In process quality control of suspensions and emulsions

IN PROCESS QUALITY
CONTROL OF
SUSPENSIONS AND
EMULSIONS

CONTENTS
 IN PROCESS QUALITY CONTROL
 OBJECTIVE
 IMPORTANCE
 USFDA -CGMP GUIDELINES
 DOCUMENTATION
 IPQC OF SUSPENSIONS
 IPQC OF EMULSIONS
 COMLETION STAGE
 RECORD&REPORT
 PACKAGING MATERIALS CONTROL
 LABELS CONTROL
 CONCLUSION

IN PROCESS QUALITY CONTROL
 IPQC means controlling the procedures
involved in manufacturing of the dosage form
starting from raw material purchase to
dispatch of the quality product in ideal
packaging.
 It monitors all the features of the product
that may affect its quality and prevent errors
during processing.
 It is the activity performed between QA&QC.

OBJECTIVE
 The primary objective of the system is to
monitor all the features of o product that may
affect its quality and to prevent error during
processing.
 The in process checking during manufacturing
plays an important role in the auditing of the
product at various stages of production.
 They are used to detect variation from the
tolerance limits of the product so that promote
and corrective actions can be taken.

PURPOSE
 To ensure detectable and significant human
errors.
 To minimize inter batch and intra batch
variability.
 To ensure quality of final product.
 To ensure continuous monitoring of process
variables which are going to affect the quality
of product.

IMPORTANCE
 Provide accurate,specific and definite
description of the procedure to be employed.
 It is a planned system to identify the
materials,equipment, processes, and
operators.
 It is to detect the errors if and when it does
occurs.
 Is to enforce the flow of manufacturing and
packing operation according to established
rules and practice.

For proper function of IPQC
the following must be
defined
 Number of samples to be taken for analysis
and frequency of sampling.
 Quantitative amounts of each sample.
 Allowable variability.
 Which process is to be monitored and at what
phase.

USFDA-CGMP guidelines
 To assure batch uniformity and integrity of
drug product,written procedures shall be
established and followed.
 Valid in process specification for such
characteristics shall be constituent with drug
product.
 In process material shall be tested for
identity,strength,quality and purity.

IPQC TESTS
 These are the tests performed between
QA&QC and provides for the organization of
approved raw materials for manufacturing
based on actual laboratory testing generally
called as IPQC tests such as
physical,chemical,microbiologic and biologic
tests.

TYPES OF IPQC TESTS
 IPQC TESTS ARE TWO TYPES
 1)Physical and chemical tests
 a)Identity test
 b)quality test
 c)purity test
 d)potency test
 2)Biologic and microbiologic tests

Documentation
 Recording the operations in a written form is
documentation.
 If it was not documented,it was not done
describes the linkage between written
records of action taken and the quality
operation.

Master formula record
 The name of the product,dosage form and its
strength.
 The complete list of ingredients.
 The quantity by weight or volume of each
ingredient.
 The standards or specifications of each ingredient
used in the product.
 An appropriate statement concerning any calculated
excess of an ingredient.
 Appropriate statements of theoretic yield at various
stages and the termination of processing.

 Manufacturing and control
instructions,specifications,precautions and
special notations to be followed.
 A detailed description of the
closures,containers,labelling,packaging,and
other finishing materials.

Areas controlled by IPQC
 Manufacturing area
 Packaging area
 Manufacturing area
General cleanliness
RH/temperature
Status label present for
a)all tanks
b)jacketed vessels
c)other manufacturing accessories
Raw materials other than that current batch removed
All tanks properly covered

Packaging area
 General cleanliness
 Status label present for
a)Packaging/filling area
b)Filling machine
c)cap sealing machine
 Packaging materials other than that required for
current batch required
 Bottle washing
 Filling tanks
 Leak test
 Check on filled bottles
 Coding details
 Labelling
 Carton

SUSPENSIONS
 Pharmaceutical suspensions may be defined
as coarse dispersions in which insoluble solids
are suspended in a liquid medium.
 The liquid medium is usually water or a water
based vehicle.
 The insoluble solid may have size range from
10 to 1000 μm.
 Suspensions are also called heterogeneous
systems,or more precisely biphasic systems.

Classification
 1)Based on proportion of solid particles
a)Dilute suspensions(2 to 10% w/v solid)
b)concentrated suspensions(50% w/v solid)
 2)Based on electrokinetic properties of
solid particles
a)flocculated suspensions
b)deflocculated suspensions
 3)Based on general classes
a)oral suspensions
b)externally applied suspensions
c)parenteral suspensions

IPQC TESTS OF SUSPENSIONS
 Appearance
 Photo microscopic examination
 Color,odor and taste
 Density
 pH value
 Clarity testing
 Pourability
 Viscosity
 Rheology

 Zeta potential measurement
 Drug content uniformity
 Particle size measurement
 Sedimentation rate and sedimentation
volume
 Redispersibility
 Potency test
 Preservative effectiveness
 Compatibility with primary container-closure
system

Appearance
 The appearance in a graduated glass cylinder
or transparent glass container is noted.It is
checked for
 Uniformity of color and appearance of the
sediment
 Any breaks or air pockets in the sediment
 Any coagulated material adhering to the
inside wall of the container.

Photo microscopic
examination
 The microscope can be used to estimate and
detect changes in particle size distribution
and crystal shape.Its usefulness can be
enhanced by attaching a polaroid type
camera to the microscope to permit rapid
processing of photomicrographs.
 This can be used to distinguish between
flocculated and non-flocculated particles and
to determine changes in the physical
properties.

Color,odor and taste
 These characteristics are especially important
in orally administered suspensions.Variation
in color often indicates poor distribution
and/or differences in particle size.Variation in
taste,especially of active constituents can
often be attributed to changes in particle
size,crystal habit and subsequent particle
dissolution.
 Changes in color,odor and taste can also
indicates chemical instability.

Density
 Specific gravity or density of the suspension
is an important parameter. Decrease in
density indicates the presence of entrapped
air with in the structure of the suspension.
 Density measurements at a given
temperature should be made using well-mixed
uniform suspension.
 Hydrometers are used to measure the
density.

pH value
 pH of the phases of suspension also contribute to
stability and characteristics of formulations.So
pH of the different vehicles,phases of suspension
before mixing and after mixing are monitored
and recorded time to time to ensure optimum
pH environment being maintained.
 Different types of methods are used in the
measurement of pH.
 a)Dip a piece of pH paper into the sample.
 b)pH meter

Clarity testing
 Clarity testing is carried out to check the
particulate matter in the sample.

Pourability
 This test is carried out on the phases of
suspension after mixing to ensure that the
final preparation is pourable and will not
cause any problem during filling and during
handling by patient

viscosity
 Stability of a suspension is solely dependant on the
sedimentation rate of dispersed phase which is
dependant on the viscosity of the dispersion
medium.So this test is carried out to ensure
optimum viscosity of the medium so a
stable,redispersible suspension can be formed.
 The viscosity of the dispersion medium is measured
before mixing with dispersed phase and also
viscosity after mixing is determined using Brook
field viscometer.
 The calculated values are compared with standard
values and if any difference is found necessary
corrective action is taken to get optimized viscosity.

Viscosity measurement
 In suspensions the flow properties have
profound influence in the manufacture,during
storage and administration of drugs.The flow
properties depends on the viscosity of the
suspension.
 The viscosity can be measured by
 a)cup and bob viscometer(destructive
method)
 b)cone and plate viscometer(destructive
method)

Cup and bob viscometer
 The sample is placed in the cup and the bob is placed
in the cup up to an appropriate height.
 The sample is accommodated between the gap of
cup and bob.
 Either the cup or bob is made to rotate and the
torque resulting from the viscous drag is measured
by a spring or sensor in the drive of the bob.
 The number of revolutions and the torque represent
the rate of shear and shearing stress respectively.
 ή=kw/v
 ή=apparent viscosity w=shearing stress
 v=rpm(shear rate) k=instrument constant

Cone and plate viscometer
 The sample is placed at the centre of the plate which is then
raised into a position under the cone.
 The cone is driven by a variable-speed motor and the
sample is sheared in the narrow gap between the stationary
plate and the rotating cone.
 The rate of shear in rpm is increased or decreased by a
selector dial and the viscous traction or torque(shear stress)
produced on the cone is read on the indicator scale.
ή=cT/v
 c=instrument constant T=shearing stress
 v=shear rate ή=viscosity

Rheology
 Rheology is the science that concerns with the flow of
liquids and the deformation of solids.
 Brookfield viscometer is used to evaluate the rheological
properties and behaviour of settling of suspensions.
 Brookfield viscometer mounted on helipath stand with T
spindle.
 The T bar rotates and descends slowly into the suspension
with the help of synchronous motor.
 The path traced by the spindle is a helix.As the T bar moves
the sediment offers resistance.
 The dial reading indicates the magnitude of resistance.
 The dial reading is plotted against the number of turns of
the spindle.
 Good suspensions show a lesser rate of increase of dial
reading as the spindle turns that is the curve is horizontal
for a longer period.

Zeta potential measurement
 Zeta potential is defined as the difference in
potential between the surface of the tightly
bound layer(shear plane) and electro-neutral
region of the solution.
 Zeta potential has practical application in
stability of systems containing dispersed
particles since this potential governs the degree
of repulsion between the adjacent similarly
charged dispersed particles.
 Value of zeta potential reflects the future
stability of suspension so it is monitored time to
time to ensure optimum zeta potential.
 The flocculated suspension is one in which zeta
potential of particle is -20 to +20 mv.

 Zeta potential can be measured by
 a)zeta meter
 b)micro-electrophoresis
 Electrophoresis
 The principle of electrophoresis is used to
determine the sign and magnitude of zeta
potential.
 Electrophoresis involves the movement of a
charged particle through a liquid under the
influence of an applied potential difference.
 An electrophoresis cell is fitted with two
electrodes.
 The dispersion is introduced into the cell.when a
potential is applied across the electrodes,particles
migrate towards oppositely charged electrodes.
 The rate of migration is a function of the charge on
a particle.

 As the potential gradient across the
electrodes increases the velocity of migration
of particles increases.
 Velocity of migration potential gradient
of particles (cm/sec) α across the electrodes
v α E
v=ζE
There are number of factors that influence
the migration so the zeta potential can be
calculated by
ζ = v4πή
Eє

Drug content uniformity
 For proper dosing of the dosage form it is
necessary that the active ingredient is
uniformly distributed throughout the dosage
form.so samples are withdrawn from the
dispersed phase after micronization and after
mixing with dispersion medium,assayed to
find out degree of homogeneity.
 If any discrepancy is found out it is suitably
corrected by monitoring the mixing step to
ensure a reliable dosage formulation.

Particle size of dispersed
phase
 Optimum size of drug particle in the
dispersed phase plays a vital role in stability
of final suspension.
 So this test is carried out to microscopically
analyse and find out particle size range of
drug then it is compared with optimum
particle size required.
 If any difference is found,stricter monitoring
of micronization step is ensured.

Particle size measurement
 Particle size can be measured by
 a)optical microscopy
 b)sedimentation method
 c)conductivity method(coulter counter
method)

Optical microscopy
 Particle size in the range of 0.2 to 100μm can be measured by
optical microscopy.
 This method directly gives number distribution.
 Method:Eye piece of the microscope is fitted with a micrometer.
 The eye-piece micrometer is calibrated using a standard stage
micrometer.
 The sample of suspension is mounted on a slide or a ruled cell
and placed it on the mechanical stage.
 The size of the particle is estimated with the help of the eye-piece
micrometer.
 Around 625 particles must be counted in order to estimate the
true mean.
 The size frequency distribution curve is plotted by taking particle
size in μm on x-axis and frequency on y-axis.

Sedimentation method
 Sedimentation method may be used over a size
range of 1 to 200μm.
 Sedimentation of particles are evaluated by
 a)Andreasen pipette method
 b)Balance method
 c)Hydrometer method
 In this methods the particle size is expressed as
Stokes diameter.

Andreasen pipette method
 Andreasen apparatus consists of a 550 ml cylindrical
vessel containing a 10 ml pipette sealed to a ground
glass stopper.
 When the pipette is placed in the cylinder its lower
tip is 20 cm below the surface of the suspension.
 Transfer the suspension into the Andreasen vessel
and place the two-way pipette and securely suspend
the vessel in a constant temperature water bath.
 At different time intervals 10 ml of samples are
withdrawn using two-way stopcock and collected in
watch-glass,evaporated and weighed.
 Particle diameter is calculated from stokes law.

Sedimentation
 An ideal suspension can be prepared by
preventing the settling of particles.
 The settling of particles can be explained by
theories related to sedimentation.
a)theory of Brownian movement
b)theory of sedimentation
 These theories provides information regarding
factors that affect the settling of solids,these
factors enable to take appropriate action in the
manufacture of suspension.

Theory of Brownian movement
 Brownian movement of particles prevents
sedimentation.
 Brownian movement can be observed,if the
size of the particle is about 2 to 5μm,provided
densities of the particles and viscosity of the
medium are favourable.
 Theory of Brownian movement proposes
particle size and viscosity as the major
factors.

Sedimentation rate
 The rate of sedimentation of particles is expressed
by Stokes law 2
d (Þ1-Þ2)g
 rate of sedimentation= 18ή
d=diameter of the particle(cm)
Þ1=density of the dispersed phase(g/ml)
Þ2=density of the dispersion medium(gm/ml)
ή=viscosity of the dispersion medium(poise)
g=acceleration due to gravity(980.7cm/sec)

 Stokes law is useful in fixing factors to prevent
sedimentation.
 Particle size:If the particle size is reduced to half
of itsoriginal size the rate of sedimentation
decreases by a factor of four.
 Viscosity of medium:The viscosity of suspension
should be optimum.
 Density of the medium:The density of medium
should be high so that the difference in densities
will be minimal.
 The density of medium can be increased by
including ingredients such as
polyvinylpyrrolidine,sugars,polyethyleneglycols,
glycerin etc.

Sedimentation volume
 It is the ratio between ultimate volume of
sediment to initial volume of the suspension.
F=Vu/V0=ultimate volume of the sediment
initial volume of the suspension
when a measuring cylinder is used to measure
the volume it can be written as Hu/H0
The F value is between the limits 0 to 1.
The higher the sedimentation volume the
better is the physical stability.

Redispersibility
 If the particles settle they should be easily
redispersible by a moderate amount of
shaking.

EMULSIONS
 Emulsion systems consisting of at least two
immiscible liquid phases,one of which is
dispersed as small globules in the other liquid
phase.
 The globule diameter may range from 0.1 to
100 μm.
 Emulsions are thermodynamically unstable
systems.
 Emulsions are also called as heterogeneous
systems ,or more precisely biphasic systems.

classification
 1)Based on nature of dispersed phase
a)oil-in-water(o/w)
b)water-in-oil(w/o)
 2)Based on the globule size
a)micro emulsions(0.01μm)
b)fine emulsions(0.25 to 25μm)

Flocculation
 Neighbouring globules come closer to each
other and form colonies in the external
phase.
 This is the initial stage that leads to instability
 The extent of flocculation of globules
depends on
 a)globule size distribution
 b)charge on globule surface
 c)viscosity of external medium

Creaming
 Creaming is the concentration of globules at the
top or bottom of the emulsion.
 The floccules move either upward or downward
leading to creaming.
 It can be observed by a difference in colour shade
of the layers.
 Creaming is influenced by
 a)globule size
 b)viscosity of the dispersion medium
 c)differences in the densities of dispersed phase
and dispersion medium

Coalescence
 Coalescence is followed by creaming stage.
 In this process the emulsifier film around the
globules is destroyed to a certain extent.
 This step can be recognised by increased globule
size and reduced number of globules.
 Coalescence is observed due to
a)insufficient amount of the emulsifying agent
b)altered partitioning of the emulsifying agent
c)incompatibilities between emulsifying agents

Breaking
 This is indicated by complete separation of oil
and aqueous phases.
 It is an irreversible process that is simple
mixing fails to resuspend the globules into an
uniform emulsion.
 In breaking the protective sheath around the
globules is completely destroyed.

Phase inversion
 This involves the change of emulsion type
from o/w to w/o or vice versa.
 When we intend to prepare one type of
emulsion say o/w and if the final emulsion
turns out to be w/o it can be termed as a sign
of instability

IPQC tests for emulsions
 Appearance
 Clarity testing
 pH value
 Viscosity
 Rheology
 Drug content uniformity
 Particle size distribution
 Densities of phases

 Phase volume ratio
 Charge of electrical double layer
 Physical properties of interface
 Temperature fluctuations
 Quality control of water
 Breaking or cracking
 Compatibility of product with container-closure
system

viscosity
 As the viscosity increases flocculation of
globules will be reduced .simultaneously the
Brownian movement of globules will also be
hindered leading to creaming.
 Due to this antagonistic effect an optimum
viscosity is desirable for good stability.
 Viscosity can be measured by
 a)cop and bob viscometer
 b)cone and plate viscometer

Particle size
 As the globule size is reduced they tend to
exhibit Brownian movement.
 According to stokes law the diameter of the
globule is considered as a major factor in
creaming of emulsion.The rate of creaming
decreases four folds when the globule
diameter is halved.
 So it is necessary to choose the optimum
globule size for maximum stability.

Particle size distribution
 Globules of uniform size impart maximum
stability.
 In such emulsions globules pack loosely and
globule to globule contact is less.
 Globule distribution is effected by
viscosity,phase volume ratio,density of
phases etc.
 An optimum degree of size distribution range
should be choosen to achieve maximum
physical stability.

Globule size determination
 Microscopic examination of globule size
distribution analysis is an useful tool to
evaluate the physical stability.

Phase volume ratio
 In an emulsion the relative volume of water to oil is
expressed as phase volume ratio.
 In general most medicinal emulsions are prepared
with a volume ratio of 50:50.This proportion brings
about loose packing of globules.
 The upper limit 74% of oil can be incorporated in an
emulsion but this may lead to breaking of the
emulsion.This value is referred to as critical point of
phase volume ratio.
 Critical point is defined as the concentration of
internal phase above which the emulsifying agent
cannot produce a stable emulsion of the desired
type.

Extent of phase separation
.
 The practical and commercial aspect of
stability is the study of phase separation.
 This is quick method and can be applied for
poorly formed and rapidly breaking
emulsions.
 Separation of phases is visible after a definite
period of time,though the signs of instability
begin quite early.

Charge of electrical double
layer
 When ionic type of emulsifier is employed,
the electrical double layer(interface between
oil and water)possesses charge.
 The repulsive forces,due to like charges on
the surface of the globules prevent the
flocculation of globules.

Physical properties of
interface
 The interfacial film of the emulsifier is responsible
for enhancing the stability of the product.
 The film should be elastic enough to form rapidly as
soon as droplets are produced.This behaviour
facilitates the production of emulsion.
 Similarly on moderate shaking the emulsion should
be reconstituted.
 After manufacture the film should be tough so that
coalescence of globules can be prevented.
 So suitable emulsifying agents such as surfactants
should be selected to achieve the above film
properties at the interface.

Densities of phases
 By adjusting the density of the phases to the
same value we can increase the stability of
emulsion.
 Oil phase density can be enhanced by adding
brominated oil when the oil is an external
phase.

Temperature fluctuations
 Elevated temperatures alter the partition
characteristics of the emulsifiers and
preservatives results in instability.
 Temperature also enhances the chemical
degradation of drugs and other ingredients.
 At lower temperature the aqueous phase may
contain ice crystals which rupture the interfacial
film and break the emulsion.
 So care should be taken to prevent temperature
fluctuations during manufacture and storage.

Phase inversion
 The emulsion is checked for phase inversion.
 Phase inversion means a change of emulsion
type from o/w to w/o or vice versa.

Completion stage
 At the completion of manufacturing process
as well as in-process stages,actual yields are
checked against theoretic value and the repre
sentative sample are withdrawn for
laboratory testing by the control inspector
according to the predetermined sampling
plan.

Record and report
 The batch production records and other
needed documents are then delivered to the
quality control office together with the
withdrawn samples of the products.

Packaging material control
 Packaging material should not interact
physically or chemically with the finished
product to alter the strength,quality or purity
beyond specified requirements.
 The following features are to be considered in
developing container specifications
 Properties of container tightness
 Moisture and vapour tightness regardless of
container construction
 Compatibility between container and product

 Toxicity and chemical/physical characteristics
of materials needed in container
construction.
 Physical or chemical changes of container
upon prolonged contact with product.

Labels control
 Production control issues a packaging form that
carries
 The name of the product
 Item number
 Lot number
 Number of labels
 Inserts
 Packaging material to be used
 Operation to be performed
 Quantity to be packaged
 A copy of this is sent to the supervisor of label control,who
in turn counts out the required number of labels.

conclusion
 IPQC tests are carried out during the
manufacturing to ensure stable,safe and
quality product.

References
 Lachman L,Lieberman H,The Theory and
Practice of Industrial pharmacy;3rd
edition,page number-810 to 835.
 C.V.S.Subrahmanyam,Text book of Physical
Pharmaceutics,page number-195 to 203,366
to 423.
 Encyclopedia volume-6 page number 3105-
3107.

In process quality control of suspensions and emulsions

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