessity for the isolation and purification of protein prepared
for Biotech drugs from micro-organisms.
 The proteins required may be extracellular or intracellular so for
isolation of extracellular products destruction of cell is not necessary but
for intracellular cell disruption is needed which is done through
following methods:
­ Detergents lysis
­ Enzymatic lysis
­ Osmotic lysis
­ Freeze-thaw cycles
­ Homogenization
ISSUE IN BIOTECH PRODUCTS
 Issues related to the use of protein based drugs:
­ Drug Delivery
 Denaturation/chemical alteration
 Rapid liver clearance
­ Antigenicity
 Foreign proteins may induce allergic reactions
 Anaphylaxis
 Loss of efficacy
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­ Stability

Denaturation leads to loss of proper 3-D conformation of
proteins.

Covalent bond breaking at high temperature and low pH.
STERILITY CONSIDERATION OF BIOTECHNOLOGY DRUGS
STERILIZATION

It is impossible to sterilize the end product therefore it is important that
­ All the raw material should be sterilized.
­ All the equipment must be sterilized.
­ Processing should be carried out in aseptic environment.
QUALITY CONTROL

Viral testing
­ There is no well-determined mean to detect viruses in the cell
culture.

Bacterial testing
­ Filtration sterilization of the final product by bacterial filter “0.22
mm membrane filter.

Pyrogen testing
­ Rabbit test
­ LAL TEST(LIMULUS AMEBOCYTE TEST)
BIOTECHNOLOGY DRUGS










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PRODUCTION OF BIOPHARMACEUTICAL – INSULIN AS EXAMPLE
 Insulin (1982) – first commercial biotech product – reliable, inexpensive
source of insulin.
 The steps involved are as follows:
­ Obtaining the human insulin gene. Extraction of mRNA from
human pancreatic cells. Making of complimentary DNA (cDNA)
from mRNA using reverse transcriptase. Mixing of bacterial
plasmids and cDNA together.
­ The cDNA is inserted into plasmid through complementary base
pairing at sticky ends. Introduction of recombinant DNA plasmid
into bacteria called as host e.g. E. coli. In host the DNA molecules
with fusion to foreign DNA can maintain autonomous replication
and the host is called as vectors.
­ Bacteria are spread onto nutrient agar containing antibiotic which
allows- growth only of transformed bacteria. Selection of bacteria
which have taken up the correct (modified) piece of DNA –
antibiotic in media kills other bacteria which do not have
resistance gene.
APPLICATIONS OF BIOTECHNOLOGICAL PRODUCTS
VACCINES
 Used to stimulate the immune system against a particular disease.
 Recombinant DNA vaccine E.g.
­ Hepatitis A and hepatitis B vaccines and Lyme disease vaccines are
commercially available
­ Interferon alfa n-1 is also available for chronic hepatitis C.
MONOCLONAL ANTIBODIES
 Trastuzumab monoclonal antibody used to treat metastatic breast
cancer.
 Palivizumab monoclonal antibodies used to treat respiratory syncytial
viral and fetal pneumonia.
 Adalimumab prepared by abbot for rheumatoid arthritis.
GENE THERAPY
 Exogenous genetic material is transferred into somatic cells to correct an
inherited or acquired defect.
 Gene therapy has been applied to diseases such as cystic fibrosis,
hemophilia, sickle cell anemia and diabetes.
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 Gene therapy has been used to treat adenosine deaminase deficiency
(ADA).
FORENSIC APPLICATIONS
 DNA fingerprinting is the classic example of a forensic application. It is
used most commonly for law enforcement and crime scene
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F. MONOCLONAL ANTIBODIES
INTRODUCTION
 An antibody is a protein used by the immune system to identify and
neutralize foreign objects including proteins, bacteria and viruses. Each
antibody recognizes a specific antigen unique to its target.
 Monoclonal antibodies (MAbs) are antibodies that are identical because
they are produced by one type of immune cell. Such Abs are clones of a
single parent cell.
 Polyclonal antibodies are antibodies that are derived from different cell
lines. They differ in amino acid sequence.
Factors Polyclonal antibodies Monoclonal Antibodies
Produced by Many B cells clones A single B cell clone
Bind to
Multiple epitopes of all
antigens used in the
immunization
A single epitope of a single
antigen
Antibody class
A mixture of different Ab
classes (isotypes)
All of a single Ab class
Ag-binding sites
A mixture of Abs with
different antigen-binding
sites
All Abs have the same antigen
binding site
Potential for cross
selectivity
High Low
CHARACTERS OF MONOCLONAL ANTIBODIES
 Monoclonal antibodies (MAbs) are a single type of antibody that are
identical and are directed against a specific epitope (antigen, antigenic
determinant) and are produced by B-cell clones of a single parent or a
single hybridoma cell line.
 A hybridoma cell line is formed by the fusion of a one B-cell lymphocyte
with a myeloma cell.
 Some myeloma cells synthesize single MAbs antibodies naturally
MONOCLONAL ANTIBODY PRODUCTION
 Monoclonal Antibody Production is largely dependent upon animal
testing, however. Because it requires immunization of mice in order for
them to create the antibodies to be grown.
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 Monoclonal Antibody Production or mAb is produced by cell lines or
clones obtained from the immunized animals with the substance to be
studied. Cell lines are produced by fusing B cells from the immunized
animal with myeloma cells. To produce the desired mAb, the cells must
be grown in either of two ways: by injection into the peritoneal cavity of
a suitably prepared mouse (the in vivo, or mouse ascites, method) or by
in vitro tissue culture.
 The vitro tissue culture is the method used when the cells are places in
culture outside the mouse's body in a flask.

 The animals are being immunized against a targeted cell “X”. This will
allow the mouse to produce antibodies for that will targeted against the
“X” antigen.
 Once the mouse has formed antibodies to the “X” antigen the cells are
then isolated in the mouse’s spleen. Monoclonal antibodies are
produced by fusing single antibody-forming cells to tumor cells grown in
culture. The resulting cell is called a hybridoma.
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 HYBRIDOMA cells are continuously/rapidly growing cell line generated
by the fusion of a myeloma cell and a normal cell that are capable of
producing antibodies.
 Each hybridoma will produce relatively large quantities of identical
antibody molecules. Because the hybridoma is multiplying in culture, it is
possible to produce a population of cells, each is producing identical
antibody molecules. These antibodies are called "monoclonal
antibodies" because they are produced by the identical offspring of a
single, cloned antibody producing cell.
PRACTICAL STEPS IN MONOCLONAL ANTIBODY PRODUCTION
 Immunize animal with antigen. Isolate spleen cells (containing antibody-
producing B cells).
 Fuse spleen cells with myeloma cells (e.g. using PEG - polyethylene
glycol). Allow unfused B cells to die. Add aminopterin to the culture to
kill unfused myeloma cells.
 Clone remaining cells (place 1 cell/well and allow each cell to grow into a
clone of cells). Screen supernatant of each clone for presence of the
desired antibody.
 Grow the chosen clone of cells in tissue culture indefinitely. Harvest
antibody from the culture supernatant.
MONOCLONAL – DIAGNOSTIC USE
 Monoclonal antibodies can be used in pregnancy detection, diagnosis of
hepatitis, influenza, herpes, streptococcal, and Chlamydia infections.
 They can be used to detect the presence and quantity in Western blot
test (to detect a substance in a solution) or an immunofluorescence test.
 Monoclonal antibodies can also be used to purify a substance with
techniques called immunoprecipitation and affinity chromatography.
 These have the ability to be used for killing cancerous cells by forming
conjugates
 These can be used for the transport or delivery of toxins or radioactive
materials to the cancerous cells.

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G. IMMOBILIZED ENZYMES
INTRODUCTION
IMMOBILIZED ENZYME
 The Enzymes which are physically/chemically confined or localized in a
certain region/ space with retention of their catalytic activities and
which can be used repeatedly and continuously.
ENZYME IMMOBILIZATION
 Enzyme immobilization may be defined as a process of detaining the
enzyme molecules to a solid support over which a substrate is passed
and converted to products.
NEED FOR IMMOBILIZED ENZYME
 Enzymes are expensive and sensitive
 Enzymes have the ability to catalyze the reaction without being utilize in
the reaction mixture, so they can be used again and again.
 Enzymes mix with final product in final reaction, which make it hard and
costly to separate enzymes from mixture for further utilization in fresh
batch reaction.
 Use of soluble enzymes is not economical due to loss after each reaction
 Enzymes Immobilization helps in preventing wastage.
METHODS FOR ENZYME IMMOBILIZATION
PHYSICAL METHODS OF ENZYME IMMOBILIZATION
1. ADSORPTION
 Involves the physical binding of the enzyme on the surface of carrier
matrix.
 The process of adsorption involves the common weak interactions
like Vander Waal or hydrogen bonding
 Carrier may be organic or inorganic material surface.
ADVANTAGES
 No alteration in enzyme activities
 Ease of immobilized process
 Readily available polymer matrix for enzyme adsorption
 Great access to the substrate by bound enzymes.

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DISADVANTAGES
 pH changes may causes the immobilized enzyme to leak into the
reaction mixture.
 Ionic portion in between substrate and polymer matrix owing to have
same charge.
 Acidity or basicity of the medium may alter enzyme activities.
2. ENTRAPMENT
 This method does not need polymer matrix as attachment surface.
Enzymes are stop up in natural or synthetic polymer.
 Permeable membrane allows the substrate and product to pass but
retains the enzyme inside the network. It can be gel or bead
entrapment.
 Commonly used polymer matrix for entrapment are collagen,
cellulose acetate, calcium alginate and polyacrylamide.
 Entrapment in calcium alginate is as follows:
­ Enzyme + Ca alginate (Mixture is added drop wise) → CaCl2
Solution → Beads of Calcium alginates.
ADVANTAGES
 Simple method of immobilization
 Requires mild conditions during procedure
 Non-living cells could be immobilized though this process.
DISADVANTAGES
 The enzyme may leak from the pores.
 Free radicals that are produced during process may be toxic for sensitive
enzymes.
 It involves entrapping enzymes within interstitial spaces of cross-linked
polymers such as polyvinyl alcohol and starches.
3. ENCAPSULATION
 It involves enclosing of the enzymes within semi
 permeable polymer membranes e.g. semi permeable such as nylon
membranes in the shape of spheres.
 Membrane must confined the enzyme along with allowing the
passage of reactants and product.
CHEMICAL METHODS OF ENZYME IMMOBILIZATION
1. COVALENT BINDING
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 Enzyme forms covalent link with active group of the matrix.(covalent
linkage of enzyme with supporting surface/base).
 The functional group of enzyme, which is involved in the linkage,
should not affect the active properties of the said enzyme.
 The functional groups that may take part in this binding are Amino,
Carboxylic, Hydroxyl and phenolic group of tyrosine amino acids.
 But covalent binding may alter conformational structure and active
center of the enzyme.
 Functional group of the enzymes that are not important for catalytic
functions of enzymes are mostly targeted for the covalent linkage
 To protect the catalytic site functional group from being used during
in this technique, the process is carried out in the presence of
substrate which act as a shield for active site.
 Examples:
­ Glucose oxidase, invertase and peroxidase.
ADVANTAGES
 Leaching of enzyme is protected by covalent immobilization
 Almost any polymer material can be used for covalent binding
 Variety of supporting materials allows every enzyme to covalently
immobilized.
DISADVANTAGES
 Inactivation of enzyme during immobilization
 Complicated immobilization process.
2. CROSS LINKING
 Cross linking involves chemical intermolecular cross linking of
enzymes molecules in the absence of solid support.
 This method produces a 3 dimensional cross linked enzyme aggregate
(insoluble in water) by means of a multifunctional reagent that links
covalently to the enzyme molecules.
 Cross linking of enzymes in most cases is performed in the presence
of inert proteins like gelatin, albumin and collagen.
 Glutaraldehyde is most commonly used bi-functional reagent in the
immobilized enzymes.
ADVANTAGES
 This techniques cheap and simple
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 It is used for the commercial preparations of immobilized enzymes.
DISADVANTAGES
 Yield very little bulk of immobilized enzymes with high intrinsic activity.
CARRIERS FOR IMMOBILIZED ENZYMES
TYPES OF CARRIERS
NATURALLY OCCURING
 Structural proteins (Ex: collagen)
 Globular proteins (Ex: albumin)
 Carbohydrates (Ex: dextran)
SYNTHETIC ORGANIC
 Ex: Polyvinyl, Epoxide, etc.
INORGANIC
 Ex: Silica gel, Bentonite
APPLICATIONS OF IMMOBILIZED ENZYMES
 Production of antibiotics
­ Immobilized penicillin amylase used for production of penicillin G ,
Amoxicillin.
­ Macrolide antibiotics can be produced by living cells of
streptomycin Immobilized with calcium alginate.
 Production of steroids
 production of amino acids
 Diagnostic purpose for example:
­ ELISA
­ Biosensor e.g. glucose biosensor that use immobilized glucose
oxidase enzyme.
 Bioremediation
­ For the removal/detoxification of contaminants.
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190. Topic Viz Past Papers Pharmaceutical Technology
GM Hamad Pharmo Hub Pakistan
PHARMACEUTICAL TECHNOLOGY PAST
PAPERS
01: PRINCIPLES OF PHARMACEUTICAL FORMULATION AND DOSAGE
FORM DESIGN
Q: Differentiate between solubility and dissolution, Name different approaches
for the improvement of solubility of poorly soluble drugs (10) Annual 2016
Q: Define phase, and what are the implication of different phases of API in drug
developmental process? (10) 2
nd
Annual 2018
Q: What is the importance of followings PARAMETERS at the stage of product
Development (02 each) Annual 2018
a) Solid state stability
b) Particle shape
c) Intrinsic dissolution rate
d) Age of patient
e) First pass effect
Q: What is the importance of followings PARAMETERS at the stage of product
Development (02 each) 2
nd
Annual 2018
f) Excipient compatibility
g) Particle size
h) pH solubility profile
i) pKa determination
j) Clinical indication of drug
Q: Describe the characteristics of an ideal dosage form, what is the importance of
solubility during dosage form development (10) Annual 2019
Q: How phenomenon of polymorphism can affect the physicochemical properties
of drug compounds? (10) Annual 2019
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191. Topic Viz Past Papers Pharmaceutical Technology
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Q: Discuss different techniques used in pre-formulation studies for the
identification and characterization of polymorphs (10) Annual 2019, Annual 2018,
Annual 2017
Q: (20) Annual 2017
a) "Formulation is a system of input and output". Comment?
b) Briefly describe the Drug Design Space
c) Why the one factor at a time (OFAT) approach fails to achieve optimum
product.
Q: One factor at a time (OFAT) approach fails to achieve optimum product?
Comment. (04) 2
nd
Annual 2017
Q: What are the factors effecting the final stages of a product (10) 2
nd
Annual
2017
Q: Write notes on the following (10) 2
nd
Annual 2016, 2
nd
Annual 2017
a) Quality by Design (QBD)
b) Process Analytical Technique (PAT) approaches
Q: What is optimization? Why sometimes a compromise in desired formulation
properties is required? (10) 2
nd
Annual 2018
Q: What is traditional formulation approach? What are its limitations as
compared to the computer-aided formulation approaches? (10) 2
nd
Annual 2018
Q: Describe one factor at; time (OFAT) approach, What are its limitations (10)
Annual 2019
Q: What are the benefits of using advanced formulation approaches (10) Annual
2020
Q: Describe the quality by design and the design space (10) Annual 2020
02: ADVANCED GRANULATION TECHNOLOGY
Q: Describe processes for coating multi-particulates (10) Annual 2018
Q: Discuss Instrumentation used in-Granule manufacturing (10) 2
nd
Annual 2018
Q: Write a note on Fluidized Bed granulators (10) Annual 2020
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192. Topic Viz Past Papers Pharmaceutical Technology
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03: POLYMERS USED IN DRUG DELIVERY SYSTEMS
Q: Write a note on Biodegradable Polymers used in Pharma industry (10) Annual
2016, Annual 2017
04: NOVEL DRUG DELIVERY SYSTEM (NDS)
Q: Describe various diffusion based formulation designs to achieve extended
release of drugs. (10) Annual 2016
Q: Differentiate between delayed and extended release drug delivery system, why
we need these systems (10) Annual 2016, 2
nd
Annual 2016
Q: Discuss in-vivo/ex-vivo evaluation of modified release delivery system (10)
Annual 2017
Q: Define Modified release drug delivery system. Briefly describe the design
parameters for Zero order released modified delivery system (10) 2
nd
Annual 2017
Q: Define microencapsulation and describe various polymer classes used in this
process (10) 2
nd
Annual 2017, Annual 2017
Q: Discuss different types of matrix systems designed for extended release of
drug (10) Annual 2018
Q: Describe the pharmacokinetic properties considered for defining the
candidature of the drug for modified delivery system (10) Annual 2018, 2
nd
Annual
2017, Annual 2017
Q: Briefly describe the theory of designing modified release delivery from
approximation to optimization (10) Annual 2018
Q: Briefly describe the followings (02 each) Annual 2019
a) Advantages of sustained release dosage form
b) Barrier Principle of sustained release dosage form
c) Solvent evaporation method of microencapsulation
d) Osmotic pressure activated systems
e) Hydrodynamically balanced system for controlled release
Q: Classify NDDS with reference to release control (10) Annual 2020
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193. Topic Viz Past Papers Pharmaceutical Technology
GM Hamad Pharmo Hub Pakistan
Q: What are various modified release dosage form. What are different
pharmacokinetic and pharmacodynamic factors in designing the modified release
dosage form (20) Annual 2020
05: NOVEL GIT DRUG DELIVERY SYSTEM (DDS)
Q: Describe different gastro retentive approaches to drug delivery? (10) 2
nd

Annual 2018
Q: What are floating drug delivery systems (FDDS)? Discuss different types and
their application (10) Annual 2020
Q: Explain different factors to be considered for the development of drug delivery
system for GIT (10) Annual 2020
Q: Write a note on Mucoadhesive dosage form (10) Annual 2020
06: DRUG CARRIER SYSTEM
Q: Describe Liposomes and their applications (10) Annual 2016, 2
nd
Annual 2016,
2
nd
Annual 2017
Q: Write down various methods for preparation of Liposomes? (10) Annual 2017
Q: Describe methods of preparation and applications of niosomes (10) Annual
2018
Q: Write down physical and chemical characterization of Liposomes? (10) 2
nd

Annual 2018
Q: Write down different applications of niosomes (10) Annual 2019
07: TARGETED DRUG DELIVERY SYSTEM
Q: Discuss carriers used for Targeted Drug Delivery? (10) Annual 2017
Q: Describe passive strategies in drug delivery and targeting system (10) Annual
2018
Q: Describe active strategies in drug delivery and targeting system (10) 2
nd
Annual
2018, Annual 2019, Annual 2020
08: PHARMACEUTICAL BIOTECHNOLOGY
Q: Briefly discuss the concepts and principles of Gene Therapy (10) Annual 2017
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194. Topic Viz Past Papers Pharmaceutical Technology
GM Hamad Pharmo Hub Pakistan
Q: Discuss the applications of gene therapy in the field of Pharmacy (10) Annual
2017
Q: What are the immobilized enzymes? How are they prepared? (10) Annual
2015, Annual 2018
Q: Discuss the production of biopharmaceuticals with special reference to insulin
(10) Annual 2015, Annual 2016, Annual 2018
Q: Define pharmaceutical biotechnology? Describe the basic principle of
biotechnology (10) 2
nd
Annual 2018
Q: How monoclonal antibodies are prepared? Describe their application (10) 2
nd

Annual 2016, 2
nd
Annual 2018
Q: Discuss in detail the Biotechnological aspects in the product development (20)
Annual 2019
Q: Write a detailed note on genetic engineering and its applications in pharmacy
(20) Annual 2020
192

195. References
GM Hamad
References for Pharmaceutical Technology Notes

1. Dr Nasir lectures
2. Dr Nadeem Irfan lectures
3. Lachman Leon, Liberman H.A and Kanig J.L., “The Theory and Practice of
Industrial Pharmacy”
4. Aulton M.E. “Hand Book of Pharamaceutics”
5. Allen. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems
193