CAREWELL PHARMACY

M Pharmacy Notes
Pharmaceutics
Modern Pharmaceutics-I

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Syllabus:-
UNIT - I Preformulation studies: Goals of Preformulation, preformulation
parameters, Polymorphs and Amorphous forms, selection of drugs- solubility,
partition coefficient, salt forms, humidity, solid state properties, Particle
Size Analysis (Laser Diffraction and Dynamic Light Scattering) drug -
excipient compatibility, flow properties, format and content of reports of
preformulation, preformulation stability studies (ICH)

UNIT - II Formulation development of solid dosage forms – I: New

materials, excipients science - diluents, disintegrants, super disintegrants,
etc, evaluation of functional properties of excipients, co-processed
materials, methods of preparation and evaluation.

UNIT - III Formulation development of solid dosage forms – II: Coating,

coating machines, coating techniques in tablet technology for product
development, computerization, inprocess control of tablets, formulation
development and manufacture of powder dosage forms for internal use.

Microencapsulation - Types, methodology, problems encountered.

UNIT - IV Formulation development of soft and hard gelatin capsules:

Introduction, production and methods of manufacture, filling equipment and
filling operations, formulations, finishing, special techniques, advances in
capsule manufacture, machines, processing and control including
pharmaceutical aspects, physical stability and packaging.

UNIT - V Optimization techniques in pharmaceutical formulation and

processing: Introduction, optimization parameters, statistical design,
response surface method, contour diagrams, factorial design, partial
factorial design, simplex methods, mixture designs, Placket Burhan method,
Box Benken method, applications in pharmaceutical formulation.

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UNIT 1 - Pre-Formulation Studies

Preformulation studies are the investigations of physical and chemical
properties of a drug substance, alone and in combination with other
excipients,

Characterization of physical, chemical and mechanical properties of

new drug molecule in order to develop safe, effective, and stable
dosage form.

Preformulation is branch of Pharmaceutical' science that utilizes

biopharmaceutical principles in the determination of physicochemical
properties of the drug substance.

Prior to the development of any dosage form new drug, it is essential

that certain fundamental physical & chemical properties of drug
powder are determined.

This information may dictate many of subsequent event & approaches

in formulation development. → This first learning phase is called as
Preformulation.

Goals of Preformulation Studies

 To establish the physicochemical parameters of a candidate drug

molecule.
 To determine the kinetic rate profile of drug substances.
 To establish the compatibility of a candidate drug molecule with
common excipients.

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Parameters in Preformulation Studies

a. Physical characteristics

 Organoleptic properties of the candidate drug molecule e.g., colour,

odour and taste.
 Bulk characterization e.g., particle size and surface area, powder
flow properties, density, compressibility, crystallinity, polymorphism
and hygroscopicity.
 Solubility analysis e.g., ionization constant/ drug Pka, partition
coefficient, solubilization, thermal effect, common ion effect (Ksp)
and dissolution.
 Stability analysis e.g., solution-state stability testing, solid-state
stability testing, and drug-excipient compatibility studies.

b. Chemical characteristics

 Hydrolysis
 Oxidation
 Reduction
 Racemization
 Polymerization
 Isomerization
 Photostability

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Polymorphs and Amorphous forms

Amorphous
 In amorphous form atom or molecule are randomly placed.
 Solubility & dissolution rate are greater for amorphous form than
crystalline, as amorphous form has higher thermodynamic energy.
Eg. Amorphous form of Novobiocin is well absorbed whereas
crystalline form results in poor absorption.
 Do not have any fixed internal structure.
 Less stable than its crystalline forms.
 Have greater solubility than its crystalline forms.
 Tend to revert to more stable forms during storage.

Polymorphism

It is the ability of the compound to crystallize as more than one

distinct crystalline species with different internal lattice.

Different crystalline forms are called polymorphs.

Polymorphs are of 2 types

1. Enatiotropic
2. Monotropic

1. The polymorph which can be changed from one form into another by
varying temp or pressure is called as Enantiotropic polymorph. Eg.
Sulphur.

2. One polymorph which is unstable at all temp. & pressure is called as

Monotropic polymorph. Eg. Glyceryl stearate.

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Polymorphs differ from each other with respect to their physical

property such as

 Solubility
 Melting point
 Density
 Hardness
 Compression characteristic

Eg. Chloramphenicol exist in A,B & C forms, of these B form is more

stable & most preferable.

Methods to identify polymorphism

 Optical crystallography
 Hot Ostage microscopy
 X-Ray Diffraction method
 NMR technique
 FTIR technique
 Microcalorimetry
 Thermal methods
 Melting point determination

Properties of Polymorphs

 Polymorphs show the same properties in liquid or gaseous state but

they behave differently in solid state.
 Polymorphs differ from each other with respect to physical
properties like
 Melting and sublimation temperature
 Vapour pressure
 Solubility and dissolution rate
 Stability
 Optical and electrical properties

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 Crystal habit
 Hygroscopicity
 Heat capacity
 Solid-state
state reactions
 Conductivity
 Compression characteristics

Selection of Drugs
1. Solubility

 Solution phase equilibrium with solid phase at a stated temperature

and pressure.
 Determines amount of drug dissolved, amount of drug available for
absorption.
 Solubility reduction is carried out in certain conditions:
 Enhancement of chemical stability.
 Taste masking products.
 Production of sustained release products. Descriptive term

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The equilibrium solubility is based on the phase-solubility technique

proposed by Higuchi-Connors.

Method

Drug dispersed in solvent in a closed container

Agitated at a constant temperature using shakers

Samples of the slurry are withdrawn as a function of time

Clarified by centrifugation and assayed by HPLC, UV, GC etc

It is important for orally administered drugs or drugs needed to be

converted into solutions.

It includes:

 pKa determinations
 pH solubility profile and common ion effects
 Effect of temperature
 Solubilization
 Partition coefficient
 Dissolution

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General Method of Increasing the Solubility

1. Addition of co-solvent
2. pH change method
3. Reduction of particle size
4. Temperature change method
5. Hydotrophy
6. Addition of Surfactant
7. Dielectrical Constant
8. Complexation

2. Partition Coefficient

Ratio of unionized drug distributed between the organic & inorganic

aqueous phase at equilibrium.

Po/w = ( Coil / CWater)equilibrium

Importance

 Screening for biological

 Drug delivery

System used are

 Octanol/water and Chloroform/water

Methods of finding Partition coefficient:

 Shake-flask method
 Chromatographic method.
 Counter current and filter probe method. Tomlinson's filter
probe method.
 Micro electro-metric titratation method
 Automated instrument is now available.

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Applications of Partition coefficient:

 Measure of Lipophilic character of molecules.

 Recovery of antibiotics from fermentation broth.
 Extraction of drug from biological fl fluid
uid for therapeutic
monitoring.
 Absorption of drug from dosage forms. (Ointments,
Suppositories, Transdermal patches).
 Study of distribution of flavoring oil between oil & water
wate in
emulsion.

3. pka determination (Salt Formation)

 pKa is the dissociation constant of a drug

 The un-ionized
ionized drug is lipid soluble thus permeates through lipid
membrane.
 The ionized substance is lipid insoluble therefore permeation is
slow
 Degree of ionizatio
ionization depends on pH

Determined by uv spectroscopy, potentiometric titration, Titrimetric

method.

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4. Hygroscopicity

Definition: Many pharmaceutical materials have a tendency to adsorb

atmospheric moisture (especially water-soluble salt forms). They are
called hygroscopic materials and this phenomenon is known as
hygroscopicity.

Equilibrium moisture content depends upon:

a. the atmospheric humidity

b. temperature
c. surface area
d. exposure time
e. mechanism of moisture uptake.

Deliquescent materials:

They absorb sufficient amount of moisture and dissolve completely in

it. (e.g. anhydrous calcium chloride).

Tests of Hygroscopicity

Procedure

Bulk drug samples are placed in open containers with thin powder bed
to assure maximum atmospheric exposure. These samples are then
exposed to a range of controlled relative humidity (RH) environments
prepared with saturated aqueous salt solutions.

The amount of moisture adsorbed can be determined by the

following methods:

a. Gravimetry
b. Thermogravimetric analysis (TGA)
c. Karl-Fischer titration (KF-titration)

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d. Gas chromatography (GC)

Time of monitoring depends on the purpose:

a. For the purpose of ‘handling’ data points from 0 to 24 hours are

taken
b. For the purpose of ‘storage’ data points from 0 to 12 weeks are
taken.

5. Solid State Stability

Objectives

Identification of stable storage conditions for drug in the solid state

and identification of compatible excipients for a formulation.

Characteristics

Solid state reactions are much slower, so the rate of appearance of

decay product is measured (not the amount of drug remaining
unchanged).

 To determine the mechanism of degradation thin layer

chromatography (TLC), fluorescence or UV / Visible spectroscopy
may be required.
 To study polymorphic changes DSC or IR-spectroscopy is required.
 In case of surface discoloration due to oxidation or reaction with
excipients, surface reflectance equipment may be used.

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Storage condition

 50C – Refrigerator
 220C – Room Temperature
 370C – Ambient humidity
 370C / 75% RH (Relative Humidity)

Light box

 Clear box
 Amber glass
 Yellow-Green glass
 No exposure (Control :- Card-board box or wrapped with
aluminium foil)

Procedure

1. Weighed samples are placed in open screw-capped vials are exposed

to a variety of temperatures, humidities an dlight intnesities. After
the desired time samples are taken out and measured by HPLC (5 –
10 mg), DSC (10 to 50mg), IR (2 to 20mg).
2. To test for surface oxidation samples are stored in large (25ml)
vials for injection capped with Teflon-lined rubber stopper. The
stoppers are penetrated with needles and the headspace is flooded
with the desired gas. The resulting needle holes are sealed with wax
to prevent degassing.
3. After fixed time those samples are removed and analyzed.

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Particle Size Analysis

Particle size analysis is used to characterize the size distribution of
particles in a given sample. It can be applied to solid materials,
suspensions, emulsions and even aerosols. There are many different
methods employed to measure particle size. It is a very important test
and is used for quality control in many different industries. particle
size is a critical factor in determining the efficiency of manufacturing
processes and performance of the final product.

Some industries and product types where particle sizing is used

includes:

 Pharmaceuticals
 Building materials
 Paints and coatings
 Food and beverages
 Aerosols

Purpose of particle size (PS) analysis

The purpose of particle size analysis in pharmacy is to obtain

quantitative data on the size, size distribution, and shapes of drug and
other components to be used in pharmaceutical formulations.

Importance of particle size (PS)

 Dissolution rate & Bioavailability.

 Production of formulated medicines as solid dosage forms.
 Formulation & Suspension Stability.
 Flow & Packing Properties.
 Grittiness of Solid Particles in Topical Semi-solids.
 Equipment Validation e.g. Particle retention by HEPA filters.
 Chemical reactivity of certain chemicals.

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 All the novel drug delivery systems like nanoparticles etc. Aerosol
formulation.
 During analysis of formulation on HPLC column.

1. Particle Sizing by Laser Diffraction

Laser diffraction has become one of the most commonly used particle
sizing methods, especially for particles in the range of 0.5 to 1000
microns. It works on the principle that when a beam of light (a laser) is
scattered by a group of particles, the angle of light scattering is
inversely proportional to particle size (ie. the smaller the particle size,
the larger the angle of light scattering). It is also a very fast, reliable
and reproducible technique and can measure over a very wide size
range.

Other Methods

There are many other methods for analysing particle size, other than
laser diffraction. Sieving is one of the oldest particle sizing methods
and is still widely used for relatively large particles (ie. > 1mm). When
measuring very small particles (i.e. < 0.5um), Dynamic Light Scattering
is by far the easiest methods to use. And if you need to measure
morphological properties of particles, (ie. shape as well as size), then
image analysis methods are the only way to gain the extra information.

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Light scattering is the alteration of direction and intensity of a light

beam that strikes an object, the alteration being due to the combined
effects of reflection, refraction, and diffraction.

Scattering = reflection+ refraction + diffraction

The amplitude of scattered light at different angles (the scattering

pattern) depends not only on concentration and particle size, but also
on the ratio of the refractive indices of the particles to the medium in
which the particle exists.

 Reflection - light bounce back from a surface.

 Refraction - light bent towards normal while passing through the
media having different refractive index.
 Diffraction - It is the bending of a wave around objects or the
spreading after passing through a gap .
 Scattering - Alteration of the direction and intensity of the
light beam that strikes an object.
 Scattering = reflection + refraction + diffraction.

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By laser diffraction analysis it is possible to measure particles sizes

between 0.5 and 3000 μm. The sample is dispersed in either air or a
suitable liquid media. The laser passes through the dispersion media
and is diffracted by the particles. The sample is dispersed well and it
is ensured that the particles pass the laser beam in a homogeneous
stream. When particles are exposed to a collima
collimated
ted beam of light a
diffraction pattern is produced. The laser beam consists of two light
sources (He-Ne)
Ne) having different wavelength.

The blue laser is used for measuring the small particles, while the red
detects the larger particles. The diffraction pat
pattern
tern is measured by
detectors, and the signal is then transformed to a particle size
distribution based on an optical model.

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2. Dynamic light scattering (DLS)

Dynamic light scattering (DLS), sometimes referred to as Quasi Elastic

Light Scattering (QELS), is a non-invasive, well-established technique
for measuring the size and size distribution of molecules and particles
typically in the submicron region, and with the latest technology, lower
than 1nm. Typical applications of dynamic light scattering are the
characterization of particles, emulsions or molecules which have been
dispersed or dissolved in a liquid.

It is based on the Brownian motion of dispersed particles. When

particles are dispersed in a liquid they move randomly in all directions.
The principle of Brownian motion is that particles are constantly
colliding with solvent molecules. These collisions cause a certain amount
of energy to be transferred, which induces particle movement. The
energy transfer is more or less constant and therefore has a greater
effect on smaller particles.

As a result, smaller particles are moving at higher speeds than larger

particles. If you know all other parameters which have an influence on
particle movement, you can determine the hydrodynamic diameter by
measuring the speed of the particles.

The relation between the speed of the particles and the particle size is
given by the Stokes-Einstein equation (Equation 1). The speed of the
particles is given by the translational diffusion coefficient D. Further,
the equation includes the viscosity of the dispersant and the
temperature because both parameters directly influence particle
movement.

A basic requirement for the Stokes-Einstein equation is that the

movement of the particles needs to be solely based on Brownian motion.
If there is sedimentation, there is no random movement, which would

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lead to inaccurate results. Therefore, the onset of sedimentation

indicates the upper size limit for DLS measurements.

Particles with a large physical dimension (radius) diffuse more slowly

through a solvent, while small particles diffuse more quickly. Intensity
fluctuations seen through time are therefore slower for large particle.

In contrast, the lower size limit is defined by the signal-to-noise ratio.

Small particles do not scatter much light, which leads to an insufficient
measurement signal.

Equation: The Stokes-Einstein equation

D=KT/6πη RH

 D = Translational diffusion coefficient [m2/

 K = Boltzmann constant [m2kg/Ks2]
 T = Temperature [K]
 H = Viscosity [Pa.s]
 RH = Hydrodynamic radius [m]

The basic DLS setup

A single frequency laser is directed to the sample contained in a

cuvette. If there are particles in the sample, the incident laser light
gets scattered in all directions. The scattered light is detected at a
certain angle over time and this signal is used to determine the
diffusion coefficient and the particle size by the Stokes-Einstein
equation.

The sample is contained in a cuvette. The scattered light of the

incident laser can be detected at different angles. The incident laser
light is usually attenuated by a gray filter which is placed between the
laser and the cuvette. The filter settings are either automatically
adjusted by the instrument or can be set manually by the user. When

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turbid samples are measured the detector would not be able to process
the amount of photons. Therefore, the laser light is attenuated to
receive a sufficient but process able signal at the detector.

Modern DLS instruments include two, or in the case of Litesizer TM 500

three, detection angles for particle size measurements. Depending on
the turbidity of the sample, side scattering (90°) or back scattering
(175°) is more suitable. A forward angle (15°) can be used to monitor
aggregation.

Advantages

 Wide range
 Advanced analyzer measure from 30nm to 3mm
 Very fast
 Easy to use
 Flexible sample handles
 Some are highly automated with self guided software.

Limitations

 High concentration can cause multiple scattering.

 Air bubbles in the dispersion medium diffract light.
 If the refractive index of the sample and of the dispersion media
is the same, the laser beam cannot be diffracted.

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Excipients Compatibility
Excipients compatibility studies are crucial in pharmaceutical
formulation development, assessing the interaction between active
drug substances and inert excipients. These studies ensure the safe
and effective integration of excipients, aiming to optimize the
stability, bioavailability, and overall quality of the final drug product.

Physical compatibility studies examine changes in color, taste, and

appearance, while chemical compatibility studies delve into molecular
interactions to prevent degradation or impurity formation. Thermal
compatibility studies assess responses to temperature variations, and
mechanical compatibility studies scrutinize the impact of mechanical
stress.

Various analytical techniques, such as Fourier Transform Infrared

Spectroscopy (FTIR) and Differential Scanning Calorimetry (DSC),
provide insights into these interactions. Considerations include pH,
moisture, and temperature sensitivity, ensuring the selected excipients
do not compromise drug stability. Regulatory agencies mandate the
documentation of these studies in the drug development process.

Mitigation strategies involve adjusting formulations or using protective

coatings if incompatibilities arise. Excipients compatibility studies are
integral for formulating pharmaceuticals that meet stringent quality
standards, ensuring the efficacy, safety, and regulatory approval of
the final product.

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Flow Property of Powder

Powder flow properties can be affected by change in particle size,
shape & density.

The flow properties depends upon following-

1. Force of friction.
2. Cohesion between one particle to another.

Fine particle posses poor flow by filling void spaces between larger
particles causing packing & densification of particles.

By using glident we can alter the flow properties. e.g. Talc

Determination of Powder Flow Properties

 By determining Angle of Repose.

 A greater angle of repose indicates poor flow.

It should be less than 30°. & can be determined by following equation.

tan θ = h/r.

Where, θ - angle of repose, H - height of pile, R - radius.

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Methods to determine angle of repose

 Static angle of repose

 Fixed-funnel method
 Fixed-cone
cone method
 Kinetic or dynamic method
 Rotating cylinder method
 Tilting box method

Determination of Powder Flow Properties

 Measurement of free flowing powder by compressibility..

 Also known as Carr's index.

Carr's Index(%) = (Tapped Density – Poured Density) /Tapped

Density X 100

 It is simple, fast & popular method of predicting powder flow

characteristics.

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Determination of Powder Flow Properties

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Format and Content of Reports of

Preformulation
The format and content of Preformulation reports can vary depending
on the specific requirements of the pharmaceutical development
process and the regulatory guidelines. However, a typical
Preformulation report should cover essential aspects related to the
physical and chemical properties of the drug substance. B

Below is a general outline that you might consider when preparing a

Preformulation report:

1. Title Page:

 Title of the Report

 Date
 Names and affiliations of the authors

2. Executive Summary:

 Brief overview of the preformulation study

 Key findings and recommendations

3. Introduction:

 Background information on the drug substance

 Purpose and objectives of the preformulation study

4. Materials and Methods:

 Description of the drug substance, including source, purity, and

characterization
 Overview of the experimental methods and techniques used in the
study (e.g., spectroscopy, thermal analysis, dissolution studies)

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5. Physical Characterization:

a. Powder Properties:
 Particle size distribution
 Bulk and tapped density
 Flow properties
b. Solid-State Characterization:
 Crystalline or amorphous nature
 Polymorphism studies
 Melting point and thermal behavior (DSC, TGA)
 X-ray diffraction (XRD) analysis

6. Chemical Characterization:

1. Chemical Structure:
 Molecular formula
 Structural formula
 Isomeric purity
2. Chemical Stability:
 Identification of potential degradation pathways
 Stress testing under different conditions (acidic, basic,
oxidative, photolytic)

7. Solubility Studies:

 Solubility in various solvents

 pH-dependent solubility
 Impact of co-solvents on solubility

8. Partition Coefficient

 Determination of partition coefficient (log P or log D)

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9. Stability in Solution:

 Solution stability under different storage conditions

 Identification of any degradation products

10. Compatibility Studies:

 Interaction with common excipients

 Assessment of physical and chemical compatibility

11. Dissolution Studies:

 In vitro dissolution profiles

 Influence of pH and media on drug release

12. Conclusion:

 Summary of key findings

 Implications for formulation development
 Recommendations for further studies

13. References:

 Citations of relevant literature and sources

14. Appendix:

 Additional data or detailed experimental procedures if necessary

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Preformulation Stability Studies (ICH)

According to ICH (International Conference on Harmonisation) Q1A
(R2) regulatory guidelines, the purpose of these guidelines is to test
drug substances under different stress conditions such as long-term
stability testing, accelerated stability testing for a minimum three
different time points, and sometimes the intermediate testing also
done for some special cases. These stability testing depend upon the
climatic zones where the testing is to be done and follow the criteria
of that particular zone.

The testing includes the effect of pH temperature, humidity, and

photolysis under stress conditions. Stability studies during the
Preformulation stage are most important to check chemical stability
and product degradation for the solid-state and liquid-state
formulations.

Furthermore, some drugs which are prone to degradation produce toxic

substances hence it is important to determine the conditions under
which this drug degradation happens. This degradation pattern of the
drug substance can suggest a way to mitigate or stabilise or to
determine the optimum storage, climatic and shelf-life improvement
conditions.

The physical observation at product development to check, caking,

liquefaction, discoloration, odour, and gel formation. After physical
observation, degradation can be identified by mass spectroscopy, HPLC
or DSC, NMR, FTIR or other relevant sophisticated analytical
techniques.

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Photo stability

The photo stability standard conditions are well mentioned in ICH-Q1B

guidelines. The photo stability of drug substances and drug products
must be understood to specify handling, packaging, labelling, adverse
effects analysis, and to consider innovative formulation strategies. The
optimum exposure for simulation during drug manufacture is casually
1.2 million lux as per the European Federation of Pharmaceutical
Industries Expert Working Group. Further, during drug/API
manufacture, the cumulative exposure of the compounds can be
accepted as 100 Klux of visible light without UV exposure, however,
the ICH guideline is not applicable here and this data may be helpful
for internal audits.

Solution State Stability Studies

Compared to solid-state reactions, liquid-state reactions are simpler to

spot. The methodologies for detecting unidentified liquid
incompatibilities are the same as for solid dosage forms. For
suspensions and solutions formulations of bulk drugs, the investigations
include listed conditions and they must be evaluated as per FDA
stability guidelines, these conditions are higher nitrogen and oxygen
environment, alkaline/acidic pH conditions, and the existence of
chelating agents and stabilisers.

The results of stability studies can help guide stabilisation strategies,

giving feedback to the chemistry team on how to modify labile groups
to improve stability, assisting researchers in determining the
compound’s developability, and providing instructions on how to handle
and store compounds.

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Unit 2 - Formulation Development of Solid

Dosage Forms - I
Formulation development of solid dosage forms involves a systematic
and interdisciplinary approach to create pharmaceutical products that
are safe, effective, and stable. This process encompasses the selection
of new materials, understanding excipient science, evaluation of
functional properties of excipients, and the use of co-processed
materials. Diluents, disintegrants, super disintegrants, and other
excipients play critical roles in the formulation of solid dosage forms.

New Materials in Formulation Development

In recent years, the pharmaceutical industry has seen the introduction

of new materials that enhance drug delivery and performance. For
example, nanomaterials and lipid-based formulations have gained
prominence due to their potential in improving bioavailability and
reducing side effects. Lipid-based formulations, such as solid lipid
nanoparticles (SLNs) or nanostructured lipid carriers (NLCs), can
enhance the solubility of poorly water-soluble drugs, leading to
improved absorption.

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Diluents
In addition to the active or therapeutic ingredients, tablets contain a
number of inert materials. The latter are known as additives or
excipients. They may be classified according to the part they play in
the dosage form. They are binders, diluents, disintegrants, lubricants,
sorbents, coating agents, preservatives, colours, flavours and
sweeteners.

Diluents are the fillers used to increase the bulk content in the dosage
form this is done in a situation where the active constituent to be
incorporated in the formulation is of less quantity.

Purpose of Selection

 To enhance bulkiness
 To provide improved cohesion
 To enhance flow
 To allow direct compression manufacturing

Ideal Properties of Diluents

 They must be non toxic

 They must be commercially available in acceptable grade
 There cost must be low
 They must be physiologically inert
 They must be physically & chemically stable
 They must be free from all microbial contamination
 They do not alter the bioavailability of drug
 They must be color compatible.

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Classification:-

Diluents are classified into 3 types.

 Based on natural source

 Based on chemical nature
 Based on solubility

Classification of Diluents

A. Based On Source

1. Sugars
 Dextrose, Lactose, Sorbitol, Mannitol, Sucrose.
2. Polysachcharides
 Starch, Micro crystalline cellulose, Modified-starch.

B) Based on Chemical Nature

1. Organic Materials
 Dextrose, lactose, mannitol, sorbitol, starch, sucrose.
2. Inorganic Materials
 Dibasic calcium phosphate,
 Tribasic calcium phosphate,
 Calcium carbonate,

C) Based On Solubility

1. Soluble Diluents
 Dextrose, lactose,
 Mannitol, Sorbitol, Sucrose.
2. Insoluble Diluents
 Starch, Dibasic calcium phosphate, Tribasic calcium phosphate,
Calcium carbonate,

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1. Starch

Starch may be obtained from corn, wheat or potatoes. It is

occasionally used as a tablet diluents.

USP grade of starch is usually possesses poor compression and flow

ability moisture content between 11 to 14%.

Specially dried types of starch that have a standard moisture level of

2-4% are available, but are costly.

Directly Compressible Starches

Sta-Rx 1500

 Free flowing, directly compressible starch

 If drug content lies between 5-10%, it require other lubricating
agent.

Emdex and cellutab - due to sweet taste and cool feeling,used in place
of mannitol.

2. Dextrose (D-Glucose)

 Available in two forms: as hydrates and anhydrous forms.

 Dextrose turns brown in the presence of alkaline compounds and
undergo reaction with amines, lactose and sucrose resulting in its
discoloration.
 Available under brand name - CERELOSE

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3. Lactose (Milk Sugar)

 Lactose is the most widely used diluent for tablet formulation.

 It is obtained in hydrous and anhydrous form. The anhydrous form
picks up moisture when exposed to elevated humidity. Such tablets
should be packed in moisture proof packets or containers.
 When a wet granulation method is employed, the hydrous form of
lactose should generally be used.

3 grades of lactose are commercially available:

i. 60 to 80 mesh - coarse

ii. 80 to 100 mesh - regular grade

iii. 200 to 450 mesh - impalpable

 Lactose is a reducing sugar and undergoes Maillard reaction.

 Available in different forms: hydrous lactose, unhydrous lactose,
spray dried lactose and fast flo lactose.
 Brand names: Pharmatose, Respitose, Tabbletose.

4. Mannitol

 It is an odourless, white, crystalline powder with slight sweet

taste. It dissolves slowly and imparts a cool sensation in the
mouth due to its negative heat of solution, hence used in
chewable tablet diluent.
 Mannitol being inert and non-hygroscopic is used in vitamin
formulations which are moisture sensitive.
 Formulations containing mannitol require large amount of
lubricants due to its less flowability.
 Available under brand name : MANNOGEN 2080.

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5. Sorbitol

 It is white, granular powder which is water soluble. Sorbitol and

mannitol are optical isomers. Sorbitol when used in co
combination
mbination with
mannitol reduces the cost of diluent.
 Available brand names: NEOSORB 60, SORBOGEN AND SORBIDEX
P.

6. Sucrose

 It is a white odourless, sweet tasting substance available in

different particle sizes like granular, fine granular, fine, super fine
fi
and confectioners’ sugar. Confectioner sugar with 3% corn starch is
used for wet granulation to avoid caking of tablets.
 Sucrose is hygroscopic, soluble in water and alcohol, it has good
compactibility and stability. Tablets containing sucrose possess long
disintegration time.
 Brand names of sucrose based diluents
diluents.

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7. Microcrystalline Cellulose (MCC)

 It is white odourless, tasteless inert crystalline powder with good

flowability and contains porous microfibres of cellulose. As length of
cellulose polymer increases, the tensile strength of the tablet also
increases.
 It is used in both direct compression and wet granulation methods
of tabletting.
 When used in wet granulation MCC promotes faster and uniform
distribution of granulating agent.
 Available brand names: AVICEL PH, VIVACEL.

8. Dibasic Calcium Phosphate

 It consists of small micro crystals of (dibasic) calcium phosphate in

the form of free flowing aggregates. It is a fine white powder,
insoluble in water.
 Directly compressible dibasic calcium phosphate occurs in dihydrate
form, and loses its water of hydration at temperature above 60
degree Celsius. It does not require lubricants.
 Available brand names : DITAB

9. Tribasic Calcium Phosphate

It has properties similar to dibasic calcium phosphate. It is a fine,

white powder, insoluble in water, slightly alkaline in nature and non-
hygroscopic. It is less used in wet granulation.

It should not be used with:

 Salts of strong acids,

 Acetate salts,
 Palmitate or acetate esters of vitamin E or vitamin A.
 Available brand names: TRITAB

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10. Calcium Carbonate

 It is dense, fine white powder which is usually insoluble whose

solubility depends on pH.
 It is obtained from grounded oyster shells and mined limestone.
 It is directly compressible diluent which exert significant
pharmacological action as an antacid and also as nutritional
supplement.

Advantages

 Provide mechanical strength to the tablet.

 Non-toxicity.
 Enhance compression and bulkiness.
 Good Organoleptic properties.

Disadvantages

 Some large amount of diluents causes hardness of tablet.

 Forms caking of tablet.
 It should not be used with salts of strong acids and acetate salts.

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Disintegrants
Disintegrants induce breakup of dosage form when it comes in contact
with aqueous fluid in the GIT and this process of desegregation of
constituent particles occurs, before the drug dissolution is known as
disintegration process and excipients which induce this process are
known as disintegrants.

Purpose of Selection - The objectives behind addition of

disintegrants are to increase surface area of the tablet fragments and
to overcome cohesive forces that keep particles together in a tablet.

Ideal Properties - The ideal properties of disintegrants include, good

hydration, poor solubility and poor gel formation capacity.

Classification of Disintegrants

1. Starch and Celluse Based Excipient - Starch, Pregelatinisied

starch, Microcrystalline cellulose,
2. Some Clays - Veegum Hv, Bentonite.
3. Some Gums - Agar, Guar Gum, Tragacanth, Alginates.
4. Some Resins - Polacrilin Potassium
5. Finely Divided Solids - Colloidal Silicon Dioxide, Magnesium
aluminum silicate.

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1. Starch

 Starch was the first disintegrating agent widely used in tablet

manufacturing, among which potato, maize and corn starches are the
most common types used.
 The typical concentration range of starch is 5-20% of tablet weight.
Cost is very low.

2. Pregelatinised Starch (STA-1500)

 Pregelatinized starch is widely used and produced by the

hydrolyzing and rupturing of the starch grain. It is a directly
compressible disintegrants and its optimum concentration is 10%.
 The main mechanism of action of Pregelatinized starch is through
swelling.

3. Microcrystalline Cellulose (AVICEL)

 Like pregelatinized starch, microcrystalline cellulose is widely

used in formulations because of its excellent flow and binding
properties.
 It is also an effective tablet disintegrant when used in a
concentration of between 10-20%.

4. Alginates

 Alginates are alginic acid and salts of alginic acid. Alginic acid is
insoluble in water, slightly acidic in reaction. Hence, it should be
used in only acidic or neutral granulation. It can be successfully
used with ascorbic acid, multivitamin formulations and acid salts
of organic bases.
 Alginic acid at a concentration of between 5-10% is an effective,
but very expensive disintegrant.

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5. Ion-Exchange Resin (Amberlite 88)

 It has disintegrant properties at a concentration of between 1-

5%. But this type of disintegrant is rarely used.
 It has highest water uptake capacity than other disintegrating
agents like starch. It has tendency to adsorb certain drugs.

Advantages

 Faster therapeutic effect

 They have good compressability and flow property with poor gel
formation.
 Used in oral disintegrating dosage forms and mouth dissolving
tablets.

Disadvantages

 Some are more hygroscopic in nature.

 Some are anionic and may cause in - vitro binding.

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Superdisintegrants
Superdisintegrants are those substances, which facilitate the faster
disintegration with smaller quantity in contrast to disintegrants.

The disintegration of dosage forms are depends upon various physical

factors of disintegrants/Superdisintegrants which are as follow:

1. Percentage of disintegrants present in the formulation

2. Proportion of disintegrants used
3. Compatibility with other excipients.
4. Presence of surfactant.
5. Hardness of the tablets.
6. Nature of Drug substances
7. Mixing and types of addition.

Selection of Superdisintegrants

Since Superdisintegrants is used as an excipient in the tablet

formulation; it has to meet certain criteria other than its swelling
properties. The requirement placed on the tablet disintegrant should
be clearly defined.

The disintegrant should have -

1. Poor solubility.
2. Poor gel formation.
3. Good hydration capacity.
4. Good moulding and flow properties.
5. No tendency to form complexes with the drugs.
6. Good mouth feel.

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Advantages of Superdisintegrants

1. Remarkable tendency on wetting causing rapid disintegration.

2. No lump formation on disintegration.
3. Compatible with commonly used therapeutic agents and
excipients.
4. Does not stick to the punches and dyes.
5. Effective in lower concentrations.
6. Less effect on compressibility and flow ability.
7. More effective intragranularly.
8. Some are anionic and may cause some slight in vitro binding with
cationic drugs.
9. Biodegradable.

Disadvantages of Superdisintegrants

1. Expensive.
2. Time consuming and fragile.
3. More sensitive and hygroscopic in nature

Ideal Properties of Superdisintegrants

1. It should produce rapid disintegration.

2. It should produce good moulding and flow property.
3. It should have good particle size, good hydration capacity and
compressibility index.
4. It should produce compactable less friable tablets.
5. Effective at very low concentration and should have greater
disintegrating efficiency.
6. Nontoxic and should have good mouth feel.
7. It should have no tendency to form complexes with the drugs.
8. It should be compatible with the other excipients and should have
desirable tableting properties.

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Types of Superdisintegrants

1. Natural Superdisintegrants
a. Xanthan Gum
b. Gellan Gum
c. Mango Peel Pectin
2. Synthetic Superdisintegrants
a. Cross-linked Polyvinyl Pyrrolidine
b. Alginates

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Evaluation of Excipients
1. Thermal Analysis
a. DSC, DTA, DTG & Isothermal calorimetry
2. Chromatography
 HPLC, TLC

3. IR, XRD

4. LC-MS/MS,NMR

1. Differential Scanning Colorimetry:-

It is used to-

 Identifying unknown polymer.

 Monitoring effects of aging.
 Determining phase separation ( polymer blend, copolymer)
 Estimating % crystallinity
 Measuring Heat capacity
 Determining Thermal stability(oxidation induction time)
 Determining effects of additives(blends, fillers, plasticizers)
 Comparing quality(failure analysis, new material evaluation)
 Determining best processing temperatures(cure, injection
molding, extrusion, heat welding)
 Heat of Fusion
 Glass transition temperature

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Principle Used in DSC:-

-

Differential scanning colorimetry or DSC is a thermo-analytical

thermo
technique in which the difference in the amount of heat required to
increase the temperature of a sample and reference is measured as a
function of temperature. Both the sample and reference are
maintained at nearly the same temperature throughout the experiment.

The sample and a reference substance, which does not undergo a

thermal transition in the temperature range of interest, are placed in 2
small metal containers and heated by individual electric heaters.

The temperature of both samples, are monitored by thermocouples, is

then
hen gradually raised in such a manner that the temperature of sample
and reference remain the same.

In this way, transition temperatures can be very accurately measured

by monitoring the electric current going to the heaters.

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2. Differential Thermal Ana

Analysis

Principle

 Monitoring of the temperature difference between a sample and an

inert reference as the heat is applied to the system.
 Endothermic and Exothermic changes in the sample lead to
characteristic deviations in temperature, which can be used for
qualitative and quantitative analyses.

Instrumentation

Apparatus for DTA consists of:

 Sample and reference holder

 A furnace
 A detector
 An amplifier
 A recorder

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Factors affecting result in DTA

1. Sample weight
2. Heating rate
3. Particle size
4. Atmospheric condition

Applications of DTA

 Qualitative and Quantitative estimation of minerals.

 Analysis of biological material (e.g., assay and thermal stability
testing of tetanus toxoid).
 Also used for the thermal stability studies of inorganic compounds
and complexes (e.g., zeolites).
 To determine melting point, boiling point and decomposition
temperature of organic compounds.

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3. High Performance Liquid chromatography

The acronym HPLC stands for High Performance Liquid

Chromatography. “Chromatography” is a separation technique,
“chromatogram” is the chromatography result, and “chromatograph” is
the chromatography apparatus. HPLC is a technique for disjointing,
determinating, and quantifying each component in a mixture.

Principle of HPLC

 A separation column separates the stationary and mobile phases

during purification.
 In a separation column, the stationary phase is a granular substance
with very small porous particles.
 The mobile phase is a solvent or solvent combination that is pushed
through the separation column under high pressure.
 The sample is loaded into the mobile flow regime from the pump to
the separation column using a syringe through a valve with a linked
sample loop, i.e. a tiny tube or capillary made of stainless steel.
 A chromatogram is generated in the HPLC software at the
conclusion of this operation/run.
 The chromatogram allows the various compounds to be identified
and quantified.
 As a result, owing to interactions with the stationary phase, the
constituent components of a mixture migrate through the column at
different speeds.
 Individual compounds are identified by an appropriate detector
after exiting the column and transmitted as a signal to the
computer’s HPLC software.

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Types of HPLC

1. Normal Phase - This method separates analyses b

based
ased on their
extreme nature. A liquid stationary stage and a non
non-polar
polar portable
stage are used in NP-HPLC.
HPLC. As a result, polar specimens are kept on
the polar surface of the column pressing for longer than less polar
ones.

2. Reverse Phase - The stationary stage is hydrophobic, whereas the

versatile stage is a polar liquid, such as water
water-methanol
methanol or acetonitrile
mixes. It is based on the hydrophobic collaboration rule, which states
that the more non-polar
polar the substance, the more it will be retained.

3. Size Exclusion - Molecules migrate into pores in a porous media and

are segregated based on their size in comparison to the pore size.
Large molecules elute first, followed by smaller ones.

4. Ion Exchange - The mobile phase is buffer, and the column packing
comprises
omprises ionic groups. It is used to distinguish between anions and
cations.

Parts of HPLC

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Solvent Reservoir - A glass reservoir holds the mobile stage

ingredient. In HPLC, the flexible stage, or dissolvable, is often a
mixture of polar and non-polar liquid segments where specific fixations
change depending on the specimen arrangement.

Pump - The pump system was developed as a result of the development

of HPLC. The pump is located in the upper stream of the liquid
chromatographic column and pumps eluent into the system from the
solvent reservoir.

Injector - Next to the pump, there is an injector. The easiest way is

to use a syringe to insert the sample into the eluent flow. Sampling
loops are the most extensively utilised injection mechanism.

Column - The separation takes place within the column. Instead of

glass columns, contemporary columns are frequently manufactured in
stainless steel housing. In comparison to calcium carbonate, silica or
polymer gels are commonly utilised as packing materials.

Detector - The separation of analytes takes place inside the column,

and the separation is seen using a detector. When no analyte is
present, the eluent has a constant composition. While the presence of
analyte alters the eluent’s composition. These differences are
measured by the detector. This disparity is measured using an
electrical signal. Different kinds of detectors are available.

Data Collection - Signals from the indicator might be collected via

outline recorders or electronic integrators with varying degrees of
multi-sided fidelity and the ability to analyse, store, and reprocess
chromatographic data. The PC coordinates the identifier’s reaction
with each component and records it in a chromatograph that is simple
to read and understand.

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Uses of HPLC

 Purification of water.
 Impurity detection in the pharmaceutical industry.
 Trace components are pre-concentrated.
 Chromatography based on ligand exchange.
 Protein chromatography via ion exchange.
 Carbohydrate and oligosaccharide anion-exchange chromatography
at high pH.

Applications of HPLC

 Drug evaluation
 Synthetic polymer analysis
 Pollution analysis in environmental analytics
 Drug determination in biological matrices
 Isolation of high-value goods

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4. Thin Layer Chromatography

Thin Layer Chromatography is a technique used to isolate non-volatile

mixtures. The experiment is conducted on a sheet of aluminium foil,
plastic, or glass which is coated with a thin layer of adsorbent material.
The material usually used is aluminium oxide, cellulose, or silica gel.

Thin Layer Chromatography Principle

Like other chromatographic techniques, thin-layer chromatography

(TLC) depends on the separation principle. The separation relies on the
relative affinity of compounds towards both the phases. The
compounds in the mobile phase move over the surface of the stationary
phase. The movement occurs in such a way that the compounds which
have a higher affinity to the stationary phase move slowly while the
other compounds travel fast. Therefore, the separation of the mixture
is attained. On completion of the separation process, the individual
components from the mixture appear as spots at respective levels on
the plates. Their character and nature are identified by suitable
detection techniques.

Thin Layer Chromatography Procedure

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Before starting with the Thin Layer Chromatography Experiment, let

us understand the different components required to conduct the
procedure along with the phases involved.

1. Thin Layer Chromatography Plates – ready-made plates are used

which are chemically inert and stable. The stationary phase is
applied on its surface in the form of a thin layer. The stationary
phase on the plate has a fine particle size and also has a uniform
thickness.
2. Thin Layer Chromatography Chamber – Chamber is used to develop
plates. It is responsible to keep a steady environment inside which
will help in developing spots. Also, it prevents the solvent
evaporation and keeps the entire process dust-free.
3. Thin Layer Chromatography Mobile phase – Mobile phase is the
one that moves and consists of a solvent mixture or a solvent. This
phase should be particulate-free. The higher the quality of purity
the development of spots is better.
4. Thin Layer Chromatography Filter Paper – It has to be placed
inside the chamber. It is moistened in the mobile phase.

Thin Layer Chromatography Applications

 The qualitative testing of Various medicines such as sedatives, local

anaesthetics, anticonvulsant tranquilisers, analgesics, antihistamines,
steroids, hypnotics is done by TLC.
 TLC is extremely useful in Biochemical analysis such as separation or
isolation of biochemical metabolites from its blood plasma, urine,
body fluids, serum, etc.
 Thin layer chromatography can be used to identify natural products
like essential oils or volatile oil, fixed oil, glycosides, waxes,
alkaloids, etc.

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 It is widely used in separating multicomponent pharmaceutical

formulations.
 It is used for the purification of samples and direct comparison is
done between the sample and the authentic sample.
 It is used in the food industry, to separate and identify colours,
sweetening agent, and preservatives
 It is used in the cosmetic industry.
 It is used to study if a reaction is complete.

Disadvantages of Thin Layer Chromatography:

 Thin Layer Chromatography plates do not have longer stationary

phase.
 When compared to other chromatographic techniques the length of
separation is limited.
 The results generated from TLC are difficult to reproduce.
 Since TLC operates as an open system, some factors such as
humidity and temperature can be can affect the final outcome of
the chromatogram.
 The detection limit is high and therefore if you want a lower
detection limit, you cannot use TLC.

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Co-Processed Materials
Co-processed excipients are combination of two or more excipients
designed to physically modify their properties in a manner not
achievable by simple physical mixing and without significant chemical
change..

Advantages

 Single excipient provide multiple function

 Improve flow properties
 Improve Compressibility
 Decrease disintegration time
 Decrease weight variations during tablet manufacturing
 Improve hardness of tablet
 Better mouth feel and improved palatability

Disadvantages

 Time consuming process

 Loss of material during various stages of processing
 Expensive due to factor such as labour, space, time, special
equipment and energy requirement.

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Excipients Selection Criteria in Co-Processing

Selected excipients must be compatible and inert with each other. Co-
processing is generally done by one excipient which is plastic in nature
and another one is brittle in nature. For optimum tableting
performance combination of both excipients are mandatory. It is
reported by the researchers that the co-processing done with a large
amount of brittle excipient and a small amount of plastic excipient.

This particular combination of excipients prevents storage of large

amount of elastic energy during compression, which results in a limited
amount of stress relaxation and reduced tendency of capping and
lamination.

Ex. Cellactose

a. Lactose (75%) -brittle excipient

b. Cellulose-25% -plastic excipient

Step involved in co-processing

1. Preliminary study on excipients to be selected for co-processing in

order to study their characteristics and functionalities.
2. Determine their ratio to be used for co-processing.
3. Study particle size distribution of each excipient to be co-
processed.
4. Out of a available technique, select the most suitable one for co-
processing.

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Methods for Co-Processing

1. Spray Drying

Fluid state (Solution, suspension, Dispersion or emulsion) >>>>>> Dried

powder, agglomerate or granular form

Factor to be considered: physical and chemical characteristics of

individual excipient, design of the equipment used, spray drying inlet
air temperature, atomization air pressure, rate of initial inlet, viscosity
of the fluid, percent of solid present in the feed, rpm of disc.

Ex. of spray-dried co-processed excipient: 30%MCC, 25% lactose, and

45% starcap - added to distiled water - mixing using magnetic stirrer -
homogenous suspension - drying by spray dryer

Set process parameters - Inlet air temperature- 190°C, Feed rate-

4ml/min, Atomization pressure- 2 bar

Result- obtain spherical shape particle improve flowability and

compressibility of poor compreseible drug like Etodolac.

2 .Roller Compaction

In this system uniform powder of the excipients to be co-processed is

compacted between counter rotating rollers to form ribbon of
compacted material that is then processed into granules. Roller
compaction is suitable for co-processing of moisture or high
temperature sensitive excipients because there is no drying.

Ex:- Polyethylene oxide and Hydroxyl Propyl methyl cellulose polymers

were accurately weighed as per specified Ratio (7:3) and mixed for 10
min to form uniform blend. These blends were used for compaction
using roller compactor (Clit roller compactor, India). The obtained
ribbons were screened through 40# and 60# sieve. The obtained fine

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powder was further recycled to get granules of uniform Size. This

granules used for tableting.

Result: co-proceseed excipient have better flowability and

compressibility than their individual or physical mixture.

3. Crystallization

In this method prepare the solution of excipients at the

supersaturated conditions. This means that solution contain more
amount of solute than saturated solution. From the solution crystal are
achieved by different method like:

1. solution cooling,
2. addition of a second solvent to reduce the solubility of the solute
3. Chemical reaction and
4. change in ph.

Then crystal are separated from the solvent by filtration and dry
them.

Ex.:- Direct compacting and tableting sugar Di-Pac is manufacturing

by crystallization method by Domino sugar industry, and contain
sucrose (97%) and maltodextrin (3%).

Result: co-processed material Di-Pac has a direct compacting property,

better flow property, low hygroscopicity and low moisture content
(LOD <1%), it prevent degradation of API. Di-Pac is a readily soluble, it
effect on the solubility of the active ingredients and reduces the need
for disintegrants.

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4. Milling

Milling or dry grinding for the production of co-processed excipients

may be carried out in a roller mill, a ball mill, a bead mill, a millstone
mill, a jet mill, and a hammer mill.

Ex :- Ball milling has been use For co-processing of cross-linked

polyvinylpyrrolidone and calcium silicate. In this particular case, ball
mill was operated for hours at a speed of 200 rpm using 25 stainless
steel balls.

Result: co- processed Excipient of cross-linked polyvinylpyrrolidone

and calcium silicate enhances the rate and extent of dissolution of
poorly soluble drug.

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Methods of Preparation and Evaluation

Methods of Preparation

1. Wet Granulation:

Procedure:

 Weigh the active and inactive ingredients.

 Mix the powders and add a liquid binder (e.g., water or alcohol) to
form wet granules.
 Dry the granules.
 Mill and sieve the dried granules.
 Blend with lubricants and compress into tablets.

2. Dry Granulation:

Procedure:

 Weigh and mix the powders.

 Compact the powder mix into slugs or ribbons using a roller
compactor.
 Mill the slugs or ribbons into granules.
 Blend with lubricants and compress into tablets.

3. Direct Compression:

Procedure:

 Weigh and mix the active and inactive ingredients.

 Blend the powders thoroughly.
 Directly compress the blend into tablets.

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4. Hot Melt Extrusion:

Procedure:

 Weigh and mix the ingredients.

 Heat the mixture to a molten state.
 Extrude the molten mass through a die.
 Mill the extrudate into granules.
 Blend with lubricants and compress into tablets.

5. Tablet Coating:

Procedure:

 Weigh and compress the tablets.

 Apply the coating solution or suspension.
 Dry the tablets.

Method of Evaluation:-

The evaluation of solid dosage forms involves a series of tests to

ensure their quality, performance, and compliance with regulatory
standards. Here are some common methods of evaluation along with
brief procedures for each:

1. Organoleptic Evaluation:

Procedure:

 Visual inspection for color, shape, and size.

 Odor assessment.
 Taste evaluation if applicable.
 Overall assessment of appearance and acceptability.

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2. Physical Testing:

a. Weight Variation:

 Weigh a specified number of tablets individually.

 Calculate the average weight and compare individual weights to
the average.
 Follow Pharmacopeial guidelines for acceptance criteria.

b. Hardness:

 Use a tablet hardness tester to measure the force required to

break the tablet.
 Compare the values with specified acceptance criteria.

c. Friability:

 Weigh a sample of tablets.

 Subject them to tumbling in a friabilator for a specified time.
 Weigh the tablets again and calculate the percentage loss.

d. Thickness and Diameter:

 Use a micrometer or a calibrated caliper to measure the

dimensions.
 Compare the values with specified acceptance criteria.

3. Disintegration Testing:

Procedure:

 Place a tablet or capsule in each tube of the disintegration

apparatus.
 Immerse the tubes in a suitable disintegration medium.
 Observe the time required for disintegration.

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4. Dissolution Testing:

Procedure:

 Use an appropriate dissolution apparatus (e.g., USP Apparatus I

or II).
 Select a dissolution medium as per pharmacopeial requirements.
 Withdraw samples at specified time intervals and analyze for
drug content.
 Compare the dissolution profile with acceptance criteria.

5. Content Uniformity:

Procedure:

 Analyze individual dosage units for the content of the active

ingredient.
 Compare the results with acceptance criteria.

6. Assay:

Procedure:

 Quantitatively extract the active ingredient from the dosage

form.
 Analyze the extract using a validated assay method.
 Compare the results with the labeled content.

7. Stability Testing:

Procedure:

 Store samples under various conditions (e.g., temperature,

humidity).
 Periodically test for physical and chemical changes, potency, and
degradation products.

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8. Microbiological Testing:

Procedure:

 Use appropriate methods to test for microbial contamination.

 Ensure compliance with Pharmacopeial limits.

9. Particle Size Distribution:

Procedure:

 Use methods such as laser diffraction or sieving to determine the

particle size distribution.
 Compare the results with acceptance criteria.

10. Moisture Content:

Procedure:

 Use methods like Karl Fischer titration or loss on drying to

determine moisture content.
 Compare the results with specified limits.

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Unit 3 - Formulation Development of Solid

Dosage Forms - II
Coating Process

In maximum coating methods the solution is being sprayed, a thin film

is formed that adheres directly to every tablet. The coating may be
shaped with the aid of an unmatched application or can be constructed
up in layers through the use of more than one spraying cycles.

Rotating coating pans are regularly used within the pharmaceutical

industry.

Uncoated tablets are located inside the pan and the liquid coating
answer is brought into the pan even as the tablets are tumbling. The
liquid part of the coating is then evaporated by using passing air over
the surface of the tumbling drugs.

In assessment, a fluid bed coater operates via passing air through a

bed of tablets at a velocity sufficient to assist and separate the drugs.

As soon as separated, the drugs are sprayed with the coating

composition. The coating method is normally such as the subsequent
steps:

As soon as separated, the drugs are sprayed with the coating

composition.

The coating method is normally such as the subsequent steps:

a. Batch identification and Recipe selection

b. Loading/Dispensing
c. Warming
d. Spraying
e. Drying

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f. Cooling
g. Unloading

Coating Techniques in Tablet Technology for Product

Development
Generally two methods are used for tablet coating:

1. Sugar Coating
2. Film Coating

1. Sugar coating

Steps in Sugar Coating:

a. 1.Seal coating
b. Sub coating
c. Syrup coating/Smoothing
d. Color coating
e. Polishing

a. Sealing (Waterproofing)

 This involved the application of one or more coats of a water

proofing substance in the form of alcoholic spray, such as
pharmaceutical Shellac or synthetic polymers, such as CAP.
 Sugar-coatings are aqueous formulations which allow water to
penetrate directly into the tablet core and thus potentially
affecting product stability and possibly causing premature tablet
disintegration.

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b. Sub coating - Large quantities of sugar-coatings are usually applied

to the tablet core, typically increasing the tablet weight by 50-100%.

c. Smoothing/syrup coating

 To cover and fill in the imperfections in tablet surface caused by

sub coating.
 To impart desired color.
 The first syrup coat contains some suspended powders and are
called "grossing syrups"
 Dilute colorants can be added to provide tinted base that
facilitates uniform coating in later steps.
 Syrup solutions containing the dye are applied until final size and
color are achieved.

d. Finishing

 Final syrup coating step

 Few clear coats of syrup may be applied.

2. Film Coating

Film coating and sugar coating shares the same equipments and process
parameters.

Two methods-

a. Pan-Pour method

 Same as that of pan-pour sugar coating.

 Method is relatively slow and relies heavily on skill and technique
of operator.
 Aqueous based film coating is not suitable due to localized over-
wetting.

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b. Pan-Spray method

 Use of automated spraying system

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Coating Machine
The equipments used for the tablet coating are ::-

1. Standard coating pan

2. Perforated coating pan
3. Fluidized bed coater

2. Perforated Coating Pan

 In general all the equipment ofthis type consists of a perforated or
partially perforated drum that is rotated on its horizontal axis in an
enclosed housing.
 In the accela-cota
cota and hi
hi-coater
coater system, drying air is directed into
the drum, is passed through the table bed, and is exhausted through
perforation in the drum.
 The driacoater introduce drying air through hollow perforated
per ribs
located on the inside periphery of th
the drum.

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 The glatt coater is the latest perforated pan coater to be

introduced in the industry.
 In all four system, the coating solution is applied to the surface of
the rotating bed of tablet through spraying nozzles that are
positioned inside the drum.

Particle Coating - The rational of particle coating:

 To modify the drug release profile, E.g. enteric coating, sustained

release coating, osmotic pumps, etc.
 Improve appearance
 Facilitate identification
 Facilitate swallowin
 Mask taste and odor
 Protect the core from external environmental factor like 0 2,
humidity, light etc.
 Obtain easier product handling

The coated tablet is packed on a high-speed packaging unit. The

coating reduces friction and increases the production rate.

Types of particle coating:

1. Wet Particle Coating

 fluidized bed coating technique
 Spray drying
 Aqueous phase separation
 Non-Aqueous phase separation
 Interfacial polymerization
 Interfacial polymerization
 Matrix polymerization

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2. Dry Particle Coating

 Hot melt coating

 Supercritical fluid coating
 Vapor coating of powders
 Rotating (Centrifugal) fluidized bed granulator/coater
 Magnetically assisted impaction coating (MAIC, pronounced
"mace")
 Hybridizer
 Mechanofusion
 Theta Composer

Wet coating particle technology

 At present, the commercially used technology for coating solid

dosage forms is the liquid coating technologies which incorporate
any kind of solvent in coating.
 Generally, a mixture of polymers, pigments and excipients is
dissolved in an appropriate organic solvent (for water insoluble
polymers) or water (water soluble polymers) to form a solution, or
dispersed in water to form dispersion, and sprayed onto the dosage
forms and dried by continuously providing heat until a dry and
smooth film coating film is formed.
 A typical liquid coating process is carried out in a rotary pan coater
for larger size solid dosages such as tablets, or in a fluidized bed
coater for smaller size dosage forms such as pellets, pills, granules
etc.

Dry particle coating technology

 Dry particle coating is used to create new-generation materials by

combining different powders having different physical and chemical

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properties to form composites, which show new functionality or

improve the characteristics of known materials.
 Materials with relatively large particle size (1–200 μm) form a core
and these core (host) particles are mechanically coated with fine
submicron (guest) particles; no liquid of any kind (solvents, binders
or water) is required.
 Dry particle coating involves mechanically fixing fine particles
(guests) onto the surface of relatively larger particles (hosts) to be
evaporated.

Advantages (Dry particle coating)

 To coat particles without using of organic solvent or water

dispersion.
 Compared to solvent and water based coating, the dry coating
method is favorable regarding environmental friendliness, safety
and cost.
 It might be a very suitable coating method in order to coat foods
and drugs which are sensitive to organic solvents or water.
 During the traditional coating process based on organic solvent, the
solvent needs to be recovered due to environmental pollution.
 Coating processes with aqueous dispersions are time and energy
consuming caused by the low concentration of coating polymer and
large amounts of water which need to be evaporated

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3. Fluidized Bed Coating

Fluidized bed coating techniques
echniques (Vacuum film coating)
coating):

A fluidized bed is a bed of solid partic

particles
les with a stream of air or gas
passing upward through the particles at a rate great enough to set
them in motion.

As the air travels through the particle bed, it imparts unique

properties to the bed. For exampl
example,
e, the bed behaves as a liquid.

The fluid bed can be used to dry the wet product, agglomerate
particles, improve flow properties, or produce coated particles for
controlled release or taste masking.

However, the conventional fluidized bed cannot be used for handling

fine particles (less than 40 microns) due to their poor fluidization.

Coating and granulation of fine parti

particles
cles (15 micron cornstarch and
an 12
micron aluminum) are performed using the Mini Glatt Fluidized Bed.

The fluidized bed process can be used with both thermoset and
thermoplastic powder coatings.

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I. Top spray coating

 Despite the fact that the top spray fluid mattress system is
extensively used for granulation its use for coating is restrained.
 Top spraying is the most effective method and gives the best
capability and lowest capital cost.
 It could be used for numerous manipulations of taste covering and
many others. This method alternative is often used in the food, feed
and chemical industries as the characteristic of the film mainly
serves to enhance the general managing situations.
 An ideal film is typically no longer required for this function,
however care should be taken that the droplets do not emerge as
too viscous before touching the substrate, so that you can hold
accurate spread ability.

II. Bottom spray coating (Air suspension process)

 The maximum normally recognized fluid-bed system for coating

inside the pharmaceutical industry is bottom-spray technique.
 The precise functions of bottom-spraying are an air distributes
plate and a partition that arrange fluidization of particles of debris
via the partition.
 The nozzle is installed at the bottom of the product box and is
focused in the coating zone.
 The quick distance between the coating materials and particles at
some point of the coating technique minimizes spray drying and
contributes to excessive uniformity and coating performance may be
seen in Figure 9 represents bottom spray coating process

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III. Tangential spray coating (Rotor pellet coating)

This processing approach is with its physical concepts pretty much like
bottom-spray coating handiest that the production motion is supplied
by a motor driven rotor disc.

Otherwise, the quality producing parameters are the same:

1. Uniform statistical residence time is warranted by defined rotor

revolution speed.
2. The coating material is sprayed simultaneously within the rotating
product.
3. The rolling movement of the particles affords an even higher
separation force, as such preventing agglomeration.
4. The benefits of this processing option are mainly for the layering
and subsequent film coating of pellets in Figure 10 represents spray
coating process.

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In process Control of Tablets

1. Hardness
2. Friability
3. Thickness
4. Disintegration
5. Weight variation
6. Content uniformity
7. Dissolution
8. Leakage testing for strip and blister packaging

1. Hardness (crushing strength)

It is the load required to crush the tablet when placed on its edge.

Why do we measure hardness?

 To determine the need for pressure adjustments on the tableting

machine.
 Hardness can affect the disintegration. So if the tablet is too hard,
it may not disintegrate in the required period of time. And if the
tablet is too soft, it will not withstand the handling during
subsequent processing such as coating or packaging.
 In general, if the tablet hardness is too high, we first check its
disintegration before rejecting the patch. And if the disintegration
is within limit, we accept the patch.
 If H. is high + disintegration is within time, accept the batch

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Factors Affecting the Hardness

 Compression of the tablet and compressive force.

 Amount of binder. (More binder then more hardness)
 Method of granulation in preparing the tablet (wet method gives
more hardness than direct method, Slugging method gives the best
hardness).

Limits:

 5 kilograms minimum and 8 kilograms maximum.

 Make hardness test on 5 tablets and then take the average
hardness

Some of devices used to test tablet hardness are:

1. Monsanto tester
2. Strong-cobb tester
3. Pfizer tester
4. Erwica tester

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2. Friability

 It is the tendency of tablets to powder, chip, or fragment and this

can affect the elegance appearance, consumer acceptance of the
tablet, and also add to tablet's weight variation or content
uniformity problems.
 Friability is a property that is related to the hardness of the tablet.
 An instrument called friabilator is used to evaluate the ability of
the tablet to withstand abrasion in packaging, handling, and shipping.
 Commonly used friabilator in industries is Roche Friabilator

Procedure:

 Weigh 20 tab altogether = W1

 Put these tablets in the friabilator and adjust the instrument at
100 rpm (i.e. = 25 rpm for 4 min)
 Weigh the 20 tablets = W2
 Friability (% loss) = It must be less than or equal to 1%.

3. Disintegration

It is the time required for the tablet to break into particles, the
disintegration test is a measure only of the time required under a given
set of conditions for a group of tablets to disintegrate into particles.

Disintegration Test

 The disintegration USP device uses 6 glass tubes that are 3

inches long open at the top and held against a 10mesh screen at
the bottom end of the basket rack assembly.
 Frequency of basket is 28-32 cycles/min.
 The test is done on 6 tablets and the test is passed when all the
6 tablets disintegrate.

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Liquids used in disintegrati

disintegration

 Water,
 Simulated
imulated gastric fluid (PH = 1.2 HCl),
 Simulated intestinal fluid (PH = 7.5, KH2PO4 (phosphate buffer)
+ pencreatin enzyme +NaOH)

Limits - For Uncoated tablets

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4. Weight Variation

 The volumetric fill of the die cavity determines the weight of the
compressed tablet. The weight of the tablet is the quantity of the
granulation that contains the labeled amount of the therapeutic
ingredient.
 After the tablet machine in operation the weights of the tablets are
routinely checked to ensure that proper tablet weights are made.
•Procedure:
 Take 20 tablets
 Determine the individual weights of each tablets
 Take average weights of 20 tablets
 Compare the individual weight of tablets with avg weight.
 Not more than 2 tablets should deviate from avg weight by percent
deviation and none should deviate more than twice the percentage

Limits according to U.S.P

 Weight of tablet 130 mg or less then % deviation +10%

 Weight of tablet 130-324 mg then %deviation= ±7.5%
 Weight of tablet 324 mg or more then %deviation = ±5%

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5. Content uniformity

This test is done to ensure that every tablet contains the amount of
drug substance intended with little variation within a batch

Procedure

 In this test 30 tablets are randomly selected for the sample and
atleast 10 of them assayed individually .
 9 of the 10 tablets must contain not less than 85% or more than
115 % of labeled drug content.
 10th tablet may not contain less than 75% or more than 125% of
labeled content.
 If this conditions are not meet the tablet remaini
remaining
ng from the 30
must be assayed individually and none may fall outside 85 to 115 %

6. Dissolution Test

1. According to USP
a. Apparatus 1(Rotating basket)
b. Apparatus 2(Rotating paddle)

Dissolution Acceptance Criteria

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Powder Dosage Forms for Internal Use

Preparation of powders

1. Reduction of particle size of all ingredients

2. Sieving.
3. Weighing of each ingredient.
4. Mixing.
5. Packaging.

Mixing Of Powders

 The aim of mixing is to obtain a homogeneous association of several

solid products.
 Factors influencing the mixing of powders- nature of surface,
density, particle size, particle shape, particle charge and proportion
of materials.
 If these factors are not under control, segregation (demixing) can
occur.
 Types of segregation include percolation, trajectory and
densification.

Methods of Powder Mixing

1. Mechanical Mixing
2. Hand Mixing:
a. Spatulation (spatula + tile)
b. Trituration (mortar + pestle)
c. Tumbling (wide mouth closed container)
3. Geometric dilution: Entire quantity of potent drug (x volume) + (x
volume) of the diluents + (2x volume) of the diluents + (4x volume)
of the diluents.........repeated until all the diluents are used.

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Microencapsulation
 Micro-en-capsulation
 Microparticles are small spherical free flowing powders
characteristically of diameter 11-1000 μm (1 mm).
 Microspheres medication is uniformly spread, either dissolved or
suspended.
 Microcapsules heterogeneous particles with a reservoir formed by a
membrane shell around the center.

Definition

 Microencapsulation is described as a process of enclosing micron

sized particles of solids or droplets of liquids or gasses in an inert
shell, which in turn isolates and protects them from the external
environment as well as control the drug release profile.
 Microencapsulated particle is having diameter between 1-1000
1 μm
which differ them from other technologies such as nanotechnology
and macro particle in their morphology and internal structure.
 Microencapsulation may be defined as the process of surrounding or
enveloping one substance within another substance on a very small
scale, yielding capsules ranging from less than one micron to several
hundred microns in size.

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 A substance or Pharmaceutical material is encapsulated over the

surface of solid,, droplet of liquid and dispersion of medium is known
has Microencapsulation.
 It is mean of applying thin coating to small particle of solid or
droplet of liquid & dispersion.

Composition - 2 phases::-

a. Core material
b. Coating material

a. Core Material

 The material to be coated.

 It may be liquid or solid or gas.
 Liquid core may be dissolved or dispersed material.

Composition of core material:

 Drug or active constituent

 Additive like diluents
 Stabilizers

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b. Coating Material

Inert substance which coats on core with desired thickness.

Composition of coating:

 Inert polymer
 Plasticizer
 Coloring agent
 Resins, waxes and lipids
 Release rate enhancers or retardants

The ideal characteristics of coating material are

 Stabilization of core material

 Inert toward active ingredients
 Controlled release under specific conditions
 Pliable,, tasteless, stable and non
non-hygroscopic
 Low viscosity
 Soluble in an aqueous media or solvent
 Should be flexible, brittle, hard, thin etc

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Reasons for Microencapsulation

 To make the formulation sustained or controlled release.

 To mask the taste & odour of bitter drugs.
 A mean of separating incompatible materials.
 The drugs, which are sensitive to oxygen, moisture or light, can
be stabilized by microencapsulation
 For converting liquid into free flowing powders.
 To prevent the gastric irritation of certain drugs.
 Water solubility or dispersability.

Advantages

 Formulation of controlled release and sustained release

formulations.
 Protection of the active agent or core material from environment
 Liquids and gases can be changed in to solids in the form of
microcapsules.
 Surface and colloidal properties of some active agents can be
altered.
 Masking bitter taste. Ex: Ofloxacin
 Conversion of liquid to pseudo solid. Ex: Eprazinone
 Environmental protection. Ex: Vit.A.Palmitate.
 Reduction of Hygroscopicity. Ex: NaCl
 Reduction of vaporization of volatile drugs. • Ex: Methyl salicylate
 Prevention of incompatibilities among drugs. Ex: Aspirin &
Chlorpheniramine maleate

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Disadvantages

 Microencapsulation techniques are of high cost.

 This causes reduction in Shelf life of hygroscopic drugs.
 Different dosage forms like tablets, capsules, lozenges cannot be
encapsulated by single microencapsulation process
 Coating may not be uniform this can effect release pattern of a
drug in the body.
 Possible cross reaction between core and shell material.
 Difficulties to achieve continuous and uniform film.
 Shelf life of Hygroscopicity drugs is reduced.
 More productive costs.
 More skills and knowledge required.
 These sorts of doses should not be fractured or bitten.

Method of Preparation

1. Single Emulsion method,

2. Double Emulsion method,
3. Polymerisation,
4. Phase Separation and Coacervation method
5. Spray Drying and Spray congealing,
6. Wax Coating and Hot melt method,
7. Air Suspension,
8. Solvent Extraction,
9. Precipitation,
10. Freeze Drying

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1. Single emulsion technique

 Prepare aq. Solution/Suspension of polymer

 Dispersion in organic phase oil/chloroform
 Microspheres in organic phase
 Microspheres

2. Double Emulsion Technique

 Aq. Sol of polymer + Drug

 Dispersion in organic phase by homogenization or sonication
 First emulsion (W/O) formed added to aqueous sol. of Polyvinyl
alcohol
 Multiple emulsion (W/O/W) formed added to large aqueous phase
 Separation, Washing, Drying
 Microspheres

3. Polymerization

1. Normal
 Monomer
 Polymerization
 Polymer block
 Mechanical fragmentation
 Microsphere formed

2. Interfacial
 Monomer + Aq. Sol. Of NaOH with surfactant(Dispersion with
vigorous stirring)
 Micellar sol. Of polymer in aq. Solution
 Polymerization
 Separation, Washing and Drying
 Microsphere formed

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4. Phase separation coacervation

Principle: Solubility of polymer is decreased in organic phase to form

polymer rich phase called coacervates.

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5. Spray Drying & Congealing

6. Ion Gelation Method

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Air Suspension
 The air suspension coating process was invented by Professor Dale
E. Wurster while at the Department of Pharmacy, University of
Wisconsin.
 Air suspension apparatus consists of different sections such as
control panel, coating chamber, air distribution plate, nozzle for
applying film coatings.
 Within the coating chamber of air suspension apparatus particles
are suspended on an upward moving air stream.
 In the coating zone, coating material is applied by spraying to the
moving core particles.
 The design and operating parameters of the chamber affect the re-
circulating flow of the core particles through the coating zone.
 The core material receives an increment of coating material, usually
a polymer solution during each pass through the coating zone.
 The cyclic process is repeated until desired coating thickness is
achieved.
 The supporting air stream helps to dry the product during
encapsulation.
 Air suspension techniques are generally applicable only to
encapsulate the solid core materials.
 The rate of drug release from the microcapsules was highly
dependent on the encapsulating materials.

Applications

 Vaccine delivery
 In Gene delivery
 In Oral drug delivery
 Transdermal delivery system
 Using a micro particulate carrier to target

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Formulation Development of Capsules

Capsules consist of two pieces in the form of cylinders closed at one
end. The shorter piece is called the cap. This cap fits over the open
end of longer piece called body. The drug substance is placed in the
body and the caps are slided over it, hence enclosing the drug
substance.

Production Of Capsule Shell

All raw materials required for the production of a capsule shell are
collected and weighed. A solution of gelatin with a concentration of
about 45-60% is prepared by mixing of gelatin in demineralised hot
water at 60-70°C in jacketed pressure vessels. Vacuum can be applied
to remove entrapped air bubbles. Gelatin solution is transferred to
stainless steel feed tanks. Dyes, opacifants, preservatives and any
water needed are added to the gelatin solution.

Finally the viscosity is is adjusted according to required thickness of

the capsule shell.

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Steps in the Production of Capsule Shell

1. Dipping
2. Spinning
3. Drying
4. Stripping
5. Trimming
6. Joining
7. Polishing

1. Dipping - 150 pairs of stainless steel mold pins are dipped in to the
prepared gelatin solution of controlled viscosity to form caps and
bodies simultaneously. This results in the formation of film on the
surface of the mold pins.

2. Spinning: - The mold pins are rotated so as to provide uniform

distribution of gelatin.

3. Drying - The gelatin is dried at the blast of cool air to form the
hard shell. The pins are moved through a series of air drying kilns
which help in removing any water content present.

4. Stripping - A series of bronze jaw strips the cap and body portion
of the capsules from the mold pins.

5. Trimming - the stripped cap and body portion of the capsule are
trimmed to the required length using stationary knives.

6. Joining - After trimming, the cap and body sections are joined and
ejected from the machine.

7. Polishing - is done using Accela cota pans and then rubbed with
clothes.

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The entire cycle of the machine lasts for approximately 45 minutes.

Inspection processes are done finally to remove the imperfect
capsules. Capsules are then ready for sterilization and packaging.
kaging.

Capsule Filling
The hard two piece capsule can be filled with materials that have a
wide range of physical properties.

Types
es of dosage forms for filling into hard capsules:

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Powdered formulations often require excipients such as fillers,

lubricants, and glident, to facilitate their encapsulation. This influences
the rate of release. Addition of wetting agents is needed in case of
hydrophobic drugs.

In case of powders that have a chance to liquefy adsorbents like

colloidal silica, magnesium carbonate must be used.

Capsule Filling Machines

1. Punch Method
2. Hand Operated Capsule Filling Machine
3. Automatic Capsule Filling Machine
4. Semi-Automatic Capsule Filling Machine

1. Hand Operated Capsule Filling Machine

Pharmacists that prepare capsules on a regular or extensive basis may

use hand operated capsule machines. These machines are also called
Feton capsule filling machine.

The machine has the following parts :-

 Capsule bed with 200-300 holes

 Loading tray
 Powder tray
 Pin plate with 200-300pins
 Sealing plate with rubber top
 Lever
 Cam handle

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Working of Hand Operated Capsule Filling Machine

 Tighten the cam handle and placed lever in the position. The machine
is ready for capsule filling.
 Place the empty capsules onto the loading tray with the body end of
the capsules oriented downwards and the cap oriented upwards.
 Placed the filled loading tray over the capsule bed.
 The cam handle is used to lock the body part of the capsules at
their place while of the cap of the capsule is separated.
 Powder tray is placed in position, and the powder is placed on to the
surface. Using a spatula, spread the powder uniformly to fill the
bodies of the capsules. Remove the excess powder.
 The pin plate
te is then lowered to press the filled powder. Again raise
the pin plate.
 Remove the powder tray after filling.
 The cap holding plate is then repositioned over the body.
 The capsules are rejoined then by manual pressure.
 Remove the loading tray and collect the filled capsules.

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2. Semi Automatic Capsule Filling Machine

Semi automatic capsule filling machine are employed when smaller

batches sizes are required. Production ccapacities
apacities can range from 6000-
6000
8000 capsules per hour. Semi automatic capsule filling m machines
achines always
require an operator in attendance at all times of the operation.

 Semi automatic machines use the Auger Filling Principle.

The machine has the following parts:-

1. Capsule fill
2. Stirrer
3. Auger
4. Capsule body holder
5. Turn table
6. Capsule ring
o Peg ring
o Capsule hopper
o Turntables
o Rectifier

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Working of Semi Automatic Capsule Filling Machine

There are 3 stages of how the capsule filling machine works :-

1. Orientation of capsule: - The capsule ring is placed on a turntable

under the Rectifier (they orient the capsule in such a way that the
body part is oriented downwards and cap part is oriented upwards).
Empty capsule shells in the capsule hopper are descended by the
rectifier in to the capsule ring. As the ring rotates on the turntable,
vacuum pulls the capsules bodies in to the lower part of the capsule
ring, leaving the caps behind in the upper ring.
2. Powder filling of capsule :- After capsule separation, the operator
separates the rings of the capsule ring and places the body ring on
another turntable that rotates beneath the foot of the powder
hopper. The auger in the hopper rotates to provide constant
downward flow of the formulation while the filling ring rotates. The
amount of formulation delivered to the capsule bodies depends on
the dwell time of the bodies under the foot of the hopper, i.e., the
speed of rotation of the body ring.
3. Capsule Closing :- Upper and the lower holding ring of the capsule
ring is joined together and positioned in front of the peg ring
holding pins. Pneumatic pressure is applied to the peg ring which
finally pushes the caps and the bodies together inside the holes of
the capsule ring. Filled capsules are then removed from the capsule
ring.

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3. Automatic Capsule Filling Machine

Automatic capsule filling machine are designed and developed to fill

capsules with powders or pellets. It is an extremely durable and
reliable machine that fills dosages to the highest accuracy. It can be
applicable to the widest range of capsules at all sizes.

Automatic filling machines employ pistons, or tamping pins that lightly

compress the powder into slugs, and eject the plugs into the empty
empt
capsule bodies. Automatic machines use the Dosing Disc Principle and
Dosator Principle.

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Working of a Automatic Capsule Filling Machine

Dosing disc Principle

 The dosing disc rotates continuously in a circular manner. The stop

plate closes the holes
es on the dosing plate. The dosing disc rotates
below the powder bed, the material flows into each hole. The pins
which are in the station compress the powder to a controlled depth.
 The process of filling and compression continues till reaching the
last compressing pin, where the machine ejects a compressed
powder through the dosing plate into the capsule.
 This is a continuous process and the production speed will depend on
the preset machine conditions.

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Dosator Principle

Diagram of a dosator or dosing tube system:

a. Compression force platen;

b. piston;
c. dosing tube;
d. powder hopper;
e. plug ejection platen;
f. capsule body in bush; and
g. powder plug

 A dosator machine has two segments: - powder bed on one side

whiles the empty capsule body on the opposite side.
 As the dosing tube goes down, penetrates the powder bed, powder
enters the open end of the dosator.
 A plug is formed inside the dosing tube with a movable piston that
controls the dosing volume and applies a fo
force
rce to form the plug.
 Dosage tube then moves up, takes a 180° rotation, and press powder
plug into the capsule body to complete capsule filling.

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4. Punch Method (Manual Filling)

To hand fill capsules; the pharmacist generally uses the Punch Method.

 Ingredients are triturated an mixed. The powder is placed on a

powder paper or ointment slab and smoothed with a spatula to a
height approximately half the length of the capsule body.
 The body of the capsule is held vertically and the open end is pushed
or punched into the powder until the capsule is filled.
 The capsule is replaced to close the capsule.
 Each filled capsule is weighed after filling. Powder is added and
removed until the correct weight has been placed in the capsule.

All the capsule filling machines have the 4 steps in common.

1. Rectification of the empty capsule shell :- orientation of the

capsule - body oriented downwards and caps oriented upwards.
2. Separation of cap and body of empty capsule shell.
3. Dosing of a fill material:- eg. Auger Principle, Dosing disc Principle,
Dosator fill principle, Punch Principle etc.
4. Replacement of the caps over the body and Ejection of the filled
capsules.

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Capsule Finishing
Filled capsules from the capsule equipment require dusting or polishing
operation before the remaining operations of inspection, bottling, and
labeling are completed.

Dusting or polishing operations vary according to the type of the filling

equipment used, the type of powder used for filling, and the individual
requirements for the finished appearance of the completed capsules.

Capsule Finishing Machines

1. Pan Polishing
2. Brushing
3. Cloth Dusting

1. Pan Polishing - Because of the unique design, especially primary in

the area of airflow, the Accela Cota Tablet Coating Pan is used to dust
and polish capsules. A polyurethane or cheese cloth liner is placed in
the pan, and the liner is used to trap the removed dust as well as
impart a gloss to the capsules.

2. Cloth Dusting - In this method, the filled capsules are rubbed with
a cloth that may or may not be impregnated with an inert oil. This
procedure is a hand operation and gives a shine to the capsules. Also it
results in a positive method for removal of resistant materials.

3. Brushing - In this method, the filled capsules are fed under

rotating soft brushes, which serve to remove the dust from the
capsule shell. This operation must be accomplished by application of
vacuum for dust removal.

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Special Techniques of Formulation of Capsules

1. Decreasing Solubility
2. Formulating Incompatible Materials
3. Filling of Semisolids
4. Filling of Liquids
5. HPMC Capsules
6. Starch Capsules
7. Cross Linked Dextran Capsules

1. Decrease of Solubility

 Solubility is retarded in this technique of formulating a special type

capsule.
 Done in an attempt delay absorption of the active ingredient or to
provide enteric properties.

Solubility is assured in two ways here:-

a. Water resistance - failure to dissolve in water in 15 mints at 20-

30°C.
b. Acid solubility - dissolve in less than 5 mints in 0.5% aq. HCl at 36
-80°C

Two ways of formulating capsules with decreased solubility are :-

a. Formalin treatment :- exposure of the gelatin film to formalin

vapours decrease the solubility of gelatin due to the cross linking
of molecules in gelatin initiated by aldehyde.
b. Coating of the gelatin capsules with coating materials like shellac,
cellulose acetate phthallate etc.

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2. Formulation of Incompatible Materials

Formulation of Incompatible materials is carried out by the use of a

two phase fill in the capsule:

a. One phase - consists of a soft capsule, or smaller hard capsule

or a pill that is filled into the capsule.
b. Other phase - powder fill is added in the usual manner.

Changes should be made to the equipment for the machine operation to

allow the two filling.

3. Filling of Semisolids - Semisolids are melted to allow the filling of

the material in the capsules at ambient temperature.

4. Filling of Liquids

 Liquids in the form of thermosetting or thixotropic mixture are

filled in the capsule.
 Gelatin banding is required for the sealing of the capsules to
prevent leakage.
 Two bands of gelatin solution are applied around the centre of the
filled capsules and this then dried using air ate ambient conditions.

5. HPMC Capsules

 Developed as an alternative to capsules.

 Odourless and flexible, low moisture content, chemically inert,
stable under low moisture conditions.
 HPMC Capsules - manufactured using 18-28% HPMC, carrageenan
(0.01 0,09% w/w) and potassium or calcium ions (0.05-0.6% w/w)
 Carrageenan and potassium or calcium ions are used as co gelling
agents to facilitate the gelling of HPMC.

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6. Cross Linked Dextran Capsules - Capsule shell are prepared by

reacting dextran. Magnesium chloride, glutaraldehyde, and
polyethylene glycol 400 in water.

7. Starch Capsules

 Capsule shell are prepared by starch obtained from potato. •

 Dissolution is independent of pH.
 Usually used for manufacture of enteric coated capsules.

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Quality Control Tests Of Capsule

1. Weight variation test
2. Content uniformity test
3. Disintegration test
4. Dissolution test
5. Moisture permeation test

1. Weight Variation Test

 Weigh 20 capsules individually and find the average weight.

 Individual weights should be within 90% - 110% of the average
weight.
 If this is requirement is not fulfilled, then the weight of
contents of each individual capsule is determined and compared
with the average weight of the contents. The difference between
the individual content weight and average content weight are
determined. The contents of the shell are removed with the help
of a small brush.

The requirements are met,

 If not more than 2 of the individual differences are greater than

10% of the average content weight, or,
 When no capsule content weight is greater than 25%

If more than 2 but less than 6 of the individual differences deviate

from the requirements said before,

 Individual content weight, is determined for another 40 capsules.

 Average of 60 capsules content weight is taken.
 The difference of the individual content weight of the previous 20
capsules and the next 40 capsules are determined from the new
average content weight of 60 capsules.

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For the test to pass:

a. Difference should not exceed 10% of the new average content

weight of 60 capsules for a minimum of 6 capsules.
b. When no capsule content weight is greater than 25%

2. Disintegration Test

 Same apparatus as used in the evaluation of disintegration in

tablets.
 To test the disintegration time, one capsule is placed in each tube of
the basket assembly, and the basket rack is position in a medium at
37°C. Perforated plastic discs are placed on top of the capsules.
 The capsules comply with the test, if all the capsules disintegrate,
and all the particles pass through the mesh screen in the specified
time. If any residue remains, it must have only a soft mass with no
firm core.
 If 1 or 2 fails to disintegrate, the test is repeated with 12
additional tablets.
 According to the IP, hard shell capsules take only a maximum of 30
minutes to disintegrate.

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3. Dissolution Test

 Same apparatus as used in the evaluation of dissolution in tablets.

 To test the dissolution or drug release from the capsule, USP
Apparatus II the rotating paddle type is used mainly.
 As the capsule comes in contact with the aqueous media at 37°C,
capsule shell absorb water and swell.
 The rate of water penetration is inversely proportional to the
thickness of the capsule shell. The shell ruptures at the shoulder of
the cap and the body part.
 Rate of gelatin solubility is dependent on the temperature of the
solution. As the temperature decreases, the solubility of the gelatin
decreases.

4. Moisture Penetration Test

 Degree and rate of moisture penetration is determined by packing

the capsules together. Expose the packaged unit to a known relative
humidity over a specified time.
 The change in initial and final weight is determined.

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Physical Stability
The formulation is totally unchanged throughout its shelf- life and has
not suffered any changes by way of appearance, organoleptic
properties, hardness, brittleness, particle size etc.

It affects:

 Pharmaceutical elegance
 Drug content uniformity
 Drug release rate.

Unprotected soft capsules (i.e., capsules that can breathe) rapidly

reach equilibrium with the atmospheric conditions under which they are
stored.

The variety of materials capsulated, which may have an effect on the

gelatin shell, together with the many gelatin formulations that can be
used, makes it imperative that physical standards are established for
each product.

The physical stability of soft gelatin capsules is associated primarily

with the pick-up or loss of water by the capsule shell.

If these are prevented by proper packaging, the above control capsule

should have satisfactory physical stability at temperature ranging from
just above freezing to as high as 60 C, for the unprotected control
capsule, low humidities (less than 20 % RH), low temperature (less than
2 C) and high temperatures (greater than 38 C) or combinations of
these conditions have only transient effects.

The capsule manufacturers routinely conduct accelerated physical

stability tests on all new capsule products as an integral part of the
product development program.

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The following tests have proved adequate for determining the effect
of the capsule shell content on the gelatin shell.

The tests are strictly relevant to the integrity of the gelatin shell and
should not be confused
used as stability tests for the active ingredients in
the capsule content.

The test conditions for such accelerated physical stability tests are
shown in Table below:

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Packaging
Definition: Packaging is the science, art and technology of enclosing,
protecting a product and providing information about the product for
distribution, storage, sale and use.

Role of packaging:

 Protection
 Identification
 Information transmission
 Storage
 Convenience

Types of packaging for capsules:

1. Blister package
2. Strip package
3. Alu-alu packaging
4. Bottle packaging

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Water vapour permeation rate of some materials used for blister

packs.

1. Blister Package:

Blister packs are commonly used for unit dose packaging for tablets
and capsules.

The principal components of a blister pack comprise of:

a. Forming film (blister): A pocket inside

e which the product fits
b. Backing: The lidding foil sticked over the back of a blister.

Materials used
ed for forming films (blisters)
(blisters):

a. Polyvinyl chloride/polyethylene combinations

b. Polystyrene
c. Polyvinyl chloride (mostly used)
d. Polypropylene

Materials used for backing:

a. Paper
b. Paper-aluminium
aluminium combinations
c. Aluminium foil

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Backing material can be either,

 Push-through type
 Peelable type (used for making child resistant packing)

Steps involved in the formation of a blister:

1. Thermoforming: This involves heat softening a sheet of

thermoplastic resin and then vacuum drawing the softened sheet of
plastic into a mold. After cooling, the sheet is released from the
mold.
2. Filling: The sheet then proceeds to the filling station for filling.
3. Sealing: Sealing is then accomplished by lidding it with a heat
sealable backing material.

2. Strip Package

A strip package is formed by feeding two webs of a heat sealable

flexible film through a heated crimping rollers. This package is used
for both capsules and tablets.

Materials used:

 Foil laminations (for moisture sensitive products)

 Paper
 Polyethylene
 Cellophane (Transparent plastic film formed from processed
cellulose)

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Steps involved in the formation of a strip package:

1. The product is fed into the pocket formed between two heat
sealable flexible films.
2. Sealing is accomplished by heat crimping rollers
3. The strip is then cut into desired no. of packets in length.

3. Alu-alu packaging

Alu-alu packing means aluminium foil at both the upper and lower side
of pack. Alu- alu packaging is similar to that of blister packing the only
difference is that the forming film is formed of aluminium foil instead
of plastic material.

4. Bottle packaging

Bottles are commonly used for liquid pharmaceuticals as well as for

tablets and capsules.

Materials used:

1. Bottle:

 Polyethylene
 Polypropylene screw cap
 Polystyrene

2. Bottle mouth seal:

 Aluminium foil

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UNIT 5 - Optimization Techniques in

Pharmaceutical Formulation and Processing
 The term “Optimize” is defined as to make perfect, effective, or
functional as possible.
 It is the process of finding the best way of using the existing
resources while taking in to the account of all the factors that
influences decisions in any experiment
 Traditionally, optimization in pharmaceuticals refers to changing one
variable at a time, so to obtain solution of a problematic formulation.
 Modern pharmaceutical optimization involves systematic design of
experiments (DOE) to improve formulation irregularities.
 In the other word we can say that -quantitate a formulation that
has been qualitatively determined.
 It's not a screening technique.

Optimization Parameters
1. Problem types

 Constraints Example: Making hardest tablet but should

disintegrate within 20 mins (Constraint)
 Unconstraint Example: Making hardest tablet ( Unconstraint)

2. Variables

 Independent variable E.g. - Mixing time for a given process step.

Granulating time.

Dependent variables, which are the responses or the characteristics

of the in process material

Eg. Particle size of vesicles, hardness of the tablet.

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 Higher the number of variables, more complicated will be the

optimization process.
 There should be a relati
relationship
onship between the given response and the
independent variable, and once this relationship is established, a
response surface is generated.
 From response surface only, we find the points which will give
desirable value of the response.

Example of Dependent & Independent Variables

Classic optimization

It involves application of calculus to basic problem for

maximum/minimum function.

Limited applications

a. Problems that are not too complex

complex.
b. They do not involve more than two variables
variables.

For more than two variables

bles graphical representation is impossible

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It is possible mathematically, but very involved, making use of partial

derivatives, matrics, determinants & so on.

Response surface representing the relationship between the

independent variables X, and X, and the dependent variable Y.

Graph representing the relation between the response variable and

independent variable

 We can take derivative, set it equal to zero & solve for x to obtain
the maximum or minimum.
 Using calculus the graph obtained can be - Y = f(x)

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 When the relation for the response y is given as the function of two
independent variables, X1, & X2

Y = f(X1, X2)

 The above function is represented by contour plots on which the

axes represent the independent variables X1, & X2.

Statistical Design
Techniques
es used divided in to two types:

1. Experimentation continues as optimization proceeds

proceeds.
It is represented by evolutionary operations (EVOP), simplex
methods.
2. Experimentation is completed before optimization takes place.
It is represented by cla
classic
ssic mathematical & search methods.

In later one it is necessary that the relation between any dependent

variable and one or more independent variable is known.

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There are two possible approaches for this:

1. Theoretical approach- If theoretical equation is known, no

experimentation is necessary.
2. Empirical or experimental approach - With single independent
variable formulator experiments at several levels.

Optimization may be helpful in shortening the experimenting time.

The design of experiments is determined the relationship between the

factors affecting a process and the output of that process.

Statistical DOE refers to the process of planning the experiment in

such a way that appropriate data can be collected and analyzed
statistically.

Flow Chart for Optimization

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Types of Experimental Design

1. Completely randomized designs
2. Randomized block designs
3. Factorial designs
a. Full
b. Fractional
4. Response surface designs
a. Central composite designs
b. Box-Behnken designs
5. Three level full factorial designs

Factorial Design
These are the designs of choice for simultaneous determination of the
effects of several factors & their interactions.

Symbols to denote levels are:

 (1) - when both the variables are in low concentration.

 a - one low variable and second high variable.
 b - one high variable and second low variable.
 ab - both variables are high.

Factorial designs are optimal to determined the effect of pressure &

lubricant on the hardness of a tablet

Effect of disintegrants & lubricant conc. on tablet dissolution.

It is based on theory of probability and test of significance.

It identifies the chance variation (present in the process due to

accident) and the assignable variations (which are due to specific
cause.)

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Factorial design is helpful to deduce IVIVC.

IVIVC are helpful to serve a surrogate measure of rate and extent of

oral absorption.

BCS classification is based on solubility and permeability issue of

drugs, which are predictive of IVIVC.

Sound IVIVC omits the need of bioequivalence study.

IVIVC is predicted at three levels:

1. Level A - point to point relationship of in vitro dissolution and in

vivo performance.
2. Level B - mean in vitro and mean in vivo dissolution is compared and
co related.
3. Level C - correlation between amount of drug dissolved at one time
and one pharmacokinetic parameter is deduced.

Types of fractional factorial designs

 Homogenous fractional
 Mixed level fractional
 Box-Hunter
 Plackett - Burman
 Taguchi
 Latin square

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Plackett-Burman
 It is a popular class of screening design.
 These designs are very efficient screening designs when only the
main effects are of interest.
 These are useful for detecting large main effects economically,
assuming all interactions are negligible when compared with
important main effects.
 Used to investigate n-1 variables in n experiments proposing
experimental designs for more than seven factors.

Taguchi

 It is similar to PBDs.
 It allows estimation of main effects while minimizing variance. O

Taguchi Method treats optimization problems in two categories:-

a. Static Problems: Generally, a process to be optimized has several

control factors which directly decide the target or desired value
of the output.
b. Dynamic Problems: If the product to be optimized has a signal
input that directly decides the output,

Latin Square

 They are special case of fractional factorial design where there is

one treatment factor of interest and two or more blocking factors.
 We can use the Latin square to allocate treatments. If the rows of
the square represent patients and the columns are weeks, then for
example the second patient, in the week of the trial, will be given
drug D. Now each patient receives all five drugs, and in each week all
five drugs are tested.

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Response Surface Designs

This model has quadratic form

γ = β0 + β1 X1 + β2 X2 +........ β11 X12 + β22 X22

Designs for fitting these types of models are known as response

surface designs.

If defects and yield are the outputs and the goal is to minimize
defects and maximize yield.

Two most common designs generally used in this response surface

modeling are:

a. Central composite designs

b. Box-Behnken
Behnken designs

a. Box-Wilson
Wilson central composite Design

 This type contains an embedded factorial or fractional factorial

design with centre points that is augmented with the group of ‘star
points'.

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 These always contain twice as many star points as there are factors
in the design.
 The star points represent new extreme value (low & high) for each
factor in the design
 To picture central composite design, it must imagined that there are
several factors that can vary between low and high values.

Central composite designs are of three types:

1. Circumscribed (CCC) designs - Cube points at the corners of the

unit cube, star points along the axes at or outside the cube and
centre point at origin.
2. Inscribed (CCI) designs - Star points take the value of +1 & -1
and cube points lie in the interior of the cube
3. Faced (CCI) - star points on the faces of the cube.

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Box-Behnken Design
Box-Behnken
Behnken designs use just three levels of each factor.

In this design the treatment combinations are at the midpoints of

edges of the process space and at the center.

These designs are rotatable (or near rotatable) and require 3 levels of
each factor

 These designs for three factors with circled point appearing

appearin at
the origin and possibly repeated for several runs.
 It's alternative to CCD.
 The design should be sufficient to fit a quadratic model, that
justify equations based on square term & products of factors.

A Box-Behnken Design

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Simplex Method (Simplex Lattice)

It is an experimental techniques & mostly used in analytical rather than
formulation & processing.

Simplex is a geometric figure that has one more point than the number
of factors.

E.g. If 2 independent variables then simplex are represented as

triangle.

 The strategy is to move towards a better response by moving away

from worst response.
 Applied to optimize CAPSULES, DIRECT COMPRESSION TABLET),
liquid systems (physical stability).
 It is also called as Downhill Simplex / Nelder
Nelder-Mead
ad Method.

In simplex lattice, the response may be plotted as 2D (contour plotted)

or 3D plots (response surface methodology)

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The worst response is 0.25, conditions are selected at the vortex, 0.6,
and, indeed, improvement is obtained. One can follow the experimental
path to the optimum, 0.721
0.721.

Example 2: Two component solvent system representing simplex

lattice.

 Constraint is the concentration of A and B must add to 100%

 Includes observing responses( solubility) at three point i.e. 100%
A, 100% B and 50-50
50 mixtures of A and B .

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A simplex lattice of four components is shown by 15 formulations.

 4 formulations of each component A, B, C&D.

 6 formulation of 50
50-50
50 mixture of AB, AC, AD, BC, BD&CD.
 4 formulation of 1/3 mixtures of three components ABC, ABD,
A
ACD, & BCD.
 1 formulation of 25% of each of four (ABCD).

100% pure component is not taken as un acceptable formulation is

obtained, thus vertices does not represent the pure single substance,
therefore a transformation is required.

Transformed % = ( Actual %
%- Minimum %) / (Maximum %-Min.
% %)

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Contour Diagrams
1. Response Surface Methodology (RSM)

 Contour diagrams are often part of RSM, a statistical technique

used to model and optimize complex relationships between
multiple variables and responses.
 In pharmaceutical formulation, RSM helps identify optimal
conditions for factors such as drug concentration, excipient
levels, and processing parameters.

2. Factorial Design: Contour diagrams are used in factorial

experimental designs to explore the combined effects of different
factors on critical quality attributes. This aids in understanding
interactions between variables.

3. Quality by Design (QbD): QbD principles involve systematic

optimization of formulation and manufacturing processes to ensure
product quality. Contour diagrams help visualize the design space and
identify optimal conditions within it.

4. Process Parameter Optimization: Contour diagrams assist in

optimizing processing parameters such as temperature, pressure, and
mixing speed, ensuring the desired product attributes are achieved
efficiently.

5. Stability Studies: Contour diagrams are applied in stability studies

to understand how different factors influence the stability of
pharmaceutical formulations over time. This helps identify conditions
that preserve product quality.

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Mixture Designs
1. Proportion Optimization:

 Mixture designs are particularly valuable when a pharmaceutical

product is a mixture of different components, such as excipients,
binders, and active pharmaceutical ingredients (APIs).
 These designs help optimize the proportions of each component
to achieve the desired product characteristics.

2. Dose Optimization: In formulations with multiple active

ingredients, mixture designs assist in determining the optimal doses of
each component to achieve the desired therapeutic effect.

3. Cost-Effective Formulations: Mixture designs contribute to cost-

effective formulations by identifying the most efficient combinations
of ingredients that meet product specifications.

4. Experimental Design for Complex Systems: Mixture designs are

used to study interactions among multiple components in a formulation.
This is crucial in efficiently exploring a complex design space.

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Applications in Pharmaceutical Formulation:

1. Drug Delivery Systems: Optimization techniques are applied to
design drug delivery systems, ensuring controlled release, targeted
delivery, and improved bioavailability.
2. Solid Dosage Forms: Contour diagrams and mixture designs aid in
optimizing the composition of tablets, capsules, and other solid
dosage forms. Factors such as disintegration, dissolution, and
stability are considered.
3. Parenteral Formulations: For injectables formulations, optimization
techniques are crucial to achieve proper solubility, stability, and
compatibility with delivery devices.
4. Biopharmaceuticals: Contour diagrams and mixture designs help
optimize conditions for the stability and activity of
biopharmaceuticals, including proteins and peptides.
5. Topical Formulations: These techniques assist in formulating
creams, ointments, and gels by optimizing factors like viscosity, drug
release, and skin permeability.

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