International Journal of Chemistry Studies

International Journal of Chemistry Studies

ISSN: 2581-348X; Impact Factor: RJIF 5.44
Received: 03-02-2019; Accepted: 05-03-2019
www.chemistryjournal.in
Volume 3; Issue 3; May 2019; Page No. 12-16

Multiple emulsions and its stabilization: A review

Navneet Kumar Verma1, Jai Narayan Mishra2
1-2
Faculty of Pharmacy, Kailash Institute of Pharmacy and Management, Gorakhpur, Uttar Pradesh, India

Abstract
Multiple emulsions are also known as emulsions of emulsions, liquid membrane system or double emulsion. These have been
proposed to have numerous uses including their use for enhancement of bioavailability or as a prolonged drug delivery system.
Multiple emulsions are often stabilized using a combination of hydrophilic and hydrophobic surfactants. The ratio of these
surfactants is important in achieving stable multiple emulsions. The two major types of multiple emulsions are the w/o/w and
o/w/o emulsions. Multiple emulsions are multifarious polydispersed systems where both oil in water and water in oil emulsion
exists all together which are stabilized by lipophillic and hydrophilic surfactants respectively. The ratio of these surfactants is
important in achieving stable multiple emulsions. Among water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) type
multiple emulsions; the former has wider areas of application. Formulation, preparation techniques and in vitro
characterization methods for multiple emulsions are reviewed. It finds wide range of applications in controlled or sustained
drug delivery, targeted delivery, taste masking, bioavailability enhancement, enzyme immobilization, etc. Multiple emulsions
have also been employed as intermediate step in the microencapsulation process and are the systems of increasing interest for
the oral delivery of hydrophilic drugs, which are unstable in gastrointestinal tract like proteins and peptides.

Keywords: multiple emulsions, surfactant, stability of emulsions

Introduction stabilize the primary W/O emulsion and one that has a high
Multiple emulsions are defined as emulsions in which both HLB value to stabilize the secondary O/W emulsion. The
types of emulsions, i.e. water-in-oil (w/o) and oil-in-water low-HLB surfactant is dominantly hydrophobic and is added
(o/w) exist simultaneously [1]. They combine the properties to the oil phase. The high HLB surfactant is dominantly
of both w/o and o/w emulsions. These have been described hydrophilic and is added to the outer continuous aqueous
as heterogeneous systems of one immiscible liquid phase. The concentration ratio of these two surfactants is
dispersed in another in the form of droplets, which usually important to obtain stable and high yields of W/O/W
have diameters greater than 1 μm1. These two liquids emulsions [16]. A unique property of W/O/W multiple
forming a system are characterized by their low emulsions com-pared to simple W/O emulsions is the
thermodynamic stability [2]. Multiple emulsions are very diffusion of water through the oil phase because of
complex systems as the drops of dispersed phase themselves unbalanced osmotic pressures between the internal and
contain even smaller droplets, which normally consist of a external aqueous phases. The oil layer acts as a membrane
liquid miscible and in most cases identical with the separating these two aqueous phases. Polar molecules
continuous phase [3]. Both hydrophilic and lipophilic dissolved in either the internal aqueous phase or the external
emulsifiers are used for the formation of multiple emulsions. continuous aqueous phase can pass through the oil layer by
Multiple emulsions were determined to be promising in diffusion because of the concentration gradient. In the case
many fields, particularly in pharmaceutics and in separation of water this is driven by osmotic pres-sure. Molecules are
science. Their potential biopharmaceutical applications3 often transported via micelles of hydrophobic surfactant
include their use as adjuvant vaccines [4], as prolonged drug present in the oil phase. Water diffusion causes swelling,
delivery systems [5-8], as sorbent reservoirs in drug overdose bursting, or shrinkage of the internal aqueous droplets,
treatments [9] and in mobilization of enzymes [10-11]. Multiple affecting the stability of the multiple droplets as well as the
emulsions were also investigated for cosmetics for their release profiles of the active ingredients loaded in the inner
potential advantages of prolonged release of active agent, dispersed aqueous phase [17]. Most cardiovascular events are
incorporation of incompatible materials and protection of attributed to high blood pressure. High blood pressure is
active ingredients by dispersion in internal phase [12-14]. Also quantitatively the largest single risk factor for premature
water-in-oil-in-water (W/O/W) multiple emulsions are death and disability due to its extremely high prevalence in
emulsion systems where small water droplets are en-trapped industrialized countries. Hence, antihypertensive therapy
within larger oil droplets that in turn are dispersed in a considerably reduces the risk of developing cardiovascular
continuous water phase. Because of the presence of a complications that cause a high mortality rate in patients
reservoir phase inside droplets of another phase that can be with hypertension [18-19]. Valsartan is a new potent, highly
used to prolong release of active ingredients [15]. Multiple selective and orally active antihypertensive drug belonging
W/O/W emulsions contain both W/O and O/W simple to the family of angiotensin II type 1 receptor antagonists.
emulsions and require at least 2 emulsifiers to be present in Valsartan inhibits angiotensin II receptors, thereby relaxing
the system when prepared using the 2-step method, one that blood vessels and causing them to widen, which lowers
has a low Hydrophile-Lipophile Balance (HLB) value to blood pressure and improves blood flow [20-21]. Valsartan is

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International Journal of Chemistry Studies

well tolerated after single and multiple dosing following among the multiple emulsions
single oral doses up to 400 mg and after multiple dosing [22-
24]
with 200 mg per day. The development of multiple Advantages of Multiple Emulsions
emulsion dosage formulation of certain active ingredients is a) They can mask the bitter taste and odour of drugs,
challenging. When formulating multiple emulsions dosage thereby making them more palatable. E.g. Castor oil,
formulations, the objective is to provide an increased release Cod-liver oil, Chloroquine Phosphate etc.
of valsartan and increased oral bioavailability of valsartan in b) They can be used to prolong the release of the drug
patient as compared to known solid oral dosage forms of thereby providing sustained release action.
valsartan. Development of multiple emulsions dosage c) Essential nutrients like carbohydrates, fats and vitamins
formulation that have improved bioavailability to the known can all be emulsified and can be administered to
oral dosage forms of valsartan is challenging due to the bedridden patients as sterile intravenous emulsions
multiplicity of challenges arising from pharmacokinetic d) Emulsions provide protection to drugs which are
aspects of oral drug delivery. Valsartan has an oral susceptible to oxidation.
bioavailability of only about 25% with a wide range of 25-
40% in humans with large inter- and intra-subject Limitations of multiple emulsions
variabilities. Valsartan also has pH dependent solubility The main problem associated with multiple emulsions is
whereby it ranges from very slightly soluble in an acidic their thermodynamic instability and their complex structure,
environment to soluble in a neutral environment of which has severely limited their usefulness in the many
gastrointestinal tract. The permeability of valsartan is low applications of multiple emulsions [29].
and also pH dependent where it decreases as environmental
pH increases from acidic to neutral pH values in the gastro Stabilization
intestinal tract. As a result of these complex It is a phenomenon which depends upon equilibrium
biopharmaceutical properties, development of a more between three phases; water, oil and surfactant.
releasable and bioavailable dosage form of valsartan with Nevertheless, multiple emulsions are thermodynamically
less inter and intrasubject variability is challenging. unstable. A little emulsifier may result in unstable systems,
Accordingly multiple emulsions dosage formulation of whereas too much emulsifier may lead to toxic effects and
valsartan which has enhanced release and bioavailability can cause destabilization. Some mechanisms have been
properties with less inter and intrasubject variability would identified which leads to instability of multiple emulsions:
be desirable. Thus the aim of the present study is to 1. Coalescence of multiple emulsion droplets or internal
“formulate and evaluate the multiple emulsion of valsartan” droplets.
[25]
. 2. Rupture of oil layer on surface of internal drops.
3. Shrinkage and swelling of internal droplets due to
Method of Preparation osmotic gradient across the oil membrane.
Multiple emulsions were prepared by two step 4. Flocculation of internal aqueous phase and multiple
emulsification process: emulsion droplets and Phase separation.

a) Preparation of primary emulsification The main problem in regards to stability is the presence of
Primary emulsification: 10 ml of distilled water containing two interfaces which are thermodynamically unstable. So,
25 mg of drug was gradually added to 14 ml of oil phase Two different emulsifiers are necessary for their
containing primary emulsifier (Span40, Span60, and Span stabilization; one with a low HLB (Hydrophile-Lipophile
80) and 25mg of drug with continuous stirring at 5000 rpm Balance) value for W/O interface and the another one with a
for 5 minutes. It gives the primary emulsion. high HLB value for O/W interface. We can stabilize the
emulsions by using electrolytes, by forming polymeric
b) Secondary emulsification [26-28] film,by interfacial complexation between non-ionic
Secondary emulsification: 20 ml of viscous primary surfactant and macro molecules. Following approaches we
emulsion was emulsified further with an external aqueous can use to overcome instability in multiple emulsions:
phase containing secondary emulsifier (Tween80) and 50
mg drug with continuous stirring at 1000 rpm for 10 min. 1.1 The inner phase
All the formulations were prepared by following the same We can stabilize the inner W/O emulsion mechanically, or
procedure. Effect of primary emulsifier was observed by in presence of better emulsifiers, reducing its droplet size.
evaluating several formulations. Also we can achieve our aim by Preparing microspheres and
Increasing the viscosity of inner water [30].
Types of multiple emulsions
a) Oil in water in oil (o/w/o) emulsion-In O/W/O systems, 1.2 The oil phase
an aqueous phase separates internal and external oil By modifying nature of oil phase by increasing its viscosity
phases. In other words, O/W/O is a system in which or by adding carriers or by adding complexing agents to the
water droplets may be surrounded in an oil phase, oil.
which in turn encloses one or more oil droplets3.
b) Water in oil in water (w/o/w) emulsion-In W/O/W 1.3 The interfaces
systems, an organic phase separates internal and This can be done by stabilizing inner and/or outer emulsion
external aqueous phases. In other words, W/O/W is a by using polymeric emulsifiers, macro molecular
system in which an oil droplet may be surrounded by an amphiphiles or colloidal solid particles to form strong as
aqueous phase, which in turn is encloses one or more well as more rigid film at the interface; also by in-situ
water droplets. These systems are the most studied polymerization at the interface. Hence, stability of multiple

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International Journal of Chemistry Studies

emulsions can be improved by forming a polymeric film or excess of water or oil phase to get a multiple emulsion of
macro molecular complex across the oil/water interfaces o/w/o or w/o/w type [32]. Second step is very crucial because
fracturing of the internal globules forming simple emulsion
2. Drug Release Mechanisms of o/w or w/o type may take place depending on various
Drug release in multiple emulsions from internal to external factors. It has a advantage that this technique is easier and
phase occurs via the middle layer. The release rates are gives a high yield.
affected by various factors such as droplet size, pH, phase
volume ratios, viscosity, nature of entrapped material 3.2 Phase inversion technique
etc.Some of the mechanisms of drug release are as follows: It is a one-step mechanism. In this, the continuous phase
become the dispersed phase and vice-versa, could be
2.1 Diffusion mechanism considered a good path to produce emulsion which are made
Most common transport mechanism where unionized drug up of very small droplets. Phase inversion could be
(hydrophobic moieties) diffuses via oil layer accompanied by altering the temperature and volume
(semipermeable liquid membrane), especially in stable fractions of the system and phases respectively and by
multiple emulsions. Drug transport has been found to follow adding salts or by imposing the flow rates. It has been
first order kinetics and obeyed Fick’s law of diffusion [31]. founded that, if we raise the temperature, nonionic
surfactants become more hydrophilic. As a result of this,
2.2 Carrier mediated transport they change their chemical configuration and phase
It involves a special molecule (carrier) which combines with inversion is done.
drug and makes it compatible to permeate via the oil
membrane. This involves either incorporation of some 3.3 Membrane emulsification technique
material into internal aqueous phase of membrane phase, In this technique the emulsifier used is a glass membrane.
which reacts with permeating compound to render it The principle which is used is dispersing one phase which is
liposoluble. Carrier compounds effectively pump the not miscible (dispersing phase) into continuous phase by
permeating compound across membrane; e.g., stearic acid applying pressure. The particle size of the w/o/w emulsion
facilitated diffusion of Cu2+ ions. This mechanism is can be restrained by selecting perfect porous glass
especially effective for transport of highly hydrophilic membrane.
compounds.
4. Methods to stabilize Multiple Emulsions
2.3 Micelle transport 4.1 Stabilization in presence of electrolyte
Since outer lipophilic nature, in this mechanism inverse Addition of electrolyte resulted in improvement of emulsion
micelles consisting of non-polar part of surfactant lying stability with respect to coalescence. So, when electrolytes
outside and polar part lying inside encapsulate hydrophilic are added in inner layer or outer aqueous layer multiple
drug in core and permeate via the oil membrane.. Inverse emulsions migrate across the oils layer and thus migrate to
micelle can epitomize both ionized and Non ionized drugs. some other aqueous layer. This migration induces changes
The presence of both lipophilic and hydrophilic surfactants in osmotic pressure with time and thus alters the stability of
in the oil phase helps in the formation of water swollen multiple emulsions.
inverse micelles, which may act as a mobile carrier for both
ionized and unionized drug. 4.2 Stabilization by forming polymeric gels
In order to improve stability of multiple emulsion, either
2.4 Thinning of oil membrane internal phase (aqueous) or secondary aqueous phase needs
Due to osmotic pressure difference oil membrane become to be gelled. Production of gels in aqueous phase leads to
thin, so water and drug easily diffuses. This mechanism system which has greater stability. If the internal aqueous
comes into existence when there is an osmotic pressure phase is gelled, it will prevent coalescence. And when the
difference between two aqueous phases, which also outer continues phase is gelled, an opaque emulsion is
provides force for transverse of molecule. Rupturing of oil produced in which the dispersed droplets are held in a
membrane can unite both aqueous phases and thus drug network of polymer from where the droplets are released on
could be released easily. Solubilization of minute amounts contact with water.
of internal phase in membrane phase results in transport of
very small quantities of materials. 4.3 Steric Stabilization
Emulsion can be stabilized by increasing the repulsion
3. Formulation Technique between the dispersed phases that is by increasing the
Emulsions are thermodynamically unstable and thus we add electrostatic or steric repulsion. This can be done by adding
emulsifier like surfactant, co polymer to maintain its an emulsifier. emulsifier are amphiphiles which reduce the
stability. So two surfactants of opposite nature are added to interfacial tension between the two phases and contribute to
the system. One stabilizes the w/o ( lipophilic) emulsion stabilization of dispersed droplet. Both electrostatic and
while the other stabilizes the o/w ( hydrophilic) emulsion. steric forces can prevent aggregation or coalescence and
When emulsion formation takes place, these emulsifiers are thus stabilize emulsions.
adsorbed on the surface of the droplets which prevents them
from aggregating. 4.4 Liquid crystal stabilized multiple emulsions
Liquid crystal at the periphery of multiple emulsion droplets
3.1 Double emulsification technique prevents the diffusion of water between inner and outer
The first step is formation of a simple w/o or o/w emulsion. aqueous system. Liquid structure has a mesomorphic
In presence of an emulsifier, this is again re- emulsified with structure between solid and liquid. When a liquid crystal is

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International Journal of Chemistry Studies

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