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MULTIPLE EMULSIONS
PRESENTED BY
SATYANARAYANA . V
M.PHARM II-SEMISTER
DEPARTMENT OF PHARMACEUTICS
UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES
KAKATIYA UNIVERSITY
WARANGAL
CONTENTS
 INTRODUCTION
 TYPES OF MULTIPLE EMULSIONS
 PREPARATION OF MULTIPLE EMULSIONS
 IN VITRO CHARACTERIZATION
 STABILITY OF MULTIPLE EMULSIONS
 APPLICATIONS
 CONCLUSION
 REFERENCES
INTRODUCTION
 Emulsions may be described as heterogenous systems, where one immiscible
liquid is dispersed in another in the form of droplets and stabilized by a third
component called emulsifying agent

The emulsions can be divided up into two Types :
 1. Oil in water (O/W) emulsions and
 2. Water in Oil (W/O) emulsions.
 1. O/W Emulsion:
 By dispersion of oil into water the oil drops are the inner, dispersed phase.
Water is the outer, continuous phase.
– Aq phase
– Oil drop
2. W/O Emulsion:
By dispersion of water into oil the water drops are the
Inner, dispersed phase. Oil is the outer, continuous phase.
Aq phase
Oil phase
MULTIPLE EMULSIONS
 Multiple emulsions are complex systems in which the
dispersed phase contain smaller droplets inside.
 They are a type of polydispersed systems where both
oil-in-water & water-in-oil emulsions exist simultaneously.
 This is made possible by double emulsification hence the
systems are also called as “Double emulsions”.
 These are also called as “Liquid membrane systems” as the
liquid film which separates the liquid phases acts as a thin
semipermeable film through which solute must diffuse in
order to transverse from one phase to another.
 Multiple emulsions are thermodynamically unstable.
 They are often stabilized by using a combination of
hydrophilic & hydrophobic surfactants.
 The ratio of these surfactants is important in achieving
stable multiple emulsions.
 CLASSIFICATION




With optical microscopy method,
multiple emulsions are classified as,
1. coarse (>3 micrometer in diameter)
2. Fine (1-3 micrometer in diameter)
3. Micro-multiple emulsions
(<1 micrometer in diameter)
TYPES OF MULTIPLE EMULSIONS
1. Water/Oil/Water (w/o/w)
1. Water/Oil/Water (w/o/w)
2. Oil/Water/Oil
(o/w/o)
w/o/w
Multiple emulsions can also be formulated by using either o 1/o2/o1
systems or o1/o2/w formulations are possible. Examples of both are
shown in Figure 4.
 WATER/OIL/WATER (W/O/W)
 Water/Oil/Water (w/o/w) multiple emulsions consist of
dispersed oil globules containing smaller aqueous
droplets; each inner aqueous droplet is separated from
the outer aqueous phase by an oil phase layer.
 The presence of atleast two surfactants is required.
 One of them is predominantly Lipophilic for stabilizing the
primary w/o emulsion & the other is Hydrophilic for the
secondary o/w emulsion.
 OIL/WATER/OIL(O/W/O)
 Oil-in-water-in-oil (o/w/o) multiple emulsions contain an inner oil
phase, a water phase, and outer oil phase.
 The inner oil phase is first dispersed in water to form an oil-in-water
(o/w) emulsion.
 Then the o/w emulsion is further dispersed in the outer oil phase to
form the o/w/o type multiple emulsion.
 Different techniques used for the
preparation of Multiple Emulsions
Two step emulsification technique,
Phase inversion technique,
Membrane Emulsification Technique,

TWO STEP EMULSIFICATION TECHNIQUE
 This method involve re-emulsification of primary W/O or O/W
emulsion using a suitable emulsifying agent.
 Multiple emulsions, either W/O/W or O/W/O emulsions, are
generally prepared using a Two-step procedure, as reported
by Matsumoto et al for W/O/W emulsions, the primary
emulsion (W/O) is first prepared using water
and a low-HLB surfactant solution in oil.
 In the second step, the primary emulsion (W/O) is reemulsified in an aqueous solution of a high-HLB surfactant to
produce a W/O/W multiple emulsion.
 The first step-that is, the preparation of the primary
emulsion-is usually carried out in a high-shear device
to produce a very fine droplets.
 The second emulsification step is carried out in a low-
shear device to avoid rupturing the multiple droplets.
 EXAMPLE
 The primary W/O emulsion was prepared by adding an aqueous
solution containing sodium salicylate to a Span 83 solution in light
mineral oil at an equal volume ratio and stirring with a magnetic
mixer (1000 rpm) for 15 minutes.
 The concentration of Span 83( sorbitan sesquioleate) in light mineral
oil varied from 0.1% to 40% wt/vol.
 In second step, the W/O primary emulsion was re-emulsified in a
Tween 80 solution containing concentrations of Tween 80 from 0.1%
to 10% wt/vol at an equal volume ratio and stirred for 5 minutes at
600 rpm to produce the W/O/W multiple emulsion.
 Recently, Okochi and Nakano,
reported a Modified two-step emulsification technique for the
preparation of W/O/W emulsion.
 This method is different from the conventional two-step technique.
 Firstly, sonicated and stirring are used to produce fine, homogenous and
stable W/O emulsion.
 Secondly, a continuous phase is poured into a dispersed phase for
preparing W/O/W emulsion.
 The composition of internal aqueous phase-oily phase-external phase is
fixed at 1:4:5,which produces most stable formulation of W/O/W
emulsions.
 PHASE INVERSION TECHNIQUE
 Matsumoto and co-workers first reported the development


of W/O/W system during the phase inversion of the
concentrated W/O emulsion.
In this technique, an increase in volume concentration of
dispersed phase may increase in phase volume ratio,
which subsequently leads to the formation of multiple
emulsion.
The method typically involves the addition of an aqueous
phase containing the hydrophilic emulsifier examples
-Tween 80 or
-Sodium dodecyl sulphate or
-CTAB
to an oil phase consisting of liquid paraffin and
containing lipophilic emulsifier ex… Span 80.
 A well-defined volume of oil phase is placed in a vessel of pin mixer.
 An aqueous solution of emulsifier is then introduced to the oil phase
in the vessel at a rate of 5ml/ min, while the pin mixer rotates
steadily at 88 rpm at room temperature.
 When volume fraction of the aqueous solution of hydrophilic
emulsifier exceeds 0.7, the continuous oil phase is substituted by the
aqueous phase containing a number of the vesicular globules among
the simple oil droplets, leading to phase inversion and formation of
W/O/W multiple emulsion.
 MEMBRANE EMULSIFICATION
TECHNIQUE
 This method uses low shear forces to produce emulsions.
 A porous glass membrane with controlled and homogenous

pores is used in this method.
Particle size of the emulsion can be controlled with the
proper selection of the porous glass membrane.
 This is based on the use of microspores with a very narrow
pore size distribution on the membrane.
 The phase which is to be dispersed is pressed through
membrane pores.
 The droplets formed at the membrane surface are detached by
the continuous external aqueous phase flowing across the
membrane surface.
 To support the emulsification and prevent coalescence of
droplets, a surface active compound must be added to the
continuous phase
 It can be successfully applied to make multiple emulsions as
drug delivery systems.
Invitro characterization
1) Average globule size and size distribution,
2) Area of interfaces
3) Number of Globules
4) Creaming volume measurement
5) Conductivity test,
6) Rheological Evaluation,
7) Measurement of Zeta potential.
8) Entrapment Efficiency
9) Invitro Drug Release
 INVITRO CHARACTERIZATION
 The emulsions are characterized by particle size
distribution measured by
-Laser diffraction
-Microscopy
-Image processing.
 Proteins were suitable emulsifiers to create coalescencestable multiple emulsions at low energy input.
 Measuring the size distribution of the oil droplets by laser
diffraction confirmed the results obtained by automated
image processing.
 Average globule size and size distribution

The optical microscopic method using calibrated ocular and
stage micrometer can be utilized for globule size
determinations of both multiple emulsions droplets as well as
droplets of internal dispersed phase.

Florence and Whitchill,
used inverted phase contrast microscope and a high
speed camera.

The droplet size distribution of freshly made emulsion can be
measured by light scattering using a
- Malvern Mastersizer and
- Surface mean droplet diameter
and the specific surface area can be derived.
 Recently,
NMR self-diffusion methods are adapted to multiple
emulsion characterization.
 In addition, the self diffusion NMR technique may be
used to obtain information regarding water exchange
across the oil film in the multiple emulsions.
 Area of interfaces
 The average globule diameter determined can be
used in the calculation of the total surface area of
interface using
S = 6/D
S = total area of interface (sq cm)
D = diameter of globule (cm)
 Number of globules
 Number of globules per cubic mm can be measured by
using the Haemocytometer cell
No. of globules ×dilution × 4000
No. of globules/mm3 =
No. of small squares counted.
.
 Creaming volume measurement
 The creaming volume was defined as the relative difference
in volume of the multiple emulsion and the volume of the
creamed phase.
Vmultiple emulsion–Vcreamed phase
% Vcream =
× 100
Vmultiple emulsion
 Conductivity test
 This test was found to be an important parameter to
study the stability and yield of W/O/W emulsions.
 The conductivity was determined by means of a
systronics digital conductivity meter.
The entrapment percent / yield value
(E%) was calculated according to the following
equation
E% = 100 . (Ci – Ct )/ Ci
Ci = conductivity of the internal aqueous phase
Ct = conductivity value of multiple emulsion at a
given time t.
 Rheological evaluation
 The rheology of multiple emulsion is an important parameter as it
relates to emulsion stability and clinical performance.



The Viscosity and Interfacial elasticity are two major parameters, which
relate to product rheology.
Viscosity (non-newtonian)– by Brookfield rotational viscometer.
Oil phase viscosity – by Stress viscometry using a Behlin controlled
rheometer.
 Three different geometries stant(5 µl) were used
according to viscosity of samples
Double gap DG 40 50
cone plate 4/40
concentric cylinder c25
 Interfacial film strength – evaluated by interfacial film
measurements by Oscillatory surface rheometer, i.e.
elasticity of w/o and o/w components of w/o/w multiple
emulsions and these data may relate to emulsion
stability.
Measurement of zeta potential
 The zeta potential and surface charge can be calculated
using Smoluchowski’s equation from the mobility and
electrophoretic velocity of dispersed globules using zeta
potentiometer.
 Nakhare and Vyas,
using
a
cylindrically
bored
micro
electrophoresis cell equipped with platinum-irradium
electrodes to measure the electrophoretic mobility of the
diluted w/o/w emulsion and using the following equation
zeta potential was calculated.
ζ = 4μηП/٤E
Where,
ζ = zeta potential
η= viscosity of the dispersion medium
٤=dielectric constant of the dispersion medium
E=potential gradient ( voltage applied/distance
b/w electrodes)
μ=migration velocity
Entrapment efficiency
 Entrapment efficiency of the system is a measure of drug
loading capacity of the system. It is necessary to estimate
the drug inside the multiple emulsion and in the aqueous
phase.
Analysed weight of drug in multiple emulsion
 Drug entrapment efficiency (%)
=
×100
Theoretical weight of drug loaded in system
In-vitro drug release
 The drug release from the aqueous phase of a W/O/W emulsion can
be estimated using the conventional dialysis technique.
 Nakhare and vyas, 1995 investigated the release the dialysis method
using cellophane tubing.
 The W/O/W emulsion was placed in the dialysis bag and dialyzed
against 200 ml of phosphate saline buffer (PBS, PH 7.4) at 37±1oC
and a sink condition was maintained while sink contents were stirred
continuously using a magnetic stirrer.
 Aliquots were withdrawn at different time intervals and estimated
using standard procedure and the data were used to calculate
cumulative drug release profile
STABILITY OF MULTIPLE EMULSIONS
Emulsion stability is a phenomenon, which depends upon the equilibrium
between water, oil and surfactant.
Multiple emulsions are thermodynamically unstable.
The possible indications of instability include:
Leakage of the contents from the inner aqueous phase.
Expulsion of internal droplets in external phase.
Constriction or distension of the internal droplets due to osmotic gradient across the oil
membrane.
Flocculation of internal aqueous phase and multiple emulsion droplets.
Disruption of oil layer on the surface of internal droplets.
Phase separation.
 APLLICATONS OF MULTIPLE EMULSIONS
 Multiple emulsions finds wide range of applications
in controlled or sustained drug delivery, targeted
delivery, taste masking, bioavailability enhancement,
enzyme immobilization, etc.
 it will be able to provide a novel carrier system for
drugs, cosmetics and pharmaceutical agents.
1. Hemoglobin multiple emulsion having specified properties is suitable
for provision of oxygen as a blood substitute and other oxygen
transfer processes.
2. W/O/W multiple emulsions are systems of potential interest in the
oral administration of insulin. Although it has been shown that a
single oral administration of insulin-loaded W/O/W multiple emulsion
to diabetic rats led to the significant decrease of blood glucose.
 3. Water-in-oil-water (w/o/w) multiple emulsions and
polymeric nanoparticle formulations containing influenza
virus surface antigen hemagglutinin (HA) are thought to
be suitable carriers for a vaccine delivery system.
 4. Using a water-in-oil-in-water multiple emulsion system
developed for pulmonary drug targeting, the
effectiveness of tetrandrine as an antifibrotic agent
 5. To develop a prolonged and sustained release
preparation , an albumin micro-sphere-in-oil-inwater emulsion was prepared. Tegafur was used as
a model drug.
 6. Vitamin c has been widely used in formulations
of skin care products.
 7. Multiple emulsions are also used in topical
application ex… a w/o/w emulsion of
Metronidazole.
Marketed Multiple Emulsions
1
Sandostatin LARTM Depot – Novartis
(hypothalamic hormones analogue)
Control of hypersecretion at the site of the tumor where hormone overproduction
starts
2. IVY FORMULA 30 Main Treatment Multiple Emulsion- IVY FORMULA 30 was
created as a futuristic skin care treatment that is concentrated into four short weeks. A
4-week concentrated treatment that restores the keratinization cycle
and awakens and boosts the skin’s “underlying strength.”-marketed by
IVY Cosmetics
 CONCLUSION
Multiple emulsions known to be promising delivery systems
for both pharmaceuticals and cosmetic materials.
The possibility of encapsulating active substances within liquid
membranes may lead to interesting opportunities in both fields.
Thus the formulation, manufacturing, stabilization, analysis and
potential application of multiple emulsions seems to be worth
surveying, putting a special emphasis on cosmetic applications.
REFERENCES
1)
Pharmaceutical Emulsions and Suspensions, edited by Francoise
Nielloud Gilberte Marti-Mestres.
2)
Pharmaceutical Dosage Forms: Disperse systems, vol.3, second
edition, Edited by Herbert A.Liberman, Martin M. Rieger and Gilbert
S. Banker.
3)
some studies on Multiple Emulsions by G.Vishwanadham, (Ph.D
thesis, KU)
4)
Advances in Controlled and Novel Drug Delivery Systems, Edited by
N.K. Jain.
5)
Targeted and controlled Drug Delivery Novel Carrier Systems
by -S.P. Vyas and R.K. Khar.

http://www.aapsj.org/view.asp

http://www.blackwell-synergy.com

http://www.rsc.org/delivery/_ArticleLinking

http://cat.inist.fr

http://iufost.edpsciences.org
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