Presented By Mahvash Ansari, M-Phil Pharmaceutics, 2008-2010, Roll # 02

Multiple Emulsions

Presented to Prof. Dr. Nazar Mohammad

Ranjha
Multiple Emulsion
Multiple emulsion systems are novel developments in the field of emulsion
technology and are more complex type of dispersed system. Multiple emulsions are
the emulsion system in which the dispersed phase contain smaller droplets that
have the same composition as the external phase. This is made possible by double
emulsification hence the systems are also called as “double emulsion”.

Like simple emulsions, the multiple emulsions are also considered to be of two
types:
• Oil-in-Water-in-Oil (O/W/O) emulsion system
• Water-in-Oil-in-Water (W/O/W) emulsion system

In O/W/O systems an aqueous phase (hydrophilic) separates internal and external

oil phase. In other words, O/W/O is a system in which water droplets may be
surrounded in oil phase, which in true encloses one or more oil droplets.

In W/O/W systems, an organic phase (hydrophobic) separates internal and external

aqueous phases. In other words, W/O/W is a system in which oil droplets may be
surrounded by an aqueous phase, which in turn encloses one or several water
droplets. These systems are the most studied among the multiple emulsions. The
immiscible oil phase, which separates two miscible aqueous phases is known as
“liquid membrane” and acts as a different barrier and semi-permeable membrane for
the drugs or moieties entrapped in the internal aqueous phase.
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Schematic Diagram of W/O/W & O/W/O
Emulsions

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Pre-Formulation of Double
Emulsion
The formulate a double emulsion, it is necessary to choose, at least, an oil
and two surfactants, one low in HLB and one high in HLB. In the example
mentioned here, we have been working with span surfactants (HLB<5) and
Tween surfactants (HLB>10) and with a vegetable oil (caprylic/ capric
triglyceride).

The first stage involves making “state diagrams” that provide the means for
pre-selecting formulas. Those selected for in-depth study are the very white
emulsions that cream slowly and/or moderately.

HBL (blend)=f +HBL (A) + (1-f) *HBL (B)

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Methods of Preparation
Multiple emulsions are best prepared by re-emulsification of primary
emulsion. The following are the method of multiple emulsions:

 Two Steps Emulsification (Double Emulsification)

 Phase Inversion Technique (One Step Technique)

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Two Steps Emulsification
(Double Emulsification)
Two steps emulsification methods involve re-emulsification of primary W/O
or O/W emulsion using a suitable emulsifier agent. The first step involves,
obtaining an ordinary W/O or O/W primary emulsion wherein an appropriate
emulsifier system is utilized. In the second step, the freshly prepared W/O or
O/W primary emulsion is re-emulsified with an excess of aqueous phase or
oil phase. The finally prepared emulsion could be W/O /W or O/W/O
respectively.

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Two Steps Emulsification

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Modified Two Steps Emulsification

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Phase Inversion Technique
(One Step Technique)
An increase in volume concentration of dispersed phase may cause an
increase in the phase volume ratio, which subsequently leads the formation
of multiple emulsions. The method typically involves the addition of an
aqueous phase contains the hydrophilic emulsifier [ Tween 80/sodium
dodecylsulphate (SDS) or Cetyl trimethyl ammonium salt CTAB)] to an oil
phase consisted of liquid paraffin and containg lipophilic emulsifier (Span
80). A well-defined volume of oil phase is placed in a vessei of pin mixer. An
aqueous solution of emulsifier is then introduced successively to the oil
phase in the vessel at a rate of 5 ml/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.

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One Step Technique

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Membrane Emulsification
Technique
In this method, a W/O emulsion (a dispersed phase) is extruded into an
external aqueous phase (a continuous phase) with a constant pressure
through a Porous Glass Membrane, which should have controlled and
homogenous pores. The particle size of the resulting emulsion can be
controlled with proper selection of Porous Glass Membrane as the droplet
size depends upon the pore size of the droplet size depends upon the pore
size of the membrane. The relation between membrane pore size and
particle size of W/O/W emulsion exhibits good correlation as described by
the following equation :

Y= 5.03 X + 0.19

Where X is the pore size and Y is the mean particle size of the multiple
prepared using membrane emulsifier technique.

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INVITRO
CHARACTERIZATION

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Average Globule Size and Size
Distribution
The optical microscopy method using calibrated ocular and stage
micrometer can be utilized for globule size determinations of both multiple
emulsion droplets as well as droplets of internal dispersed phase.

Brightfield micrographs equipped with differential interference contrast

optics have been used to characterize the internal droplet of multiple
emulsions. Various other techniques used to characterize colloidal carriers
like Coulter counter, freeze-fracture electron microscopy and scanning
electron microscopy are also used to determine average globule size and
size distribution of multiple emulsions. Recently, NMR self-diffusion
methods are adapted to multiple emulsion characterization.

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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/d

S = Total area of interface (sa, cm)

d = Diameter of globules (cm)

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Number of Globules
Number of globules per cubic meter can be measured using the haemecytometer cell. The globules in five groups of 16 small squares
(total 80 small squares) are counted and the total number of globules in per cubic mm are calculated using the formula (Chatterjee, 1985) :

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Rheological Evaluation

The rheological of multiple emulsions 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. The
viscosity of the multiple emulsions can be measured by Brookfield rotational
Viscometer.

Interfacial rheology (i.e., interfacial elasticity at the oil-aqueous interface)

can be investigated at the mineral oil/water interface using an Oscillatory
Surface rheometer.

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Zeta Potential
The zeta potential measurements are pivotal in the designing of surface modified or
ligand anchored multiple emulsion systems. The zeta potential and surface charge
can be calculated using Smoluchowski’s equation from the mobility and
electrophoretic velocity of dispersed globules using the Zeta-potentiometer. Zeta
potential was calculated using following formula:

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Percent Drug Entrapment
Percent equipment of drug or active moiety in the multiple emulsion is generally
determined using dialysis, centrifugation, filtration and conductivity measurements. The
% Entrapment can be calculated using the following equation :

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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 technique. Aliquots were
withdrawn at different time intervals and estimated using standard
procedure and the data were used to calculate cumulative drug release
profile.

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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 and the volume of aqueous phase separated (Vsep) is measured at
suitable time intervais and percent phase separation is calculated using following
formula:

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Stability of Multiple Emulsions
Emulsion stability is a phenomenon, which depends upon the equilibrium
between water, oil and surfactant. Unfortunately multiple emulsions are
thermodynamically unstable. The possible indications of instability includes:

 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.

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Methods to Stabilize Multiple
Emulsions
The followings are some of the attempt or studies made to restore or
strengthen the stability of multiple emulsions :

 Liquid crystal stabilized multiple emulsion

 Stabilization in presence of electrolytes
 Stabilization by forming polymeric gel
 Stabilization by interfacial complexation between non-ionic
surfactant and macromolecules
 Steric stabilization
 Phase-inversion stabilization of W/O/W emulsion

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Drug Release Mechanisms &
Models
Some of the mechanisms includes :

• Diffusion of unionized drug (hydrophobic species) through the oil layer

• Carrier medicated transport
• Micellar transport
• Rupture of oil membrane
• Thinning of oil membrane

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Applications in Therapeutics &
Cosmetics
Multiple emulsion systems are finding unlimited uses because of their
vesicular structure with innermost phase closely similar to that of liposomal
vesicles and the selective permeability characteristic of liquid membrane.

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Biomedical & Pharmaceutical
Applications of Multiple Emulsions
Applications Drug entrapped
Enhanced oral bioavailability Insulin
Masking action Chloroquin
Drug over dosage treatment Salicylates, Barbiturates, Quinine
Sulphate
Vaccine adjuvant Influenza virus
Separation and extraction technique Different hydrocarbons
in the fabrication of micro capsulated Diclofenac sodium
dosage form

In cancer therapy and drug targeting 5-Fluorouracil, Bleomycin

Other applications Food and cosmetics
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Triple and Multiple Emulsions

One of the potential applications of double emulsions is to use to

encapsulate substances. By the evaporation of the intermediate phase it is
possible to prepare capsules made by polymers (or polymerossomes), solid
particles (or colloidossomes) and vesicles.

Using the same procedure to prepare double emulsions we prepare micro

fluidics devices made by glass capillaries to prepare triple emulsions of
w/o/w/o. The device consists in two concentric similar capillaries carefully
aligned facing another capillary. Four fluids are pumped through the
channels and forced to pass in a small orifice forming the triple emulsion, as
shown below.

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Triple and Multiple Emulsions

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Examples Of W/O/W/O Emulsions

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Other Examples

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Examples

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Examples
This kind of emulsion can be used as templates to prepare capsules with two
layers made by different chemical species

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