Novel Drug Delivery Systems

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

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

Chapter 1 – Principles of Pharmaceutical Formulation and Dosage Form Design
GM Hamad
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).
1

GM Hamad
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
2

GM Hamad
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
3

GM Hamad
 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.
𝑇𝑎𝑛θ =
ℎ
𝑟
 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.
4

GM Hamad
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.
𝐶𝑎𝑟𝑟 𝑠 𝑖𝑛𝑑𝑒𝑥 =
𝑇𝑎𝑝 𝑑𝑒𝑛𝑠𝑖𝑡𝑦 − 𝑃𝑜𝑟𝑒 𝑑𝑒𝑛𝑠𝑖𝑡𝑦
𝑇𝑎𝑝 𝑑𝑒𝑛𝑠𝑖𝑡𝑦
𝑋 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.
5

GM Hamad
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.
6

GM Hamad
 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.
7

GM Hamad
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.
8

GM Hamad
 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)
9

GM Hamad
 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
10

GM Hamad
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.
11

GM Hamad
 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:
12

GM Hamad
𝑙𝑜𝑔𝑃 =
(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.
13

GM Hamad
 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
14

GM Hamad
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
15

GM Hamad
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
𝐼𝑛𝑆 =
∆𝐻𝑠
𝑅
(1) + 𝐶
𝑇
 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.
16

GM Hamad
 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:
𝑑𝐶/𝑑𝑡 =
𝐴𝐷 (𝐶 − 𝐶)
ℎ𝑣
 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.
17

GM Hamad
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
18

GM Hamad
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 2nd
order kinetics as there are two reacting species,
water and API. In aqueous solution, water is in excess so the reaction is
1st
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
19

GM Hamad
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.
20

GM Hamad
 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.
21

GM Hamad
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
22

GM Hamad
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.
23

GM Hamad
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
24

GM Hamad
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
25

GM Hamad
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.
26

GM Hamad
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
27

GM Hamad
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.
28

GM Hamad
 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
29

GM Hamad
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.
30

GM Hamad
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
31

GM Hamad
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
32

GM Hamad
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
33

GM Hamad
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
34

GM Hamad
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
35

GM Hamad
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=109
) Few neurons (n=102
– 103
)
 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
36

GM Hamad
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
37

GM Hamad
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
38

GM Hamad
practices, and the total quality concept. QBD, PAT and 6σ have emerged
as the new GMP’s concepts for the 21st
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
39

GM Hamad
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
40

GM Hamad
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.
41

GM Hamad
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
42

Chapter 2 – Advanced Granulation Technology
GM Hamad
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.
43

GM Hamad
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:
44

GM Hamad
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
Fluid bed granulator / dryer
Spray 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.
45

GM Hamad
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
46

GM Hamad
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.
47

GM Hamad
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.
48

GM Hamad
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.
49

GM Hamad
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.
50

GM Hamad
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.
51

GM Hamad
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.
52

GM Hamad
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.
53

GM Hamad
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).
54

GM Hamad
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
55

GM Hamad
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.
56

GM Hamad
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.
57

GM Hamad
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
58

Novel Drug Delivery Systems

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Novel Drug Delivery Systems

Similar to Novel Drug Delivery Systems (20)

More from Ghulam Murtaza Hamad

More from Ghulam Murtaza Hamad (17)

Recently uploaded

Recently uploaded (20)

Novel Drug Delivery Systems