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International Journal of Trends in Pharmacy and Life Sciences
Vol. 1, Issue: 3, 2015: 457-467.
A REVIEW ON MICROEMULSION IN NOVEL DRUG DELIVERY SYSTEM
N.Srija*, Sharada Srikanth & V. Uma Maheshwar Rao
Dept. of Pharmaceutics, CMR College of Pharmacy, Kandlakoya (V), Medchal Road,
Hyderabad - 501 401.
E.Mail: [email protected]
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
*Corresponding Author:
N.Srija
Dept. of Pharmaceutics, CMR College of
Pharmacy, Kandlakoya (V), Medchal Road,
Hyderabad - 501 401.
E.Mail: [email protected]
Received: 06/08/2015
Revised: 20/09/2015
Accepted: 30/09/2015
INTRODUCTION
The formulation and development of novel drug delivery system with the nature of enhancing the
effectiveness of existing of drug is an ongoing process in pharmaceutical research. Since there are many
types of drug delivery systems that have been developed. The microemulsion concept was introduced in
1940s by Hoar and Schulman who generated a clear single-phase solution by triturating a milky emulsion
with hexanol [1]. They prepared the first microemulsion by dispersing oil in an aqueous surfactants solution
and adding an alcohol as a co-surfactant, leading to transparent stable formulation. Microemulsion is defined
as microemulsion are clear, transparent, thermodynamically stable dispersions of oil and water, stabilized by
an interfacial film of surfactant frequently in combination with a co-surfactant [2].Alternative names for
these systems are often used, such as swollen micelle, transparentemulsion, solubilized oil and micellar
solution. Microemulsions are discontinuous systems that are essentially composed of bulk phases of water
and oil separated by a surfactant/cosurfactant rich interfacial region [3]. These systems have advantages over
conventional emulsions in that they are thermodynamically stable liquid systems and are spontaneously
formed [4]. Microemulsions are currently the subject of many investigations because of their wide range of
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potential and actual utilizations. The high capacity of Microemulsions for drugs makes them attractive
formulations for pharmaceuticals. These systems also offer several benefits for oral administration,
including increased absorption, improved clinical potency and decreased toxicity [5].
Advantages of Microemulsion system:
1. Microemulsions are easily prepared and require no energy contribution during preparation this is due to
better thermodynamic stability.
2. The formation of microemulsion is reversible. They may become unstable at low or high temperature but
when the temperature returns to the stability range, the microemulsionreforms. 3. Microemulsions are
thermodynamically stable system and allow self-emulsification of the system.
4. Microemulsions have low viscosity compared to emulsions.
5. Microemulsions act as super solvents for drug can solubilise both hydrophilic and lipophilic drugs
including drugs that are insoluble in both aqueous and hydrophobic solvents.
6. Having the ability to carry both lipophilic and hydrophilic drugs.
7. The dispersed phase, lipophilic or hydrophilic (O/W, or W/O Microemulsions) can act as a potential
reservoir of lipophilic or hydrophilic drugs, respectively. 8. The use of microemulsion as delivery systems
can improve the efficacy of a drug, allowing the total dose to be reduced and thus minimizing side effects [6,
7].
Disadvantages of Micro emulsion Systems:
1. Having limited solubilizing capacity for high melting substances.
2. Require large amount of Surfactants for stabilizing droplets.
3. Micro emulsion stability is influenced by environmental parameters such as temperature and pH [8].
Difference between Emulsion and Microemulsions [9]:
Table 1: Comparison between Emulsion and Microemulsion
S.No
Emulsion
Microemulsion
1
Emulsions
are
thermodynamically
unstable, they may remain stable for long
periods of time, will ultimately undergo
phase separation on standing to attain a
minimum in free energy.
Microemulsions
are
thermodynamically stable, it can have
essentially infinite lifetime assuming
no change in composition, temperature
and pressure, and do not tend to
separate.
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2
They are lyophobic.
They are on the borderline between
lyophobic and lipophilic colloids
3
Most emulsions are opaque (white)
because bulk of their droplets is greater
than wavelength of light and most oils have
higher refractive indices than water
Microemulsions are transparent or
translucent as their droplet diameter
are less than ¼ of the wavelength of
light, they scatter little light
4
Emulsions consist of roughly spherical They constantly evolve between
droplets of one phase dispersed into the various structures ranging from droplet
other.
like swollen micelles to bi-continuous
structure
5
Droplet diameter 1–20mm.
Droplet diameter 10–100nm.
6
Inefficient molecular packing
Efficient molecular packing
7
Direct oil/water contact at the interface.
No direct oil/water contact at the
interface.
STRUCTURE OF MICROEMULSION
Microemulsions or Micellar emulsion are dynamic system in which the interface is continuously and
spontaneously fluctuating. Structurally, they are divided in to oil in water (o/w), water in oil (w/o) and bicontinuous Microemulsions. In w/o Microemulsions, water droplets are dispersed in the continuous oil
phase while o/w Microemulsions are formed when oil droplets are dispersed in the continuous aqueous
phase. In system where the amounts of water and oil are similar, the bi-continuous Microemulsions may
result [32]. The mixture oil water and surfactants are able to form a wide variety of structure and phase
depending upon the proportions of component [10].
Fig. 1: Microemulsion Structure
TYPES OF MICROEMULSION SYSTEMS:
According to Winsor, there are four types of microemulsion phases exists in equilibria, these phases are
referred as Winsor phases. They are:
Winsor I: With two phases, the lower (o/w) microemulsion phases in equilibrium with the upper excess oil.
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Winsor II: With two phases, the upper microemulsion phase (w/o) microemulsion phases in equilibrium
with lower excess water.
Winsor III: With three phases, middle microemulsion phase (o/w plus w/o, called bi-continuous) in
equilibrium with upper excess oil and lower excess water.
Winsor IV: In single phase, with oil, water and surfactant homogenously mixed [11].
Fig. 2: O/W, W/O and Bi-continuous Microemulsions
THEORIES OF MICROEMULSION FORMULATION
The formulation of microemulsion is based on various theories that effect and control their stability and
phase behavior.
These theories are:
1. Thermodynamic theory
2. Solubilization theory
3. Interfacial theory
Thermodynamic theory: Formulation and stability of microemulsion can be expressed on the basis of a
simplified thermodynamic mechanism. The free energy of microemulsion formation can be dependent on
the extent to which surfactant lowers the surface tension of the oil–water interface and the change in entropy
of the system, thus [12]:
DG f = γDA - T DS
Where, DG f = Free Energy of formation, γ =Surface Tension of the oil–water interface, DA = Change in
interfacial area on micro emulsification, DS = Change in entropy of the system which is effectively the
dispersion entropy, and T = Temperature.
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It is found that when a micro emulsion is formed, DA is changed to a large extent due to the large number of
very small droplets formed. It is must to know that while the value of γ is positive at all times, it is very
small, and is offset by the entropic component. The dominant favorable entropic contribution is the very
large dispersion entropy arising from the mixing of one phase in the other in the form of large numbers of
small droplets. However, favorable entropic contributions also come from other dynamic processes such as
monomer-micelle surfactant exchange and surfactant diffusion in the interfacial layer. When large
reductions in surface tension are found by significant favorable entropic change, a negative free energy of
formation is achieved. In that case, micro emulsification is spontaneous and the resulting dispersion is
thermodynamically stable [13].
Solubilization theory: The formation of microemulsion is oil soluble phase and water phase by micelles or
reverses micelles in micellar gradually become larger and swelling to a certain size range results [14].
Interfacial theory: The interface mixed-film theory i.e. a negative interfacial tension theory, according to
this theory the micro-emulsion has been capable to form instantaneous and spontaneously generate a
negative interfacial tension in the surfactant and co-surfactant in working together. The film, which may
consist of surfactant and cosurfactant molecules, is considered as a liquid ‘‘two dimensional’’ third phase in
equilibrium with both oil and water. Such a monolayer could be a duplex film, i.e. giving different
properties on the water side and oil side. According to the duplex film theory, the interfacial tension γT is
given by the following expression [14]:
γT = γ(O/W) --- π
Where, γ (O/W) a = Interfacial Tension (reduced by the presence of the alcohol).
γ (O/W) a is significantly lower than γ(O/W) in the absence of the alcohol.
COMPONENTS OF MICROEMULSIONS
Microemulsions are isotropic system, which are difficult to formulate than ordinary emulsion
because their formulation is highly specific process involving spontaneous interaction among the constituent
molecules. Generally, the Microemulsions formulation involves the following components:
a. Oil phase: Toluene, cyclohexane, mineral or vegetable oil, silicone oil, or esters of fatty acids etc. widely
used as oil component.
b. Aqueous phase: The aqueous phase may contain hydrophilic active ingredients and preservatives. Buffer
solutions are used as aqueous phase by some researchers
c. Surfactant: In order to reduce the interfacial tension, surfactant is necessary one. Hence surfactant with a
balanced hydrophilic and lipophilic property (HLB) is desirable.
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The selection of surfactant must be:
1. Reduce the interfacial tension during the preparation of Microemulsions.
2. Provide a flexible film that can readily deform round small droplets.
3. Appropriate hydrophile-lipophile character to provide the correct curvature at the interfacial region for the
desired Microemulsions type o/w, w/o or discontinuous [15].
METHOD OF FORMULATION
Microemulsions are prepared when interfacial tension at the oil/water is kept at very low level.
Interfacial layer is kept very much flexible and fluid concentration of surfactants should be high enough to
give surfactant molecules to be stabilized the microemulsion at an extremely low interfacial tension. Two
main method are reported for the formulation of microemulsion, these are
1. Phase Inversion Method
2. Phase Titration Method
1. Phase titration method:
Microemulsions are prepared by spontaneous emulsification method which is illustrated with help of phase
diagrams. Phase diagram construction is practical approach to study complex series of interaction which
occurs when different components are mixed. The aspect of the phase diagram is phase equilibrium and
demarcation of phase boundaries. Most often pseudo-ternary phase diagrams are constructed to figure out
microemulsion zone as quaternary phase diagram is time consuming and difficult to interpret [16].
2. Phase inversion method:
Phase inversion of microemulsion happens upon addition of excess of dispersed phase. Phase inversion
leads to radical physical changes as change in particle size that alters drug release. During cooling, this
system crosses the point of zero spontaneous curvature and minimal surface tension, prompting the
formation of finely dispersed oil droplets. Microemulsions can be prepared by controlled addition of lower
alkanols (butanol, pentanol and hexanol) to milky emulsions to produce transparent solutions comprising
dispersions of either o/w or w/o or colloidal dispersions. The lower alkanols are called co-surfactants. They
lower the interfacial tension between oil and water [16].
MARKETED MICROEMULSIONS
There are certain Microemulsions which are commercially available in the market. (Table 2) [17].
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Table 2: Microemulsions based marketed product
Brand name
Composition
Manufactured by
Sandimmune
Cyclosporin A
Novartis
Neoral®
Fortovase ®
Saquinavir
Roche laboratories
Norvir ®
Ritonavir
Abbott Laboratories
EVALUATION PARAMETERS OF MICROEMULSION SYSTEM
Physical appearance: For Physical appearance microemulsion can be inspect visually for homogeneity,
fluidity and optical clarity [18].
Scattering Techniques: Scattering techniques such as small angle neutron scattering, small angle X-ray
scattering and light scattering have found applications in studies of microemulsion structure, particularly in
case of dilute monodisperese spheres, when polydisperse or concentrated systems such as those frequently
seen in Microemulsions [19].
Limpidity Test (Percent Transmittance): The limpidity of the microemulsion can be measured
spectrophotometrically using spectrophotometer [19].
Drug stability: The optimized microemulsion was kept under cold condition (4-8°C), room temperature and
at elevated temperature (50 ± 2 °C). After every 2 months the microemulsion can be analyzed for phase
separation, % transmittance, globule size and % assay [19].
Globule size and zeta potential measurements: The globule size and zeta potential of the microemulsion
can be determined by dynamic light scattering, using a Zetasizer HSA 3000 [20].
Assessment of the Rheological Properties (viscosity measurement): The rheological properties play an
important role in stability. It can be determined by Brookfield digital viscometer. Change in the rheological
characteristics help in determining the microemulsion region and its separation from other region.
Discontinuous microemulsion are dynamic structures with continuous fluctuations occurring between the
discontinuous structure, swollen reverse micelle, and swollen micelles [20].
Electrical conductivity: The water phase was added drop wise to a mixture of oil, surfactant and cosurfactant and the electrical conductivity of formulated samples can be measured using a conduct meter at
ambient temperature and at a constant frequency of 1 Hz [20].
Drug solubility: Drug was added in excess to the optimized microemulsion formulation as well as each
individual ingredient of the formulation. After continuous stirring for 24 h at room temperature, samples
were withdrawn and centrifuged at 6000 rpm for 10 min. The amount of soluble drug in the optimized
formulation as well as each individual ingredient of the formulation was calculated by subtracting the drug
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present in the sediment from the total amount of drug added. The solubility of drug in microemulsion was
compared with respect to its individual ingredients [21].
In-vitro drug release: 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
cellophane membrane, containing the microemulsion formulation and the plain drug solution,
separately. At predetermined time intervals samples were withdrawn from the receptor compartment and
analyzed for drug content, using a UV spectrophotometer at specific wavelength [21].
APPLICATIONS OF MICROEMULSION
Microemulsion in pharmaceuticals:
Parenteral administration: Parenteral administration (especially via the intravenous route) of drugs with
limited solubility is a major problem in the pharmaceutical industry because of the extremely low amount of
drug actually delivered to a targeted site. Microemulsion formulations have distinct advantages over
Microemulsion systems when delivered parenterally because of the fine particle, microemulsion is cleared
more slowly than the coarse particle emulsion and, therefore, have a longer residence time in the body. Both
O/W and W/O microemulsion can be used for Parenteral delivery [22].
Oral administration: Oral administration of microemulsion formulations offer several benefits over
conventional oral formulation including increased absorption, improved clinical potency, and decreased
drug toxicity. Therefore, microemulsion has been reported to be an ideal delivery of drugs such as steroids,
hormones, diuretic and antibiotics [23].
Topical administration: Topical administration of drugs can have advantages over other methods for
several reasons, one of which is the avoidance of hepatic first pass metabolism of the drug and related
toxicity effects. Another is the direct delivery and targetability of the drug to the affected area of the skin or
eyes [24].
Ocular and pulmonary delivery: Ocular and pulmonary delivery for the treatment of eye diseases, drugs
are essentially delivered topically. O/W Microemulsion have been investigated for ocular administration, to
dissolve poorly soluble drugs, to increase absorption and to attain prolong release profile [24].
Microemulsions in biotechnology:
Many enzymatic and biocatalytic reactions are conducted in pure organic or aqua-organic media. Biphasic
media are also used for these types of reactions. The use of a pure polar media causes the denaturation of
biocatalysts. The use of water-proof media is relatively advantageous.
Enzymes in low water content display and have:
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1. Increased solubility in non-polar reactants.
2. Possibility of shifting thermodynamic equilibria in favour of condensations.
3. Improvement of thermal stability of the enzymes, enabling reactions to be carried out at higher
temperatures [25].
Solubilization of drug in microemulsion:
Microemulsion possesses interesting physicochemical properties, i.e. transparency, low viscosity,
thermodynamic stability, high solubilization power. Because of these specific properties of microemulsion
can be useful as a drug delivery system. Different categories of drugs can be solubilized in microemulsion
systems for their better therapeutic efficacy [26].
CONCLUSION
Microemulsions have a very crucial importance in the drug delivery system as well as in the
industrial process. They can be used to optimize drug targeting without a concomitant increase in systemic
absorption. The role of microemulsion in providing novel solutions to overcome the problems of poor
aqueous solubility of highly lipophilic drug compounds and provide high, more consistent and reproducible
bioavailability. Microemulsions can also be used to achieve drug targeting however challenges remain,
primarily because of the layers of barriers that these systems need to overcome to reach to the target.
Microemulsion has been shown to be able to protect labile drug, control drug release, and reduce patient
variability. Furthermore it has proven possible to formulate preparations suitable for most routes of
administration. In today's world Microemulsion is accepted as full of potential for novel drug delivery
systems. Current research work is focused on the preparation of safe, efficient and more compatible
microemulsion constituents which will further enhance the utility of these novel vehicles.
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