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Review Article Microemulsions: Current Trends in Novel Drug Delivery


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Journal of Pharmaceutical, Chemical and Biological Sciences


February 2014 ; 1(1):39-51
Available online at http://www.jpcbs.info

Review Article

Microemulsions: Current Trends in Novel Drug Delivery Systems

Pranjal Kumar Singh1*, Mohd. Kashif Iqubal2, Vikesh Kumar Shukla3, Mohd. Shuaib4
1, 2, 4
Department of Pharmacy, Kalka Institute for Research and Advanced Studies, Meerut, Uttar Pradesh,
India
3
Department of Pharmacy, IIMT College of Medical Sciences, Meerut, Uttar Pradesh, India

ABSTRACT

Microemulsions are one of the best candidates as novel drug delivery system because of their long shelf life,
improved drug solubilization with ease of preparation and administration. Microemulsions are
thermodynamically stable and optically isotropic liquid solutions of oil, water and amphiphile. They have
emerged as novel vehicles for drug delivery which allow controlled or sustained release for ocular,
percutaneous, topical, transdermal, and parenteral administration of medicaments. Microemulsions can be
easily distinguished from normal emulsions by their low viscosity, transparency and more accurately their
thermodynamic stability. Microemulsions have great range of applications and uses such as in
pharmaceuticals, agrochemicals, cutting oils, biotechnology, food, cosmetics, analytical applications,
environmental detoxification etc. The main objective of this review paper is to discuss microemulsions as
drug carrier system with other possible applications.

Key words: Microemulsions, thermodynamically stable, amphiphile, solubilization

Received: 12 February 2014 Revised and Accepted: 19 February 2014

* Corresponding author: Email: Pranjal.pharmacy@gmail.com

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Singh et al 40

INTRODUCTION Advantages of Microemulsion system [6-11]

The formulation and development of novel drug 1. Microemulsions are easily prepared and
delivery system with the nature of enhancing the require no energy contribution during
effectiveness of existing of drug is an ongoing preparation this is due to better
process in pharmaceutical research. Since there thermodynamic stability.
are many types of drug delivery systems that have 2. The formation of microemulsion is reversible.
been developed. The microemulsion concept was They may become unstable at low or high
introduced in 1940s by Hoar and Schulman who temperature but when the temperature
generated a clear single-phase solution by returns to the stability range, the
triturating a milky emulsion with hexanol [1]. They microemulsionreforms.
prepared the first microemulsion by dispersing oil 3. Microemulsions are thermodynamically stable
in an aqueous surfactants solution and adding an system and allows self-emulsification of the
alcohol as a co-surfactant, leading to transparent system.
stable formulation. Microemulsion is defined as 4. Microemulsions have low viscosity compared
microemulsion are clear, transparent, to emulsions.
thermodynamically stable dispersions of oil and 5. Microemulsions act as supersolvents for drug,
water, stabilized by an interfacial film of surfactant can solubilise both hydrophilic and lipophilic
frequently in combination with a co-surfactant drugs including drugs that are insoluble in both
[2].Alternative names for these systems are often aqueous and hydrophobic solvents.
used, such as swollen micelle, 6. Having the ability to carry both lipophilic and
transparentemulsion, solubilized oil and micellar hydrophilic drugs.
solution. Microemulsions are bicontinuous 7. The dispersed phase, lipophilic or hydrophilic
systems that are essentially composed of bulk (O/W, or W/O microemulsions) can act as a
phases of water and oil separated by a potential reservoir of lipophilic or hydrophilic
surfactant/cosurfactant rich interfacial region [3]. drugs, respectively.
These systems have advantages over conventional 8. The use of microemulsion as delivery systems
emulsions in that they are thermodynamically can improve the efficacy of a drug, allowing the
stable liquid systems and are spontaneously total dose to be reduced and thus minimizing
formed [4]. Microemulsions are currently the side effects.
subject of many investigations because of their
Disadvantages of Microemulsion Systems [6-8]
wide range of potential and actual utilizations. The
high capacity of microemulsions for drugs makes
1. Having limited solubilizing capacity for high-
them attractive formulations for pharmaceuticals.
melting substances.
These systems also offer several benefits for oral
2. Require large amount of Surfactants for
administration, including increased absorption,
stabilizing droplets.
improved clinical potency and decreased toxicity
3. Microemulsion stability is influenced by
[5].
environmental parameters such as
temperature and pH.

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Singh et al 41

BASIC DIFFERENCES BETWEEN MACROEMULSION AND MICROEMULSION [12-14]


Sl.No MACROEMULSION MICROEMULSION

1. They are lyophobic in nature. They are the border between lyophilic and
lyophobic.
2. Droplet diameter 1 to 20 mm. Droplet diameter 10 to 100 mm.
3. Macroemulsion droplets exist as individual Microemulsion droplets disappear within
entities. fraction of seconds.
4. Emulsion droplets are roughly spherical Microemulsions are the structures of various
droplets of one phase dispersed into the other droplets like bi-continous to swollen micelles.
phase.
5. Macroemulsions requires quick agitation for Microemulsions are obtained by gentle
their formation. mixing of ingredients.
6. Most of the emulsions are opaque (white) in Microemulsions are transparent or
appearance. translucent in nature.

TYPES OF MICROEMULSIONS [15-18] Water - in - oil microemulsion or winsor II

Microemulsions are thermodynamically stable, In Water-in-oil type of microemulsions droplets of


but are only found under carefully defined water surrounded by a continuous oil phase.
conditions. According to Winsor, there are four These are recognized as “reversemicelles”, where
types of microemulsion phases exists in equilibria, the polar headgroups of the surfactant are facing
these phases are also referred as Winsor phases. into the droplets of water, with the fatty acid tails
They are, facing into the oil phase. A w/o microemulsion
used orally or parenterally may be destabilized by
1. Oil- in- water microemulsion or winsor I the aqueous biological system.
2. Water – in oil microemulsion or winsor II
3. Bicontinuousmicroemulsion or winsor III Bicontinuousmicroemulsion or winsor III
4. Single phase homogeneous mixture or
In bicontinuousmicroemulsion system the amount
winsor IV
of water and oil present are similar, In this case,
both water and oil exist as a continuous phase. An
Oil- in- water microemulsion or winsor I irregular channel of oil and water are combined,
and looks like a “sponge-phase”. Transitions from
In Oil-in-water type of microemulsions droplets of o/w to w/o microemulsions may pass through this
oil is surrounded by a surfactant (and may be bicontinuous state. Bicontinuous microemulsion,
cosurfactant) film that forms the internal phase may show non-Newtonian flow and plasticity.
distributed in water, which is the continuous These properties make them especially useful for
phase. This type of microemulsion generally has a topical delivery of drugs or for intravenous
larger interaction volume than the w/o administration.
microemulsions.

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Singh et al 42

Single phase homogeneous mixture or winsor IV molecules that contain a polar head group and a
polar tail. Surfactant molecules self-associate due
In single phase homogeneous mixture or winsor IV to various inter- and intra-molecular forces as well
the oil, water and surfactants are homogenously as entropy considerations. For example, when
mixed. surfactant is mixed with oil and water, they
accumulate at the oil/water interface, because it is
INGREDIENTS OF MICROEMULSION [18-20]
thermodynamically favorable. The surfactant
Various ingredients are used in the formulation molecules can arrange themselves in a variety of
and development of microemulsions. Mainly oil shapes. They can form spherical micelles, a
and surfactants are used in microemulsion they hexagonal phase, lamellar (sheet) phases,
should be biocompatible, non-toxic and clinically rodshaped micelles, reverse micelles, or hexagonal
acceptable. Main components of microemulsion reverse micelles. At low concentrations of
are dispersed (internal) phase, spherical, isolated
droplets are present in the microemulsions. The
1. Oil phase various types of surfactants that help in the
2. Aqueous phase progressive development of microemulsion
3. Surfactant system are
4. cosolvent
1. Cationic
Oil phase [21] 2. Anionic
Oil is one of the most important components of 3. Non-ionic
microemulsion because it can solubilise the 4. Zwitterionic surfactants.
required dose of the lipophilic drug and it
increases the fraction of lipophilic drug Cationic surfactant
transported via the intestinal lymphatic system. Cationic Surfactants when come in contact with
Oil is defined as any liquid having low polarity and water they come into amphiphiliccation and anion
low miscibility with water. The examples of such form, most often of halogen type. A very large
phase are cyclohexane, mineral oil, toulene, & quantity of this class corresponds to nitrogen
vegetable oil etc. compounds such as quaternary ammoniums and
fatty amine salts, with one or several long chain of
Aqueous phase the alkyl type, often coming from natural fatty
Generally the aqueous phase contains hydrophilic acids. The most well-known examples from the
active ingredients and preservatives. Sometimes cationic surfactant class are hexadecyl trimethyl-
Buffer solutions are used as aqueous phase. ammonium bromide and didodcecyl ammonium
bromide. These surfactants are in general more
Surfactant [22] expensive than anionics.
The term surfactant (surface-active-agent)
denotes a substance which exhibits some Anionic surfactant
superficial or interfacial activity & used to lower When anionic Surfactants are dissociated in water
the surface or interface tension. It has affinity for in an amphiphilic anion, and a cation, which is in
polar & nonpolar solvents. Surfactants are the general an alkaline metal (Na, K) or a quaternary

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Singh et al 43

ammonium. These are the most commonly used flexible to take up different curvatures required to
surfactants. The anionic charge in these form microemulsion over a wide range of
surfactants comes from the ionized carboxyl excipients. If a single surfactant film is desired, the
group. Anionic surfactants account for about 50 % lipophilic chains of the surfactant should be
of the world production. Alkalialkanoates, also sufficiently short, or contain fluidizing groups (e.g.
known as soaps, are the most common anionic unsaturated bonds). Basic co-surfactants are short
surfactants. This is the most well-known type of chain alcohols (ethanol to butanol), glycols such as
surfactant when it comes to their shape and propylene glycol, medium chain alcohols, amines
function. The three most important anionic or acids. The use of co-surfactant is to destroy
groups in all of these surfactants are carboxylate, liquid crystalline or gel structures that come in
sulfonate and sulfate groups. place of a microemulsion phase.

Non-ionic surfactant METHOD OF FORMULATION [24, 25]


Non-ionic surfactant is stabilized by dipole and
Microemulsions are prepared when interfacial
hydrogen bond interactions with the hydration
tension at the oil/water is kept at very low level.
layer of water on its hydrophilic surface. They do
Interfacial layer is kept very much flexible and
not ionize in aqueous solution, because their
fluid concentration of surfactants should be high
hydrophilic group is of non-dissociable type, such
enough to give surfactant molecules to be
as phenol, alcohol, ester, or amide. A large
stabilized the microemulsion at an extremely low
proportion of these nonionic surfactants are made
interfacial tension.
hydrophilic by the presence of a polyethylene
glycol chain. Two main method are reported for the
formulation of microemulsion, these are
Zwitterionic surfactant
Zwitterionic surfactants contain both positively 1. Phase Inversion Method
and negatively charged groups and form 2. Phase Titration Method
microemulsions by addition of co-surfactants. Phase Inversion Method [26]
Phospholipids, such as lecithin, obtained naturally
from soybean or egg are common zwitterionic In the phase inversion method phase inversion of
surfactants. Unlike other ionic surfactants, which microemulsions occurs by addition of excess
are somewhat toxic, lecithin which contains diacyl amount of the dispersed phase. During phase
phosphatidylcholine as the major constituent inversion quick physical changes occur including
show excellent biocompatibility. Other important changes in particle size that can affect drug
class of zwitterionic surfactants is the betaines, release both in vivo and in vitro. For non-ionic
such as alkylbetaines, and heterocyclic betaines . surfactants, this can be completed by changing the
temperature, forcing a transition from oil in water
Cosolvent [23] microemulsion at low temperatures to water in oil
It has been observed that single-chain surfactants microemulsion at higher temperatures
are unable to reduce the o/w interfacial tension (transitional phase inversion). During cooling, the
sufficiently to form a microemulsion. The addition system crosses a point of zero spontaneous
of co-surfactants allows the interfacial film to be curvature and minimal surface tension, promoting

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Singh et al 44

the formation of finely dispersed oil droplets. This THEORIES OF MICROEMULSION


method is also known as phase inversion FORMULATION [28-30]
temperature (PIT) method. Other than
temperature, other parameters such as pH value The formulation of microemulsion is based on
or salt concentration may be considered more various theories that effect and control their
effectively instead of the temperature alone. stability and phase behavior. These theories are
Additionally, a transition in the spontaneous
1. Thermodynamic theory
radius of curvature can be obtained by changing
2. Solubilisation theory
the water volume fraction. By successively adding
3. Interfacial theory
water into oil, initially water droplets are formed
in a continuous oil phase. By increasing the water Thermodynamic theory [29]
volume fraction changes the spontaneous
curvature of the surfactant from initially stabilizing Formuation and stability of microemulsion can be
a w/o microemulsion to an o/w microemulsion at expressed on the basis of a simplified
the inversion point. thermodynamic machanism. The free energy of
microemulsion formation can be dependent on
Phase Titration Method [27] the extent to which surfactant lowers the surface
tension of the oil–water interface and the change
Microemulsions are formulated by the
in entropy of the system, thus
spontaneous emulsification method (phase
titration method) and can be shown with the help DG f = γDA - T DS
of phase diagrams. A mixture of fatty acid and oil Where,
is added to a caustic solution to prepare a DG f = Free Energy of formation,
microemulsion, then after it is titrated with a γ =Surface Tension of the oil–water interface,
cosurfactant, an alcohol, until the system turned DA = Change in interfacial area on
clear. Microemulsions are formed along with microemulsification,
various association structures (including emulsion, DS = Change in entropy of the system which is
micelles, lamellar, hexagonal, cubic, and various effectively the dispersion entropy, and
gels and oily dispersion) depending on the T = Temperature.
chemical composition and concentration of each
component. It is found that as the chain length of It is found that when a microemulsion is formed,
the surfactant increased, microemulsions with DA is changed to a large extent due to the large
significant transmittances by visible spectrum can number of very small droplets formed. It is must
be formed with oils of longer chain lengths. It is to know that while the value of γ is positive at all
also found that different alcohols affect the times, it is very small, and is offset by the entropic
formation of microemulsions in different ways. component. The dominant favorable entropic
The best results, in terms of the greatest percent contribution is the very large dispersion entropy
transmittance coupled with the widest range of oil arising from the mixing of one phase in the other
(dispersed in water) concentration, are obtained in the form of large numbers of small droplets.
from short or branched alcohols. However, favorable entropic contributions also
come from other dynamic processes such as
monomer-micelle surfactant exchange and

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Singh et al 45

surfactant diffusion in the interfacial layer. When FACTOR AFFECTING FORMULATION OF


large reductions in surface tension are found by MICROEMULSION SYSTEM [31-33]
significant favorable entropic change, a negative
free energy of formation is achieved. In that case, Property of surfactant
microemulsification is spontaneous and the
Surfactant contains two group lipophilic and
resulting dispersion is thermodynamically stable.
hydrophilic groups. Hydrophilic single chain
Solubilisation theory surfactants such as cetylethyl ammonium bromide
dissociate completely in dilute solution and have a
The formation of microemulsion is oil soluble tendency to form o/w microemulsion. When the
phase and water phase by micelles or reverse surfactant is in presence of salt or when high
micelles in micellar gradually become larger and concentration of surfactant is used, degree of
swelling to a certain size range results. dissociation of polar groups becomes lesser and
resulting system may be w/o type.
Interfacial theory [30]
Property of Oil Phase
The interface mixed-film theory i.e a negative
interfacial tension theory, according to this theory Oil phase also influence curvature by its ability to
the micro-emulsion has been capable to form penetrate & Swell the tail group region of the
instantaneous and spontaneously generate a surfactant monolayer, swelling of tail results into
negative interfacial tension in the surfactant and an increased negative curvature to w/o
co-surfactant in working together. The film, which microemulsion.
may consist of surfactant and cosurfactant
molecules, is considered as a liquid ‘‘two Packing Ratio [34]
dimensional’’ third phase in equilibrium with both
HLB of surfactant determines the type of
oil and water. Such a monolayer could be a duplex
microemulsion through its influence on packing
film, i.e. giving different properties on the water
and film curvature. The analysis of film curvature
side and oil side. According to the duplex film
for surfactant association`s leading to the
theory, the interfacial tension γT is given by the
formation of microemulsion.
following expression
Temperature [35]
γT = γ(O/W) --- π
Temperature is extremely important in
Where,
determining the effective head group size of
γ (O/W)a = Interfacial Tension( reduced by the nonionic surfactants. At low temperature, they are
presence of the alcohol). hydrophilic and form normal o/w system. At
higher temperature, they are lipophilic and form
γ (O/W)a is significantly lower than γ(O/W) in the w/o systems. At an intermediate temperature,
absence of the alcohol. microemulsion coexists with excess water and oil
phases and forms bicontinuous structure.

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Singh et al 46

EVALUATION PARAMETERS OF Assessment of the Rheological Properties


MICROEMULSION SYSTEM (viscosity measurement) [40]

Physical appearance The rheological properties play an important role


in stability. It can be determined by Brookfield
For Physical appearance microemulsion can be digital viscometer. Change in the rheological
inspect visually for homogeneity, fluidity and characteristics help in determining the
optical clarity. microemulsion region and its separation from
other region. Bicontinuous microemulsion are
Scattering Techniques [36]
dynamic structures with continuous fluctuations
Scattering techniques such as small angle neutron occurring between the bicontinuous structure,
scattering, small angle X-ray scattering and light swollen reverse micelle, and swollen micelles.
scattering have found applications in studies of
Electrical conductivity [41]
microemulsion structure, particularly in case of
dilute monodisperese spheres, when polydisperse The water phase was added drop wise to a
or concentrated systems such as those frequently mixture of oil, surfactant and co-surfactant and
seen in microemulsions. the electrical conductivity of formulated samples
can be measured using a conductometer at
Limpidity Test (Percent Transmittance) [37]
ambient temperature and at a constant frequency
The limpidity of the microemulsion can be of 1 Hz.
measured spectrophotometrically using
Drug solubility [42]
spectrophotometer.
Drug was added in excess to the optimized
Drug stability [38]
microemulsion formulation as well as each
The optimized microemulsion was kept under cold individual ingredient of the formulation. After
condition (4-8°C), room temperature and at continuous stirring for 24 h at room temperature,
elevated temperature (50 ± 2 °C). After every 2 samples were withdrawn and centrifuged at 6000
months the microemulsion can be analyzed for rpm for 10 min. The amount of soluble drug in the
phase separation, % transmittance, globule size optimized formulation as well as each individual
and % assay. ingredient of the formulation was calculated by
subtracting the drug present in the sediment from
Globule size and zeta potential measurements the total amount of drug added. The solubility of
[39] drug in microemulsion was compared with respect
to its individual ingredients.
The globule size and zeta potential of the
microemulsion can be determined by dynamic In-vitro drug release [43, 44]
light scattering, using a Zetasizer HSA 3000.
The diffusion study can be carried out on a
modified Franz diffusion cell, within volume of
20mL. The receptor compartment was filled with
of buffer .The donor compartment was fixed with

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Singh et al 47

cellophane membrane, containing the reasons, one of which is the avoidance of hepatic
microemulsion formulation and the plain drug first-pass metabolism, salivary and degradation of
solution, separately. At predetermined time the drug in stomach and related toxicity effects.
intervals samples were withdrawn from the Another is the direct delivery and targetability of
receptor compartment and analyzed for drug the drug to affected areas of the skin or eyes.
content, using a UV spectrophotometer at specific Now a day, there have been a number of studies
wavelength. in the area of drug penetration into the skin. They
are able to incorporate both hydrophilic (5-
APPLICATION OF MICROEMULSION SYSTEM flurouracil, apomorphine hydrochloride etc) and
lipophilic drugs (estradiol, finasteride,
Microemulsion in Pharmaceutical
ketoprofenetc) and enhance their permeation.
From last two decades there has been a revolution Since formation of microemulsion formation
in the utilization of microemulsion systems in a requires high surfactant concentration, the skin
variety of pharmaceuticals. irritation aspect must be considered especially
when they are intended to be applied for a longer
• Parenteral Delivery [45] period.
Parenteral administration (especially via the • Ocular and Pulmonary Delivery[48]
intravenous route) of drugs with limited solubility
is a major problem in industry because of the For the treatment of eye diseases, drugs are
extremely low amount of drug actually delivered essentially delivered topically. O/W
to a targeted site. Microemulsion formulations microemulsions have been investigated for ocular
have distinct advantages over macroemulsion administration, to dissolve poorly soluble drugs, to
systems when delivered parenterally because of increase absorption and to attain prolong release
the fine particle microemulsion is cleared more profile.
slowly than the coarse particle emulsion and,
Other pharmaceutical applications [49,50,51,52]
therefore, have a longer residence time in the
body. • Nasal delivery
• Oral Delivery [46] • Drug targeting
• Cellular targeting
Microemulsion formulations offer the several • Brain targeting
benefits over conventional oral formulation • Periodontal delivery
including increased absorption, improved clinical • Tumor targeting
potency, and decreased drug toxicity. Therefore,
microemulsions have been reported to be ideal Other application
delivery of drugs such as steroids, hormones,
• Microemulsions in analytical applications[53]
diuretic and antibiotics.
Microemulsions are widely used in the field of
• Topical delivery [47] analytical techniques such as chromatography etc.
In microemulsion electrokinetic chromatography
Topical administration of drugs can have (MEEKC), characterization of solute hydro -
advantages over other methods for several phobicity was carried out, which provides a quick

Journal of Pharmaceutical, Chemical and Biological Sciences, February 2014; 1(1):39-51


Singh et al 48

and reproducible method to obtain hydrophobic • Microemulsions in detergency.


parameters for solvents. Microemulsions are able • Microemulsions in cosmetics.
to enhance analytical spectroscopic techniques by • Microemulsions in agrochemicals.
functioning as solubilized media, spectral shift • Microemulsions in food.
reagents, intensity amplification agents, etc. The • Microemulsions in environmental remediation
utilization of microemulsion media in analytical and detoxification.
spectroscopy and the analytical sensitivities of the • Microporous media synthesis (microemulsion
three systems o/w, w/o and bi continuous gel technique).
microemulsion have been assessed. A series of • Microemulsions in analytical applications.
studies have been reported on the determination • Microemulsions as liquid membranes.
of aluminium, zinc, copper, manganese ions using • Novel crystalline colloidal arrays as chemical
both microemulsion and mixed microemulsion sensor materials.
systems.
CONCLUSION
• Microemulsions in biotechnology[54]
Microemulsions have a very crucial importance in
Many biocatalytic and enzymatic reactions are
the drug delivery system as well as in the
conducted in aquo-organic or pure organic as well
industrial process. They can be used to optimize
as in biphasic media .Their use is seriously limited
drug targeting without a concomitant increase in
because they can inactivate or denature the
systemic absorption. The role of microemulsion in
biocatalysts. Recently, interest on micro-
providing novel solutions to overcome the
emulsions is being focused for various applications
problems of poor aqueous solubility of highly
in biotechnology, viz, enzymatic reactions,
lipophilic drug compounds and provide high, more
immobilization of proteins and bioseparation.
consistent and reproducible bioavailability.
• Microemulsions in enhanced oil recovery[55] Microemulsions can also be used to achieve drug
The understanding of the mechanisms of
targeting however challenges remain, primarily
enhanced oil recovery (EOR) using surfactant and because of the layers of barriers that these
microemulsion can help in obtaining
systems need to overcome to reach to the target.
unrecoverable underground oil. If the interfacial
Microemulsion has been shown to be able to
tension between the crude oil and reservoir brine
protect labile drug, control drug release, and
can be reduced to around 10-3 mN/m, a
reduce patient variability. Furthermore it has
substantial fraction of the residual oil in the
proven possible to formulate preparations suitable
porous media in which it is trapped can be
for most routes of administration. In today's world
mobilized. Low interfacial viscosity of the system is Microemulsion is accepted as full of potential for
also advantageous.
novel drug delivery systems. Current research
work is focused on the preparation of safe,
• Microemulsions for bioseparations efficient and more compatible microemulsion
• Microemulsion as a chemical sensor materials constituents which will further enhance the utility
• Microemulsions as lubricants, cutting oils and of these novel vehicles.
corrosion inhibitors
• Microemulsions as coatings and textile
finishing.

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Singh et al 49

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