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.

Andreasen apparatus

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.

Sedimentation volume

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)

Instability of emulsions

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.

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