MULTIPLE EMULSIONS

BY-ANKITA KISHORE M.PHARM

(second SEMESTER)

PHARMACEUTICS

LAKSHMI NARAIN COLLEGE OF PHARMACY,BHOPAL

CONTENTS1.Introduction2.Multiple emulsions3.Preparation techniques4.Characterization5.Appliocations6.Conclusion7.references

1.INTRODUCTION-Emulsion is a heterogeneous

system of one immiscible liquid dispersed in another in the form of droplets.

Simple emulsion are classified according to the nature of their continuous or dispersed phase as,

1.Water-in-oil (w/o) emulsion2.Oil-in-water (o/w) emulsionAn emulsifier is present to

stabilize the system.

2.MULTIPLE EMULSIONS-These are also known as DOUBLE EMULSIONS.

These are more complex system, as the drops of the dispersed phase contain even smaller dispersed droplets, in most cases identical with the continuous phase, but separated physically from the continuous phase, these are known as “EMULSIONS OF EMULSIONS”

Based on the nature of dispersed medium multiple emulsions are of two types-

1.o/w/o emulsions 2.w/o/w emulsions1.O/W/O EMULSIONS-In this system water droplets may be

surrounded by oil phase which in turn enclose one or more oil droplets.

2.W/O/W EMULSION-In this system oil droplets may be

surrounded by an aqueous phase, which in turn enclose one or several water droplets.

W/O/W EMULSION

ADVANTAGES OF MULTIPLE EMULSIONS-1.A remarkable degree of

biocompatibility.2.Compelete biodegradability.3.Hydrophilic as well as

hydrophobic drug can be entrapped.

4.Protection from the inactivation by the endogenous factors.

5.Increase in drug dosing intervals.6.Taste masking of bitter drugs.

DISADVANTAGES-1.Emulsions have short shelf life.2.These dosage forms are packed in a plastic or glass containers.

so, care should be taken in handling and storage.

3.PREPARATION TECHNIQUES-For the preparation of multiple

emulsions two different surfactants of opposite nature is used.

One surfactant stabilizes the w/o (lipophilic) emulsion while the other stabilizes the o/w (hydrophilic) emulsion.

Emulsifier get adsorbed at the surface of droplets during the emulsion formation & prevent them from drawing close enough to aggregate.

METHODS OF PREPARATION-1.Two step emulsification (double emulsification)

2.Modified two step emulsification

3.Phase inversion4.Membrane emulsification method

5.Micro channel emulsification

1.TWO STEP EMULSIFICATION-Most common method because it is

easy & gives high yield with reproducibility.

Multiple emulsions are prepared by re-emulsification of a primary emulsion.

In this method two stages involved-Stage 1- It involves the preparation of

the primary emulsion either w/o or o/w type which is then re-emulsified with an excess of aqueous or oil phase in presence of second emulsifier to get the multiple emulsion of w/o/w or o/w/o respectively.

[Aqueous] + [oil + lipophilic surfactant] [w/o emulsion]

Stage 2- Generally two emulsifiers are used in the preparation of multiple emulsions.

One is lipophilic and other is hydrophilic surfactant.

[w/o emulsion] + [ hydrophilic surfactant] [w/o/w emulsion]

2.MODIFIED TWO STEP EMULSIFICATION TECHNIQUE-This method is different from the

conventional two step technique in 2 points-

1.Sonication & stirring are used to obtain fine, homogenous and stable w/o emulsion.

2. A continuous phase is poured into a dispersed phase for preparing w/o/w emulsion.

This modified method gives high yield and stable emulsion.

3.PHASE INVERSION (ONE STEP METHOD)-A well defined volume of oil phase is

placed in a vessel of pin mixer.An aqueous solution of emulsifier is

then introduced successively to the oil phase at the rate of 5 ml/minute, pin mixer rotate steadily at 88 r.p.m. at room temperature.

When volume fraction of the aqueous solution of hydrophilic emulsifier exceeds 0.7,

the continuous oil phase is substituted by aqueous phase containing a no. of the vesicular globules among the simple oil droplets, leading to the phase inversion and formation of w/o/w multiple emulsion.

Aqueous phase oil, lipophilic W/O/W

containing + surfactant emulsion

hydrophilic emulsifier

4.MEMBRANE EMULSIFICATION TECHNIQUE-In this ,a micro porous glass membrane with a defined pore size can be used as a emulsifying tool.

It is based on the principle of dispersing one immiscible phase into other phase by applying pressure.

The particle size of the w/o/w emulsion can be controlled with the proper selection of the porous glass membrane.

The relation between membrane pore size & particle size of emulsion exhibit good correlation as described by the formula-

y=5.03 x + 0.19 where- x=pore size y=mean particle size

5.MICRO CHANNEL EMULSIFICATION

It is a novel technique.A two step emulsification process employing micro channel as the second step was used for preparing w/o/w emulsions.

The w/o/w emulsion entrapment yield was measured flourimatrically and was found to be 91%.

4.CHARACTERIZATION OF MULTIPLE EMULSION-1.Average globule size & size distribution

2.Area of interfaces3.Number of globules4.Rheological evaluation5.Zeta potential6.Percentage drug entrapment7.In vitro drug release8.In vitro stability studies

MACROSCOPIC EXAMINATION-Primary observations like color, consistency & homogeneity are frequently used to ensure formation of an emulsion.

Type of multiple emulsion can be validated by dilution with the external phase.

1.AVERAGE GLOBULE SIZE & SIZE DISTRIBUTION-The optical microscopy method using

calibrated occular & stage micrometer can be utilized for globule size determination of both multiple emulsion droplets as well as droplets of internal dispersed phase.

However this method has two main drawbacks-

1.Simple small drops passes to form large simple drop which gives a false impression of multiple nature.

2. If the internal droplets are very small in size these can not be viewed due to reflection light from the oil droplets surface.

Various other techniques are used to characterize the emulsion like coulter counter, freeze fracture electron microscopy and scanning electron microscopy are also used to determine average globule size and size distribution of multiple emulsion droplets.

2.AREA OF INTERFACES-The average globule diameter determined can be used in the calculation of the total area of interface using the formula-

s = 6/dWhere s = total area of interface

d = diameter of globules

3.NUMBER OF GLOBULES-Number of globule per cubic millimeter

can be measured using a haemocytometer cell after appropriate dilution of the multiple emulsion.

The globules in 5 groups of 16 small squares (total 80 small squares) can be counted and the total no. of globules in per cubic mm. is calculated using the formula-

No. of globules/mmᶾ=no. of globules × dilution × 4000

No. of small square counted

4.PERCENTAGE DRUG ENTRAPMENT-

% drug entrapment of drug in the multiple emulsion is generally determined using dialysis, centrifugation, filtration & conductivity measurement.

However recently an internal tracer/marker was used to evaluate the entrapment of an impermeable marker molecule contained in the inner phase of w/o/w emulsion.

% entrapment can be calculated using the following equation-

c=100/[1-n1v*/(n10-n1)v1]

v*=v2 + vd(v1 +v2 + v0 )/vs

Where- n10 =initial concentration of drug in

inner aqueous phase n1 =concentration of drug in dilysate

v1,v2,v0 =represent the volume of inner & outer aqueous & middle oil phase respectively

5.RHEOLOGICAL EVALUATION-The rheology of multiple emulsion relates to emulsion stability and clinical performance.

The viscosity and interfacial elasticity are two major parameter which relate to product rheology.

The viscosity of multiple emulsion can be measured by Brookfield rotational viscometer.

6.ZETA POTENTIAL-Zeta potential measurements are pivotal in the designing of surface modified or ligand anchord multiple emulsion system.

Zeta potential can be calculated using Smoluchowski’s equation from the mobility & electrophoretic velocity of dispersed globules using the zeta potentiometer.

Zeta potential was calculated using the following formula-

Ȥ= 4 π η μ / εE x 103

Ȥ= zeeta potential (m.v.) η=viscosity of dispersion medium(poise) μ= migration velocity (cm/sec.) ε= dielectric constant of dispersion

medium E= potential gradient (voltage applied/distance between electrodes)

7.IN VITRO DRUG RELEASE-The drug released from the aqueous inner phase of a w/o/w emulsion can be estimated using the conventional dialysis method using a cellophane tubing.

Typically 5 ml. of (w/o/w) multiple emulsion is placed in the dialysis bag & dialysed against 200 ml. of phosphate saline buffer (PBS pH 7.4) at 37±10c &

sink condition is maintained while sink contents are stirred continuously using a magnetic stirrer.

Aliquots are withdrawn at different time interval & estimated using standard procedure & the data are used to calculate the cumulative drug release profile.

8.IN VITRO STABILITY STUDIES-Emulsion stability is determined by phase separation on storage of w/o/w emulsions.

Freshly prepared multiple emulsion allowed to stand for one week at room temperature & the volume of aqueous phase separated (vsep) is measured at suitable time interval & % phase separation is calculated using following formula-

Formula- B%= 100 ( vsep / 20 )

[(v1+v2)/v1 +v2+v0)]

where- v1=volume of internal aqueous phase

v2=volume of external aqueous phase

v3=volume of middle oil phase

5.APPLICATIONS-Pharmaceutical applications- It includes-1.Immobilization of enzymes2.R.B.C. substitute3.Transdermal delivery4.Bioavailability5.Taste masking6.Drug targeting7.Prolonged delivery of drug

Some important applications of multiple emulsions-

1.Controlled & sustained drug delivery

2.Drug targeting3.Vaccine adjuvant4.As a preparation tool for microencapsulation technology.

5.Drug overdose treatment/detoxification

6.Protection action7.Cosmetics and health care

6.CONCLUSION-Multiple emulsions known to be promising delivery system for both pharmaceutical and cosmetic materials.

The possibility of encapsulating active substances within liquid membranes may lead to interesting opportunities in both fields.

Thus the manufacturing, stabilization analysis & potential applications of multiple emulsions are discussed.

7.REFERENCES-1.Vyas S.P. , Khar R.K., “Targeted & controlled Drug Delivery Novel Carrier System” , First edition 2002, CBS PUBLISHERS & DISTRIBUTERS,

303-3282. www.authorstream .com

Thank you