Modern Pharmaceutics

CAREWELL PHARMACY
M Pharmacy Notes
Pharmaceutics
Modern Pharmaceutics
Connect With Us
Website - www.carewellpharmacy.in
Telegram - Carewell Pharmacy
For More Notes - Visit www.carewellpharmacy.in Page 1

CAREWELL PHARMACY
Syllabus: -
Unit 1. a. Preformulation Concepts – Drug Excipient interactions -
different methods, kinetics of stability, Stability testing. Theories of
dispersion and pharmaceutical Dispersion (Emulsion and Suspension,
SMEDDS) preparation and stability Large and small volume parental –
physiological and formulation consideration, Manufacturing and evaluation.
Unit 1 b. Optimization techniques in Pharmaceutical Formulation: Concept

and parameters of optimization, Optimization technique in pharmaceutical
formulation and processing. Statistical design, Response surface method,
Contour designs, Factorial designs and application in formulation.
Unit 2 - Validation: Introduction to Pharmaceutical Validation, Scope &

merits of Validation, Validation and calibration of Master plan, ICH & WHO
guidelines for calibration and validation of equipments, Validation of specific
dosage form, Types of validation. Government regulation, Manufacturing
Process Model, URS, DQ, IQ, OQ & P.Q. of facilities.
Unit 3 - cGMP & Industrial Management: Objectives and policies of

current good manufacturing practices, layout of buildings, services,
equipments and their maintenance Production management: Production
organization, , materials management, handling and transportation, inventory
management and control, production and planning control, Sales forecasting,
budget and cost control, industrial and personal relationship. Concept of
Total Quality Management.
Unit 4 - Compression and compaction: Physics of tablet compression,

compression, consolidation, effect of friction, distribution of forces,
compaction profiles. Solubility.
Unit 5 - Study of consolidation parameters; Diffusion parameters,

Dissolution and Pharmacokinetic parameters, Heckel plots, Similarity factors
– f2 and f1, Higuchi and Peppas plot, Linearity Concept of significance,
Standard deviation , Chi square test, students T-test , ANOVA test.

CAREWELL PHARMACY
UNIT 1.a - Pre-Formulation Concepts

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 Concept
 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.

CAREWELL PHARMACY
Parameters in Preformulation Concept
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

CAREWELL PHARMACY
Drug Excipient Interactions

Pharmaceutical Excipients
An excipient is a pharmacologically inactive substance formulated

alongside the API of a medicine to impart specific qualities to them.
Role of Excipients
 Provide bulk to the formulation

 Protect, support or enhance the stability of formulation.
 Improve bioavailability of drug
Drug Excipient Interaction
Drug substances are usually in intimate contact with excipient.

Although these are pharmacologically inert, they can undergo chemical
and physical interaction with drug substance under favorable condition.
These interactions can lead to instability resulting in the formulation
of new entities.
Importance of these Studies
 To find out how compatible an excipient is with API

 Maximizes the stability of a dosage form.
 Do not have impact on stability of API
 Determine the list of excipient that can be used in final dosage
form.
 Helps to avoid surprise problem during formulation process
 These studies are the part of Preformulation study and this
study data is essential for IND submission.

CAREWELL PHARMACY
Mechanism of Drug Excipient Interaction
They can be classified as

as-
1. Physical interaction
2. Chemical interaction
3. Biopharmaceutical interaction
1. Physical Interaction
These are very common in dosage form and also difficult to detect.
These involve change in -
 Dosage uniformity, color, odor, dissolution, stability or

sedimentation rate etc.
 These interactions can either be beneficial or detrimental to the
product performance.
Eg. of some these interactions are as follows
follows-

CAREWELL PHARMACY
2. Chemical Interaction
Chemical interaction involves chemical reaction between drugs and

excipients or drugs and impurities/ residues present in the excipients
to form different molecules. Chemical interactions are almost
detrimental to the product because they produce degradation
degradati
products.
They are as follows-
1. Chemical interactions between drug and excipients - Eg are as

follows-
 Maillard reaction- eg chlorpheniramine and dextrose interaction
 Release of diclofenac sodium from matrix tablet was inhibited by

polymer chitosan at low pH, due to formation of ionic complex
between diclofenac sodium and ionized cationic polymer
 Sodium alginate dissolve in water to form large negatively charged
anions, co-formulation
formulation in aqueous systems with drugs such as
neomycin and polymixin (positi
(positively
vely charged) result in precipitation.
2. Interaction of drug with excipient residues/ impurities-

impurities
 Excipients are not exquisitely pure. They have some residues which
affect the drug action.
 Impurities found in common excipients
excipients-

CAREWELL PHARMACY
 Sterilization by autoclaving of par

parenteral
enteral preparations containing
dextrose can cause isomerization of dextrose in fructose and
formation of aldehyde which react with primary amino group to
cause color change.
 Peroxide residues in povidone responsible for the enhanced
formation of the N-- oxide degradation product of the oestrogen
receptor modulator, Raloxifene.
3. Biopharmaceutical Interaction
These are the interactions which are observed after administration of

medicine. These interactions occur in the form of
of-
 The interaction is between the medicine (drug substance and

excipients) and the body fluids
fluids.
 The interactions have the tendency to influence the rate of
absorption of the drug.
 Various eg. of these inter
interactions are as follows-
a) Premature Breakdown of Enteric Coat
 Enteric coating polymers e.g., cellulose acetate phthalate and

hydroxyl propyl cellulose acetate phthalate,
 dissolve prematurely in the stomach in the presence of antacids
or drugs
 cause increase in the pH of the stomach

CAREWELL PHARMACY
 Cause premature release of API in stomach itself, which results

in degradation of drug in stomach.
e.g., side effects like gastric bleeding as in the case of NSAIDs.
b) Increase in gastrointestinal motility - Many excipients such as

sorbitol and xylitol have the tendency to increase gastrointestinal
motility, thus reducing the available time for absorption of drugs like
Metoprolol.
c) Effect on P-glycoprotein efflux transporter-
P-glycoprotein thus interferes in the bioavailability of different

anticancer and other drug substances. Thus, several excipients e.g.,
Span 20, Tween 20, Tween 80, Pluronic, Poloxamer etc. are
incorporated in the formulations which help in inhibition of P-
glycoprotein to enhance availability of the drug into the cell, to
produce the desired action.
Analytical Techniques Used To Detect Drug-Excipient Interaction-
1. Thermal methods-
a. DSC- Differential Scanning Calorimetry
b. DTA- Differential Thermal Analysis
c. Isothermal micro Calorimetry
d. Hot stage microscopy
2. Spectroscopic techniques-
a. FT-IR Spectroscopy
b. Powder X-ray diffraction
c. Solid state NMR
3. Chromatography - SIC-Self Interactive Chromatography
a. TLC-Thin Layer Chromatography and HPTLC HPLC-High

Pressure Liquid Chromatography

CAREWELL PHARMACY
4. Accelerated stability study
5. Miscellaneous-
 Radiolabelled Techniques
 Fluorescence Spectroscopy
1. DSC-Differential
Differential Scanning Calorimetry
 DSC is widely used technique to predict any interaction involving

thermal changes.
 Method - The preformulation screening of drug-excipient
drug
interaction requires (1: 1) Drug:excipient ratio, to maximize the
likehood of observing an interaction. - Mixture should be examined
under N2 to eliminate oxidative and pyrrolytic effects at heating
rate (2,5 or10 degree C/min) on DSC apparatus.
Interaction detected by DSC
 Elimination of endothermic peak

 Any new peak appeared
 Change in melting point / peak temperature
 Change in peak shape (height and width)
 Change in area of peak or enthalpy

CAREWELL PHARMACY
2. DTA-Differential Thermal Analysis
 This technique is useful in the investigation of solid-state

interactions and detection of eutectics.
 In this change in temperature between test sample and reference
material is measured under controlled and identical condition.
 This differential temperature is plotted against time or
temperature.
 Interaction can be identified by comparing DTA curve obtained
from the test sample with those of reference material.
3. SIC-Self Interactive Chromatography
SIC is useful for proteinous drug and excipients.
Principle - For different mobile phases (i.e. different excipients) the

injected drug have different interactions (may be repulsive or
attractive) with the stationary phase of drug leads to shift in
retention time
Method - It is a modified type of affinity chromatography. Here, drug

is made immobilized as the stationary phase & solution to be tested(
excipient solution) acts as mobile phase.
Measure retention time and compare with non-retained marker.
Eg. INF-Tau(an antiviral drug)- Interactions of it with different types

of buffers were studied by SIC. Here, buffer is used to prevent
aggregations.

CAREWELL PHARMACY
TLC & HPTLC
 TLC is generally used as confirmative test of compatibility after

performing DSC because if sample undergo negligible thermal
changes, it will difficult
ifficult to detect by thermal method
 Method- stationary phase consist of powder (silica, alumina,
polyamide, cellulose etc.) adhered onto glass, plastic or metal plate.
 Solution of drug, excipient & drug: excipient mixture are prepared &
spotted on the samee baseline at the end of plate.
 The plate is then placed upright in a closed chamber containing the
solvent which constitutes the mobile phase.
 Any change in chromatograph such as appearance of a new spot or a
change in Rf values of component is indicative of an interaction.

CAREWELL PHARMACY
Kinetics of Stability
Kinetics
Kinetics deals with the study of the rate at which processes occur and
mechanism of chemical reactions.
It involves the study of rate of change and the way in which this rate
is influenced by the concentration of reactants, products, and other
chemical species that may be present, and by factors such as solvents,
pressure, and temperature.
Kinetics applies to:
 Stability
 Incompatibility,
 Dissolution,
 Absorption,
 Distribution
 Drug action at molecular level
 Elimination processes
Drug Stability
 The resistance of the drug to the various chemical, physical, and

microbiological reactions that may change the original properties of
the preparations during transport, storage and use.
 Quantitatively it is expressed as shelf life.
Shelf life
 It is the time during which the medicinal product is predicted to

remain fit for its intended use under specified conditions of
storage.

CAREWELL PHARMACY
 It is the time from manufacture or preparation until the original

potency or content of the active ingredient has been reduced by
10% [t10 or t] which is the limit of chemical degradation.

CAREWELL PHARMACY
Rates of Reactions
 The speed or velocity of a reaction with which a reactant or
reactants undergoes a change.
 It is determined by the change in the concentration of the
reactants or products as a function of time.
 The rate may be determined by the slowest or rate determining
step.
Dc/dt = Rate = kcn
Zero Order Reactions

 Rate is constant and is independent of the concentration of any of
the reactants.
 A constant rate of drug release from a dosage form is highly
desirable.
Units of the rate constant K
 c = co - Kt
 K = co- c/t
Where,
 K = Concentration / time
= mole/liter. Second
= M. sec-1

CAREWELL PHARMACY
Determination of t1/2
 Let c = co /2 and t1/2 = t

 Substitute in equation - c=co-kt
 t1/2 = Co/2k
Note: Rate constant (k) and t1/2 depend on co
Determination of t0.9
 Let c = 0.9 co, and t= t0.9

 Substitute in equation - c = c0-k t
 t90% = t0.9 -0.1 c0/k
First Order Reaction

 The most common pharmaceutical reactions.
 e.g. drug absorption & drug d
degradation
 The reaction rate of change is proportional to drug concentration.
 dc/dt = kc1 = kc
 dc/c = kdt
 1n c - 1n c0 = -kt
 log c = log c0 - kt/2.303

CAREWELL PHARMACY
Determination of t1/2
 Let t = t1 2 and C = C0/2

 Substitute in ln C = ln C0 - Kt
 t1/2 = In 2/ K = 0.693 / K
 K units = 0.693/t1/2 = time-1
Determination of t0.9
 Let t = to.9 C = 0.9 Co

 Substitute in Inc In co - Kt
 t0.9 = 0.105 / K and K = 0.105/ t0.9

CAREWELL PHARMACY
Second Order Reaction

 Rate depends on the product of two concentration terms.
 When you have two components reacting with each other or one
component reacting with itself.
Example: 2Hl = H2 + l2, here the reaction is not simply a matter of an
HI molecule falling apart, but relies on the collision of two HI
molecules.
 The rate of reaction from the law of mass action is given by:
by
Rate = dc/dt = k[Hl][Hl] = k[Hl]2
2nd Order reaction
 dc/dt = -kc2
 dc/c2 = -kdt
 1/c=1/c0 + kt

CAREWELL PHARMACY
Units of K:
 1/C = 1/C0 + Kt
 K = (1/C - 1/C0)/t
 K = M-1. sec -1
i.e., K is dependent on initial drug concentration.
Derive equation for t1/2 and shelf life
 Half life: t1/2 = 1 / KC0

 Shelf life: t0.9 = 0.11/KC0

CAREWELL PHARMACY
Stability Testing
Stability defined as capability of a particular formulation in a specific
container/closure system to remain within its physical, chemical,
microbiological, toxicological, protective and informational
specifications.
It is the extent to which a product retains, within the specified limits,

throughout its period of storage and use, the same properties and
characteristics possessed at the time of its packaging.
Scope of Stability Testing
 Provide evidence as to how the quality of drug product varies with

time.
 Establish shelf life of drug product.
 Determines recommended storage conditions.
 Determine container closure system suitability.
Importance of Stability Testing
 Assurance to patient that drug is safe.

 Legal requirement to provide data.
 To protect the reputation of the manufacturer.
 To provide a database.
 To determine shelf life and storage conditions.
 To verify that no changes have been introduced in the
formulation or manufacturing process that can adversely affect
the stability of the product.

CAREWELL PHARMACY
Stability Testing Methods
1. Real Time Stability Testing

2. Accelerated Stability Testing
3. Retained Sample Stability Testing
4. Cyclic Temperature Stress Testing
1. Real Time Stability Testing
 Performed for longer duration of the test period in order to allow

significant product degradation under recommended storage
conditions.
 Depends
epends upon the stability of the product which should be long
enough to indicate clearly that no measurable degradation occurs.
2. Accelerated Stability Testing
 A product is stressed at several high temp. & the amount of heat

input required to
o cause product failure is determined.
 This is done to subject the product to a condition that accelerates
degradation.
 This information is then projected to predict shelf life or used to
compare the relative stability of alternative formulations.

CAREWELL PHARMACY
The concept of accelerated stability testing is based upon the

Arrhenius equation:
ln K = ln A+ ΔΕ/RT
Where,
 K = degradation rate/s,
 A = frequency factor/s,
 ΔE = activation energy (kJ/mol),
 R = universal gas constant (0.00831 kJ/mol),
 T = absolute temperature (K)
3. Retained Sample Stability Testing
 Usual practice for every marketed product for which stability data
are required.
 Only one batch a year is selected.
 If the number of batches marketed exceeds 50, stability samples
from two batches are recommended to be taken.
 Stability testing by evaluation of market samples is a modified
method which involves taking samples already in the market place
and evaluating stability attributes.

CAREWELL PHARMACY
4. Cyclic Temperature Stress Testing
 Is not a routine testing method for marketed products.

 In this method, cyclic temp. stress tests are designed on
knowledge of the product so as to mimic likely conditions in
market place storage.
 The period of cycle mostly considered is 24 hours.
 The min. and max. temp. for the cyclic stress testing is
recommended to be selected on a product by-product basis and
considering factors like recommended storage temp. for the
product and specific chemical and physical degradation properties
of the products. the test should normally have 20 cycles.

CAREWELL PHARMACY
Theories of Dispersion and Pharmaceutical Dispersion

(Emulsion and Suspension, SMEDDS)
1. Pharmaceutical Dispersion
2. Theories of dispersion:
a. Viscosity theory
b. Film theory or adsorption theory
c. Wedge theory
d. Interfacial tension theory
3. Emulsion - Definition, Mechanism of emulsification, Method of
preparation and stability of emulsion.
4. Suspension - Definition, Mechanism, Method of preparation and
stability of suspension.
1. Pharmaceutical Dispersion
 Dispersed system consists of particulate matter, known as the

dispersed phase, distributed throughout continuous or dispersion
medium.
 The dispersed material may range in size from particles of atomic
and molecular dimensions to particle whose size is measured in
millimeters.
Coarse Dispersion System
 Emulsion
 Colloids
 Suspension

CAREWELL PHARMACY
2. Theories of Dispersion
a. Viscosity theory
As per this theory increase in viscosity of emulsion will leads to

increase in stability of it.
Limitations - This theory fails to explain the viscosity related to milk,

as milk don't possess viscous nature but still it shows the good
stability.
b. Film Theory or Adsorption Theory
 As per this theory, the added emulsifying agent forms a mechanical

film by getting adsorbed at the interface of the liquids (i.e. at the
interface between the dispersed globules and the dispersion
medium).
 This offers stability to the emulsion.
Limitations - This theory could not explain the formation of type of

emulsion.
c. Wedge theory
 According to this theory, monovalent soaps like sodium stearate

gives o/w type emulsion and divalent soaps like calcium stearate
gives w/o type emulsion.
 This was explained by the successful accommodation of the soap
molecules at the interface and subsequent possible orientation of
the soap molecules to give the type of emulsion
Limitations
 This theory could not explain the formation of type of emulsion.

 The calcium stearate will not obey this theory, it will ionize and will
not exist as a wedge.

CAREWELL PHARMACY
d. Interfacial Tension Theory
 Initially when the oil and water are mixed together, they will
become immiscible due to the interfacial tension formed between
surface of oil and water.
 The added emulsifying agent reduces the interfacial tension
between the oil and the water phase by emulsifying the mixture.
 Hence a stable emulsion is formed.

CAREWELL PHARMACY
3. Emulsions
 An emulsion is a biphasic liquid preparation containing two immiscible

liquids, one of which is dispersed as minute globules into the other.
 The liquid which is converted into minute globules is called the
'dispersed phase' and the liquid in which the globules are dispersed
is called the 'continuous phase'.
 Normally, two immiscible liquids cannot be dispersed for a long
period.
 So, an emulsifying agent is added to the system.
 It forms a film around the globules in ordeorderr to scatter them
indefinitely in the continuous phase, so that a stable emulsion is
formed.
 The globule size in emulsion varies from 0.25 to 25 μm.
HLB (Hydrophilic lipophilic balance) values of emulsifying agents
 HLB ca. 1 to 3.5: Antifoams

 HLB ca. 3.5 to 8: Water
Water-in-Oil Emulsifiers
 HLB ca. 7 to 9: Wetting and spreading agents
 HLB ca. 8 to 16: Oil
Oil-in-Water Emulsifiers
 HLB ca. 13 to 16: Detergents
 HLB ca. 15 to 40: Solubilizer

CAREWELL PHARMACY
Mechanism of Emulsification
 When two immiscible liquids are in contact with each other, the
molecules at the interface experience a perpendicular force.
 The net forces at the interface are called as interfacial tension and
tend to minimize the surface are of individual liquids.
 In emulsion, the process of dispersion of one liquid in the other
results in an increase in the surface area between the dispersed
droplets and dispersion medium, and surface free energy, which can
be expressed as follows:
ΔW=gΔA
Where,
 ΔW = increase in the free energy at the interface

 ΔA increase in the surface area
Methods of preparation of emulsion
Commercially, emulsions are prepared in large volume mixing tanks and

refined and stabilized by passage through a colloid mill or homogenizer.
Extemporaneous production is more concerned with small scale
methods.
Methods of preparation:
1. Dry gum method

2. Wet gum method
3. Bottle method
4. Beaker method
5. In-situ soap method

CAREWELL PHARMACY
1. Dry Gum Method
Dry gum method is used to prepare the initial or primary emulsion from
oil, water, and a hydrocolloid or "gum" type emulsifier.
Dry Gum Methodology includes (4 parts oil,2 parts water, and,1 part of
emulsifier).
Procedure:
 Take mortar, 1 part gum is levigated with tile 4 parts oil until the
powder is thoroughly wetted; then the 2 parts water are added all
at once, and the mixture is vigorously triturated until the primary
emulsion formed is creamy white and produces a clicking sound as it
is triturated.
 Active ingredients, preservatives, color; flavors are added as a
solution to the primary emulsion.
 When all agents have been incorporated, the emulsion should be
transferred to a calibrated vessel, brought to final volume makeup
by water.
2. Wet Gum Method
Methodology - (Oil 4 parts + Water 2 parts + Emulsifier 1 parts)
Procedure
 In this method, the proportions of oil, water, and emulsifier are the
same (4:2:1), but the order and techniques of mixing are different.
 The 1 part of gum is triturated with 2 parts of water to form
mucilage; while triturating add 4 parts oil is slowly.
 After all the oil is added, the mixture Is triturated for several
minutes to form the primary emulsion.
 Then other ingredients may be added as in the continental method.

CAREWELL PHARMACY
3. Bottle Method
This method may be used to prepare emulsions of volatile oils,

oleaginous substances of very low viscosities. This method Is a
variation of the dry gum method.
Procedure
 One-part powdered acacia (or other gum)ls placed in a dry bottle

and four parts oil are added.
 The bottle is capped and thoroughly shaken.
 To this, the required volume of water is added all at once, and the
mixture is shaken thoroughly until the primary emulsion forms.
4. Beaker Method
 Dividing components into water soluble and oil soluble components.

 All oil soluble components are dissolved in the oily phase in one
beaker and all water-soluble components are dissolved in the water
in a separate beaker
Procedure
 Oleaginous components are melted and both phases are heated to

approximately 70*C over a water bath.
 The Internal phase is later added to the external phase with
stirring until the product reaches room temperature.
5. In-Situ Soap Method
Two types of Soaps developed by this methods:
1. Calcium Soaps
2. Soft Soaps

CAREWELL PHARMACY
Procedure
1. Calcium Soaps: W/O type Emulsions.
 E.g., Oleic acid + lime water.

 Prepared by simple mixing of equal volumes of oil and lime water.
 Calcium salts of free fatty acids are used as emulsifying agent.
Example: Olive Oil + Oleic acid
Stability of Emulsion

CAREWELL PHARMACY
4. Suspension
 Suspension are the biphasic liquid dosage form of medicament in

which the finely divided solid particles ranging from 0.5 to 5.0
micron are dispersed in a liquid or semisolid vehicle.
 The solid particles act as disperse phase whereas liquid vehicle
acts as the continuous phase.
 Suspension is generally taken orally or by parenteral route.
 They are also used for external applications
Mechanism of suspension formation
A Pharmaceutical suspension is a coarse dispersion in which internal

phase (therapeutically active ingredient)is dispersed uniformly
throughout the external phase, maintained uniformty through out the
suspending vehicle with aid of single or combination of suspending
agent.
Suspending agent is a kind of viscous hydrophilic colloidal substance,

which can increase the viscosity of the dispersion medium to slow down
the sedimentation speed of particles and adsorb on the surface of the
particles to become a barrier to prevent the aggregation and
agglomeration of particles.
Method of preparation - Suspension can be prepared by 2 methods:
1. Dispersion method
2. Precipitation method
a. Organic solvent precipitation
b. Precipitation effected by changing pH of the medium
c. Double decomposition

CAREWELL PHARMACY
1. Dispersion method
2. Precipitation method

CAREWELL PHARMACY
Stability of Suspensions
1. Small particle size
 Reduction in the size of the dispersed particle increase the total

surface area of the solid. The greater the degree the subdivision of
a given solid the larger the surface area.
 The Increase in surface area leading to increase in viscosity of a
system.
2. Temperature
 Another factor which negatively affects the stability and

usefulness of pharmaceutical suspensions is fluctuation of
temperature.
 Temperature fluctuations can lead caking of claying.
3. Increasing the viscosity
 Increasing the viscosity of the continuous phase can lead to the

stability of suspension, this happens because the rate or
sedimentation can be reduce by increase in viscosity.
 Viscosity increase is brought about by addition of thickening agents
to the external phase and they must be soluble or swell in water.
 It is important to note that the rate or release of a drug from a
suspension also dependent on viscosity of a product.
 The more viscous the preparation, the slower is the release of a
drug and this sometimes give desirable for depot preparations.

CAREWELL PHARMACY
5. SMEDDS
Introduction
 Microemulsions are an isotropic mixture of natural or synthetic oils,

solid or liquid surfactants, co
co-surfactant and drugs.
 Upon mild agitation followed by dilution in aqueous media, such as
gastrointestinal (GI) fluids, the system can form fine oil in water
(O/W) microemulsions which usually have droplet size less than 100
nm.
 Micro emulsion have been successively used to improve the
solubility, chemical stability and oral bioavailability of poorly water
soluble drugs. ( classs II & IV as per BCS classification)
Mechanism of action:
Self-emulsification
emulsification takes place when the entropy change favoring the
dispersion is greater than the energy required to increase the surface
area of the dispersion.
The interface between the oil and aqueous phases is formed upon
addition of a binary mixture. This is followed by the solubilization of
water within the oil phases as a result of aqueous penetration through
the interface.

CAREWELL PHARMACY
Following gentle agitation of the self-emulsifying system, water will

rapidly penetrate into the aqueous cores and lead to interface
disruptions and droplet formation.
Improvement of oral absorption by SMEDDS
 The release of drug compound takes place upon its partitioning into
the intestinal fluids during droplet transport and disintegration
along GI tract.
 Two main factors; small particle size and polarity of the resulting oil
droplets determine the efficient release of the drug compound from
SMEDDS.
 Many studies carried out in animals for assessment of oral
bioavailability of hydrophobic drugs formulated in o/w emulsions
indicated better absorption profiles.
Formulations
This isotropic systems are usually easier to formulate than ordinary

emulsion. The type of associated structure formed from these
components at particular temperature depends not only on the chemical
nature of each component but also on their relative concentration.
SMEDDS formulation contains following 4 components:
1. Oil phase: Oils from natural sources and their derivatives. The
extension of a microemulsion region generally depends on the nature of
oil. This is due to the differences in oil penetration onto the
surfactant layer.
Examples: castor oil, sunflower oil, seseam oil, hydrogenated specialty

oils.

CAREWELL PHARMACY
2. Surfactant: Compounds that lower the surface tension (or

interfacial tension) between two liquids or between a liquid and a solid.
Surfactants used to stabilize may be non-oinic, zwitterionic, cationic
and anionic non-ionic are effective at increasing the extent of
microemulsion system surfactants. Ionic and microemulsion region.
Microemulsion formulations can be administered as a form of water-in-

oil microemulsion of surfactant-oil mixture, and are expected to
convert to oil-in- water microemulsion in small intestine.
Examples:
 Polyoxethylene (20) sorbitan monooleate (Tween 80)

 Polyoxyethylene glyceryl trioleate (Tagat TO)
 Propylene glycol monocaprylate (Capryl 90)
3. Co-surfactant: Under certain condition, a combination of oil, water

and surfactant will result in a phase where there are orderly planes of
oil and water separated by monolayer of surfactant. Co-surfactants are
added to further lower the interfacial tension between the oil and
water phase, to fluidize the hydrocarbon region of interfacial-film, and
to influence the film curvature.
Examples:
 short chained alcohol (ethanol, propanol, butanol)

 Glycols (propylene glycols)
4. Co-solvents: The production of an optimum SMEDDS require

relatively high concentrations (generally more then 30% w/w) of
surfactants. Organic solvents like ethanol, propylene glycol (PG),
polyethylene glycol (PEG) are suitable for oral delivery.
They enable dissolution of large quantities of either the hydrophilic

surfactant or the drug in lipid base.

CAREWELL PHARMACY
Alcohol-free formulations have been designed but their lipophilic drug

dissolution ability is limited.
Stability testing
1. Temperature stability: SMEEDS is diluted with purified distilled

water and to check the temperature stability, they were kept at 3
different temperature range (4°C, 25°C,40°C) and evidence of any
phase separation, flocculation or precipitation is observed.
2. Centrifugation: SMEDDS formulation was diluted with purified
distilled water and was centrifuged at 1000 rpm for 15 min at 0°C
and observed for any change in homogeneity.
3. In vitro release: SMEDDS was placed in dialysis bag during release
period to compare the release pattern with conventional tablet. 10ml
of sample solution was withdrawn at predetermined time intervals,
filtered through 0.45 micrometer membrane filter, dilute suitably
and analyzed spectrophotometrically.
Percentage drug dissolved at different time intervals was calculated
using Beer Lambert's equation.
Advantages
a. Enhanced oral bioavailability and AUC enabling reduction in dose

b. More consistent temporal profile of drug absorption
c. Selective drug targeting towards specific absorption window in GIT
d. Protection of sensitive drug from hostile environment in gut
e. Fine oil droplets empty rapidly from the stomach and promote wide
distribution of drug throughout the intestinal tract at short time
period
f. Ease of manufacture and scale up
g. Potential to deliver peptides that are processed to enzymatic
hydrolysis in GIT.

CAREWELL PHARMACY
Disadvantages
Lack of good predicative in vitro models for assessment of the

formulation is the most important problem in the development of
SMEEDS.
To mimic this, in-vitro model simulating the digestive processes of the

duodenum has been developed. This in-vitro model needs further
development and validation before the strength can be evaluated.
Further development will be based on in vitro, in vivo correlations and

therefore different prototype lipid based formulations need to be
developed and tested in vivo in a suitable animal model.

CAREWELL PHARMACY
Large and Small Volume Parental – Physiological

and Formulation Consideration, Manufacturing
and Evaluation
Parenteral
 The term derived from Greek word 'Para' outside & 'Enterone'
intestine.
 Parenteral are sterile solutions or suspension of drug in aqueous or
oily vehicle
 Parenteral drugs are administered directly in to the veins, muscles
or under the skin, or more specialized tissues such as spinal cord
 Term parenteral used for any drug/fluid whose delivery doesn't
utilize the alimentary canal for entering in to the body tissues.
General requirements for parenteral dosage forms
 Stability
 Sterility
 Free from pyrogens & toxins
 Free from foreign particles
 Isotonic
 Chemical purity
Parenteral Routes
The term parenteral literally means to avoid the gut (gastrointestinal

tract) and refers to any route of administration outside of or beside
the alimentary tract.
Thus, parenteral are injectable drugs that enter the body directly and
are not required to be absorbed in the gastrointestinal tract before
they show their effect.

CAREWELL PHARMACY
Parenteral routes of administration usually have a more rapid onset of

action than other routes of administration.
1. Intravenous
2. Intramuscular
3. Subcutaneous
4. Intradermal
5. Intra-arterial
6. Intracardiac
7. Intrathecal
8. Peridural
9. Intraarticular
10. Intracerebral
Advantages
 Useful for patients who cannot take drugs orally Rapid onset of
action
 Useful for emergency situations
 Avoid first pass metabolism
 Can inject drug directly in to a tissue (target drug delivery)
 Useful for delivering fluids, electrolytes, or nutrients (TPN)
 Can be done in hospitals, ambulatory infusion centers and home
health care centers.
 Complete bioavailability.
Disadvantages
 Pain on injection
 Difficult to reverse an administered drug's effect.
 Sensitivity or allergic reaction at the site of injection.
 Requires strict control of sterility & non- pyrogenicity than other
formulation.

CAREWELL PHARMACY
 Trained person is required.

 Require specialized equipment, devices, and techniques to prepare
and administer drugs.
 More expensive and costly to produce.
Classification - Based on volume they are classified into two types:
1. Small volume parenteral (SVP's)

2. Large volume parenteral (LVP's)
1. Small volume parenteral (SVP's)
 The volume is generally less than or equal to 100ml.

 They are supplied in single or multiple doses.
 They are used to dispense most of the drugs.
Examples: Ampoules, Vials, etc
Types of small volumes parenteral
a. Solution
b. Suspension
c. Emulsion
d. Dry Powders
a. Solutions
 Typically used for delivering medications at a controlled infusion

rate
 Most commonly solutions of 5% dextrose, normal saline, 45%
normal saline or 5% dextrose with normal saline.
 Dextrose contributes glucose to meet energy needs and saline
contributes sodium, an electrolyte that maintains fluid balance
and cellular functions.

CAREWELL PHARMACY
b. Suspension
 They should be sterile, pyrogen free, stable, re-suspendable,

syringeable, injectable, isotonic & non-irritating.
 They are usually administered by either subcutaneous (S.C.) or
intramuscular (I.M.) route.
 These suspensions usually contain between 0.5% and 5.0% solids &
should have particle size less than 5 micrometer for I.M. or S.C.
administration.
 Certain antibiotic antibiotic preparations (For example procaine,
Penicillin G) may contain up to 30% solids.
Advantages of Parental suspension
 It is better for the therapeutic use of drugs that are insoluble in

convention solvents.
 In this dosage from there is increased resistance to hydrolysis &
oxidation as drug is present in the solid form.
 Formulation of controlled released drug is possible in this dosage
form.
 There is elimination of hepatic first pass effect.
c. Injectable Emulsion
 An emulsion is a heterogenous dispersion of one immiscible liquid in

another.
 This inherently unstable system is made possible through the use of
an emulsifying agent, which prevent coalescence of the dispersed
droplet.
 Parenteral emulsion are rare because it is necessary (and difficult)
to achieve stable droplet of less than 1 micron to prevent emboli in
blood vessels and it is not usually necessary to achieve an emulsion
for drug administration.

CAREWELL PHARMACY
2. Large Volume Parenteral

arenteral (LVP's)
 These are supplied for single dose having more than 100 ml.
 These are delivered through IV route.
 These generally
erally provide electrolytes, nutrition to the body.
Examples: normal saline
Types of Large Volume Parenteral
a. Hyper alimentation solutions

b. Cardiolpagic Solutions
c. Peritonial Dialysis solution
d. Irrigating solutions
a. Hyperalimentation Solution
Admin. of large amount of nutrients to patients who unable to take

food orally.
Formulation: mix. Of dextrose, amino acids, lipids, electrolytes, &

vitamines. TOTAL PARENTERAL NUTRITION
Def.: A method of feeding patients by infusing a mixture of all

necessary nutrients
nts into the circulatory system, thus bypassing the
GIT.

CAREWELL PHARMACY
b. Cardiolplegic Solutions
 LVP are used in heart surgery to prevent injury to myocardium

during reperfusion, as well as to maintain bloodless operating
field.Maintains the diastolic arrest.
 Administered in cold form.
 Slightly alkaline to compensate metabolic acidosis,
 Hypertonic
Use: To minimize reperfusion injury resulting from tissue edema.
c. Peritoneal Dialysis Solution - Infused continuously into abdominal

cavity, bathing peritonium & are then continously withdrawn.
Use
 Removal of toxic substances from body.

 To aid & accelerate excretion normal.
 To treat acute renal insufficiency.
d. Irrigating Solutions
 To irrigate,flush, & aid in cleaning body activities & wounds.

 Certain IV solution (normal saline) may be used as irrigating
solution, but solution designed as irrigating solution should not be
used parenterally.
Use: - Treatment of serious wounds infused in to blood stream.

CAREWELL PHARMACY
Comparison:-

CAREWELL PHARMACY
Overview of Manufacturing Process of Parenteral
Flow of Materials:

CAREWELL PHARMACY
Production Facilities
1. Clean-up area.
2. Preparation area
3. Aseptic area
4. Quarantine area
5. Finishing and packaging area
Formulation Aspects
1. Therapeutic agents.
a. Insulin,
b. Antibiotics,
c. Vaccines,
d. Antipyretics,
e. Analgesics,
f. Dextrose,
g. Nacl,
h. Electrolytes.
2. Vehicles.
a. Water - WFI, BWFI, SWFI.
b. Aqueous vehicles. E.g.: Ethyl alcohol, Propylene Glycol.
c. Non-aqueous vehicles. E.g: Fixed oils (corn oil, peanut oil, and
cotton seed oil.)

CAREWELL PHARMACY
Added substances (Additives)
1. Antimicrobials.
E.g.: Phenyl mercuric acetate - 0.01%, Thiomersal - 0.01%,
Benzothenium chloride - 0.01%, Phenol and cresol - 0.5%.
2. Anti oxidants. E.g.: Sodium bisulfide. ascorbic acid - 0.02-0.1%,
Thiourea - 0.005%
3. Buffering agents - E.g.: Citric acid, sodium citrate.
4. Bulking agents - E.g.: lactose - 0.14-0.5% mannitol - 0.4 – 2.5%
5. Chelating agents - E.g.: Disodium edetate – 0.003 -0.05% Tetra
sodium edetate – 0.01 %
6. Protectants - E.g.: sucrose, lactose (2-5%)
7. Solubilizing agents. E.g.: Tweens & polysorbates.
8. Tonicity adjusting agents. E.g.: sodium sulfate – 1.1%, sorbitol - 2%
9. Surfactants. E.g.: polyethylene- 0.1 -0.5% sorbitan monooleate-0.05-
0.25%
Vehicles
Water for Injection (WFI):
 Water that is intended for use in the manufacture of parenteral

(i.e. injectable) drugs whose solvent is water.
 The USP (United States Pharmacopeia) defines this as highly
purified waters containing less than 10 CFU/100 ml of Aerobic
bacteria.
Sterilized Water For Injection (SWFI):
 Sterile, nonpyrogenic, distilled water in a single dose container

for intravenous administration after addition of a suitable solute.
 It may also be used as a dispensing container for diluent use.
 The pH is 5.5 (5.0 to 7.0).
 No antimicrobial or other substance has been added.

CAREWELL PHARMACY
Bacteriostatic Water for Injection (BWFI):
 Sterile water containing 0.9% benzyl alcohol that is used to dilute

or dissolve medications.
 The container can be reentered multiple times. (usually by a
sterile needle) and the benzyl alcohol suppresses or stops the
growth of most potentially contaminating.
Manufacturing of WFI
The source water usually must be pretreated by one or a combination

of following treatment:
 Chemical softening,
 Filtration,
 Deionization,
 Carbon absorption, or
 Reverse osmosis purification.
There are three types of distillation still to produce water for

injection.
1. Compression distillation process

2. Multiple-effect still process
3. Reverse osmosis process
Containers
1. Glass:
1. Type-I: Highly Resistant Borosilicate Glass

2. Type II: Treated Soda lime Glass
3. Type III: Regular Soda Lime Glass
4. Type IV: N.P (Non-parenteral) Glass

CAREWELL PHARMACY
2. Plastic: Plastic containers are used but they face following

problems.
 Permeation
 Sorption
 Leaching
 Softening
3. Rubber - To provide closure for multiple dose vials, IV fluid

bottles, plugs for disposable syringes and bulbs for ophthalmic
pipettes, rubber is the material of choice.
Problems associated with rubber closures are:
 Incompatibility
 Chemical instability
 Physical instability

CAREWELL PHARMACY
Evaluation of Parenteral Preparations

The finished parenteral products are subjected to following tests in
order to maintain quality controls:
1. Sterility test
2. Clarity test
3. Leakage test
4. Pyrogens test
5. Assay
1. Sterility test
It is a procedure carried out to detect and conform absence of any

viable form of microbes in or on pharmacopeia preparation or product.
Method of sterility testing
1. METHOD 1: Membrane filtration method

2. METHOD 2: Direct inoculation method
1. Membrane filtration method (Method 1)
Membrane filtration Appropriate for: (advantage)
 Filterable aqueous preparations

 Alcoholic preparations
 Oily preparations
 Preparations miscible with or soluble in aqueous or oily (solvents
with no antimicrobial effect)
All steps of this procedure are performed aseptically in a Class 100

Laminar Flow Hood.

CAREWELL PHARMACY
Composition of Culture Medium for Sterility Testing Components

CAREWELL PHARMACY
2. Directt inoculation method (METHOD 2)
 Suitable for samples with small volumes

 Volume of the product is not more than 10% of the volume of the
medium
 Suitable method for aqueous solutions, oily liquids, ointments and
creams
 Direct inoculation of the culture medium suitable quantity of the
preparation to be examined is transferred directly into the
appropriate culture medium & incubate for not less than 14 days.
2. Clarity test
 Particulate matter is defined as unwanted mobile insoluble matter

other than gas bubble present in the product.
 If the particle size of foreign matter is larger than the size of
R.B.C. It can block the blood vessel.
The permit limits of particulate matter as per I.P. are follows:

CAREWELL PHARMACY
3. Leakage test
The sealed ampoules are subjected to small cracks which occur due to
rapid temperature changes or due to mechanical shocks.
Filled & sealed ampoules
Dipped in 1% Methylene blue solution
Under negative pressure in vacuum chamber
Vacuum released colored solution enter into the ampoule
Defective sealing
Vials & bottles are not suitable for this test because the sealing
material used is not rigid

CAREWELL PHARMACY
4. Pyrogen test
 Pyrogen = "Pyro" (Greek = Fire) + “gen” (Greek = beginning).

 Fever producing, metabolic by-products of microbial growth and
death.
 Bacterial pyrogens are called "Endotoxins". Gram negative bacteria
produce more potent endotoxins than gram + bacteria and fungi.
 Endotoxins are heat stable lipopolysaccharides (LPS) present in
bacterial cell walls, not present in cell-free bacterial filtrates.
Types of Pyrogen test
a. Rabbit test
b. Limulus amebocyte lysate [LAL] test
a. Rabbit test method
 Dissolve the subs being examined in, or dilute it with a pyrogenic

free saline solution.
 Warm the liquid being examined to approx. 38.50 C temp before
injection.
 The volume of injection is NLT 0.5ml/kg & NMT 10ml/kg of body
weight.
 Withhold water during test.
 Clinical thermometer is inserted into the rectum of rabbit to record
body temperature.
 2 normal reading of rectal temp are should be taken prior to the
test injection at an interval of half an hour’s & its mean is
calculated- initial temperature.
 The solution under test is injected through an ear vein.
 Record the temp of each rabbit in an interval of 30 min for 3 hrs.
 The difference between initial temp & maximum temp is recorded-
taken as response.

CAREWELL PHARMACY
b. Limulus amebocyte lysate [LAL] test
 Limulus amebocyte lysate [LAL] test another method for the

determination of pyrogenic endotoxins.
 In this method the test solution is combined with a cell lysate from
the ameabocyte [blood cells] of horse shoe crab.
 Any endotoxin that might be present will be coagulated with protein
fraction of the amebocyte and results in the formation of a gel.
 This consider to be simple, rapid and of greater sensitivity that the
rabbit test.
5. Assay
Assay is performed to standardize according to the method given in

the monograph of that parenteral preparation in the pharmacopoeia.
Assay is done to check the quantity of medicament present in the

parenteral preparation.

CAREWELL PHARMACY
UNIT 1.b Optimization techniques in Pharmaceutical

Formulation
Concept of Optimization
 The term optimize is defined as “to make perfect".

 In terms of sentence it is defined as choosing the best element
from some set of available alternatives.
 According to Merriam Webster dictionary, optimization means, "An
act, process or methodology of making something (as a design,
system or a decision) as a fully perfect, functional or effective as
possible; specially the mathematical procedures.
 Optimization is also defined as "The process of finding the best
values for the variables of a particular problem to minimize or
maximize an objective function."
 It is used in pharmacy relative formulation and processing.
 It is involved in formulating drug products in various forms.
 Final product not only meets the requirements from the bio-
availability but also from the practical mass production criteria.
 It helps the pharmaceutical scientist to understand theoretical
formulation and the target processing parameters which ranges for
each excipients & processing factors.
 In development projects, one generally experiments by a series of
logical steps, carefully controlling the variables & changing one at a
time, until a satisfactory system is obtained.
 "It is not a screening technique."

CAREWELL PHARMACY
Optimization is necessary because,
1. It reduces the cost.

2. It provides safety
afety and reduces the error.
3. It provides innovation and efficacy.
4. It saves the time.
Parameters of Optimization
Parameters of optimization are divided into two main

ain types which is
shown schematically:
a. Problem type
There are two general type are there in the problem type of
optimization technique:
1. Constrained
2. Un constrained
1. Constrained: These are the restrictions placed on the system by
physical limitations or perhaps by simple practicality.
Example: Economical considerations

CAREWELL PHARMACY
2. Un constrained: Here there are no restrictions.

With the help of flow chart we can predict these two problem type
very easily viz.,
b. Variables:
Mathematically, they can be divided into two groups:
1. Independent
pendent or primary variables
2. Dependent or secondary variables
1. Independent or primary variables:
 Formulations and process variables directly under control of the

formulator.
Example: Ingredients
Ingredients, Mixing time for given process step.

CAREWELL PHARMACY
2. Dependent or secondary variables:
 These are the responses or the characteristics of the in-progress

in
material or the resulting drug delivery system.
Example: Direct result of any change in the formulation or process.
 If greater the variables in a given system, then greater will be the

complicated job of optimization.
 But regardless of the no.of variables, there will be relationship
between a given response and independent variables.
 Once we know this relationship for a given response, then will able
to define a response surface i.e.,

CAREWELL PHARMACY
 It involves application of calculus to basic problem for

maximum/minimum function.
Limited applications
a. Problems those are not too complex.

b. They do not involve more than two variables.
For more than two variables, graphical representation is impossible, but

it is possible mathematically.

CAREWELL PHARMACY
Optimization Techniques in Pharmaceutical

Formulation and Processing
Deming and king presented general optimization techniques:
techniques
Considering the changes in input and effect on output, the optimization

techniques are categorized into five types:
1. Evolutionary operations
2. Simplex method
3. Lagrangian method
4. Search method
5. Canonical analysis
1. Evolutionary Operations
 It is the one of the most widely used methods of experimental

optimization in fields other than pharmaceutical technology is the
evolutionary operation(EVOP),
 It is well suited to production situation.

CAREWELL PHARMACY
 The basic idea is that the production procedure(formulation and

process) is allowed to evolve to the optimum by careful planning and
constant repetition.
Method: This process is run in a such a way that
a. It produces a product that meets all specifications.

b. Simultaneously, it generates information on product improvement.
 Experimenter makes a very small change in the formulation or
process but makes it so many times i.e., repeates the experiment so
many times.
 Then he or she can be able to determine statistically whether the
product has improved.
 And the experimenter makes further any other change in the same
direction, many times and notes the results.
 This continues until further changes do not improve the product or
perhaps become detrimental.
Applications:
a. It was applied to tablets by Rubinstein.

b. It has also been applied to an inspection system for parenteral
products.
Drawbacks:
a. It is impractical and expensive to use.

b. It is not a substitute for good laboratory scale investigation.

CAREWELL PHARMACY
2. Simplex Method
 It is most widely applied technique.

 It was proposed by Spendley et.al.
 This technique has even wider appeal in areas other than formulation
and processing.
 A good example to explain its principle is the application to the
development of an analytical method i.e., a continuous flow anlayzer,
it was predicted by Deming and king.
 Simplex method is a geometri
geometric
c figure that has one or more point
than the number of factors.
 If two factors or any independent variables are there, then simplex
is represented triangle.
 Once the shape of a simplex has been determined, the method can
employ a simplex of fixed size or o of
f variable sizes that are
determined by comparing the magnitude of the responses after each
successive calculation techniques in pharmaceutical

CAREWELL PHARMACY
Explanation
 The two axes in the figure are nothing but two independent
variables show the pump speeds for the two reagents required in
the analysis reaction.
 The initial simplex is represented by the lowest triangle.
 The vertices represent the Spectrophotometric response.
 The strategy is moves towards a better response.
 The worst response is 0.25, conditions are selected at the vertex,
0.6 and indeed improvement is obtained.
 Then the experiment path is followed to obtain optimum, 0.721.
3. The Lagragian method:
 This optimization method represents the mathematical technique, is

an extension of the classic method.
 Fonner.et.al gave ideas of understanding this technique by applying
it to a tablet formulation and by considering two independent
variables.
Explaination:
 The active ingredient, phenylpropanolamine HCl, was kept at a

constant level, and the levels of disintegrant (corn starch) and
lubricant (stearic acid) were selected as the independent variables
x1 and x2
 The dependent variables include tablet hardness, friability, volume,
in vitro release rate and urinary excretion rate in human subjects.
 This techniques requires that the experimentation to be completed
before optimization so that mathematical models can be generated.

CAREWELL PHARMACY
The experimental data for the taken example:
Tablet formulation:
The analysis is performed on a polynomial form.
And these terms were retained and eliminated according to stand

stepwise regression techniques.
In above equation,
 y = Any given response

 B1 = The regression co
co-efficient
efficient for the various terms containing
levels of the independent variables,
 Each response have its own equation.
 A graphic technique may be obtained from the polynomial equations.

CAREWELL PHARMACY
It shows the contours for tablet hardness as the levels of the independent
variables are changed.
It shows similar contour for the dissolution response t50%

CAREWELL PHARMACY
The above graph shows the feasible space with the limits of hardness be 8-10 kg
and t50% be 20-33 min. This figure is obtained by superimposing a and b.
In the mathematical technique slightly different constraints are used.
In this example:
The constrained optimization problem is to locate levels of stearic acid

(x1) and starch (x2).
That minimizes the time of Invitro release (y2)
Such that the average tablet volume (y) did not exceed 9.422 cm2 and
the average friability (y3) did not exceed 2.72%.
To apply the Lagrangian method, this problem must be expressed

mathematically as follows:
 y2 = F2 (X1, X2)………………………1
 Y3F3 (X1, X2)≤2.72………….…….2
 Y4 = F4 (X1, X2) ≤ 0.422.………3
 And 5≤ x ≤ 45…………….………….4
 1 ≤ x ≤ 41…………………………………5
Equation (4) and (5) are the solution within the experimental range.

CAREWELL PHARMACY
 The foregoining inequality constraints must be converted to

equality constraints before the operation begins and this is done
by introducing a slack variable 'q' for each.
 The several equations are then combined into a Lagrange
Lagran function
F and this necessitates the introduction of a Lagrange multiplier
λ for each constraint.
 The partial differentiation of Lagrange function and solving the
resulting set of six simultaneous equations, value are obtained for
x1 and x2 to yield an optimum invitro time of 17.9mm (t50%).
 The solution to a constrained optimization program may depend
heavily on the constraints applied to the secondary objectives.
 A technique called "sensitive analysis" can can provide information
so that thee formulator can further trade off one property for
another.
 For sensitivity analysis the formulator solves the constrained
optimization problem for systemic changes in the secondary
objectives.
Example:

CAREWELL PHARMACY
The several steps in the Lagrangian method can be written as

follows:
1. Step-1: Determine objective function.

2. Step-2: Determine constraints.
3. Step-3: Change inequality constraints to equality constraints.
4. Step-4: Form the Lagrange function, F
a. One Lagrange multiplier & for each constraint.
b. One slack variable q for each inequality constraint.
5. Step-5: Partially differentiate the Lagrange function for each
variable and set derivatives equal to zero.
6. Step-6: Solve the set of simultaneous equations.
7. Step-7 Substitute the resulting values into the objective functions.
This can be phased into four phases, this was given by Buck et.al
The phases are:
a. A preliminary planning phase

b. An experimental phase
c. An analytical phase
d. A verification phase

CAREWELL PHARMACY
4. Search methods
It is defined by appropriate equations. It does not require continuity

or differentiability of function. It is applied to pharmaceutical system
For optimization 2 major steps are used
a. Feasibility search--used
used to locate set of response constraints that
are just at the limit of possibili
possibility.
b. Grid search – experimental range is divided in to grid of specific
size & methodically searched
Steps involved in search method
 Select a system
 Select variables
 Perform experiments and test product
 Submit data for statistical and regression analysis
 Set specifications for feasibility program
 Select constraints for grid search
 Evaluate grid search printout

CAREWELL PHARMACY
Experimental conditions
 Then the data is subjected to statistical analysis followed by

multiple regression analysis.
 The equation used in this design is second order polynomial.
 A multivariate statistical technique called principle component

analysis (PCA) is used to select the best formulation.
 PCA utilizes variance
variance-covariance
covariance matrix for the responses involved
to determine their interrelations
interrelationship.
Advantages of search method:
 It takes five independent variables in to account.

 Persons unfamiliar with mathematics of optimization & with no
previous computer experience could carry out an optimization
study.

CAREWELL PHARMACY
5. Canonical Analysis
 It is a technique used to reduce a second order regression equation.

This allows immediate interpretation of the regression equation by
including the linear and interaction terms in constant term.
 This was firstly adopted by Box and Wilson,
 It is used to reduce second orde
orderr regression equation to an equation
consisting of a constant and squared terms as follows
follows:
 It is described as an efficient method to explore an empherical

response.

CAREWELL PHARMACY
Statistical Design
Techniques used divided in to two types:
1. Experimentation continues as optimization proceeds.

It is represented by evolutionary operations (EVOP), simplex
methods.
2. Experimentation is completed before optimization takes place.
It is represented by classic mathematical & search methods.
In later one it is necessary that the relation between any dependent

variable and one or more independent variable is known.
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.

CAREWELL PHARMACY
Flow Chart for Optimization
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

CAREWELL PHARMACY
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.)
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.

CAREWELL PHARMACY
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

CAREWELL PHARMACY
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 designs
a. Box-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'.
 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.

CAREWELL PHARMACY
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
Faced (CCI) - star points on the faces of the cube

CAREWELL PHARMACY
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.

CAREWELL PHARMACY
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.

CAREWELL PHARMACY
UNIT 2 - Validation
Validation - The term validation has been defined by many different
authors. Although the wording may be different, the sense is always
the same. One of today's commonly accepted definitions of validation
was given by the FDA and it defines validation as 'Establishing
documented evidence which provides a high degree of assurance that a
specific process will consistently produce a product meeting its
predetermined specifications and quality attributes.'
Types of Validation
1. Prospective Validation
2. Concurrent Validation
3. Retrospective Validation
4. Revalidation
1. Prospective Validation
Prospective validation is conducted before a new product is released

for distribution or, where the revisions may affect the product's
characteristics, before a product made under a revised manufacturing
process is released for distribution.
Criteria for performing the prospective validation:
 Facilities and equipments should meet GMPs requirements

 Personnel has to be trained properly
 Critical processing steps and processing variables should be
identified and provisional operational control limits for each
critical test parameter should be provided using pilot laboratory
batches (10 x)
Points to be considered:

CAREWELL PHARMACY
 Different lots of raw materials should be used.

 Batches should be run in succession on different days
 Batches should be manufactured in equipment and other facilities
meant for commercial production.
 Critical process variables should be set with in their upper and
lower limits during process operation.
 If failure occurs it should be subjected to process requalification
and subsequent revalidation.
2. Concurrent Validation
Concurrent validation is used for establishing documented evidence

that a facility and processes do what they purport to do, based on
information generated during actual imputation of the process.
Concurrent validation is a subset of prospective validation and is

conducted with the intention of ultimately distributing product
manufactured during the validation study.
In-process tests that can be monitored in solid and liquid dosage

forms are:
 Powder-blend uniformity
 Moisture content
 Particle/granule size distribution Weight variation
 Content uniformity
 Disintegration time / dissolution time
 Tablet hardness
 pH value
 Color/clarity
 Viscosity/density
 Average unit potency

CAREWELL PHARMACY
Selection of the in-process test process parameters should be on the

basis of the critical processing variables to be evaluated.
3. Retrospective Validation
Retrospective validation is the validation of a process based on

accumulated historical production, testing, control, and other
information for a product already in production and distribution. This
type of validation makes use of historical data and information which
may be found in batch records, production log books, lot records,
control charts, test and inspection results, customer complaints or lack
of complaints, field failure reports, service reports, and audit reports.
Historical data must contain enough information to provide an in-depth
picture of how the process has been operating and whether the
product has consistently met its specifications.
Retrospective validation-method:
 Collect commercial values of in-process data and end product

testing results.
 Organize these data in chronological order.
 Include data from at least 20-30 batches for analysis.
 Isolate critical processing steps data.
 Subject the data to statistical analysis and evaluation.
 Draw the conclusions on the state of control of the
manufacturing process
 Issue a report of findings.

CAREWELL PHARMACY
4. Revalidation
Repeated validation of an approved process (or a part thereof) to

ensure continued compliance with established requirements.
Revalidation should be performed following a change that could have an

effect on the process, procedure, quality of the product and/or the
product characteristics.
Revalidation should be performed following a change that could have an

effect on the process, procedure, quality of the product and/or the
product characteristics.

CAREWELL PHARMACY
Advantages of Validation
a. Process parameters and controls are determined during the
validation of any process or system.
b. It helps to determine the worst case and risks that may arise during
the manufacturing of the quality products.
c. Validation helps to investigate the deviations caused during the
process.
d. Deep study and understanding of the system and equipment are
made possible due to the validation.
e. The risk of the regulatory non-compliance is minimized after the
validation.
f. A validated process required less process control and the finished
product testing.
g. Batch to batch variation is minimized due to the validation of
processes, systems and equipment.
h. Reduces the production cost of the product.
i. Increases the production of manufacturing facility due to the
minimized rework and rejection.
j. Decreases the chances of the failure of the batches.

CAREWELL PHARMACY
Validation and Calibration Master Plan

Validation Master Plan
 A document that provides information on company's validation

program.
 It should define the details and time scales for validation work to
be performed.
 Responsibilities relating to the plan should be stated.
A Validation Master Plan, also referred to as "VMP", outlines the

principles involved in the qualification of a facility, defining the areas
and systems to be validated, and provides a written program for
achieving and maintaining a qualified facility.
A VMP is the foundation for the validation program and should include
process validation, facility and utility qualification and validation,
equipment qualification, cleaning and computer validation.
It is a key document in the GMP (Good manufacturing practice)

regulated pharmaceutical industry as it drives a structured approach
to validation projects.
Food and Drug Administration inspectors often look at VMPs during

audits to see whether or not a facility's validation strategy is well
thought-out and organized.
A VMP should have logical reasoning for including or excluding every

system associated with a validation project based on a risk assessment.

CAREWELL PHARMACY
Methodology
 This section should address the predetermined requirements by

identifying the standards that are to be applied to the facility.
 These are then used in the development of the acceptance criteria
cri
that are used to judge the validation
 It also involves planning and execution of documents such as,
protocols, records, reports, or other.
The standard will involve three elements:
1. Regulatory and guidance documents

2. National standards
3. Company standards

CAREWELL PHARMACY
Calibration Master Plan
"Automatic, mechanical, or electronic equipment or other types of

equipment, including computers, or related systems that will perform a
function satisfactorily, may be used in the manufacture, processing,
packing, and holding of a drug product. If such equipment is so used, it
shall be routinely calibrated, inspected, or checked according to a
written program designed to assure proper performance. Written
records of those calibration checks and inspections shall be
maintained."
Calibration Process
 Calibration process must be managed and executed in a professional

manner.
 A particular place for all calibration operations to take place and
keeping all instruments for calibration.
A separate room is preferred:
 Better environmental control

 Better protection against unauthorized handling or use of the
calibration equipment.
 The performance of all calibration operations is assigned as the
clear responsibility of just one person.
 Calibration procedures, used for quality control functions, are
controlled by the international standards ISO 9000.

CAREWELL PHARMACY
Master Instrument List
 Serial Number
 Name of Instrument
 Location
 Accuracy Required
 Range of Measurement
 Calibration Done Date
 Due Date for Next Calibration
 Calibration Certificate Number & Date
Equipment Classification
Critical Equipment
 Direct measurement that affect the final product quality.

 Measurement on critical process parameters in the process
specification
Non Critical Equipment
 Indirect measurement that will not directly affect the final

product quality
 Shall be maintained based on company maintenance schedule
Verification
 Applicable to equipment that cannot be calibrated (adjustment,

correlation, etc)
 Verification against measurement standard with correction factor
documented
 Actual reporting of result shall include the correction factor
 Temperature correction factor "- 2°C".
 Measured value: 24°C
 Reported value = 24°C -2°C 22°C

CAREWELL PHARMACY
Out of Calibration
 Remove equipment from use

 Out of Calibration Investigation to be carried out to determine the
source of inaccuracy
 Evaluate the impact of OOC result on the final product quality and
other previously measured data
 All investigation findings should be documented.
Calibration Certificate
 Name and address of contracted calibration laboratory

 Name and address of client
 Description and identification of item calibrated
 Environment conditions when calibration was made
 Date of receipt of instrument, date of calibration date of next
calibration
 Calibration method
 Result of calibration
 Signature and title of person responsible for the calibration
 External calibration contract shall be awarded to Accredited by the
nation institution.

CAREWELL PHARMACY
ICH & WHO Guidelines for Calibration and

Validation of Equipments
WHO Guideline:-
1. Design qualification (DQ);

2. Installation qualification (IQ);
3. Operational qualification (OQ); and
4. Performance qualification (PQ).
1. Design Qualification (DQ)
The following are the key considerations for DQ:
 Physical dimensions of the equipment and accessories.

 Suitable operating environment of the instrument.
 Health and safety requirement.
2. Installation Qualification (IQ)
Details of the equipment:
 Equipment name, made by & model no. shall be noted down.

 Location for the installation equipment shall be checked.
 Utilities required shall be listed down.
 Any deviation observed during above procedures should be informed
for corrective action.
Installation procedure:
 After checking all the specifications as mentioned in the selection

criteria, service engineer shall commission the equipment.
 Authorized validation team shall carry out installation qualification.

CAREWELL PHARMACY
3. Operational Qualification (OQ)
 Check the OQ parameters against their specifications.

 Document the deviation details. The quality head and the
department head shall decide whether deviation is acceptable or
not.
 It should support USP I (300 taps/min) and USP II (250 taps/min).
 It should have simultaneous rotating and tapping motion assures an
evenly packed surface. Calculation of test results like tapped
density, compressibility index and hausner ratio.
 It should have printer port for documenting test results as per
GMP/GLP standards.
 The acoustic cabinet reduces the sound level to 71 dB to meet
laboratory standards.
4. Performance qualification (PQ)
 It is determined by placing a graduated cylinder containing known

mass or volume of drug or formulation on a mechanical tapper
apparatus, which is operated for a fixed no. of taps until the power
bed volume has reached a minimum.
 Count and check RPM as per international standards.
 Other procedures specified by relevant international standards.
Such as in pharmaceutical test, weigh the tapping assembly including
the cylinder and cylinder holder and check if weight is in the right
range.

CAREWELL PHARMACY
ICH Guidelines
ICH Q2 defines typical analytical validation characteristics, to which

tests to apply them and examples on the "how to".
It include:
1. Specificity is the ability to assess unequivocally the analytes in the

presence of components which may be expected to be present.
2. Detection Limit of an individual analytical procedure is the lowest
amount of analyte in a sample which can be detected but not
necessarily quantitated as an exact value.
3. Accuracy of an analytical procedure expresses the closeness of
agreement between the value which is accepted either as a
conventional true value or an accepted reference value and the value
found. This is sometimes termed trueness.
4. Precision expresses the closeness of agreement (degree of scatter)
between a series of measurements obtained from multiple sampling
of the same homogeneous sample under the prescribed conditions.
Precision may be considered at three levels: repeatability,
intermediate precision and reproducibility.
5. Linearity of an analytical procedure is its ability (within a given
range) to obtain test results which are directly proportional to the
concentration (amount) of analyte in the sample.
6. Robustness is a measure of its capacity to remain unaffected by
small, but deliberate variations in method parameters and provides
an indication of its reliability during normal usage.
a. Change in pH of mobile phase.
b. Change of column
c. A little bit change of temperature
7. Range of an analytical procedure is the interval between the upper
and lower concentration (amounts) of analyte in the sample (including

CAREWELL PHARMACY
these concentrations) for which it has been demonstrated that the

analytical procedure has a suitable level of precision, accuracy and
linearity.
8. Quantization Limit of an individual analytical procedure is the
lowest amount of analyte in a sample which can be quantitatively
determined with suitable precision and accuracy. The quantitation
limit is a parameter of quantitative assays for low levels of
compounds in sample matrices, and is used particularly for the
determination of impurities and/or degradation products.

CAREWELL PHARMACY
Validation of Specific Dosage Form

Process Validation of Solid Dosage Forms (Tablet)
A tablet is a most known solid pharmaceutical dosages form and

comprises of a mixture of active substances and suitable excipients.
Binders, glidants, lubricants etc are some the popularly used excipients
in the tablets.
The excipients are used for different purposes in the tabletting; like
disintegrants used to enhance the breakdown, glidants used to increase
the flow of the powder, flavouring agents to impart different flavours
in the tablets.
The knowledge of stepwise manufacturing process of any dosages form

is a must for validating any process. It helps in determining the critical
areas which need special consideration in terms of causing problems
during the process.
1. Mixing or Blending
Mixing is one of the most critical step and used at various stages
during manufacturing of tablets. Materials with like physical properties
can easily form a uniform mix or blend and not segregate as soon as
materials with large differences.
Parameters to consider:
a. Mixing Or Blending Technique: The techniques like Diffusion

(tumble), convection (planetary or high intensity), or pneumatic
(fluid bed) are used to mix or blend materials. The choice of
technique depends on whether the drug and excipients are mixed
for a direct compression formulation or for adding the lubricant
(e.g., magnesium stearate) to the granulation.

CAREWELL PHARMACY
b. Mixing or Blending Speed: Mixing the drug and excipient requires

more intense mixing than adding the lubricant to the final blend.
c. Mixing or blending time: The mixing or blending time of the
product will be dependent on the mixing or blending technique and
speed.
d. Drug uniformity: The test for content uniformity is usually
performed to estimate the uniformity of drug throughout the mix
or blend.
e. Excipient uniformity: Besides drug uniformity, excipients
uniformity is also necessary in the granulation or blend.
Two key excipients are:
1. Lubricant: Uneven distribution of the lubricant can result in

picking and sticky problems during compression. It can also lead
to tablet performance problems (low dissolution due to excessive
lubricant in some tablets).
2. Color: The colorant(s) need(s) to be evenly distributed in the
mixture so that the tablets have a uniform appearance (e.g.,
color, and intensity).
2. Wet Granulation
Wet granulation parameters to be considered during development and

validation are:
a. Binder Addition: Adding the binder dry avoids the need to

determine the optimal binder concentration and a separate
manufacture for the binder solution.
b. Binder Concentration: The optimal binder concentration will need to
be determined for the formulation. If the binder is to be sprayed,
the binder solution needs to be dilute enough so that it can be

CAREWELL PHARMACY
pumped through the spray nozzle. It should also be sufficiently

concentrated to form granules without over wetting the materials.
c. Amount of Binder Solution/Granulating Solvent: Too much binder

or solvent solution will over wet the materials and prolong the drying
time. The amount of binder solution is related to the binder
concentration.
d. Binder Solution/Granulating Solvent Addition Rate: The rate or

rate range at which the binder solution or granulating solvent can be
added to the materials should be defined properly.
e. Mixing Time: Granulations that are not mixed long enough can form
incomplete or weak granules. These granules may have poor flow and
compression properties. On the other hand, over mixing the granulation
can lead to harder granules and a lower dissolution rate.
3. Wet Milling
Sometimes wet milling of granules is needed before subjecting it for

drying to efficiently dry them. Factors to consider are:
a. Equipment Size and Capacity: The mill should be large enough to de

lump the entire batch within a reasonable time period to minimize
manufacturing time and prevent the material from drying during this
operation.
b. Screen Size: The screen needs to be small enough to de lump the

material, but not too small to cause excessive heating of the mill,
resulting in drying of the granulation.
c. Mill Speed: The speed should be sufficient to efficiently de- lump

the material without straining the equipment.
d. Feed Rate: The feed rate of the wet granulation is interrelated to

screen size and mill size and speed.

CAREWELL PHARMACY
4. Drying
The type of drying technique (e.g., tray, fluid bed, and microwave)
required for the formulation needs to be determined and justified. The
type of technique may be dependent on such factors as drug or
formulation properties and equipment availability. Changing dryer
techniques could affect such tablet properties as hardness,
disintegration, dissolution, and stability.
The optimal moisture content of the dried granulation needs to be

determined.
a. High moisture content can result in

i. Tablet picking or sticking to tablet punch surfaces and
ii. Poor chemical stability as a result of hydrolysis.
b. An over dried granulation could result in poor hardness and
friability.
Parameters to consider are:
a. Inlet/Outlet Temperature: The inlet temperature is the

temperature of the incoming air to the dryer, while the outlet
temperature is the temperature leaving the unit. The inlet
temperature is critical to the drying efficiency of the granulation
and should be set high enough to maximize drying without affecting
the chemical/physical stability of the granulation. The outlet
temperature is an indicator of the granulation temperature and will
increase toward the inlet temperature as the moisture content of
the granulation decreases (vaporization rate).
b. Airflow: There should be sufficient airflow to ensure removal of
moisture laden air from the wet granulation. Insufficient air flow
could prolong drying and affect the chemical stability of the drug.

CAREWELL PHARMACY
c. Moisture Uniformity: The moisture content could vary within the

granulation.
4. Equipment Capability/Capacity: The load that can be efficiently

dried within the unit needs to be known.
5. Dry Milling
The milling operation will reduce the particle size of the dried
granulation. The resultant particle size distribution will affect such
material properties as flow, compressibility, disintegration, and
dissolution. An optimal particle size/size distribution for the
formulation will need to be determined.
Factors to consider in dry milling are same as that of wet milling.
6. Lubrication
Lubricants are added in order to remove the problem of sticking and

picking in the tablets.
a. Selection of Lubricant: Grade of the lubricant used and

compatibility with other ingredients should be studied thoroughly
and then the appropriate one must be chosen.
b. Amount of Lubricant Added: How much lubricant is required? Too
much lubricant will form hydrophobic layer on the tablet resulting in
dissolution problems.
c. Mixing Time: The optimum mixing time must be decided on proper
trial of batches because if not mixed long enough form problems like
chipping, capping, etc.

CAREWELL PHARMACY
7. Tablet Compression
Compression is a critical step in the production of a tablet dosage

form. As for the compressibility properties of the formulation, it
should be examined on an instrumented tablet press.
Factors to consider during compression are as follows:
a. Tooling: The shape, size, and concavity of the tooling should be

examined based on the formulation properties and commercial
specifications.
b. Compression speed: The formulation should be compressed at a
wide range of compression speeds to determine the operating range
of the compressor.
c. Compression/ejection force: The compression profile for the tablet
formulation will need to be determined to establish the optimal
compression force to obtain the desired tablet hardness.
The following in-process tests should be examined during the

compression stage:
1. Appearance
2. Hardness
3. Tablet weight
4. Friability
5. Disintegration
6. Weight uniformity
7. Tablet Coating

CAREWELL PHARMACY

CAREWELL PHARMACY
Process Validation of Liquids

They are liquid preparation in which the drugs are dissolved, suspended
or disperse in a suitable vehicle and generally several doses are
contained in the bottle.
Two main types:
1. Monophasic liquids:
a. Solutions
b. Elixirs
c. Syrup
d. Liquid drops...etc.
2. Biphasic liquids:
a. Emulsions
b. Suspensions
Process Variables

CAREWELL PHARMACY
Process validation concerns to following operations:
 Raw material validation.

 Monitoring outputs.
 Filling and packaging validation.
Raw material validation - It includes mainly following tests:
 Particle size and size distribution

 Particle shape or morphology
 Microbial count
 Rheology of solvent or vehicle
 PH of the solvent or vehicle
Raw materials are checked and validated for,
1. Particle size and size distribution - Particle size distribution range

is 0.2-2microns for suspensions.
2. Particle shape (Morphology) - It is also important to consider
because it affects the product appearance, solubility, settling rates
and drug stability.
3. Microbial content - To prevent microbial growth on the final
product.
4. PH of The Solvent: Solubility of the drug in the solvent or vehicle
can be markedly influenced by the PH of the solvent.PH of the
solvent is important because large number of chemotherapeutic
agents are either weak acids or weak bases so their solubility
markedly affected by the PH of the solvent.

CAREWELL PHARMACY
Rheology of Solvent
It will determine how well liquid will suspend the insoluble particles.
Viscosity of the External phase is generated by one or more of
following components:
 Suspended solids
 Blend of oils and waxes
 Presence of polyols and polyoxyethylene derivatives
 High concentration of dispersed solids in water
 Dispersed clays, gums, cellulosic, and/or polymers
Monitoring Outputs - Some outputs to be monitored are as under:
a. Appearance
b. pH
c. Viscosity
d. Specific gravity
e. Microbial count
f. Content uniformity
g. Dissolution testing
a. Appearance:
 Appearance of the final product is checked and validated because

it indicates the signs of instability and degradation. For e.g.
settling of solid particles in case of suspension and turbidity in
case of emulsion.
 Time for mixing or agitation and temperature of process can
affect the appearance greatly.

CAREWELL PHARMACY
b. PH Value
 PH of aqueous oral formulations should be taken at a given

temperature and only after equilibrium has been reached in order
to minimize the PH drift.
 Electrolytes, such as potassium chloride, may be added to the
aqueous external phase to stabilize their PH drift
c. Viscosity
 Viscosity is defined as the study of fluid flow or It is a

measurement of the applied stress per unit area to maintain a
certain flow rate.
 The viscometer used for the measurement of viscosity should be
properly calibrated at equilibrium at a given temperature to
establish system reproducibility.
 Viscosity of the liquid oral dosage form is important because it
affects the settling rate of suspended particles in suspension and
of globules of internal phase in emulsions and also in case of oral
solutions it affects the overall appearance of the final product so
it must be measured and validated properly.
d. Specific gravity
 Specific gravity is the weight of the product per unit volume. ▸

 For most of the liquid oral products it is 1gm/cube centimeter.
 A decrease in specific gravity of the product like suspensions
indicates the presence of air within the structure of the
formulation.
e. Hydrometer is used to measure the specific gravity of liquid orals

at a given temperature using well mixed uniform solution.

CAREWELL PHARMACY
f. Microbial count
 Microbial count for the final product is essential to validate

because by performing microbial count we can select the
preservative for the final product storage.
 There are specifications for each liquid oral product for the bio
burden content.
g. Preservative system used in the formulation - The use of small

amounts of propylene glycol (5-15%) or disodium edentate (about 0.1%)
or decrease in the PH of the disperse system have often been use to
increase the efficiency of the preservative system.
Criteria for selection of preservatives:
 Must be effective against a broad spectrum of microorganisms.

 Must be chemically, physically, and microbiologically stable.
 It must be nontoxic, non-sensitizing, soluble and compatible with
other formulation components
h. Content uniformity
In solution, suspensions and emulsions determination of content

uniformity affects the dose uniformity in case of multidose
formulations and also affects the homogeneity of the drug within
solvent system.
Content uniformity of suspension is affected by settling rate which is

governed by following factors
 Particle size of the internal phase.

 Particle density of the internal phase.
 Density of the external phase.
 Viscosity and structure of the external phase.

CAREWELL PHARMACY
i. Dissolution testing:
There is not any official method for dissolution testing of dispersed

system, but the best way to perform dissolution of suspension like
system is to place a small amount of formulation inside a secure Dura
pore (polyvinylidene fluoride) membrane pouch of suitable viscosity and
suspend it in a suitable dissolution medium using a USP method 1 paddle
apparatus.
Test parameters specific for suspension
 Re suspendibility
 Sedimentation rate
 Particle size & particle size distribution
 Zeta potential measurement
Test parameters specific for solution
 Clarity of solution
 Color of solution
Type of emulsion determination by
 Dilution test
 Conductivity test
 Dye solubility test
 COCl2, filter paper
 Fluorescence test

CAREWELL PHARMACY
Process Validation of Semisolid Dosages Form

(Ointment/ Cream)
They are mainly meant for external application e.g. cream, jelly, pastes
etc. The consistency of semisolids lies between the solid and liquid and
thus the preparation is a challenge for manufacturers.
Critical Parameters to be validated
Process Temperature: It is critical to process at right temperature

for successful manufacturing. Too much heating during processing can
result in chemical degradation and insufficient heat can lead to batch
failures, and excess cooling can result in the precipitation of solubilize
ingredients.
Heating and Cooling Rates: The successful consistency of ointments,

for example, depends on proper rates of heating and cooling.
Flow Rates - Optimizing flow rate involves determining the amount of

shear or throughput needed. For example, a water-in oil emulsion may
require a slower addition speed than a traditional, oil-in-water
emulsion, and the flow rate must be modified appropriately. Care must
be taken for any product using a pump. Overhearing can occur if the
formulation is pumped too quickly. If pumping is too slow, the
formulation will experience extra time in an in-line homogenizer, thus
also exposing the formulation to additional shear.
Addition of Polymers and Gums - Addition of polymers (Carbomers)

and gums (Xanthan) must be performed in a very controlled manner if
adding directly to batch. Likewise there are other alternate methods
of incorporation are: Eductors such as Tri Blenders and preparation of
slurry of polymers or gum in a medium of low or no solubility.

CAREWELL PHARMACY
Unit Operation for Semisolid System
There are five unit operations in manufacturing of semisolid dosages

form.
1. Mixing of Liquids
2. Mixing of Solids
3. Mixing of Semisolid
4. Dispersing
5. Milling and Size reduction of solid and semisolid

CAREWELL PHARMACY
Government Regulation
What Is Regulation?
A regulation is a binding instruction issued by an agency (in our case,

the FDA) that tells you how to interpret and comply with law.
Regulations are MUST FOLLOWS that is, if you fail to follow a

regulation, and you have an inspection, the FDA inspector must write up
your failure on 483; failures to follow regulation usually end up in the
"issued warning letter" section of the FDA Web site, not a good place
to be.
The most important regulations applying to validation are good

manufacturing practices (GMP), good clinical practices (GCPs) and good
laboratory practices (GLP).
The best-known quality standards are the ISO 9000 series, which
provide generic standards for development, manufacturing and service.
The most frequently used quality and accreditation standard in
chemical testing laboratories is the ISO17025 std.

CAREWELL PHARMACY
Regulation for Validation under USFDA

Section211.100 (a): Written procedures/deviations - "There shall
be written procedures for production and process control designed to
assure that the drug products have the identity, strength, quality, and
purity.”
Section 211.110: Sampling and testing of in-process materials and

drug products - "....control procedures shall be established to monitor
the output and Validate the performance of those manufacturing
processes that may be responsible for causing variability in the
characteristics of in-process material and the drug product"
21CFR211.133: Control of Microbiological Contamination -

“Appropriate written procedures, designed to prevent microbiological
contamination of drug products purporting to be sterile, shall be
established and followed. Such procedures shall include Validation of
any sterilization process."
FDA must inspect every drug manufacturing establishment at least

once every 2 years.

CAREWELL PHARMACY
Regulation for Validation Under cGMP

Owing to the dynamic nature of the GMPs, in the year 1976, the term
cGMP came into existence. The next revision of the cGMP took place in
1978, and these are in effect at present.
In fact, the word "current" in reference to suggest that they are

dynamic and the regulatory agency constantly updates and maintains
them in relation to the current state of the art and science of drug
manufacturing practice in the revision
Regulation defined the “GMP as a system for ensuring that product are
consistently produced and controlled according to quality standard. It
is designed to minimize the risk involved in any pharmaceutical
production that cannot be eliminated through testing the final
product.”
The first cGMP regulations based largely on the Pharmaceutical

Manufacturers Association's-manufacturing control guidelines.
the Medicines Act (1968) covers most aspects of cGMP in what is

commonly referred to as "The Orange Guide" Validation under
document of cGMP covers procedure, process qualification, equipment
& facilities.
Validation under document of cGMP covers procedure, process

qualification, equipment and facilities.
The current regulations are covered in Code of Federal Regulations

(CFR)
 211.68: Validation of automated process.

 211.84 (d) (2): Validation of supplier's test results for
components.

CAREWELL PHARMACY
 211.84 (d) (3): validation of supplier's test results for container

and closures.
 211.110 (a): validation of manufacturing process to ensure content
uniformity& integrity.
 211.1113 (b): validation of sterilization process.
 211.165: validation of analytical methods. By June 2010, the same
GLP/GMP Validation requirements will apply to all manufacturers of
dietary supplements.
Plans of FDA cGMP
 The FDA plans to oversee 591 national GMP inspections in 2014

and 2015, reduced from 967 performed last year.
 Consequently the agency plans to perform 30 percent more
foreign GMP inspections, increasing last year's total of 604 to a
new grand total of 843 inspections.
 Companies will now be chosen for inspection using the agency's
risk-based inspection model that equates inspection periodicity to
company quality practices and procedures.
 This risk based model develop specifically for FDA GMP PLANS
use, takes into account risk factors; such as, Class I recalls,
adverse events, as well as compliance history as it assigns an
appropriate inspection cycle.

CAREWELL PHARMACY
Validation Requirement for WHO

WHO (World Health Organization) cGMP Guidelines state Validation
studies are an essential part of current good manufacturing practice
(cGMP) and should be conducted in accordance with predefined
protocols.
WHO validation definition: "The documented act of proving any

procedure, process, equipment, material, activity or system which
actually leads to the expected results."
1. DQ: Design Qualification

2. OQ: Operational qualification.
3. IQ: Installation Qualification
4. PQ: Performance qualification
1. DQ: The compliance of the basic design (location plan) with the user
requirements & regulatory requirements should be submitted &
documented.
2. IQ: Documentary evidence to prove that the premises & equipment
have been built & installed in compliance with their specifications.
IQ include:
a. Preventive maintenance.
b. Equipment info.
c. Calibration.
d. Verification of the equipment.
3. OQ: A series of tests to measure the performance capability of
equipment. The OQ for HPLC system is the operation of pump,
injector & detector will be tested at this stage.
4. PQ: Process to verify that the system is repeatable & capable for
consistently producing a quality product.

CAREWELL PHARMACY
Validation Requirement for EU
The European Union requirements for validation is an extract from ICH

Q8, Q9 and Q10 documented guidelines and helps to study continuous
process verification.
EU Validation Definition: "Documented evidence that the process,

operated within established parameters, can perform effectively and
reproducibly, To produce a medicinal product meeting its
predetermined specifications and quality attributes."
Strategies of validation under EU include:
1. Traditional process verification (TPV)

2. Continuous process validation (CPV)
3. Critical process parameter (CPP)
4. Critical quality attributes (CQA)
1. Traditional process verification: process validation should focus on
the control strategy, which primarily includes critical process
parameters and other relevant studies demonstrating that the
process is capable of delivering the desired product quality.
2. Continuous process validation (CPV): an alternative approach to
process validation in which manufacturing process performance is
continuously monitored & evaluated.
3. Critical process parameter (CPP): Process parameters whose
variability has an impact on a critical quality attribute and therefore
should be controlled to ensure the process produce the desired
quality.
4. Critical quality attributes (CQA): a physical, chemical, biological or
microbiological property should be within an appropriate limit, range
to ensure product quality.
OMEMA

CAREWELL PHARMACY
Validation Requirement under PIC/S
According the EU Guidelines to Good Manufacturing Practice for

Medicinal Products in Annex 15 the principles of qualification &
validation of the PIC/S is given under document PIC/S PI 006-3:
“Doc states: GMP for medicinal products Recommendations on

Validation Master Plan Installation and Operational Qualification ( Non-
Sterile Process Validation Cleaning Validation) can assist with the
interpretation and the implementation."
This document applies primarily to inspectorates of the PIC/S member

for whom it is intended as instruction for preparing an inspection, and
as an advanced training aid for qualification/validation.

CAREWELL PHARMACY
URS, DQ, IQ, OQ & P.Q. of facilities

1. URS
User Requirement Specification (URS) is a list of all requirements of
buyer regarding the equipment to be purchased. URS is prepared by
the equipment user department. It is sent to equipment manufacturer
to make it as desired criteria.
Following points should be included in a pharmaceutical user

requirement specification:
1. Introduction - A brief introduction of the equipment should be

written.
2. Overview
a. Intended Use: Write the use of the equipment in the

manufacturing.
b. Capacity: Write the required capacity if the equipment in the
liter or kgs.
c. Space Availability: Write the available space for installation of
the equipment including height, width and height in mm.
d. Accuracy of Instrument: Write the desired accuracy of the
instrument in decimal places if applicable.
e. Cleaning Requirements: Instrument should be easy to clean.
Write, if there is any specific cleaning requirement.
f. Equipment Specific Requirements: for example, required quality
of Stainless Steel (SS) as SS-308, SS-316 or SS-316L if
applicable.
3. Operational Requirements

CAREWELL PHARMACY
a. Functional Requirements: Specify all technical requirements for

the equipment.
b. Operation: Write the operational requirements.
c. Control System: Specify ON, OFF or other specific equipment
control requirements.
d. Power: Write the requirements on power failure as autostart or
manual.
e. Safety: Write the requirements of safety guard and MCB trips
on short circuit or overload
f. Environment: Temperature and humidity of the area where the
equipment will be installed.
g. Other Requirements: Write the other requirements as the metal
of construction (MOC) of non-contact parts and specific
requirements of seals and tubing.
4. Compatibility and Support
1. Utilities: Available power supply on which instrument shall be

operated. The requirement of the uninterrupted power supply
(UPS) and other specific utility requirements.
2. Availability: Continuous operating time of the equipment in hours
or working shifts.
3. Supporting Documents: Requirements of operating manual, circuit
diagrams, warranty letter, change part list, spare part list etc.
5. Abbreviations
1. List all abbreviations used in this user requirement specification

document.
6. References
7. Approval

CAREWELL PHARMACY
2. Design Qualification
Documented evidence that the premises, supporting systems, utilities,
equipment and processes have been designed in accordance with the
requirements of GMP
Design qualification should provide documented evidence that the

design specifications were met. DQ should ensure that instruments
have all the necessary functions and performance that will enable them
to be successfully implemented for the intended application and to
meet business requirements.
While IQ, OQ, and PQ are being performed in most regulated

laboratories, DQ is not so well known to many laboratories. It is rarely
performed officially in those cases where the equipment is planned for
use in multiple applications, not in a specific one.
DQ is performed in most laboratories but are not called DQ. DQ is

officially required by Annex 15 of the EU Guide for Good
Manufacturing Practices. Therefore inspectors from Europe and from
other PIC/S member countries are quite familiar with the term and
may ask for DQ documents. An FDA inspector may ask for documented
user requirements.
The main purpose of DQ is to ensure that
 The right type of equipment is selected for specific tasks,

 The equipment will have the right functional and performance speci-
fications, and
 The vendor meets the user firm's qualification and support criteria.

CAREWELL PHARMACY
DQ should be performed
 When a new instrument is being purchased, or

 When an existing instrument is being used for a new application
not previously specified.
3. Installation Qualification
Installation qualification establishes that the instrument is delivered
as designed and specified, that it is properly installed in the selected
environment, and that this environment is suitable for the operation
and use of the instrument.
Installation qualification should provide documented evidence that the

installation was complete and satisfactory.
The purchase specifications, drawings, manuals, spare parts lists and

vendor details should be verified during installation qualification.
Control and measuring devices should be calibrated.
The main purposes of IQ are to ensure that the
 Equipment has been received as purchased,

 The equipment meets the physical hardware specification,
 The selected environment meets the vendor's environmental
specifications, individual hardware modules and all accessories
are properly installed and connected to each other,
 The software is completely installed on the designated storage
device,
 Computer systems are properly configured for the intended use,
 The instrument functions in the selected environment, and
 All equipment hardware and software are registered in some kind
of a laboratory equipment database.

CAREWELL PHARMACY
Protocol
1. Develop an operating procedure for IQ.

2. Generate a database for equipment.
3. Ask the vendor to perform IQ as part of the installation.
4. Correct installation of software should be verified for computer
systems. Develop an installation verification master file.
5. An installation check with known chemical standards should be
performed for complex modular systems.
6. Document IQ. If IQ was done by the vendor, the IQ document
should also be signed by the vendor and user.
4. Operational Qualification
Operational qualification is the process of demonstrating that an
instrument will function. According to its operational specification in
the selected environment.
OQ should be carried out after initial installation; after instrument

repair and after other major events, such as upgrades; and at regular
intervals during routine use.
OQ is an important part of the overall equipment qualification process.

The careful selection of test items, the test procedures, and
acceptance limits is extremely important, because if set too
stringently, the instrument's test may have an unnecessarily high
failure rate and/or the maintenance efforts will be too intense. If the
limits are too relaxed, the equipment will not prove itself fit for its
purpose.

CAREWELL PHARMACY
The general procedure to qualify an instrument for operation is as

follows:
1. Define the intended use and the functional and operational

specifications (use criteria as defined during DQ).
2. Develop test procedures and protocols.
3. Define acceptance criteria.
4. Perform the tests.
5. Check if test results meet acceptance criteria
6. Document the results.
7. Develop criteria and steps for requalification, e.g., after repair.
8. Develop procedures in case the equipment does not perform to
specifications.
5. Performance Qualification
Performance qualification (PQ) is the process of demonstrating that an
instrument consistently performs according to a specification
appropriate for its routine use.
Ongoing activities may include the following:
1. Preventive instrument maintenance

2. Regular calibration
3. Full or partial OQ checks
4. Daily check of critical performance characteristics, for example,
baseline noise of a UV detector if limit of detection is critical
5. Daily system suitability testing
6. Analysis of blanks
7. Duplicate analysis
8. Analysis of QC samples
9. Procedures to detect, record, and handle errors and other
unforeseen events

CAREWELL PHARMACY
10. Regular security checks

11. Changes to the system in a controlled manner and controlled
requalification after the change, if necessary
12. Internal audits
13. Participation in proficiency testing schemes
14. Ongoing training programs for employees.
15.
General procedures
1. Develop an equipment logbook.

2. Develop maintenance procedures (with the help of the vendor).
Develop procedures and acceptance limits for performance testing

(criteria: regulations, instrument type, application, performance
requirements).

CAREWELL PHARMACY
UNIT 3 - cGMP & Industrial Management

cGMP refers to Current Good Manufacturing Practice (CGMP)
regulations enforced by US FDA.
Current Good Manufacturing Practices are the methods to be used in,

the facilities or controls to be used for, the manufacturing, processing,
packaging or holding of a drug to assure that such drug meets the
requirements of the act, and has the identity and strength and meets
the quality and purity characteristics that is represented to possess.
Objectives
 Ensure that products are consistently manufactured and controlled

to the specified quality.
 Concerned with all aspects of production and quality control.
 In the manufacture of cosmetic products, overall control and
monitoring
 Ensure that the consumer receives products of specified quality.
 The quality of a product depends on the starting materials,
production and quality control processes, building, equipment and
personnel involved.
 cGMP regulations assures the identity, strength, quality and purity
of drug products

CAREWELL PHARMACY
Layout of Buildings
Plant Layout
 Plant layout is a coordinated effort to achieve the final objective to

integrate machines, materials, and personnel for economic
production.
 Involves location of different departments and arrangement of
machinery in each department.
Types of Plant Layout
1. Process layout or functional layout

2. Product or straight line layout
1. Process layout or functional layout
Arrangement of machines of a particular class doing a particular

process as separate department.
Advantage
 More effective supervision

 Division of labor can be provided
Disadvantage
 May not be possible as a number of unit operations have to be

performed

CAREWELL PHARMACY
2. Product or straight line layout
The arrangement of machines doing various operations in a line as one

department.
Advantages
 Processing of work is quick and smooth

 Cost of handling is reduced using conveyers
 Manufacturing time can be reduced
 Floor space can be properly utilized
Factors Influencing Plan Layout
 Basic managerial policies and decisions

 Nature of plant location
 Type of industry and process
o Intermittent industries
o Continuous industries
 Types of methods of production
o Job production.
o Batch or lot production
o Continuous or mass production

CAREWELL PHARMACY
Stores-Layout
Should be planned in the objectives of:
 Achieving minimum wastage of space

 Achieving maximum ease of operations
The layouts should:
 Make optimum utilization of floor space and height

 Should be 1.5- 3m wide to facilitate traffic
 Permit effective and orderly segregation of various categories
of materials and allow rotation of stock (1st in 1st out)
 Should be ventilate
 Have provisions for storage as per specific conditions
 Adequately protected from waste, damage and deterioration.

CAREWELL PHARMACY
Services
1. Lighting - Adequate lighting shall be provided in all areas.
2. Ventilation, air filtration, air heating and cooling
 Adequate ventilation shall be provided.

 Equipment for adequate control over air pressure, micro-
organisms, dust, humidity, and temperature shall be provided
appropriate for the manufacture, processing, packing, or holding
of a drug product.
 Air filtration systems, including pre-filters and particulate
matter air filters, shall be used appropriate on air supplies to
production areas.
3. Plumbing - Potable Water shall be supplied under continuous

positive pressure in a plumbing system free of defects that could
contribute contamination to any drug product. Potable water shall meet
the standards as prescribed.
4. Sewage and refuse - Sewage, trash, and other refuse from the
building and premises shall be disposed of in a safe and sanitary
manner.
5. Washing and toilet facilities - Adequate washing facilities shall be

provided, including hot and cold water, soap or detergent, air driers or
single-service towels, and clean toilet facilities easily accessible to
working areas.
6. Sanitation
 Any building used in the manufacture, processing, packing, or

holding of a drug product shall be maintained in a clean and
sanitary condition, Any such building shall be free of infestation
by rodents, birds, insects, and other vermin (other than

CAREWELL PHARMACY
laboratory animals). Trash and organic waste matter shall be held

and disposed of in a timely and sanitary manner.
 Sanitation procedures shall apply to work performed by
contractors or temporary employees as well as work performed
by full-time employees during the ordinary course of operations.

CAREWELL PHARMACY
Equipments & Maintenance

Equipment should be designed and located to suit the production of the
product.
Design and Construction
 The equipment surfaces coming into contact with any in-process

material should not react with or adsorb the materials being
processed.
 Equipment should not adversely affect the product through
leaking valves, lubricant drips and through inappropriate
modifications or adaptations.
 Equipment should be easily cleaned.
 Equipment used for flammable substances should be explosion
proof
Installation and Location
 Equipment should be located to avoid congestion and should be

properly identified to assure that products do not become
admixed or confused with one another.
 Water, steam and pressure or vacuum lines, where applicable,
should be installed so as to be easily accessible during all phases
of operation. They should be clearly identified.
 Support systems such as heating, ventilation, air conditioning,
water (such as potable, as potable, purified, distilled), steam,
compressed air and gases (example nitrogen) should function as
designed and identifiable.

CAREWELL PHARMACY
Equipment cleaning and maintenance
 Equipment and utensils shall be cleaned, maintained, and sanitized

at appropriate intervals to prevent malfunctions or contamination
that would alter the safety, identity, strength, quality, or purity
of the drug product
 Written procedures shall be established and followed for cleaning
and maintenance of equipment, including utensils, used in the
manufacture, processing, packing, or holding of a drug product.

CAREWELL PHARMACY
Production Management
Production is defined as the step by step conversion of one for of
material into another form through chemical or mechanical process to
create or enhance the utility of the product to the user
Production management
 It is the process in which the raw material is converted into

finished goods & products. It deals with the decision making
regarding the quality, quantity, cost, etc. of production.
 Production in pharmaceutical company consists of the creation &
maintenance of a clearly defined organization & makes effective &
coordinated use of personnel, land, buildings & equipment, including
the management of inventory assets.
 The production management when done in a pharmaceutical company
is known as Pharmaceutical Management.
 Its main aim is to produce goods of right quality & quantity by time
at minimum cost, also tries to improve the efficiency of the product.
Importance of production management
 Important role to the business firm or the industry.

 Satisfy the customer's needs and achieve its objectives & maintain
the reputation, goodwill and image.
 It helps to introduce new products.
 It helps to face competition in the market by making products of
right quality, quantity and at time.
 It also facilitates optimum utilization of resources such as
manpower, machine, etc.

CAREWELL PHARMACY
Objectives of Production Management
1. Right Quality: The quality of product is established based upon the

customers’ needs. The right quality is not necessarily best quality. It
is determined by the cost of the product and the technical
characteristics as suited to the specific requirements.
2. Right Quantity: The manufacturing organization should produce the
products in right number. If they are produced in excess of demand
the capital will block up in the form of inventory and if the quantity
is produced in short of demand, leads to shortage of products.
3. Right Time: Timeliness of delivery is one of the important
parameter to judge the effectiveness of production department. So,
the production department has to make the optimal utilization of
input resources to achieve its objective.
4. Right Manufacturing Cost: Manufacturing costs are established
before the product is actually manufactured.
Productivity
 Defined as the ratio of output to input. If we increase the output

and reduce the input then we can increase the production efficiency
 Reduction in wastage of resources such as labor, machines,
materials, power, space, time, capital, etc.
 Human endeavor (effort) to produce more and more with less and
less inputs of resources so that the products can be purchased by a
large number of people at affordable price. Implies development of
an attitude of mind and a constant urge to find better,
 Cheaper, easier, quicker, and safer means of doing a job,
manufacturing a product and providing service.

CAREWELL PHARMACY
Methods to Increase Productivity:
1. Just in time Inventory

2. Outsourcing
3. Operations research
4. Value engineering
5. Total quality management
Master
ster Production Instructions
To ensure the uniformity from batch to batch, master production

instructions for each intermediate & API should be prepared, dated &
signed by one person & independently checked, dated & signed by a
person in the quality unit.
It should include following information:
 Name
me of intermediate or API being manufacture & an identifying
 document reference code, if applicable.
 A complete list of raw materials & intermediates.
 An accurate statement of the quantity & ratio of each raw material
or intermediate to be used, including the unit of measure.
 The production location & major production equipment to be used.
 Detailed production instructions including the following:
following:--
o Sequences to be followed
o Ranges of process parameter to be used

CAREWELL PHARMACY
o Sampling instructions & in-process controls with their

acceptance criteria where appropriate
o Times limits for completion of individual processing steps &/or
the total process where appropriate
o Expected yield ranges at appropriate phases of processing or
time
Where appropriate, special notation & precautions to be followed or

cross references to those.
The instructions for the storage of intermediates or API to ensure its

suitability for use, including the labeling & packaging materials &
special storage conditions with time limit, where appropriate.
Batch Production Record
Batch production record should be prepared for each record should be

prepared for each intermediate & API & should include complete
information relating to the production & control of each batch.
The batch production record should be checked before issuance to

ensure that it is the correct version & a legible, accurate reproduction
of appropriate master production instructions.
Documentation of completion of each significant step in the batch

production records (batch production & control records) should include
the following information:
 Dates and, when appropriate, times

 Identity of major equipment (eg, reactors, driers, mills) used
 Specific identification of each batch, including weights, measures,
and batch numbers of raw materials, intermediates, or any
reprocessed materials used during manufacturing.
 Actual results recorded for critical process parameters.

CAREWELL PHARMACY
 Any sampling performed

 Signatures of the persons performing and directly supervising or
checking each critical step in the operation
 In-process and laboratory test results
 Actual yield at appropriate phases or times
 Description of packaging and label for intermediate or API
 Representative label of API or intermediate if made commercially
available
 Any deviation noted, its evaluation, investigation conducted (if
appropriate) or reference to that investigation if stored separately
 Results of release testing

CAREWELL PHARMACY
Material Management
Definition: - It is an organizational concept which i the authority &
responsibility of all activities principally concerned with the flow of
materials in the organization.
 Material management works continuously with production,

marketing, sales & quality control.
 It has the responsibility of determining the amount of inventory
& its accountability.
 It is concerned with planning, directing & controlling the kind,
amount, location, movement of the various flows of materials used
in & produced by a business enterprise.
Functions of Material management
 Material planning & programming.

 Simplification, standardization & value analysis.
 Inventory control & management.
 Purchasing of materials in desired quantities without delays.
 Receiving of incoming materials.
 Storage, preservation & administration of materials.
 Production planning & scheduling.
 Transportation (internal & external) & material handling.
 Disposing of rejects & obsolete materials.
 Improving operation efficiency through training.

CAREWELL PHARMACY

CAREWELL PHARMACY
Materials - Quality & Quantity - Four factors are considered to be

essential...
1. Quality,
2. Quantity,
3. Price
4. Delivery date.
1. Quality
 It is defined as the suitability of an item to accomplish the

intended purpose.
 The best is not necessarily the highest quality.
 A quality standard is the description of an acceptable quality of a
particular item.
 Size reduction equipment, punches, dies, filling equipment, size
separation equipment etc. should comply with quality
specifications.
 The quality of the material used has direct relationship with the
end use of the product.
2. Quantity
From the inventory point of view, quantity standards are decided on

the following parameters:
 Maximum inventory
 Minimum inventory
 Standard order
 Reorder point.
The quantity is mainly based on the calculation of Economic order

quantity (EOQ).

CAREWELL PHARMACY
3. The prices of materials are negotiated with the firms based on

certain procedures.
4. Delivery dates are finalized based on the needs of organization.
Value analysis
It is a systematic study of every element for its cost in a part,
material or service to make certain that it performs its function at the
lowest possible cost.
Benefits of Value analysis:-
 Cost of existing product or services decreases.

 Unnecessary expenditure can be identified & eliminated in
products, processes or services.
 Product value gets improved for new materials & processes.
 Greater profits acquired
i.e. higher returns on investment.
Types of value:-
1. User value
2. Esteem value
3. Cost value
4. Exchange value.
Value ratio: Value = Function/Total Cost
The value can be improved by the following ways
 Reducing the costs

 Improving the function.
 Achieving both the above.

CAREWELL PHARMACY
Purchasing - Centralized & Decentralized
Purchasing is an activity directed towards securing the materials,

supplies, equipment & services required in the operations of an
enterprise.
Functions of purchasing department: -
 Ordering section places orders with the vendors

 Service section fallows the progress of the purchase orders, its
shipment by the vendor and its final receipt by the company
 Records-section maintains all records of quotation, costs, and
purchases.
Types of Purchasing
1. Centralized purchasing:
Advantages:
 It is an efficient system
 It permits a greater degree of specialization for buying
 Bargaining capabilities are better
 Procuring becomes uniform & consistent materials are procured
without price differentiation
 Duplication of efforts is eliminated
 Purchasing procedure & payment of invoices become simple.
2. Decentralized purchasing - Advantages
 Purchasing system becomes more flexible & efficient

 Procurement is faster
 When purchases are made in a local place, it promotes better
public relations
 Control over purchases is no longer remote.

CAREWELL PHARMACY
Handling and Transportation

Materials handling is the art and science of moving, packing and storing
of substances in any form.
Objectives:
 To Lowers unit materials handling cost.

 To reduce manufacturing cycle time
 To provide better control of the flow of materials
 To provide better working conditions
 To provide Contribution for better quality by avoiding damages to
products
 To Increase storage capacity
 To provide higher productivity at lower manufacturing cost
Principle:
 Material should be moved as little as possible

 Reduction in time by using shortest routers and mechanical
material handling equipment
 The material movement should be in lots rather than in individual
units
 Design of material handling equipment should be such that it can
increase the effectiveness
 Gravity should be used
 Rehandling and back tracking of materials should be avoided
 Periodically Repairing,Maintaince & Checkup of existing material
handling equipments

CAREWELL PHARMACY
Factors affecting the Selection of Materials Handling
Equipment
 Production problem
 Human element involved
Capabilities of the handling equipment available
Production Problem
 Volume of Production to be maintained

 Layout of plant & building facilities ✓Class of materials to be
handled
Human Factors
 Capabilities of manpower
 Safety of Personnel
Equipment factors:
 Flexibility
 Adaptability
 Load capacity
 Space requirement
 Speed
 Supervision required
 Ease of maintainance
 Power
 Cost
 Envioronment

CAREWELL PHARMACY
Types of Material Handling System
1. Equipments oriented systems:

a. Convey or Systems
b. Tractor transfer system
c. Fork lift truck
d. Industrial truck system
e. Underground system
2. Material Oriented Systems
a. Unit handling system
b. Bulk handling system
c. Liquid handling system
3. Methods oriented system
a. Manual systems
b. Automated systems
c. Job shop handling system
d. Mass production system
4. Function oriented system
a. Transportation systems
b. Conveying systems
c. Transferring systems
d. Elevating systems
Type of material handling equipment
1. Conveyers
2. Cranes, Elevators and Hoists
3. Industrial Trucks
4. Auxiliary Equipments

CAREWELL PHARMACY
1. Conveyors: Gravity or powered devices. Used for moving loads from

one point to point over fixed paths.
2. Cranes, elevator and hoist: These are overhead devices used for
moving varying loads intermittently between points within an area.
3. Industrial trucks: May be electric, gasoline, gas powered, diesel.
4. Auxiliary equipment: Devices or attachement used with handling
equipments to make their use more effective and versetile.
Transportation
 "The process of moving an item from point A to point B."

 "Safe, efficient, reliable, and sustainable movement of persons and
goods over time and space"
 The progress in techniques and management principles improves the
moving load, delivery speed, service quality, operation costs, the
usage of facilities and energy saving.
Importance of Transportation
 Without well-developed transportation systems, logistics could not

bring its advantages into full play.
 A good transport system in logistics activities could provide better
logistics efficiency, reduce operation cost, and promote service
quality.
 A well-operated logistics system could increase both the
competitiveness of the government and enterprises.
 Transport system is the most important economic activity among the
components of business logistics systems.
Transportation Functionality
1. Product movement
2. Product storage

CAREWELL PHARMACY
1. Product Movement
Temporal
 Product is locked up during transit, hence inaccessible

 Positive amount of time is spent in transporting material
 Time is a resource [Temporal Resource] expended in
Transportation
 During the time product is locked up costs are incurred in
proportion of time
Financial - Administration costs, Salaries, Maintenance costs are

expended.
Environmental - Fuel costs are high[Creates air pollution, congestion,

Noise pollution.
2. Product Storage
 When unloading and loading is more expensive then storage.

 When storage space is limited [situation when inventory levels are
high].
Principles of Transportation
 Economy of scale
 Economy of distance
Types of Transportation
 Rail
 Road
 Water
 Air

CAREWELL PHARMACY
Inventory Management
Definition: The 'inventory' can be defined as stock of items(includes
raw materials, in process goods, finished goods, packaging, & other
spares) in order to meet an unexpected demand/ distribution in the
future.
(Or)
Inventory is defined as an itemized list of goods with their estimated

worth, specifically, annual account of stock taken in any business.
Category
1. Production Inventory - Special items manufactured to company

specification.
2. MRO Inventory - Maintenance, repair & operating supplies which is
consumed in production process. Do not become part of the product.
3. In-Process Inventory - Semi finished products found at various
stages in the production operation.
4. Finished Goods Inventory - Complete product ready for shipment.
Objectives
 To reduce dependence of one another

 To enable each organisation schedule its operation independently
of another
 To reduce material handling costs.
 To obtain a reasonable utilization of people & equipment.
 Maximize customer service
 Longer production runs
 Flexibility in production scheduling.
 To avoid stock out and shortage.

CAREWELL PHARMACY
Benefits
 Inventory control ensures an adequate supply of material & stores,

minimizes stock out & shortage & avoid costly interruption.
 It keeps down the investment in inventory.
 Eliminate duplication in ordering / replenishing stocks.
 Better utilization of available stocks by facilitating inter-dept
transfer within a company
 Serves as means for the location and disposition of inactive &
obsolete item of services.
 Provide a consistent and reliable basis for preparing financial
statement.
Inventory Costs
 Cost factors must be considered while taking any decision regarding

inventories.
 Includes ordering costs, carrying cost, out of stock/shortage cost
and set up cost.
1. Ordering Cost
 Costs of placing an order with a vendor of material such as preparing

a purchase order (receiving and ordering calls), processing payments
(typing costs), transportation, receiving & inspecting the material.
 This cost does not depend on or vary on the number ordered.
2. Carrying Costs/Holding Cost
 Costs connected directly with material such as deterioration,

pilferage, storage facilities, and obsolescence.
 Financial costs includes taxes, insurance, handling charges & interest

CAREWELL PHARMACY
3. Out Of Stock/Shortage Cost
 Back ordering
 Lost sales
 Customers goodwill
4. Cost of Item - Direct cost of item.
5. Set Up Cost - It include production charge- equipment change

over, report preparation etc.
Role of Pharmacist in Drug Procurement
The hospital pharmacist should be in collaboration with the purchase

officer, assuming the following duties:
 Maintaining a list of names, addresses, and telephone numbers of

drug manufacturers, wholesalers and local representatives.
 Preparing detailed specifications for drugs, chemicals, and
biological.
 Preparing request for purchase form.
 Preparing receipt memo, if the drugs are received directly by the
pharmacy.
 Preparing return goods memo whenever applicable.
Techniques in Inventory Management
1. ABC Analysis
2. VED Analysis
3. EOQ Analysis
4. Perpetual Inventory System
5. Lead time
6. Buffer Stock

CAREWELL PHARMACY
1. ABC Analysis
 Always Better Control

Control.
 It is an inventory categorization method used for the analysis of
range of items that have different levels of significance and
should be controlled differently.
 As per the analysis, the inventories are grouped into 3 categories
based on cost of the material and mmoney
oney value of consumptions.
consumptions
Advantages
 The investment in inventory can be regulated and funds can be

utilized in best possible manner.
 There is a closer and strict control on those items which represent
a major portion of total stock value.
 It helps in enough
nough safety stock of C categories of items.
 The scientific and selective control helps in maintenance of high
stock turnover rate.

CAREWELL PHARMACY
2. VED Analysis
This system is based on utility of the material.
The different brands of the drug formulation are classified as:
a. V - Vital Items
b. E - Essential Items
c. D - Desirable Items
a. Vital Items
 They are very useful and important in daily patient care.

 Maximum levels of such drugs should be maintained always in
order to have a continuous supply.
b. Essential items
 These are such items which can affect the pharmacy services to
some extent. They require a lesser stock level when compared to
vital drugs.
 Essential items are those items whose stock - out cost is very
high for the company.
c. Desirable items
 These are required by the pharmacy but they do not affect the
quality of service to the patient.
 Desirable items are those items whose stock-out or shortage
causes only a minor disruption for a short duration in the
production schedule.

CAREWELL PHARMACY
3. EOQ Analysis
 EOQ is the quantity of materials to be ordered at one time,

which minimizes the cost.
 The correct quantity to buy is the quantity at which the ordering
cost and inventory cost is minimum.
EOQ = √2AB/C
 annual requirement
 ordering cost
 carrying cost
Perpetual Inventory System
The method of recording the store balance after every receipt and
issue to facilitate regular checking and to prevent closing down for
stock taking.
It comprises of:
1. Bin Card
2. Store Ledger
3. Continuous Stock Taking
1. Bin Card
 It is a document maintained by the store keeper in his store.

 It serves the purpose of ready reference.
 It shows quantity of each material received, issued and in stock.
2. Store Ledger
 It is kept in the accounting department.

 Generally maintained in form of loose leaf cards, so that they can
be easily removed and inserted.

CAREWELL PHARMACY
3. Continuous Stock Taking
 Only a limited no. of items is verified on a day.

 Selection of the item should be such that each item gets checked
at least a certain no. of times in a year, and checking is evenly
distributed during the period.
Lead Time
 It is the time taken between the placing of order and receipt of

drugs to the department.
 The longer the lead time, longer the safety stock, resulting in
excess of investment in inventory.
Buffer Stock
Is used in emergency to meet the unseen demands ,i.e, the minimum

quantity of particular item which must be kept in the stock at all the
time.
Buffer stock needs the following factors to be taken into consideration

like:
 lead time
 Nature of items, rate of consumption
 Availability of substance
 Re-order level
 Stock out cost

CAREWELL PHARMACY
Production and Planning Control

"Production planning and control is the coordination of a series of
functions according to a plan which will economically utilize the plant
facilities and regulate the orderly movement of goods through the
entire manufacturing cycle, from the procurement of all materials to
the shipping of finished goods at a predetermined rate.'
The process should be,
a. Economical and hence needs planning.

b. Validated, so as to produce products consistent with the
established specifications.
 The production schedule is planned as per the needs of marketing.
 Planning is needed for meeting the changing economic and social
conditions, seasonal demands and market fluctuations.
Characteristics of PPC
1. It is the planning and control of manufacturing process in an

enterprise.
2. All types of inputs like materials, men, machines are efficiently
used for maintaining efficiency of the manufacturing process.
3. Various factors of production are integrated to use them
efficiently and economically.
4. None of the work centers is either overworked or under worked.
5. The work is regulated from the first stage to the stage of
finished goods.

CAREWELL PHARMACY
A. Planning
 It is the first element of production planning and control with a

separate department.
 Planning is deciding in advance what is to be done in future.
 Control devices are also decided in advance so that all activities are
carried on properly.
 An organizational set up is created to pre
prepare
pare plans and policies.
Various charts, manuals and production budgets are also prepared.
 If production planning is defective then control will also be
defective. Planning provides a sound base for control.

CAREWELL PHARMACY
B. Routing
It is determining the exact path or route which will be followed in

production.
"Production routing involves the planning of the exact sequence of

work stations to be used in processing a part of product. Once a layout
has been established the routing of an item is the determination of the
path that item should follow as it is manufactured."
Routing Procedure:
1. Deciding what Part to be made /Purchased

a. The relative cost involved;
b. Purchase policies of the firm;
c. Technical considerations; and
d. Availability of equipment and personnel.
2. Determining Materials Required: The right type of quality,
quantity, and time when needed should also be decided in advance.
3. Determining Manufacturing Operations and Sequences: The
manufacturing operations and their sequences can be determined
from technical experience and layout of machines.
4. Determining of Lot Sizes: A decision has to be taken about the
number of units to be produced in one lot. If production is carried
on the basis.
 Of orders => size of the lot.
 For the stock => lot is decided by considering various
economies which may accurate.
5. Determining of Scrap Factors:
 There may be some scrap during the course of manufacture.
 The finished products are generally less than the units
introduced at the beginning.

CAREWELL PHARMACY
 If products pass through three processes and a normal scrap is

5% of input at every stage then it will be easy to anticipate the
units entering various processes and arrange equipments and
manpower.
6. Analysis of Cost of the Product: The determination of cost of
products may be the duty of cost department but still production
department makes records of direct materials, labour, direct and
indirect expenses. These estimates are greatly useful to costing
department also.
7. Preparation of Production Control Forms: The carrying out of
routing will be facilitated if forms are prepared to collect
information for control purpose. The requirements are: job cards,
inspection cards, labor cards, tool tickets, etc.
C. Scheduling
 Production scheduling may be defined as a process of decision taking

to start the work for production.
 Production scheduling optimizes the production and inventory cost
by properly sequencing the orders and time phasing.
Types: -
1. Master Scheduling
2. Manufacturing or Operation Scheduling
3. Retail Operation Scheduling

CAREWELL PHARMACY
1. Master Scheduling
 This schedule is prepared by keeping in view the order or likely sales

order in near future.
 Master scheduling is the breakup of production requirements. This
may be prepared for a week, a fortnight, a month etc.
 It becomes complex when more products are required to be
produced.
 Master schedule has to be adjusted as per the new order received.
 No definite pattern may be suggested for master schedules because
it differs from industry to industry or in the same industry.
The following information is provided in them:
a. The number of personnel available and the projected man hours in

various shifts etc.
b. The estimated requirements in man-hours per product.
c. The requirements of direct materials for the projected
production.
d. The amount of normal overhead expenses required at the
projected work-load.
2. Manufacturing/Operation Scheduling
 Manufacturing schedule is used where production process is

continuous.
 The name and number of the product and the quantity to be
produced in a given time are required to prepare a manufacturing
schedule.
 If the product to be produced is in a variety of sizes, colors,
weights, types etc. then these things should also be mentioned in
the schedule.

CAREWELL PHARMACY
 The order of preference for the manufacture is also mentioned in

the schedule for a systematic production planning.
3. Detail Operation Scheduling
It indicated the time required to perform each and every detailed

operations of a given machine or process.
D. Loading
 Load indicates the assignment of work to men, machines or

department in advance without specifying when the work is to be
done.
 Loading is used for ensuring efficient utilization of plant and
labor.
E. Dispatching
 Key link between production and sales

 Dispatching function may be routine one of issuing authorization
to start work operation
 Few section authorization are follows
 Stores -authorized to deliver materials
 Tool stores- authorized to release necessary tools • Line
ticketing-It record the beginning and ending time of operations
 Inspection order-to carry out quality of the products

CAREWELL PHARMACY
Dispatching Procedures:
a. Centralized Dispatching:
 Under centralized dispatching orders are directly issued to

workmen and machines.
 The dispatching section keeps full information of the capacity and
work loads of various machines or work centers and sends
instructions as per requirements.
 Centralized dispatching helps in exercising effective control.
b. Decentralized Dispatching:
 Under this procedure all work orders are issued to the foreman or
despatch clerk of the department or section.
 It is the responsibility of the department or section to decide about
the actual start of work on priority among different products.
 The dispatch of orders of materials is left to the decision of the
foreman or dispatch clerk.
 This system minimises red-tape, duplication of posting, production
delays and other drawbacks involved in centralised dispatching.
 This procedure suffers from difficulties in achieving coordination
among different departments.
F. Follow Up and Expediting
 It regulates the progress of materials and part through the

production process.
 This is an important function of production control. If goods are to
be produced as per the plans then a proper follow-up of work is
essential to see whether production schedule is properly adhered to
or not.
 In case there are any bottlenecks then these must be removed in
time.

CAREWELL PHARMACY
G. Inspection
 It is an important step in production control, because it tells

whether the product is of desired quality or not.
 If inspection is not regularly undertaken then there may be a
possibility of more rejections.
 Inspection is undertaken both of products and inputs. On the one
hand work-in-progress
progress and finished products are inspected.
 On the other hand the quality of materials issued, equipment's used
and machines employed is also taken into account.
 The final product will c
certainly
ertainly be influenced by the quality of
various inputs used in production. So inspection ensures the
maintenance of predetermined quality of products.
H. Corrective Actions
According to schedule received from production departments, the

control of production
ion consists of 2 parts - progress reporting &
Corrective action.
Limitation of PPC
 Lack of reliable data

 Time consuming process
 Expensive
 External factors may reduce utility
 Sudden emergencies
 Resistance to change

CAREWELL PHARMACY
Sales Forecasting
 Sales forecasting is the process of estimating future sales.
 According to American Marketing Association, "Sales forecast is an
estimate of sales, in monetary or physical units, for a specified
future period under a proposed business plan or programme and
 Under an assumed set of other forces outside the unit for which
the forecast is made."
 Sales forecast is an art of anticipating what buyers are likely to do
under a set of condition.
 Sales forecasting is an integral part of business planning.
 It is estimate of during specific future period which made according
to proposed marketing plan.
 In sales forecasting, several factors such as government actions,
economics trends, competition, changes in technologies and markets
are considered.
Importance of Sales Forecasting
 Sales forecast is essential for drafting accurate sales budgets,

production and purchasing schedules.
 Enables a business organization to work systematically.
 Enables the production manager to set target for his workers.
 Helps to determine the production capacity that is actually
required.
 Helps to cut down wasteful expenditure.

CAREWELL PHARMACY
Steps of Sales Forecasting Process
Methods for Sales Forecasting - There are mainly two methods:

methods -
1. Qualitative
 Executive opinion met

method
 Delphi method
 Sales force composite method
 Survey of buyer's intentions
2. Quantitative
 Time series analysis

 Market series analysis
 Regression analysis
Benefits of sales forecasting
 Better control of inventory

 Staffing
 Customer information
 Use for sales people
 Obtaining financing

CAREWELL PHARMACY
Limitation of Sales Forecasting
 Part hard fact, part guesswork

 Forecast may be wrong
 Times may change
 The tastes and preferences
 Entry of competitors
 Progress in science and technology
 Economic conditions

CAREWELL PHARMACY
Budget and Cost Control

Budget
An estimate of future costs and revenues expressed in monetary term,

covering over a specific period of time.
Helps in-Prioritizing your spending
 Identify wasteful expenditures

 Adapt quickly as your financial situation changes
 Achieve your financial goals
Budget control
 The exercise of control in the organization with the help of budgets.

 To ensure that planned performance as laid down in the budgets are
being achieved.
 A comparison of plans and actual performance is done and the
difference is reported.
 Regulating the activity of business to follow the pattern which was
planned in the budget.
Types of budget
1. Sales Budget
2. Production Budget
3. Capital Budget
4. Marketing Budget
5. Project Budget
6. Revenue Budget
7. Expenditure Budget

CAREWELL PHARMACY
Objective of Budgetary Control
1. Planning
 It is the process to making a plan for something.

 Force management of all levels to plan for future activities.
2. Coordination
 The process of organizing people or group so that they work

together properly and well.
 Coordinates C - Operation so that objective is successfully
achieved.
3. Communication
 Communication is the process by which we convey our thought,

ideas, and emotion to the receiver.
 In which includes sender and receiver.
4. Motivation - It is the internal and external factors that stimulate

desire in the people to be interested and committed to job.
5. Control - Ensuring the performance by continuous comparisons for

corrective action.
Principles of good budgetary Control
 Managerial responsibilities are clearly defined.

 Budgets must include plan of action.
 Performance must be monitored against the budget.
 Corrective action to be taken if performance differs.
 Budgetary control must enhance 'Management by Exception'.

CAREWELL PHARMACY
Process of Budget Control
 Preparation of various budgets.

 Continuous comparison of actual performance with budgetary
performance.
 Revision of budgets according to circumstances.
Budget Control Tool
 The budget control system (BCS) is designed to allow flexible

customer specific adjustments to all important functions.
Advantages
 Economy in working: Efficiency in business economy.

 Buck passing avoided: Divisional and department responsibility.
 Establishes coordination: Coordinates the various divisions.
 Acts as a safety signal: Shows when to be caution and when to
expand.
 Adoption of uniform policy: Military type of organization.
 Decreases in production costs: By developing new fill in
products.
 Optimum mix: Obtaining the most profitable combination of
different factors of production.
 Favour with credit agencies: Well ordered budget plan
organization receive greater favour from credit agencies.
Disadvantages
 Reduces initiative and innovation for employees

 Impossible to obtain money for new ideas.
 De-motive employees because of lack of participation
 Cause perceptions of unfairness
 Create competition for resources.

CAREWELL PHARMACY
 Based on estimate: Estimate must be based on only available fact

and good.
 Need for continuous adaption: continuously adapted and cannot be
installed and
nd perfected in a short time
 Only
nly a tool of the management: The budget control should be
regarded not as a master but as a servant
Cost control
 Cost control is a process which focuses on controlling the total
cost through competitive analysis.
 It is a practice which works to maintain the actual cost in
accordance with the established norms.
 It ensures that that the cost incurred on an operation should not
go beyond the pre--determined cost.
 It is achievement of pre
pre-determined target of costs.
Step in cost control

CAREWELL PHARMACY
1. Establishing Norms: The first step in cost control is to set norms

or standard which may serve as yardsticks for measuring performance.
These standards are set on the basis of past performance adjusted
for changes in future and on the basis of studies conducted.
2. Comparison with Actual: The actual cost incurred is compared with

established standard costs to know the level of achievement. The
variations are analyzed so as to arrive at the causes which are
controllable.
3. Corrective Action - Remedial measures are taken to avoid the

recurrence of variation in future and for revision of standards
wherever necessary.
Techniques of Cost Control
a. Budgetary control
b. Standard costing
c. Inventory control
d. Ratio analysis
e. Variance analysis
a. Standard costing - Standard costing is one of the prominently

used systems of cost control. Aims at establishing standards of
performance and target costs which are to be achieved under a given
set up working conditions. It is a predetermined cost which
determines what each product or service should cost under certain
situation.
 It starts with an estimate of what a product should cost during a

future period given reasonable efficiency standard costs are
established by bringing together information collected from various
sources within the company.

CAREWELL PHARMACY
 The degree of success is measured by a comparison of actual

performance and standard performance.
Advantages of cost control
 It helps to improve its profitability and competitiveness.

 It helps in reducing the cost and thus reduces its prices.
 It is indispensable of achieving greater productivity.
 If the price of the product is stable and reasonable, it can maintain
higher sales and thus employment of work force.
Disadvantages of cost control
 Reduces the flexibility and process improvement in a company.

 Restriction on innovation.
 Requirement of skilful personnel to set standards.

CAREWELL PHARMACY
Industrial and Personal Relationship

Industrial Relationship
The term of 'Industrial Relation' comprises of two terms:
“Industry
Industry” and “Relations”
 Industry refers to any productive activity in which an individual (or

a group of individual) is engaged.
 Relation we means within the industry between the employer and his
work.
 The term industrial relations explain the relationship between
employees and management which stem directly or indirectly from
union-employer
employer relationship.
 Industrial relations are the relationships between employees and
employers within the organizational settings.
 The term industrial relations has a broad as well as a narrow outlook.
Originally, industrial relations was broadly defined to include the
relationships and interactions between employers and employees.
Parties of IR

CAREWELL PHARMACY
Objectives
 To maintain industrial democracy based on participation of labor in

the management and gains of industry.
 To establish a proper channel of communication.
 To increase the morale and discipline of the employees.
 To safeguard the interests of the labor as well as management by
securing the highest level of mutual understanding and good will
between all sections in an industry.
Importance of IR
 Uninterrupted Production: The most important benefit of industrial

benefits is that it ensures continuity of production. This means
continuous employment for all involved right from managers to
workers.
 Reduction in Industrial disputes: Good Industrial relations reduce
Industrial disputes. Industrial peace helps in promoting co-operation
and increasing production.
 High morale: Good Industrial relations improve the morale of the
employees and motivate the worker workers to work more and
better.
 Reduced wastage: Good Industrial relations are maintained on the
basis of co-operation and recognition of each other. It helps to
reduce wastage of material, manpower and costs.
Cause for Poor IR
1. Economical causes
2. Organizational causes
3. Social causes
4. Psychological causes
5. Political causes

CAREWELL PHARMACY
1. Economical causes - Poor working condition are the main causes for
unhealthy relations between management and labour.
2. Organizational causes - Faulty communications system, unfair
practices, non- recognition of trade unions and labour laws are also
some other causes of poor relations in industry.
3. Social causes - Uninteresting nature of work is the main social
cause of poor Industrial relations.
4. Psychological causes - Lack of job security, non recognition of
merit and performance, poor interpersonal relations are the
psychological reasons for unsatisfactory employer-employee
relations.
5. Political causes - Multiple unions, interunion rivalry weaken the
trade unions. Defective trade unions system prevailing in the
country has been one of the most responsible causes for Industrial
disputes in the country.

CAREWELL PHARMACY
Personal Relationship
Introduction:
 All the regulatory requirements throughout the word talk about

handling the pharmaceutical process by trained people.
 Trained people are those who have knowledge, skill and attitude,
which is appropriate positive.
 WHO remark about personal – it says.' The establishment and
maintenance of a satisfactory system of quality assurance and the
correct manufacture and control pharmaceutical product and active
ingredient rely upon people.
 Individual responsibilities should be clearly understood by the
individuals and recorded.
 All personnel should be aware of the principles of Good
Manufacturing Practice (GMP) that affect them and receive initial
and continuing training, including hygiene instructions, relevant to
their needs.

CAREWELL PHARMACY
Concept of Total Quality Management

A core definition of total quality management (TQM) describes a
management approach to long-term success through customer
satisfaction. In a TQM effort, all members of an organization
participate in improving processes, products, services, and the culture
in which they work.
Concept of TQM
1. Customer-focused: The customer ultimately determines the level of

quality. No matter what an organization does to foster quality
improvement—training employees, integrating quality into the design
process, or upgrading computers or software—the customer
determines whether the efforts were worthwhile.
2. Total employee involvement: All employees participate in working
toward common goals. Total employee commitment can only be
obtained after fear has been driven from the workplace, when
empowerment has occurred, and when management has provided the
proper environment. High-performance work systems integrate
continuous improvement efforts with normal business operations.
Self-managed work teams are one form of empowerment.
3. Process-centered: A fundamental part of TQM is a focus on
process thinking. A process is a series of steps that take inputs
from suppliers (internal or external) and transforms them into
outputs that are delivered to customers (internal or external). The
steps required to carry out the process are defined, and
performance measures are continuously monitored in order to
detect unexpected variation.
4. Integrated system: Although an organization may consist of many
different functional specialties often organized into vertically

CAREWELL PHARMACY
structured departments, it is the horizontal processes

interconnecting these functions that are the focus of TQM.
a. Micro-processes add up to larger processes, and all processes
aggregate into the business processes required for defining
and implementing strategy. Everyone must understand the
vision, mission, and guiding principles as well as the quality
policies, objectives, and critical processes of the organization.
Business performance must be monitored and communicated
continuously.
b. An integrated business system may be modeled after the
Baldrige Award criteria and/or incorporate the ISO 9000
standards. Every organization has a unique work culture, and it
is virtually impossible to achieve excellence in its products and
services unless a good quality culture has been fostered. Thus,
an integrated system connects business improvement elements
in an attempt to continually improve and exceed the
expectations of customers, employees, and other stakeholders.
5. Strategic and systematic approach: A critical part of the
management of quality is the strategic and systematic approach to
achieving an organization’s vision, mission, and goals. This process,
called strategic planning or strategic management, includes the
formulation of a strategic plan that integrates quality as a core
component.
6. Continual improvement: A large aspect of TQM is continual process
improvement. Continual improvement drives an organization to be
both analytical and creative in finding ways to become more
competitive and more effective at meeting stakeholder
expectations.
7. Fact-based decision making: In order to know how well an
organization is performing, data on performance measures are

CAREWELL PHARMACY
necessary. TQM requires that an organization continually collect and

analyze data in order to improve decision making accuracy, achieve
consensus, and allow prediction based on past history.
8. Communications: During times of organizational change, as well as
part of day-to-day operation, effective communications plays a large
part in maintaining morale and in motivating employees at all levels.
Communications involve strategies, method, and timeliness.

CAREWELL PHARMACY
UNIT 4 - Compression and Compaction

Physics of Tablet Compression
Tablet compression is a critical step in the pharmaceutical

manufacturing process, where powdered or granular materials are
compacted into solid tablets.
The physics of tablet compression involves a complex interplay of

forces, material properties, and process parameters.
Basic Principles of Interactions
1. Powder Properties - Powder properties, such as particle size, shape,

and density, significantly influence tablet compression. Smaller,
spherical particles with good flow properties are often desirable for
uniform tablet formation.
2. Interparticle Forces - Van der Waals forces, electrostatic forces,
and capillary forces between particles affect their arrangement and
compaction behavior. The interplay of these forces determines the
powder's flowability and compressibility.
3. Binder and Lubricant Effects: Binders enhance particle adhesion,
promoting tablet cohesion, while lubricants reduce friction between
particles and the die walls, facilitating tablet ejection.

CAREWELL PHARMACY
Compression and Consolidation

1. Primary Compression
ion - During the initial stage of compression, the
powder bed experiences primary compression. This involves the
reduction of void spaces between particles, resulting in
densification.
2. Plastic Deformation - Plastic deformation occurs as particles
rearrange and deform under pressure. This leads to the formation
of interparticulate bonds, contributing to tablet strength.
3. Elastic Deformation - Elastic deformation is temporary and

reversible. It occurs when pressure is applied, causing particles to
move closer
ser together. Upon the release of pressure, the tablet
partially regains its original shape.
4. Consolidation - Consolidation involves the compaction of the powder
bed into a solid tablet. It includes both plastic and elastic
deformation, resulting in a coher
coherent
ent and mechanically stable tablet.

CAREWELL PHARMACY
Compression and Consolidation under High Loads

1. High Pressure Considerations - High compression forces lead to
increased interparticulate forces and greater plastic deformation.
However, excessive pressure can lead to tab
tablet over-consolidation,
consolidation,
affecting dissolution and disintegration properties.
2. Deformation Behavior - Under high loads, particles experience
more significant deformation, resulting in tighter packing and
increased tablet hardness. The compression force must be carefully
controlled to achieve the desired tablet characteristics.
3. Pressure-Volume
Volume Relationships - The compression process can be
analyzed using pressure
pressure-volume
volume relationships. This involves
monitoring changes in tablet volume and density at varying
compression pressures to understand the consolidation behavior.
4. Tablet Porosity - Higher compression forces generally lead to
reduced tablet porosity. While lower porosity enhances tablet

CAREWELL PHARMACY
strength, it may impact the tablet's disintegration and dissolution

rates, affecting drug release.
5. Fracture Behavior - Under high loads, tablets may experience
internal stresses and exhibit different fracture behaviors.
Understanding the fracture mechanics is crucial for designing
tablets with controlled disintegration properties.

CAREWELL PHARMACY
Effect of Friction
These factors influence the quality and characteristics of the final
tablets, including hardness, friability, and uniformity.
1. Role of Friction: Friction occurs between the powder particles, as

well as between the powder and the surfaces of the tablet press
components (punches and dies). Frictional forces resist the movement
of particles during compaction.
2. Compaction Efficiency: Frictional forces can impede the movement

of particles, affecting the compaction efficiency. Higher friction may
lead to a greater resistance to compaction, requiring higher
compression forces to achieve the desired tablet hardness.
3. Die Wall Friction: Friction between the powder and die walls can
result in a phenomenon known as die wall lubrication. Excessive die wall
friction may cause sticking of the powder to the die, leading to
difficulties in tablet ejection and affecting tablet uniformity.
4. Punch Face Friction: Friction between the powder and the punch
faces affects the powder's ability to flow and fill the die cavity.
Proper lubrication is often applied to the punch faces to reduce
friction and ensure smooth ejection of tablets.
5. Impact on Tablet Quality: The level of friction can impact the

mechanical properties of tablets, including hardness and friability.
Proper control of frictional forces is crucial for achieving uniform
tablets with consistent characteristics.

CAREWELL PHARMACY
Distribution of Forces in Compaction

1. Force Application: During compaction, forces are applied to the
powder bed through the punches in a tablet press. The distribution of
these forces is critical for achieving uniform compaction throughout
the tablet.
2. Uneven Force Distribution: Non-uniform distribution of forces may

result in uneven tablet hardness and density. Variations in force across
the tablet surface can lead to defects like capping, lamination, or over-
compression.
3. Die Fill and Powder Flow: Force distribution affects die fill and
powder flow characteristics. An even distribution of forces promotes
uniform powder compaction, reducing the risk of air entrapment and
ensuring consistent tablet properties.

CAREWELL PHARMACY
4. Impact on Tablet Uniformity: The distribution of forces directly

impacts tablet uniformity. If forces are unevenly distributed, certain
regions of the tablet may experience over-compression or under-
compression, leading to variations in hardness and disintegration.
5. Preventing Edge Defects: Adequate force distribution is crucial

for preventing edge defects, such as chipping or feathering. Uneven
forces can cause localized stress concentrations at tablet edges,
compromising their integrity.

CAREWELL PHARMACY
Compaction Profiles
Compaction profiles are hysteresis curves that establish the
relationship between
tween axial pressure and radial pressure.
In the compaction cycle, two forces are considered
1. Axial force: This vertical component is applied by the upper punch

during compression.
2. Radial pressure: This is the horizontal component observed in the
die wall, when the powder mass attempt to expand in the die.
Compression Phase:
 OA - Represents repacking of granules or powders.

 AB - Represents elastic deformation which continues up to B
(elastic limit)
 BC - Represents plastic deformation and brittle fracture. Point C
indicates the maximum compression force.
Decompression phase:
 CD - Represents elastic recovery on the removal of applied force.

 DE - Represents recovery from plastic deformation

CAREWELL PHARMACY
 E- Represents residual force, which holds the compact in the

sides of the die.
 Ejection force must be greater than residual force.
How they are measured?
It is analysed by compaction simulators, these are attached to

punching machines
chines which collect or measure the data from forces on
punches, displacement of punches, die wall friction, ejection force and
a
temperature change.
Types of compaction profiles
1. Force-time profile
2. Force-displacement
displacement profile
3. Die wall force profile
1. Force-Time Profile
Compression force-time
time profiles are used to characterize the
compression behavior of the active ingredients, excipients and
formulations with respect to their plastic and elastic deformation.
a. Compression phase
b. Dwell phase
c. Decompression/relaxation phase

CAREWELL PHARMACY
a. Compression phase - Compression is the process in which maximum

force is applied on powdered bed in order to reduce its volume.
b. Dwell phase - When compression force reaches a maximum value,

this maximum force is maintained for prolonged period before
decompression. The time period b/w the compression phase and
decompression phase is known as dwell time.
c. Decompression phase - Removal of applied force on powder bed i.e,

both punches moving away from upper and lower surfaces.
2. Force-Displacement
Displacement profile
 Assessment of the compaction behavior of materials is done by

force-displacement
displacement profile.
 Force-displacement
lacement profile can be used to determine the behavior
of plastic and elastic materials.
 Stress relaxation is observed to be minimal in case of plastic
deformation; whereas materials that undergo elastic deformation
tend to relax to a greater extent during and/or after compression.
 At a given fmax the displacement area of plastic deformation is more
when compared to the displacement area of elastic deformation.

CAREWELL PHARMACY
3. Die Wall Force Profile
 During tableting, friction arises b/w the material and the die wall
which is called Die wall force friction.
 The die wall force reaches maximum just after the maximum upper
and lower force, and a constant residual value after upper and lower
forces become zero.
 The high die wall force during ejection is a sign of adhesion of
powders to the die.
Applications
 These can be used to monitor compaction cycle.

 Compaction profiles give a good assessment of the elastic
component of the powder.
 Provides information regarding the radial transmission of applied
force to the die wall
wall.
 Helps in calculating possible ejection force and lubricant
requirements.

CAREWELL PHARMACY
Solubility
The term 'solubility' is defined as maximum amount of solute that can
be dissolved in a given amount of solvent. • It is represented through
various concentration terms such as parts, percentage, molarity,
molality, mole fraction, volume fraction etc.
 Solute is the substance being dissolved - Powder.

 Solvent is the dissolving agent - Water.
 Solubility can also be defined quantitatively as well as qualitatively
 Quantitatively it is defined as the concentration of the solute in a
saturated solution at a certain temperature.
 Qualitatively it may be defined as the spontaneous interaction of
two or more substances to form a homogenous molecular dispersion.

CAREWELL PHARMACY
Importance of Solubility
 Solubility is one of the important parameter to achieve desired

concentration of drug in systemic circulation for achieving required
pharmacological response
response.
 Most of the drugs (>40%) belongs to BCS class II (low solubility and
high permeability). As for BCS class II drugs rate limiting step is
drug release from the dosage form and solubility in the gastric
ga
fluid, so increasing the solubility in turn increases the bioavailability
for BCS class II drugs
drugs.
BCS Classification
Factors Affecting Solubility
 Particle size
 Molecular size
 Temperature
 Pressure
 Nature of solute and solvent
 Polarity

CAREWELL PHARMACY
Solubilization: Solubilization can be defined as a preparation of

thermodynamically stable isotropic solution of a substance normally
insoluble or slightly soluble in a given solvent by introduction of an
additional component or components
components.
Process of Solubilization
ation
Solubilization by Co-Solvency
Solvency
 Substances like weak electrolytes and non

non-polar
polar molecules are poorly
soluble in water.
 The solubility of these substances can be enhanced by the addition
of water miscible solvents in which the drug has good solubility
 This process of improving solubility is called as co
co- solvency and the
solvents used are known as co
co- solvents.
 This technique is mainly used in the formulation of parenteral.
 Commonly used co co-solvents
solvents are Ethanol, Sorbitol, Glycerin,
Polyethylene
ene glycol, propylene glycol etc
etc.
 The Solubilizing effect by coco-solvency
solvency depends on the polarity of
the drug with respect to solvent and co
co-solvent.
solvent. That means more

CAREWELL PHARMACY
non polar the solute the greater is the solubilization achieved by the
added solvents.
 Mechanism responsible for solubility enhancement through co-
solvency is by reducing the interfacial tension predominantly
between the aqueous solution and hydrophobic solutes and reducing
the contact angle between the solid and liquid
 Co-solvents increases the solubility by reducing the difference
between the polarity of the drug and water system
Ex. For co-solvency.
The solubility of Diazepam can be increased by using 10% ethanol
and 40% propylene glycol.
Phenobarbitone is relatively insoluble in water but its solubility can
be increased by using mixture of solvents like water, alcohol and
glycerin.
Solubilization by Use of Surfactants
Surfactants are termed as surface-active agents also wetting agents,

emulsifying agents or suspending agents depending on its properties
and use.
Surface-active agents are substances which, at low concentrations,

adsorb onto the surfaces or interfaces of a system and alter the
surface or interfacial free energy and the surface or interfacial
tension.
Surfactants are monomers, it has a characteristic structure possessing

both hydrophobic groups / non-polar regions (their "tails") usually
contain a C12-C18 hydrocarbon chain and hydrophilic groups / Polar
Regions (their heads).

CAREWELL PHARMACY
Therefore, they are soluble in both organic solvents a

and
nd water, so they
called amphiphilic.
 The functional groups such as alcoholic ((-OH),

OH), carboxylic acid (-
(
COOH), sulphate (-SOSO4) & quaternary ammonium(NH4+) contribute to
hydrophilic portion.
 Alkyl chains contribute to lipophilic nature of molecules
 The polar
ar end is oriented towards the water and the non polar end is
projected upwards to space
space.
Mechanism of Action - Surfactants can work in three different ways:
a. Roll-up mechanism: The surfactant lowers the oil/solution and

fabric/solution interfacial tensions and in this way lifts the stain of
the fabric.
b. Emulsification: The surfactant lowers the oil/solution interfacial
tension and makes easy emulsification of the oil
oil.
c. Solubilization: Through interaction with the micelles of a surfactant
in a solvent (water), a substance spontaneously dissolves to form a
stable and clear solution.

CAREWELL PHARMACY
Solubilization by Complexation
 It is reversible association of a substrate and ligand molecule.

molecule
 The
he most common complexing ligands are cyclodextrins, caffeine,
urea, polyethylene glycol, N
N-methyl glucamide.
 Cyclodextrins are unique since they increase the water solubility of
poorly soluble drugs by fitting them into the hydrophobic cavity of
the cyclodextrin
dextrin molecule
molecule.
 These cyclodextrins have the ability to form molecular inclusion
complexes with hydrophobic drugs having poor aqueous solubility.
 These are formed by the insertion of the nonpolar molecule or the
nonpolar region of one molecule into the c
cavity
avity of another molecule
or group of molecules. The most commonly used host molecules are
cyclodextrins Cyclodextrins are non
non- reducing, crystalline, water
soluble, cyclic, oligosaccharides. Cyclodextrins consist of glucose
monomers arranged in a donut shshape ring.
 Complexation of drugs with cyclodextrins has been used to enhance

aqueous solubility and drug stability.
 Cyclodextrins of pharmaceutical relevance contain 6, 7 or 8
dextrose molecules (a, ẞ, y-cyclodextrin)
cyclodextrin) bound in a 1,4-
1,4
configuration to form rings of various diameters.

CAREWELL PHARMACY
 The ring has a hydrophilic exterior and lipophilic core in which

appropriately sized organic molecules can form non covalent inclusion
complexes resulting in increased aqueous solubility and chemical
stability.
 Complexation relies on relatively weak forces such as London forces,
hydrogen bonding and hydrophobic interactions.
Techniques of Complexation
1. Physical Mixture: Active drug with suitable polymer in different

ratios is mixed in a mortar for about one hour with constant
trituration. The mixture is passed through sieve no. 80 and stored in
dessicator over fused calcium chloride.
2. Kneading Method
 Active drug with suitable polymer in different ratios is added to

mortar and triturated with small quantity of ethanol to prepare a
slurry.
 The prepared slurry is then air dried at 250c for 24hours.
 The resultant product is pulverized and passed through sieve
number 80 and stored in dessicator over fused calcium chloride.
3. Co-Precipitate Method
 Active drug is dissolved in ethanol at room temperature and suitable

polymer is dissolved in distilled water.
 Different molar ratios of active drug and suitable polymers are
mixed respectivel.
 The mixture is stirred at room temperature for 1hour and solvent is
evaporated. The resultant mass is pulverized and passed through
sieve number .80 and stored in dessicator.

CAREWELL PHARMACY
UNIT 5 - Study of Consolidation Parameters

Consolidation
An increase in the mechanical strength of the material resulting from

particle-particle interaction. (Increasing in mechanical strength of the
mass).
Consolidation Process
1. Cold welding: When the surfaces of two particles approach each

other closely enough, their free surface energies results in strong
attractive force, a process known as cold welding.
2. Fusion bonding: Multiple point contacts of the particle upon
application of load produces heat which causes fusion / melting.
Upon removal of load it gets solidified and increase the mechanical
strength of mass.
Consolidation Mechanisms
1. Mechanical theory: As the particles undergo deformation, the

particle boundaries that the edges of the particle intermesh,
forming a mechanical bond.
2. Intermolecular forces theory: Under pressure the molecules at the
point of true contact between new, clean surface of the granules are
close enough so that van der Waals forces interact to consolidate
the particle.
3. Liquid-surface film theory: Thin liquid films form bond between
the particles which binds them together at the particle surface. The
energy of compression produces melting of solution at the particle
interface followed by subsequent solidification or crystallization
thus resulting in the formation of bonded surfaces.

CAREWELL PHARMACY
Factors Affecting Consolidation
 The chemical nature of the material

 The extent of the available surface
 The presence of surface contaminants
 The inter surface distance
Diffusion Parameters
This is given by Higuchi.
Q = K√T
Where,
 Q is the amount of drug released in time 't' per unit area

 K is higuchi constant
 T is time in hr.
 Plot: The data obtained is to be plotted as cumulative percentage
drug release versus Square root of time.
 Application: modified release pharmaceutical dosage forms,
transdermal systems and matrix tablets with water soluble drugs.

CAREWELL PHARMACY
Dissolution Parameters
Dissolution is a process in which a solid substance solubilizes in a given
solvent i.e. mass transfer from the solid surface to the liquid phase.
Dissolution parameters:
 Effect of agitation
 Effect of dissolution fluid
 Influence of pH of dissolution fluid
 Effect of viscosity of the dissolution medium
 Effect of the presence of unreactive and reactive additives in
the dissolution medium.
 Volume of dissolution medium and sink conditions
 Deaeration of the dissolution medium
 Effect of temperature of the dissolution medium
Effect of Agitation
 The relationship between the intensity of agitation and the rate of

dissolution varies considerably according to the type of agitation
used, the shape and design of the stirrer and the physicochemical
properties of the solid.
 For the basket method, 100 rpm usually is utilized, while for the
paddle procedure, a 50-75 rpm is recommended.
Effect of Dissolution Fluid - Selection of proper medium for

dissolution testing depends largely on the physicochemical properties
of the drug.
Influence of PH of Dissolution Fluid - Simulated gastric fluid as the

test medium for tablets containing ingredients which reacted more
readily in acid solution than in water (e.g., calcium carbonate).

CAREWELL PHARMACY
Effect of Viscosity of the Dissolution Medium
 If the interaction at the interfaces occurs much faster than the

rate of transport, such as in the case of diffusion controlled
dissolution processes, it would be expected that the dissolution rate
decreases with an increase in viscosity.
 The rate of dissolution of zinc in HCl solution containing sucrose was
inversely proportional to the viscosity of solution.
Effect of the Presence of Un-reactive and Reactive Additives in

the Dissolution Medium
 When neutral ionic compounds, such as sodium chloride and sodium

sulfate, or non ionic organic compounds, such as dextrose, were
added to the dissolution medium, the dissolution of benzoic acid was
dependent linearly upon its solubility in the particular solvent.
 When certain buffers or bases were added to the aqueous solvent,
an increase in the dissolution rate was observed.
Volume of Dissolution Medium and Sink Conditions
 The proper volume of the dissolution medium depends mainly on the

solubility of the drug in the selected fluid.
 If the drug is poorly soluble in water, a relatively large amount of
fluid should be used if complete dissolution is to be expected.
Deaeration of The Dissolution Medium
 Presence of dissolved air or other gases in the dissolution medium

may influence the dissolution rate of certain formulations and lead
to variable and unreliable results.
 Example, the dissolved air in distilled water could significantly lower
its pH and consequently affect the dissolution rate of drugs that
are sensitive to pH changes, e.g., weak acids.

CAREWELL PHARMACY
Effect of Temperature of T
The Dissolution Medium
 Drug solubility is temperature dependent, therefore careful

temperature control during the dissolution process is extremely
important.
 Generally a temperature of 37°+0.5 is maintained during dissolution
determination of oral dosage fo
forms and suppositories.
 For topical preparations as low as 30° and 25°have been used.
Pharmacokinetic Parameters
Pharmacokinetics is defined as the kinetics of drug absorption,
distribution, metabolism, and excretion and their relationship with
pharmacologic, therapeutic or toxicological response in mans and
animals.
Plasma Drug Concentration Time Profile
Three important
ortant pharmacokinetic parameters:
1. Peak plasma concentration (Cmax)

2. Time of peak concentration (t max)
3. Area under the curve (AUC)

CAREWELL PHARMACY
1. Peak Plasma Concentration (Cmax)
 The point of maximum concentration of a drug in plasma is called as

peak and the concentration of drug at peak is known as peak plasma
concentration.
 It is also called as peak height concentration and maximum drug
concentration.
 Cmax is expressed in mcg/ml.
2. Time of Peak Concentration (tmax)
 The time for drug to reach peak concentration in plasma (after

extravascular administration) is called the time of peak
concentration.
 It is expressed in hours.
3. Area under the Curve (AUC)
 It represents the total integrated area under the plasma level- time
profile and expresses the total amount of drug that comes into the
systemic circulation after its administration.
 AUC is expressed in mcg/ml X HRS.
 It is important for the drugs that are administered repetitively for
the treatment of chronic conditions like asthma or epilepsy.

CAREWELL PHARMACY
Heckel Plots
 In 1961, Heckel postulated a linear relationship between the relative
porosity (Inverse density) of a powder and the applied pressure
 Plotting the value of (1/(1
(1/(1-D))
D)) against applied pressure, P, yields a
linear graph having slope, K and intercept, A
 Reciprocal of K i.e., Heckel Constant, yields a material-
material dependent
constant known as Yield Pressure.
 The slope of the linear regression is Heckel constant

constant.
 Large values of Heckel constant indicate susceptibility to plastic
deformation at low pressures
pressures.
 Yield Pressure is inversely related to the ability of the material to
deform plastically under pressure
pressure.
 Low values of yield pressure indicate a faster onset of plastic
deformation.
 Intercept of the line indicates degree of densification by
rearrangement.
 Heckel plot allows for interpretation of the mechanism of bonding.

CAREWELL PHARMACY
Type of Materials - On basis of Heckel Plot
1. Type A - Soft, Readily undergo plastic deformation

2. Type B - Harder materials, Higher yield pressure, First brittle
fracture then plastic flow
flow.
3. Type C - Rearrangement stage is absent, Densification is due to
plastic deformation
1. Type A
 A linear relationship is observed, with the plots remaining parallel as

the applied pressure is increased
increased.
 Indicative that deformation is apparently only by plastic
deformation.
 They are comparatively soft and readily undergo deformation plastic
 They retain different degrees of porosity depending on the initial
packing of the powder in the die.
Example - Sodium Chloride.

CAREWELL PHARMACY
2. Type B
 There is a initial curved region followed by a straight line

 Indicates that the particles are fragmenting at the early stages of
the compression process
 Brittle fracture precedes plastic flow
 Occur with harder materials with higher yield pressures
 Such materials undergo compression by fragmentation
agmentation first, to
provide a denser packing.
 Example - Lactose.
Type C
 In such materials there is an initial steep linear region which become

superimposed.
 This superimposed region flattens out as the applied pressure is
increased.
 This behavior was ascribed due to the absence of a rearrangement
stage.
 Densification is due to plastic de
deformation
formation and asperity melting.
 Example - Starch.

CAREWELL PHARMACY
Interpretation
 Type A Heckel plots usually exhibit a higher final slope than type B
which implies that the former materials have a lower yield pressure
 This is because fragmentation with subsequent percolation of
fragments is less efficient than void filling by plastic deformation.
 In fact, as the porosity approaches zero, plastic deformation is the
predominant mechanism for all materials
 Two regions of Heckel plot type B are thought to represent the
initial repacking stage and subsequent deformation process
 The point of intersection corresponding to the lowest force at which
a coherent tablet is formed.
Applications
 The crushing strength of tablets can be correlated with the values

of K of Heckel plot - Larger K values indicate harder tablets.
 Information from Heckel plot can be used as a means of binder
selection while designing tablet formulations.
 Heckel plot can be used to check lubricant efficacy.
 Information from plot can be used to interpret consolidation
mechanism.
 Heckel plots are also used to distinguish between substances that
have different consolidation mechanism.
 It can also be used as a means of assessing plasticity.
Limitations
Heckel plots can be influenced by -
 Slight variation in true density

 Variation in particle size
 Overall time of compression
 Degree of lubrication

CAREWELL PHARMACY
Similarity Factors F1 and F2

Difference Factor (F1) - The difference factor (f1) as defined by
FDA calculates the % difference between 2 curves at each time point
and is a measurement of the relative error between 2 curves.
Similarity Factor (F2) - The similarity factor (f2 ) is a logarithmic

reciprocal square root transformation of the ssum
um of squared error and
is a measurement of the similarity in the percent (%) dissolution
between the two curves.
Where,
 n = number of time points,

 Rt = % dissolved at time t of reference product (pre change),
 Tt = % dissolved at time t of test produc
productt (post change)
Applications of F1
 F1 is specially used to compare two dissolution profiles, being

necessary to consider one of them as the reference standard
product.
 It can measure the percent of error between two curves over all
time points.
Applications of F2
 This method is more appropriate when more than three or four

dissolution time points are available.
 The f2 may become invariant with respect to the location change
and the consequence of failure to take into account the shape of the

CAREWELL PHARMACY
curve and the unequal spacing between sampling time points lead to
errors.
 Nevertheless, with a slight modification in the statistical analysis,
similarity factor would definitely serves as an efficient tool for
reliable comparison of dissolution profiles.
Advantages
1. They are easy to compute.

2. They provide a single number to describe the comparison of
dissolution profile data.
Disadvantages
1. The values of f1 and f2 are sensitive to the number of dissolution

time points used.
2. The basis of the criteria for deciding the difference or similarity
between dissolution profile is unclear.

CAREWELL PHARMACY
Higuchi Equation (Diffusion Matrix Formulation)

Higuchi proposed this model in 1961 to describe drug release from
matrix system. It is developed to study the water soluble and low
soluble drugs incorporated in semisolids and solid matrices.
It is based on the hypothesis that;
1. Initial drug concentration in the matrix is much higher than drug

solubility.
2. Drug diffusion takes place in only one direction (edge effect must
be negligible).
3. Drug particles are much smaller than system thickness.
4. Matrix swelling and dissolution are negligible.
5. Drug diffusivity is constant.
6. Perfect sink conditions are always attained in the release
environment.
Higuchi model is given by
Q=KH.√T (or) Q=A√D(2C-Cs) Cs. T
Where,
 Q = Amount of drug released in time 't' per unit area.

 K = Higuchi constant.
 T = Time (in hours).
 C = Initial frug concentration
 Cs = Drug solubility in matrix media.
 D = Diffusivity of drug molecules in solvent.

CAREWELL PHARMACY
Plot: The dataa obtained were plotted as cumulative percentage drug

release Vs square root of time.
Applications: Modified release pharmaceutical dosage forms,

transdermal systems and matrix tablets with water soluble drugs.

CAREWELL PHARMACY
Korsmeyer - Peppas Plot

The KORSEMEYER AND PEPPAS described this method.
It is given by the equation:
Mt/M∞ = Ktn
Where,
 Mt/M∞ is fraction of drug released

 t = time K=constant includes structural and geometrical
characteristics of the dosage form
 n = release component which is indicative of drug release
mechanism where, n is diffusion exponent.
 If n= 1, the release is zero order, n 0.5 the release is best
described by the Fickian diffusion 0.5 < n < 1 then release is through
anomalous diffusion or case two diffusion.
 In this model a plot of percent drug release versus time is linear.
Plot - The data obtained were plotted as log cumulative percentage

drug release Vs log time.
Applications: It is applicable to linearization of release data from

microcapsules and microspheres.

CAREWELL PHARMACY
Linearity Concept of Significance

Tests of statistical significance are invariably applied now-a-days by
research scientists. Good medical journals refuse to accept papers for
publication if the authors have not used the philosophy of significance
testing in evaluating their results.
It is not adequate to mechanically undertake significance tests, the

scientists/experimental workers must fully understand the basic
concepts underlying a significance test, the assumptions involved and
the limitations, for making the proper interpretations.
Generally, the existence of statistical significance difference is

regarded as a proof of the existence of an important difference
between two sample results. Similarly, the non-significant differences
are regarded as proof of no differences in two sample results.
Standard Deviation
 Standard Deviation is a number that describes how much data vary

or spread out.
 It uses difference of each data value from the mean.
 The higher the number, more data is spread out.
Finding Standard Deviation
1. Find the mean, ẍ

2. Find the difference of each data value from the mean,
x- ẍ,
3. Square each difference

(x- ẍ)2
4. Sum all the squared values
5. Divide by the number of data taken by the sample minus 1.

CAREWELL PHARMACY
6. Take the square root

CAREWELL PHARMACY
Chi-Square Test
 The chi-square
square test is an important test amongst the several tests
of significance developed by statisticians.
 It was developed by Karl Pearson in 1900.
 Chi Square Test is a non parametric test not based on any
assumption or distribution of any varia
variable.
 This statistical test follows a specific distribution known as chi
square distribution.
 In general, the test we use to measure the differences between
what is observed and what is expected according to an assumed
hypothesis is called the chi
chi-square test.
Chi-Square
Square as a Parametric Test
Test for comparing variance
Chi-Square as a Non-Parametric
Parametric Test
 Test of Goodness of Fit

 Test of Independence
Where,
 O= observed frequencies
 E= expected frequency

CAREWELL PHARMACY
As a Test of Goodness of Fit - It enables us to see how well does

the assumed theoretical distribution (such as Binomial distribution,
Poisson distribution or Normal distribution) fit to the observed data.
When the calculated value of x2 is less than the table value at certain
level of significance, the fit is considered to be good one and if the
calculated value is greater than the table value, the fit is not
considered to be good.
As a Test of Independence - X2 test enables us to explain whether

or not two attributes are associated. Testing independence determines
de
whether two or more observations across two populations are
dependent on each other (i.e., whether one variable helps to estimate
the other). If the calculated value is less than the table value at
certain level of significance for a given degree of freedom, we
conclude that null hypotheses stands which mean that two attributes
are independent or not associated. If calculated value is greater than
the table value, we reject the null hypotheses.
Steps involved are:
1. Determine The Hypothesis:
 Ho: The two variables are independent

 Ha: The two variables are associated

CAREWELL PHARMACY
2. Calculate Expected frequency
E = (Row total) (Column total)

total)/Grant total
3. Calculate test statistic
4. Determine degree of Freedom
Df= (R-1)(C-1)
Where,
 R = number of levels in row variable and

 C = number of levels in column variable.
5. Compare computed test statistic against a tabled/critical value
The computed value of the Pearson chi

chi-square
square statistic is compared
with the critical value to determine if th
thee computed value is improbable
the critical tabled values are based on sampling distributions of the
Pearson chi-square
square statistic. If calculated x2 is greater than the x2
table value, reject Ho.

CAREWELL PHARMACY
Student's t-test
 The test is used to compare samples from two different batches.
 It is usually used with small (<30) samples that are normally
distributed.
 Types of "t" test are:
 Single sample t test – we have only 1 group; want to test against a
hypothetical mean.
 Independent samples t test - we have 2 means, 2 groups; no
relation between groups, E.g.: When we want to compare the mean
of T/T group with Placebo group.
 Paired t test - It consists of samples of matched pairs of similar
units or one group of units tested twice. E.g.: Difference of mean
pre & post drug intervention.
Equation for a one-sample

sample tt-test
Where,
 t = the t statistic
 x = the mean of the sample
 μ = the comparison mean
 s = the sample standard deviation
 n = the sample size

CAREWELL PHARMACY
Equation for the Independent samples tt-test
The independent samples tt-test

test procedure compares means for two
groups of cases.
Paired t-test
A paired t-test
test is used to compare two population means where you
have two samples in which observations in one sample can be paired
with observations in the other sample.
A comparison of two different methods of measurement or two

different treatments where the measurements/treatments are applied
to the same subjects.
E.g.:
1. Pre-test/post-test
test samples in which a factor is measured before
and after an intervention
intervention.
2. Cross-over trials
rials in which individuals are randomized to two
treatments and then the same individuals are crossed
crossed--over to the
alternative treatment
treatment.
3. Matched samples, in which individuals are matched on personal
characteristics such as age and sex
sex.

CAREWELL PHARMACY
 Suppose a sample of “n” subjects was given an antihypertensive drug

we want to check blood pressure before and after treatment. We
want to find out the effectiveness of the treatment by comparing
mean pre & post t/t.
To test the null hypothesis that the true mean difference is zero, the
procedure is as follows:
1. Calculate the difference (di = yi - xi) between the two observations

on each pair.
2. Calculate the mean difference, d.
3. Calculate the standard error of the mean differences. S.E=S.D/√n
4. Calculate the t-statistic, which is given by T = d/S.E, Under the null
hypothesis, this statistic follows a t-distribution with n - 1 degrees
of freedom.
5. Use tables of the t-distribution to compare your value for T to the
tn-1 distribution. This will give the p-value for the paired t-test.

CAREWELL PHARMACY
Analysis of Variance (ANOVA)

The analysis of variance (ANOVA) was developed by R. A. Fisher in
1920.
It is possible to study the significance of the difference of mean

values of a large number of samples at the same time because of
ANOVA.
The ANOVA is classified into two ways:
1. One-way classification
2. Two-way classification
 In one-way classification we take into account the effect of only one
variable.
 If there is a two-way classification, the effect of two variables can
be studied.
 The basic principle of ANOVA is to test for differences among the
means of the populations by examining the amount of variation
within each of these samples, relative to the amount of variation
between the samples.
1. One-way (or single factor) ANOVA:
 t is the simplest type of ANOVA, in which only one source of

variation, or factor, is investigated.
 It is an extension to three or more samples of the t test procedure
for use with two independent samples.
In another way t test for use with two independent samples is a
special case of one- way analysis of variance.

CAREWELL PHARMACY
The technique involves the following steps:
1. Obtain the mean of each sample i.e.,

CAREWELL PHARMACY
Two Way ANOVA
 Two-way
way ANOVA technique is used when the data are classified
on the basis of two factors.
 For example, the agricultural output may be classified on the
basis of different varieties of seeds and also on the basis of
different varieties of fertilizers used.
 It is a statistical test used to determine the effect of two
nominal predictor variables o
onn a continuous outcome variable.
 Two-way ANOVA test analyzes the effect of the independent
variables on the expected outcome along with their relationship
to the outcome itself.
 Two-way design may have repeated measurements of each factor
or may not have repeated
epeated values.
Types of two-way
way ANOVA
1. ANOVA technique in context of two

two-way
way design when repeated
values are not there.
2. ANOVA technique in context of two
two-way
way design when repeated
values are there.

CAREWELL PHARMACY
ANOVA technique in context of two-way design when repeated

values are not there.
 It includes calculation of residual or error variation by subtraction,

once we have calculated the sum of squares for total variance and
for variance between varieties of one treatment as also for variance
between varieties of the other treatment.
ANOVA technique in context of two-way design when repeated

values are there.
 We can obtain a separate independent measure of inherent or

smallest variations.
 Interaction variation: Interaction is the measure of inter
relationship among the two different classifications.
Graphical method for studying interaction in two-way design
 For graphs we shall select one of the factors to be used as the x-

axis.
 Then we plot the averages for all the samples on the graph and
connect the averages for each variety of other factor by a distinct
line.
 If the connecting lines do not cross over each other, then the graph
indicates that there is no interaction.
 But if the lines do cross, they indicate definite interaction or inter-
relation between the two factors.

CAREWELL PHARMACY
The graph indicates

cates that there is a significant interaction because the different
connecting lines for groups of people do cross over each other. We find that A and B are
affected very similarly, but C is affected differently.
Applications of ANOVA
 Similar to t-test.
 More
re versatile than tt-test.
 ANOVA is the synthesis of several ideas & it is used for multiple
purposes.
 The statistical Analysis depends on the design and discussion of
ANOVA therefore includes common statistical designs used in
pharmaceutical research.
 In the
he bioequivalence studies the similarities between the
samples will be analyzed with ANOVA only.
 Pharmacokinetic data also will be evaluated using ANOVA.
 Pharmacodynamic (what drugs do to the body) data also will be
analyzed with ANOVA only.

Modern Pharmaceutics

Uploaded by

Copyright:

Available Formats

Modern Pharmaceutics

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Modern Pharmaceutics

Uploaded by

Copyright:

Available Formats

CAREWELL PHARMACY

For More Notes - Visit www.carewellpharmacy.in Page 1

Unit 1 b. Optimization techniques in Pharmaceutical Formulation: Concept

Unit 2 - Validation: Introduction to Pharmaceutical Validation, Scope &

Unit 3 - cGMP & Industrial Management: Objectives and policies of

Unit 4 - Compression and compaction: Physics of tablet compression,

Unit 5 - Study of consolidation parameters; Diffusion parameters,

For More Notes - Visit www.carewellpharmacy.in Page 2

UNIT 1.a - Pre-Formulation Concepts

Characterization of physical, chemical and mechanical properties of

Preformulation is branch of Pharmaceutical' science that utilizes

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

This information may dictate many of subsequent event & approaches

Goals of Preformulation Concept

 To establish the physicochemical parameters of a candidate drug

For More Notes - Visit www.carewellpharmacy.in Page 3

Parameters in Preformulation Concept

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

For More Notes - Visit www.carewellpharmacy.in Page 4

Drug Excipient Interactions

An excipient is a pharmacologically inactive substance formulated

 Provide bulk to the formulation

Drug Excipient Interaction

Drug substances are usually in intimate contact with excipient.

Importance of these Studies

 To find out how compatible an excipient is with API

For More Notes - Visit www.carewellpharmacy.in Page 5

Mechanism of Drug Excipient Interaction

They can be classified as

 Dosage uniformity, color, odor, dissolution, stability or

For More Notes - Visit www.carewellpharmacy.in Page 6

Chemical interaction involves chemical reaction between drugs and

They are as follows-

1. Chemical interactions between drug and excipients - Eg are as

 Release of diclofenac sodium from matrix tablet was inhibited by

2. Interaction of drug with excipient residues/ impurities-

For More Notes - Visit www.carewellpharmacy.in Page 7

 Sterilization by autoclaving of par

These are the interactions which are observed after administration of

 The interaction is between the medicine (drug substance and

a) Premature Breakdown of Enteric Coat

 Enteric coating polymers e.g., cellulose acetate phthalate and

For More Notes - Visit www.carewellpharmacy.in Page 8

 Cause premature release of API in stomach itself, which results

b) Increase in gastrointestinal motility - Many excipients such as

c) Effect on P-glycoprotein efflux transporter-

P-glycoprotein thus interferes in the bioavailability of different

Analytical Techniques Used To Detect Drug-Excipient Interaction-

3. Chromatography - SIC-Self Interactive Chromatography

a. TLC-Thin Layer Chromatography and HPTLC HPLC-High

For More Notes - Visit www.carewellpharmacy.in Page 9

4. Accelerated stability study

 DSC is widely used technique to predict any interaction involving

Interaction detected by DSC

 Elimination of endothermic peak

For More Notes - Visit www.carewellpharmacy.in Page 10

2. DTA-Differential Thermal Analysis

 This technique is useful in the investigation of solid-state

3. SIC-Self Interactive Chromatography

SIC is useful for proteinous drug and excipients.