Review On Microemulsion-As A Potential Novel Drug Delivery System

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Bhattacharya et al. World Journal of Pharmacy and Pharmaceutical Sciences

SJIF Impact Factor 6.041
Volume 5, Issue 6, 700-729 Review Article ISSN 2278 – 4357
REVIEW ON MICROEMULSION- AS A POTENTIAL NOVEL DRUG

DELIVERY SYSTEM
Rohit Bhattacharya*, Sayantan Mukhopadhyay, Prof. Dr. Preeti Kothiyal
India.
Article Received on ABSTRACT

15 April 2016, The industrial process and research have made a tremendous
Revised on 06 May 2016,
Accepted on 27 May 2016 advancement in the application of microemulsion since the
DOI: 10.20959/wjpps20166-7052 microemulsions were discovered by Jack H. Shulman. Microemulsions
are macroscopically and optically isotropic mixtures of at least a
*Corresponding Author hydrophobic, a hydrophilic and an amphiphillic part. These are stable
Rohit Bhattacharya than other emulsion forms, clear, frequently combined with a co-
India.
surfactant their diameter is in the range of 10-140μm. Nowadays, the
microemulsion formulations are used all over to deliver the hydrophilic as well as the
lipophillic drugs as drug carriers because they have much better drug solubilizing ability,
improved bioavailability, long shelf life, the ease of preparations, ultra low interfacial tension
and large interfacial area. In this review article, the various advantages of microemulsions in
the pharmaceuticals, methods of preparation, classification of microemulsion, evaluation
parameters and the different research works on the microemulsions are described.
Microemulsions show effective topical delivery mechanisms for various Active
pharmaceutical ingredients for the therapeutic as well as the cosmetic applications. The
topical microemulsions show very fast penetration of the active molecules which is basically
due to the large surface area of the internal phase, also their contents minimize the barrier
property of the stratum corneum. Hence the microemulsions enhance the topical absorption
as compared to the other primitive formulations, so they are thus a very promising carrier due
to their vast ability and potential for the transdermal drug delivery.
KEYWORD: Microemulsions, corneum, hydrophilic, lipophilic.
www.wjpps.com Vol 5, Issue 6, 2016. 700

INTRODUCTION
Microemulsions are homogenous, transparent, thermodynamically stable dispersions of water
and oil which are usually stabilized by a surfactant, preferredly in combination to a surfactant
and their average droplet diameter lies in the range of within 10-140μm.[1-5]
In modern pharmaceutical research the main focus is laid on the designing and the
development of the new drug delivery system with the motive to enhance the efficacy of the
already existing drugs.
HISTORY, DEFINITION & RELATED CONCEPTS

The concept of microemulsion was introduced as early as the 1940s by Hoar & Schulman.
They discovered a clear single phasic solution by titrating a milky emulsion with Hexanol.[6]
The first microemulsion was prepared by them when they dispersed oil in an aqueous
surfactant solution & added alcohol as a co-surfactant, which lead to the formation of
transparent & a stable formulation. Schulman & his co-workers termed it as microemulsion &
since then it has been defined and redefined many times.[7]
However, for the purpose of this review the definition of microemulsion which was provided
by Danielsson & Lindman in the year 1981 will be used as a point of reference.[8] Thus,
microemulsions are defined as the “System of water, oil & amphiphile which is a single
optically isotropic & thermodynamically stable liquid solution.
In general, the major difference between the emulsions and the microemulsions is that the
emulsions may show excellent kinetic stability, but thermodynamically they are very much
unstable and hence the phases will seperate eventually.[9] Another major difference is in their
physical appearance. Emulsions are cloudy while the microemulsions are clear or translucent.
Plus, there are various considerable differences in the preparation methods of them. This is
because the emulsions need a huge input of energy where as the microemulsions do not
require any such energy considerations.[10]
There is a spontaneous formation of the microemulsion with an average droplet diameter

being 10-140μm.[11] There is a specific external boundary between the water and oil phases
where the surfactant is located. The primitive surfactant molecules are made up of a polar
head group region and a non polar tail region. Microemulsions can be asymmetric in shape
and very frequently they adopt the shape of prolate ellipsoid.[12] Microemulsions can be used

to transport hydrophilic substances through the lipoidal medium and can also be used to carry
the lipophillic substance through an aqueous medium as liquid membrane carriers[13].
Microemulsions are transparent and their structure can not be observed by an optical
microscope because the wavelength of visible light is much larger than the size of the
particles.[14] Since, microemulsions are liquid they are not very viscous and behave as a
Newtonian liquid.[15-16]
A lot of study and research have been done over the microemulsions as a potential drug
delivery system.[17-18] The characteristics such as increased drug solubilization, better
thermodynamic stability and the ease of manufacturing gives microemulsions the edge over
the other formulations.[19-20]
Microemulsion systems have a great diversity and can be used to deliver the drugs by
different routes. But the microemulsion systems have been very widely studied for the topical
administration since they can enhance the systemic or the local delivery of the drugs by
different mechanisms as topical drug carriers.[20-22]
The fact that both the oil soluable and water soluable materials are solubalized in the
microemulsions is due to the existance of the micro domains having different polaraties
within the same single phase solution. The composition of the microemulsion is the major
factor upon which the modification of the diffusional barrier of the skin depends. The
partitioning in the skin is favoured by an increased thermodynamic activity of the drug [23].
The microemulsions are preferred over the coarse emulsions because of their higher
thermodynamic stability, enhanced penetrations through the biological membranes, ease of
preparation due to the spontaneous formation, increased bioavailability, their transparency &
elegant appearance and their less inter & intra-individual variability in drug
pharmacokinetics. The various applications for which the microemulsions are reviewed
recently are their use in the cosmetics, topical use, parentral use and oral use.[24] So, for the
dermal delivery of the drugs microemulsions serves to be pretty much promising as this
proves to be an efficient route for the drug administration.[25-26]
The microemulsion- based gels are better for the topical applications than the microemulsions
which are used as the vehicles for the drug delivery purposes.[27-28] So, to increase the
viscosity of the microemulsions and to form microemulsion based gels (MBG)[29] some
gelling agents may be used. For delivering the poorly water soluable drugs orally,

microemulsion systems serves to be a promising vehicle because the microemulsion systems

can positively enhance the drug solubalization. As the thermodynamic activity of the drug in
the vehicle increases, its absorption rate also increases.[30] The thermodynamic activity can be
expressed approximately in the terms of the relative solubility which is the ratio of the
current concentration of the drug to the concentration in the saturated vehicle).[31]
Microemulsion systems are better than the other conventional lotions and creams which are
used for the topical delivery of the drugs. They are incorporated to enhance the topical drug
availability and are also used to solubalise the poorly soluable drugs.[32] They can enhance the
depth and the rate of penetration of the moisturizing agents into the skin. It is also thought
about that the microemulsions may solubalise the ordered structure of the lipids of stratum
corneum, which further leads to the decrease of the barrier properties of the skin.[33]
DIFFERENCE BETWEEN EMULSIONS AND MICROEMULSIONS

The emulsions and microemulsions are different in many ways, but some of the major
differences between the emulsions and the microemulsions are as follows: the most
important difference between the emulsions and the microemulsions is that their particles are
of different sizes and different shapes which are further dispersed into the continous phase.
The microemulsions (10-140μm) are atleast an order of magnitude smaller than the
traditional emulsions (1-20μm). Another major difference is of their physical appearance,
while the emulsions are cloudy the microemulsions are clear or may be translucent.
Additionally, there are a lot of different other differences in their preparation methods
because the conventional emulsions require a huge input of energy investment but the
microemulsions do not require any large amount of energy investment which is why it is
further related to their cost of commercial production because the microemulsions require
very less energy considerations and it has two types of the systems, while in the case of
emulsions, it only consists of rough spherical droplets of one phase dispersed into the other.
The microemulsions continuously grow between the different structures which may be
droplet like or may even be swollen up misclles or the bicontinous structures which
sometimes make the “water in oil” and the “oil in water” difference irrelevant.[34]
TABLE 1: Difference between Microemulsion & Emulsion.[35]

` Microemulsion Macroemulsion
Appearence Transparent Cloudy
Optical isotropy Isotropic Anisotropic
Interfacial tension Ultra low High

Dynamic (interface is
continously and
Microstructure Static
spontaneously
fluctuating)
Droplet size 10-200μm >500 μm
Facile preparation,
Require a large input
Preparation relatively low cost of
of energy, higher cost
commercial production
Viscosity Low viscosity Higher viscosity
ADVANTAGES OF THE MICROEMULSION BASED SYSTEMS OVER THE

OTHER DOSAGE SYSTEMS [36,37, 38, 39, 40, 41]
Microemulsions offer various advantages as a drug delivery system:
 It can be used to carry both the lipophillic drugs as well as the hydrophilic drugs.
 Microemulsions are thermodynamically stable and require minimum energy for their
formulation.
 Microemulsions are easy to manufacture and scale up.
 The absorption rate is tremendously increased in the case of microemulsions.
 Since the microemulsions are thermodynamically stable systems which allows the self
emulsification of the system.
 The problems of variations in absorption is eliminated.
 The microemulsions can act as the super solvents for the drugs because they can
solubilise both the lipophillic drugs and the hydrophilic drugs which are somewhat not
very much soluable in the hydrophobic and the aqueous solvents.
 It increases the bioavailability.
 The microemulsion systems are very much advantageous because of its many
applications in the colloidal drug delivery systems for the purpose of controlled release of
the drugs and for drug targetting.
 The lipophillic part, the dispersed phase and the hydrophilic part (w/o microemulsions, oil
in water microemulsions, o/w, or water in oil.) can serve as the potential reservoir for the
hydrophilic drugs or the lipophillic drugs respectively.
 Depending upon the volume of the dispersed phase, the transport rate of the drug, the
partition of the drug, the drug release with pseudo-zero-order kinetics can be obtained.
 The drug can be delivered by various routes such as oral, topical, and even by intravenous
route.
 The liquid dosage form increases the patient compliance.

 The mean diameter of the droplets of the microemulsion are below 22μm. This yields a
large interfacial area from which the drug is released very quickly into the external phase
when the absorption (in-vitro or in-vivo) takes place which further maintains the
concentration in the external phase close to initial levels.
 The microemulsion systems are very much helpful in the taste masking of the bitter
drugs.
 Another advantage in the case of microemulsion is the efficient and rapid penetration of
the drug moiety.
 The microemulsions have low viscosity as compared to the primary and multiple
emulsions.
 The microemulsions provide protection from the hydrolysis and oxidation as drug in oil
phase in o/w microemulsion is not exposed to attack by water and air.
 The use of the microemulsion systems as delivery system can improve the efficacy of a
drug, which allows the total dose to be reduced and thus minimizes the side effects.
 The formation of microemulsion is a reversible process. They may further become
unstable at high or low temperatures but when the temperature returns to the stability
range, the microemulsion is formed again.
STRUCTURE OF MICROEMULSION
Micellar emulsions or the microemulsions are the active formulation systems in which the
interface keeps on changing very quickly and continuously.[42] Depending upon their
structures they can be water in oil (W/O) microemulsion systems, oil in water (O/W)
microemulsion systems, and can even be bi-continous microemulsions. In the case of water in
oil microemulsions, in the continous oil phase the water droplets are dispersed where as in the
oil in water microemulsions, they are formed due to the dispersion of the oil droplets into the
continous aqueous phase. But in the case of the systems where the amounts of both oil and
water are the same, the formation of the bi-continous microemulsions takes place.[43] A very
vast variety of the phases and structures can be formed depending upon the different
proportions of the water, oil and surfactants when used in different ratios together.

FIGURE 1: MICROEMULSION SKELETAL STRUCTURE
DISADVANTAGES OF THE MICROEMULSION BASED SYSTEMS.[44,45,46]

 Large amount of the S/C’s are needed to stabilize the droplets of the microemulsion
systems.
 The environmental factors such as temperature and pH has a great impact on the stability
of the microemulsion systems. If the microemulsion is administered to the patients these
factors may further vary.
 In order to be used in the pharmaceutical preparations the surfactants to be used must be
non toxic.
 For the substances with very high-melting points which are used in the microemulsion
systems, there is a limited solubilizing capacity.
LIMITATIONS OF THE MICROEMULSION SYSTEMS[44,45,46]

There are certain factors which limits the use of the microemulsion systems in the
pharmaceutical applications:
 There is a common problem of phase separation seen in the case of microemulsions.
 For toxicity reasons, the concentrations of the co-surfactants and the surfactants must be
kept low.
 The microemulsion systems are not that much suitable for the intravenous use due to the
toxicity of the formulation and till now only a very few studies have been reported on
them.
 To reduce the toxicity of the microemulsion systems, the surfactants which are to be used
are to be of “Generally Regarded as Safe” (GRAS) category.

TYPES OF MICROEMULSION SYSTEMS [45,47,48,49,50,51]

Winsor classification of microemulsions
Four different types of situations may arise by mixing oil, water,
amphiphiles as shown by Winsor.
 Type – I System
It consists of O/W microemulsions in equilibrium with excess oil phase. The surfactant is
preferentially soluble in water and oilin- water (O/W) microemulsions form (Winsor I). The
surfactantrich water phase coexists with the oil phase where surfactant is only present as
monomers at small concentration.
 Type – II
It consists of W/O microemulsions in equilibrium with excess water phase. The surfactant is
mainly in the oil phase and waterin- oil (W/O) microemulsions form. The surfactant-rich oil
phase coexists with the surfactant-poor aqueous phase (Winsor II).
 Type – III
It consists of microemulsion phase in equilibrium with both excess water and excess oil
phase. A three-phase system where a surfactant-rich middle- phase coexists with both excess
water and oil surfactant-poor phases (Winsor III or middle-phase microemulsion).
 Type – IV
A single-phase (isotropic) micellar solution, that forms upon
addition of a sufficient quantity of amphiphile (surfactant plus
alcohol).
THEORIES OF MICROEMULSION FORMATION

Since the very beginning, three approaches have been used to explain the formation of the
microemulsion and their stability. They are:
1.) Interfacial or mixed film theories
2.) solubilization theories.
3.) Thermodynamic treatments.
The free energy of the microemulsion formation depends on to the extent upon which the
surfactant lowers the surface tension of the oil water interface and the change in the entropy
of the systems such that
Gf = γ a - T S

Where, Gf = free energy of formation

A = change in interfacial area of microemulsion
S = change in entropy of the system
T = temperature
γ = surface tension of oil water interphase.
During the formation of the microemulsion, the degree of change in “A” is very large, this is
because of the very large number of the very minute particles which are formed.
If a microemulsion is to be formed (for a short time), it always requires a negative value, but
it is considered that value of “A” is positive every time, it is offset by the entropic component
and is very small. The dominant favourable entropic contribution is a very large dispersion
entropy which arises from the mixing of of the two different phases together which further
forms very fine droplets in a large number. But, it is also expected that the other dynamic
processes for example monomer-micelle surfactant exchange and surfactant diffusion into the
interfacial layer etc will have a facilitating entropic contribution. When there is a
considerably important favourable entropic change, along with the greater decrease in the
surface tension, a negative free energy of formation is attained. In those conditions, the
microemulsion is self generated and the dispersion formed is thermodynamically much more
stable[52,53,54]
COMPONENTS OF THE MICROEMULSION SYSTEM

There are so many surfactants and oils available but due to their toxicity levels their use is
restricted. Moreover, the unclear mechanism of action and the irritation potential are also to
be considered first before they are used in the formulation of microemulsion. The ideal
properties for the oil and surfactants to be used in the formulation of the microemulsions are
as follows:
 They must be non toxic.

 They should be clinically acceptable.
 They must be bio compatible.
The main focus and the stress is laid on the selection of the components which falls under the
“Generally Regarded As Safe (GRAS)”.[52]
The main components of the microemulsion system are as follows:

 Oil phase
 Aqueous phase
 Primary surfactant
 Secondary surfactant or co-surfactant
 Co-solvent.
1.) Oil Phase

The oily phase is considered to be the most vital component in the formulation of the
microemulsion not only because of its ability to solubilise the desired quantity of the
lipophillic drugs, but also it can enhance the transport of the lipophillic drugs through the
intestinal lymphatic system. Hence, depending upon the molecular type of the triglyceride, it
can increase the absorption from the gastrointestinal tract. Due to its ability to permeate and
thus swell the tail part of the surfactant monolayer the curvature is very much influenced by
the oil component. As compared to the long chain alkanes, the short chain oils permeate the
tail group region to a greater extent, which further causes the increase in the negative
curvature and the effective HLB is decreased.
The different types of oils which are mainly used for the formulation of microemulsion are as
follows:
 Saturated fatty acids: Capric acid, Lauric acid and Myristic acid.
 Unsaturated fatty acids: Linoleic acid, oleic acid, linolenic acid.
 Fatty acid esters: Ethyl or methyl esters of the lauric, oleic and myristic acids.
The criterion which is to be considered for the selection of the oil component is that the drug
should be highly soluable into it. The main advantage of this will be that it will reduce the
volume of the formulation to a large extent to deliver the therapeutic drug dose which further
can be administered in an encapsulated form.[55,56]
2.) Aqueous Phase

The aqueous phase can have both preservatives and hydrophilic active ingredients. Some
researchers use the buffer solutions as the aqueous phase.[57] The most commonly used
aqueous phase is water. Only due to the considerable effect on the phase behavior of
microemulsions, the pH of the aqueous phase always needs to be altered.[58,59] As in the case
of the microemulsions used for the parentral administration, the aqueous phase must be iso-
osmotic to the blood which is adjusted by dextrose, sodium chloride, glycerol and sorbitol.

3.) Primary Surfactants

The surfactants are basically used to reduce the interfacial tension to a very less value that
will further enhance the dispersion process during the formation of the microemulsion and
also they help in providing a flexible film which can easily deform around the droplets and
can be of the desired lipophillic character to ensure the right curvature at the interfacial
region.
The surfactants that are used to stabilize the microemulsion system can be:
I. non-ionic,
II. zwitter-ionic,
III. cationic, or
IV. anionic surfactants.
In the microemulsion formation the surfactant used can be non-ionic or ionic which further
influences the stabilizing interactions of the aqueous phase with the hydrophilic end of the
surfactant. Hence, the ionic surfactants are stabilized due to the electrical double layer
additionally, whereas the hydrogen bond interactions with the hydration layer of the water on
its hydrophillic surface and by dipole causes the stabilization of the non-ionic surfactants.
Hence, on the stability of the microemulsion, the effect of the salt concentration is much
more influential in the case of the ionic surfactants rather than the non-ionic surfactants. But,
due to their toxicity issues the ionic surfactants are hardly used in the pharmaceutical
preparations.[60]
The non-ionic surfactants are usually allowed for the oral formulations.
They are: Polyoxyl 40, Polyoxyl 35, Polysorbate 80 (Tween 80), Polyoxyl 40 Stearate, Castor
Oil (Cremophor EL), Sorbitan mono oleate (Span 80), Polysorbate 20 (Tween 20),
Hydrogenated Castor Oil (Cremophor RH-40) etc.[61]
The surfactants which are usually preferred for the formulation of the W/O microemulsion
are generally of low HLB values (3-6). On the other hand for the formation of O/W
microemulsion, the surfactants with high HLB values (8-18) are favoured. The surfactants
which have the HLB values higher than 20 usually needs to be added with co-surfactants
which adjusts their effective HLB value within the range which is required for the formation
of the microemulsion.[62]

4.) Co- Surfactants

Research shows that it is very much difficult to reduce the O/W interfacial tension
sufficiently to enable the formation of the microemulsion by using only single chain
surfactants. And if the co-surfactants are added, it enables the interfacial film enough
flexibility to take up different curvatures required for the formation of the microemulsion
over a wide range of composition. If it is required to form a single surfactant chain then the
surfactant’s lipophillic chains must be enough short or must have fluidizing groups (eg.
Unsaturated bonds) within them. To enhance the fluidity of the interface and to decrease the
interfacial tension, short to medium chain length alcohols (C3-C8) are usually added as co-
surfactants. Most surfactants are short chain alcohols (ethanol-butanol), medium chain
alcohols, acids or amines, glycols like propylene glycol etc. If the co-surfactants are added it
hampers the gel structures or the liquid crystalline structures that are formed instead of a
microemulsion phase and except at high temperatures co-surfactant free microemulsions
cannot be made in most systems.
The co-surfactants are added because:

 It destroys liquid crystalline or gel structure which would hamper the formation of
microemulsion.
 It adjusts the HLB value and the spontaneous curvature of the interface by changing the
surfactant partitioning characteristics.
 It enhances the interface fluidity.[63,64]
5.) Co-Solvents
Comparatively higher concentrations (usually more than 30% w/w) of surfactants are needed
for the formation of the stable microemulsions. For the oral delivery, the organic solvents like
Polyethylene glycol (PEG), propylene glycol and ethanol are suitable which enables the
solublisation of a large quantity of either the drug in the lipid base or the hydrophilic
surfactant. In the microemulsion systems these solvents can also perform the function of co-
surfactants.[63,64]
FACTORS TO BE CONSIDERED DURING THE PREPARATION OF

MICROEMULSION
There are 3 most important factors which are to be kept in mind while preparing a
microemulsion system:

 To promote the microemulsion formation the interface should be fluid or flexible enough.
 To provide the no. of surfactant molecules needed to stabilize the microdroplets to be
produced by an ultra low interfacial tension the concentration of the surfactant should be
high enough.
 The most important requirement for the formation of a microemulsion system is the
selection of the surfactants which is really a critical process because a very low interfacial
tension (<10-3 mN/m) is to be achieved at the oil water interface.
METHODS OF PREPARATION OF MICROEMULSION[65,66]

 Phase Inversion Method
Due to the addition of excess of dispersed phase or in the response of temperature the phase
inversion of the microemulsion takes place. At the time of phase inversion, severe physical
changes occur which includes the changes in the particle size also which can further affect
the drug release both invitro and invivo. This method utilizes the changing in the spontaneous
curvature of the surfactant. This can be attained by changing the temperature of the system in
the case of Non-Ionic surfactants, which forces the transition from an O/w microemulsion at
low temperaturesto a w/o microemulsions at higher temperatures (transitional phase
inversion.) at the time of cooling, the system crosses the point of zero spontaneous curvature
and minimal surface tension, which promotes the formation of the finely dispersed oil
droplets. This method is also called the phase inversion temperature method (PIT). But
instead of the temperature other parameters namely the pH value or the concentration of the
salt can even be considered just instead of the temperature alone. In addition to this, a
transition in the spontaneous radius of curvature can be obtained by changing the water
volume fraction. By successively adding water into oil, initially water droplets are formed in
a continous oil phase. By just merely increasing the water volume fraction changes the
spontaneous curvature of the surfactant from initially stabilizing a w/o microemulsion to an
o/w microemulsion at the inversion locus. The short-chained surfactants form flexible
monolayers at the o/w interface resulting in a bi-continous microemulsion at the inversion
point.

Figure 2 : Hypothetical Phase region of Microemulsion system
From the above figure it is clear tha

 When the concentration of oil is very high, then the surfactant forms the reverse miscles
which are capable of solublising more water molecules in their hydrophilic interior.
 The formation of the w/o microemulsion may result if the water is added to the system
continuously. In this case water exists as the droplets surrounded and stabilized by the
interfacial layer of the surfactant/ co-surfactant mixture.
 The isotropic clear region changes to a turbid, birefringent one if the water content is less.
 The formation of the liquid crystalline region may take place when further water is added
for dilution. In this case the water molecules are sandwiched between the surfactant
double layers.
 At last, as the water amount increases eventuallythis lamellar structure will break down
and the water will form a continous phase which contains the droplets of oil stabilized by
a surfactant or a co-surfactant (o/w microemulsions).
Phase titration method

The microemulsions can be prepared by the phase titration method (spontaneous
emulsification method which can be depicted with the help of phase diagrams). To study the
complex series of the interactions that can occur when different components are mixed
together, the construction of the phase diagrams serves very much useful. Depending on the
chemical composition and the concentration of each component, the microemulsions are
formed along with various association structures (which includes miscelles, lamellar,
emulsion, hexagonal, cubic, and various gels and oily dispersions). The understanding of
their phase equilibrium and demarcation of the phase boundaries are the essential parameters
of the study. As quaternary phase diagram (four component system) is very much time
consuming and very difficult to interpret, the pseudo ternary phase diagram is often

constructed to find out the different zones including the microemulsion zone, in which each
corner of the diagram represents 100% of the particular component.
Fig. 3: A ternary phase diagram portraying various struct ures a) o/w microemulsion;
b) w/o microemulsion; c) bicontinuous microemulsion; d) and e) various dispersions
Advantages of Microemulsion
The region can be separated into w/o or o/w microemulsions by simply considering the
composition that is whether it is oil rich or water rich. Observations should be made carefully
so that the metastable systems are not included.
SOLUBILITY STUDIES FOR THE PREPARATION OF MICROEMULSION[67,68]

The solubility of the drug in the different oils (Glyceryl mono & di caprate, isopropyl
myristate, sunflower oil, soya bean oil, labrafac ®)
Surfactants (Cremophor ® EL, Labrasol® ), and co-surfactants (transcutol® P, isopropyl
alcohol, PEG- 600 and glycerol) was determined. Excess drug (100mg) was added to each
cap vial containing 5ml selected vehicle was added and vortexed for half an hour and placed
in shaker for 48 hours at 25°C, then the contents were centrifuged at 5000 r.p.m for 10
minutes. The undissolved drug as well as solubilized drug in the supernatant was quantified
by U.V. spectroscopy and the mass balance was obtained.

HYPOTHETICAL PHASE DIAGRAM[69]
Figure 4: Hypothetical Phase region of Microemulsion system
It is clear from the above figure that

 If the concentration of oil is high then reverse misclles are formed by the surfactant which
can solubilize comparatively large no. of water molecules in their hydrophilic interior.
 If in this system water is added continuously then, it may cause the formation of w/o
microemulsions in which the water exists as droplets surrounded and stabilized by the
interfacial layer of the surfactant/ co-surfactant mixture.
 The isotropic clear region changes into a bifringent, turbid one at a limited water content.
 The liquid crystalline region with water sandwiched between the surfactant double layers
may be formed, on further dilution with water.
 Finally, this lamellar structure will break down and the water will form a continous phase
containing the droplets of oil stabilized by a surfactant/co-surfactant (o/w
microemulsion), as the amount of water is increased.
FACTORS AFFECTING FORMATION AND PHASE BEHAVIOUR OF

MICROEMULSIONS
1) Factors affecting the microemulsion system formation:[70,71]
The property of the surfactant, temperature, packing ratio, oil phase, type and nature of
co-surfactant and the chain length are the main factors on which the formation of the oil
or water swollen microemulsions depends.
 PACKING RATIO: The type of microemulsion through its influence on film curvature
and molecular packing is determined by its H.L.B.

Israclachvili et al (1976) and Mitchell and Ninhain (1977) explained the analysis of film
curvature for the surfactant associations which leads to the microemulsion formation, in
the terms of packing ratio. This is also known as critical packing parameter.
Critical packing parameter (CPP)= V/a*l
Where,
 V is the partial molar volume of the hydrophobic portion of the surfactant.
 a is the optimal head group area.
 l is the length of the surfactant tail.
o If CPP (0-1) interface curves towards water (positive curvature) and o/w systems are
favoured
o If CPP is greater than 1, the interface curves spontaneously towards oil (negative
curvature), so w/o microemulsion are favoured.
o At zero curvature, when the H.L.B. is balanced (P is equivalent to 1) then either bi-
continious or lamellar structures may form according to the ridgidity of the film (zero
curvature).
 PROPERTY OF SURFACTANT, OIL PHASE AND TEMPERATURE

On the nature of surfactants the nature of the microemulsions formed depends. A surfactant
consists of the lipophillic tail group and a hydrophilic head group. The points of these groups
that are measure of the differential tendency of the water to swell the head group and oil to
swell the tail area are important for specific formulations while estimating the H.L.B. of the
surfactant in a particular system. When the surfactant is in the presence of a salt or when a
high concentration of the surfactant is used then the degree of polar group dissociation
becomes lesser and the resulting system may be w/o type.
Temperature influences the ionic surfactants strongly which mainly causes increased
surfactant counter-ion dissociation. The tail group region of the surfactant monolayer swells
up which is influenced curvature by it’s ability to penetrate due to the presence of oil
component. For the determination of the effective head group size of the non-ionic
surfactants, the temperature plays a very important role. They form normal o/w systems
which are hydrophilic when the temperature is very low, but when the temperature is high
they form w/o systems and are lipophillic. The microemulsion forms a bi-continious structure
and can co-exist with oil phases and excess water when the temperature is intermediate.

 CHAIN LENGTH, TYPE AND NATURE OF THE CO-SURFACTANT

The alcohols are very widely used as the co-surfactants for the formation of the
microemulsion. If a shorter chain co-surfactant is added, it gives a positive curvature effect
because due to the presence of alcohol the head region gets swelled up more than that of the
tail region. Hence, they become more hydrophilic and the o/w type is favoured, but in the
case of the longer chain co-surfactants, they favour the w/o type by the alcohol which swells
more in the chain region than the head region.
FACTORS AFFECTING THE PHASE BEHAVIOUR[70,72]

 SALINITY
When the salinity is less in the case of o/w microemulsion, the droplet size increases. This
further causes the oil to solubilize more. The system becomes bi-continious over an
intermediate salinity range, as the salinity increases. Continuous microemulsion formation
with reduced globule size is caused by increased salinity. Complete phase transition occurs
finally if the salinity is increased further.
 ALCOHOL CONCENTRATION
The phase titration from w/o to bi-continious and finally to o/w type microemulsion is caused
if the concentration of low molecular weight alcohol, exactly opposite phase transition can be
noticed.
 SURFACTANT HYDROPHOBIC CHAIN LENGTH
When the hydrophobic chain length of the surfactant is increased it shows the change of o/w
microemulsion to w/o via bi-continious phase.
 pH
The pH sensitive surfactants are influenced by the change in the pH. In the case of the
alkaline or acidic surfactants this effect can be seen precisely. By increasing the pH, the
phase behavior can be seen from w/o to o/w when the carboxylic acids and the amines are
present.
 NATURE OF OIL
if the aromaticity of the oil is increased, then the phase transitions occur from o/w to w/o and
is opposite to that if the oil alkane carbon no. is increased.
 IONIC STRENGTH
With the increase in the ionic strength the microemulsion systems changes from o/w
microemulsion in equilibrium with excess oil to the middle phase and finally to the w/o
microemulsion in equilibrium with excess water.

CHARACTERIZATION OF MICROEMULSION[65,73]
There are various techniques by which microemulsions are characterized. Because the
microemulsions are very complex, they have various components involved in their systems,
they have a very large variety of structuresand also there are various limitations attached to
their methods of characterization, it is very difficult to characterize microemulsions, but their
characterization knowledge is very much important for their commercial exploitation.
Hence, complementary studies using the combination of various techniques are usually
required to obtain an impressive view of the structure and the physicochemical properties of
the microemulsions.
For the physicochemical characterization of microemulsion the basic components are:

 The diamension and the microstructure of the microemulsion.
 Phase behavior and phase stability.
 The local molecular rearrangement.
 The surface features like charge distribution and the specific area.
 Shape.
 Interaction and dynamics.
From these properties, the interactions and dynamics and the particle size are very much
important as many general properties of the microemulsions are governed by them.
There are various parameters on which the drug release from the microemulsions depends
such as droplet size, oil aqueous phase ratio, the distribution of drug in the phases of
microemulsion system and the rate of diffusion or the absorption in both phases.
 VISUAL OBSERVATION
Microemulsion s are usually observed to check their flowability and clarity.
 INTERFACIAL TENSION[75]
By measuring the interfacial tension of the microemulsion system, their properties and
formation can be studied. The very low values of the interfacial tension of the microemulsion
system are correlated with phase behavior particularly the existance of the surfactant phase or
the middle-phase microemulsion in equilibrium with aqueous and oil phases. For measuring
the very low interfacial tension spinning drop apparatus is used. The interfacial tensions are
taken out to measure the shape of the drop of very low density phase and to rotate that into
the cylindrical capillary filled up with very high density phase.


CENTRIFUGATION[74]
The microemulsion systems can be centrifuged at 5000 r.p.m for 30 minutes and then
checked for phase separation.
EVALUATION OF THE MICROEMULSION SYSTEM

 VISUAL INSPECTION
By the visual inspection we can check the properties such as fluidity, homogenicity, and
optical clarity.
 EXAMINATION UNDER CROSS-POLARISING MICROSCOPE[76,77]

For the absence of bifringence to eliminate liquid crystalline systems, the microemulsion
must be examined under cross polarizing microscope.
 ASSESMENT OF THE RHEOLOGICAL PROPERTIES[79]

For the stability of microemulsion the rheological properties play a very important role and
can be determined by using the Brookfield digital viscometer.
 LIMPIDITY TEST (PERCENT TRANSMITTANCE)[78]

A spectrophotometer is used to measure the limpidity of the microemulsion
spectrophotometrically.
ACCELERATED STABILITY TESTS[80,81]

 CENTRIFUGATION STRESS TESTING
Because the stability studies take too much time, so the preference is given to accelerated
stress testing. Centrifugation of the microemulsion is done at the speed of 5000-10,000 rpm
for 30 mins to check the physical instabilities such as phase inversion, phase separation,
creaming, aggregation and the cracking of the formulation. The formulations which are
thermally tested previously are taken in the centrifuge sample tubes and are then placed into
the centrifugation basket at a correctly balanced equilibrium position at suitable temperature
conditions.
 FREEZE-THAW CYCLES (FTC)

The microemulsions are stored at 25°c for 24 hours and followed by being stored at -5°c for
24 hours. This cycle is repeated 3 times and the change in the stability parameters are noticed.

LONG TERM STABILITY

On the basis of the ICH guidelines the stability can be examined. For 6 months, the
microemulsion are stored under ambient conditions and the microemulsion system were
examined time to time after 1,3 and 6 months. By visual inspection and the pH, percent
transmittance, rheological evaluation and the specific gravity are measured.
 DETERMINATION OF THE GLOBULE SIZE[82]

The size of the globules can be determined by the light scattering method. By the
photomicroscope method the size determination of the globules are much easier.
 DETERMINATION OF THERMAL STABILITY[83]

20ml of the microemulsion loaded with drugswere stored in a 25 ml transparent borosil
volumetric container at three different temperatures i.e. 4°, 25° and 40°c, 1°c in BOD for 1
month. The samples were taken out at definite intervals of time to inspect visually to check
any physical changes such as turbidity, coalescence and the loss of clarity. The samples can
also be checked to determine the loss of the aqueous phase which is an important aspect of
the stability of the microemulsion.
 pH OF THE MICROEMULSION[83-85]
Different samples of the microemulsions are taken in the sample tubes. Then a micro pH
meter is used to check the pH of the different samples. Since the pH of the formulation is the
factor upon which the microemulsion stability and the bioavailability of the drug through
microemulsion at the permeation site depends upon.
 IN-VITRO SKIN-PERMEATION STUDIES[86-90]

To check the permeation of the drug through the skin, skin penetration studies are conducted.
Under the guidelines given by the committee for the purpose of control and supervision of
experiments of animal (CPCSEA, ministry of culture, Government of India). The
microemulsions with best evaluation test results are further used. From male Wistar rats
weighing 230± 20gm (age 6-8 weeks) the abdominal skins were obtained to conduct the in-
vitro permeation studies for the formulations. With the help of the electric clippers, the hair
of the rats are shaved carefully, of each sacrificed rat, the skin is excised from the abdominal
region. The extraneous tissues and the subcutaneous fat are removed from the sacrificed rat
without damaging the epidermal surface. The excised skins of rats are washed thoroughly and
are checked for their integrity and then stored at 4°C for 24 h in phosphate-buffered saline pH

6.8 (PBS), and then used for the permeation experiments. The permeation experiments is
performed using Franz diffusion cells fitted with excised rat skins having epidermal surface
outward. The effective diffusion area is about 3.14 cm2 (20 mm diameter orifice), and the
receptor compartment is filled with 12 ml of PBS. The diffusion cell was maintained at
37±1°C using a recirculating waterbath and the solution in receptor chamber is stirred
continuously at 600 rpm throughout the experiment. The specified amount of formulation is
gently placed in a donor chamber. At 1, 2, 4, 6, and 8 h aliquot of 2 mL sample is withdrawn
from the receptor compartment for spectrophotometric determination and replaced
immediately with an equal volume of fresh PBS. Average values of three readings of in vitro
permeation data is calculated and the average cumulative amount of drug permeated per unit
surface area of the skin is plotted versus time. The permeation rate of FLZ at steady-state
(Jss, micrograms per centimeter per hour) through rat skin is calculated from the slope of
linear portion of the cumulative amount permeated through the rat skins per unit area versus
time plot. In order to obtain the permeability coefficient Kp (centimeters per hour), the
following equation was used Kp ¼ Jss = Cdonor Where, Kp is the permeability coefficient,
Jss is the flux calculated at steady-state, and Cdonor represents the applied drug concentration
in the donor compartment.
Figure: 5 Applications of Microemulsions.
CONCLUSION
Thermodynamically stable liquid solution of oil, water and amphiphillic microemulsions can
be easily distinguished from the normal emulsions by their low viscosity, better transparency

and more thermodynamic stability of microemulsions. The drug delivery through the
microemulsion is a promising area for the continued research with the aim of achieving the
controlled release with enhanced bioavailability and for drug targeting to various sites of the
body. Today microemulsions have been shown to be able to protect liable drug, controlled
drug release, increase drug solubility, increase bioavailability, reduce patient variability,
increase the rate of absorption, helps to solubalize the lipophillic drugs, various routes like
topical, oral and intravenous, can be used to deliver the products, helpful in taste masking,
provides and increases the patient compliance. So, use of microemulsion based delivery
systems is the most attractive and suitable area of research, offering not only many challenges
to overcome but potential extraordinary benefits. Furthermore, it has proven possible to
formulate the preparation suitable for most routes of administration.
ACKNOWLEDGEMENT
The authors thankful to the authorities of Shri Guru Ram Rai Institute Of Technology and
Sciences, Dehradun (Uttarakhand) for providing all the support to study and all other
necessary facilities like internet surfing, library and other technical support to write the
review article.
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WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Bhattacharya et al. World Journal of Pharmacy and Pharmaceutical Sciences

Volume 5, Issue 6, 700-729 Review Article ISSN 2278 – 4357

REVIEW ON MICROEMULSION- AS A POTENTIAL NOVEL DRUG

Rohit Bhattacharya*, Sayantan Mukhopadhyay, Prof. Dr. Preeti Kothiyal

Article Received on ABSTRACT

KEYWORD: Microemulsions, corneum, hydrophilic, lipophilic.

www.wjpps.com Vol 5, Issue 6, 2016. 700

HISTORY, DEFINITION & RELATED CONCEPTS

There is a spontaneous formation of the microemulsion with an average droplet diameter

www.wjpps.com Vol 5, Issue 6, 2016. 701

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microemulsion systems serves to be a promising vehicle because the microemulsion systems

DIFFERENCE BETWEEN EMULSIONS AND MICROEMULSIONS

TABLE 1: Difference between Microemulsion & Emulsion.[35]

www.wjpps.com Vol 5, Issue 6, 2016. 703

ADVANTAGES OF THE MICROEMULSION BASED SYSTEMS OVER THE

www.wjpps.com Vol 5, Issue 6, 2016. 704

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FIGURE 1: MICROEMULSION SKELETAL STRUCTURE

DISADVANTAGES OF THE MICROEMULSION BASED SYSTEMS.[44,45,46]

LIMITATIONS OF THE MICROEMULSION SYSTEMS[44,45,46]

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TYPES OF MICROEMULSION SYSTEMS [45,47,48,49,50,51]

THEORIES OF MICROEMULSION FORMATION

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Where, Gf = free energy of formation

COMPONENTS OF THE MICROEMULSION SYSTEM

 They must be non toxic.

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1.) Oil Phase

2.) Aqueous Phase

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3.) Primary Surfactants

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4.) Co- Surfactants

The co-surfactants are added because:

FACTORS TO BE CONSIDERED DURING THE PREPARATION OF

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METHODS OF PREPARATION OF MICROEMULSION[65,66]

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Figure 2 : Hypothetical Phase region of Microemulsion system

From the above figure it is clear tha

Phase titration method

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SOLUBILITY STUDIES FOR THE PREPARATION OF MICROEMULSION[67,68]

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HYPOTHETICAL PHASE DIAGRAM[69]

Figure 4: Hypothetical Phase region of Microemulsion system

It is clear from the above figure that

FACTORS AFFECTING FORMATION AND PHASE BEHAVIOUR OF

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 PROPERTY OF SURFACTANT, OIL PHASE AND TEMPERATURE

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 CHAIN LENGTH, TYPE AND NATURE OF THE CO-SURFACTANT

FACTORS AFFECTING THE PHASE BEHAVIOUR[70,72]

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For the physicochemical characterization of microemulsion the basic components are:

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