International Bulletin of Drug Research.

, 1(1): 54-83

EMERGING TREND OF MICROEMULSION IN

FORMULATION AND RESERACH
SARKHEJIYA NAIMISH A.*1, NAKUM MAYUR A.1, PATEL VIPUL P.2, ATARA
SAMIR A., DESAI THUSARBINDU R.3
___________________________________________________________________________
ABSTRACT
Microemulsions are clear transparent, thermodynamically stable dispersion of oil and water,
stabilized by interfacial film of surfactant frequently in combination with a co-surfactant.
Recently there has been a considerable interest for microemulsion formulation, for the
delivery of hydrophilic as well as liphophlic drug as drug carriers because of its improved
drug solubilisation capacity, long shelf life, ease of preparation and improvement of
bioavailability. In this present review, we have discuss biopharmaceutical aspects,
advantages, disadvantage, theories, formulations, marketed lipid based formulations, factors
affecting formulation and phase behaviour, preparations, characterization and pharmaceutical
application of microemulsions.
KEY WORDS
Microemulsion, lipid based formulations, surfactant based formulations of microemulsion,
characterization of microemulsion, pharmaceutical application
AFFILIATION
1.

Research Scholar, School of Pharmacy, RK University, Kasturbadham, Rajkot.

2.

Assistant professor, Department of pharmaceutics, School of Pharmacy, RK

University, Kasturbadham, Rajkot.

3.

Dean, Department of pharmacology, School of Pharmacy, RK University,

Kasturbadham, Rajkot.

Address For correspondence:

School of Pharmacy, RK. University, C/O : R.K. College of Physiotherapy Center, Near:
Bhaktinagar Circle, Rajkot.
Email Address: naimish_patel2019@yahoo.com
Mo: 9428253680, 7405472599

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INTRODUCTION
1.1 Introduction to Lipid-Based Formulations
Successful oral delivery of drugs has always remained a challenge to the drug delivery field,
since approximately 40% of the new drug candidates have poor water solubility, and thus oral
delivery is frequently associated with implications of low bioavailability. Many approaches
have been meticulously explored to improve the oral bioavailability of such drugs including
particle size reduction (micronization or nanosizing), complexation with cyclodextrins, salt
formation, solubilization based on cosolvents, surfactants, etc. Modification of the
physicochemical properties, such as by salt formation and particle size reduction of the drug
may improve the dissolution rate of the drug but these methods are not always practical, for
example, salt formation of neutral compounds is not feasible. Moreover, the salts of weak
acid and weak base may convert back to their original acid or base forms and lead to
aggregation in the gastrointestinal tract. Particle size reduction may lead to build up of static
charges, present handling difficulties and is not desirable where poor wettability are
experienced for very fine powders. To overcome these limitations, various other formulation
strategies have been attempted such as use of cyclodextrins, nanoparticles, solid dispersions
and permeation enhancers. Indeed, in some selected cases, these approaches have been
successful.1 Some of the approaches have been highlighted in figure 1.1. Of late lipid-based
formulations have attracted great deal of attention to improve the oral bioavailability of
poorly water soluble drugs. In fact, the most favoured approach is to incorporate lipophilic
drugs into inert lipid vehicles such as oils, surfactant dispersions, microemulsions, selfemulsifying formulations, self microemulsifying formulations, and liposomes. This could
lead to increased solubilization with concomitant modification of their pharmacokinetic
profiles, leading to increase in therapeutic efficacy.1
Microemulsions have been widely studied to enhance the bioavailability of the poorly soluble
drugs. They offer a cost effective approach in such cases. Microemulsions have very low
surface tension and small droplet size which results in high absorption and permeation.
Interest in these versatile carriers is increasing and their applications have been diversified to
various administration routes in addition to the conventional oral route. This can be attributed
to their unique solubilization properties and thermodynamic stability which has drawn
attention for their use as novel vehicles for drug delivery. The results obtained have been
indeed very promising. In recent past, microemulsion formulation of a poorly soluble
immunosuppressant was marketed as a soft capsule which contains a mixture of drug
dissolved in oil and surfactant. It converts into an oil-in-water (o/w) microemulsion in situ in
an aqueous environment in the stomach and the small intestine. Microemulsion formulation
made the bioavailability and plasma concentration profiles of the drug more reproducible
which is clinically important in the case of drugs showing serious adverse effects. This is a
significant step forward in the delivery of poorly soluble drugs. Microemulsion systems are
also now being increasingly investigated for transdermal, ocular, nasal, pulmonary, vaginal,
rectal and intravenous drug delivery.1

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Figure 1.1

Some of the formulation approaches to improve the oral bioavailability of

poorly water soluble drugs1

The reasons which contribute to poor oral bioavailability includes low aqueous solubility,
inappropriate partition coefficient, degradation of the drug in gastrointestinal tract, first pass
metabolism and P-glycoprotein (PGP) efflux of certain drugs. High first pass hepatic
metabolism is the major contributory factor responsible for inactivation of the drug before it
reaches the systemic circulation. Drugs administered orally are absorbed in the systemic
circulation either via portal circulation or lymphatic transport2, figure 1.2.

Figure 1.2A: Enterocyte-based transport and metabolic processes B: Uptake either

from portal vein or by lymphatic system2
Drug which are transported via portal circulation and which are susceptible to the enzymes
present in liver undergo first pass metabolism. Drugs having low solubility (falling in BCS
class II and IV) are particularly susceptible to first pass metabolism. (e.g. carvedilol,
cyclosporine, glypizide, indinavir, tacrolimus, amphotericin). Such drugs have to be
administered by alternative routes such as parenteral which have very less patient
compliance. Thus, oral bioavailability improvement is the most rational approach in efficient
and effective drug delivery.2 Enhancement in oral bioavailability can be achieved by reducing
the first pass metabolism. This can be accomplished by co-administration with enzyme
inhibitors, prodrug approach, and use of novel lipid based drug delivery system such as
microemulsion (khoo et al-lymphatic transport of halofantrine)5, SMEDDS (Neoral
cyclosporine product)6, lipid nanoparticles (lovastatin SLN)7. Although the exact mechanisms
responsible for this enhanced absorption are not fully known, the possible reasons for the
enhancement of bioavailability are as follows3,4:
1. Enhanced dissolution/solubilisation:
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Increase pancreatic and gall bladder secretions which increase solubilization of drugs.
An exogenous surface active agent facilitates the solubilization.
2. Prolongation of gastric residence time:
Lipid in gastric tract provokes delay in gastric emptying.
3. Stimulation of lymphatic transport-due to triglyceride core of chylomicrons.
4. Increase intestinal permeability:
Lipid formulations will convert into fine emulsion droplets.
Exogenous surfactants facilitate absorption.
5. Reduced first pass metabolism.
1.2 Introduction to Microemulsions
1.2.1 Definition1,8
Microemulsions (E) are isotropic, thermodynamically stable, transparent (or translucent)
systems of oil, water and surfactant, frequently in combination with a co-surfactant with a
droplet size usually in the range of 10-100 nm. These homogeneous systems, which can be
prepared over a wide range of surfactant concentration and oil to water ratio, are all fluids of
low viscosity. Microemulsions as drug delivery tool show favourable properties like
thermodynamic stability (long shelf-life), easy formation (zero interfacial tension and almost
spontaneous formation), optical isotropy, ability to be sterilized by filtration, high surface
area (high solubilization capacity) and very small droplet size. The small droplets also
provide better adherence to membranes and transport drug molecules in a controlled fashion.
1.2.2 Structure of Microemulsions1
Microemulsions are dynamic systems in which the interface is continuously and
spontaneously fluctuating. Structurally, they are divided into oil-in-water (o/w), water in oil
(w/o) and bicontinuous microemulsions. In w/o microemulsion, water droplets are dispersed
in the continuous oil phase while o/w microemulsion is formed when oil droplets are
dispersed in the continuous aqueous phase, figure 1.3. In systems where the amounts of water
and oil are similar, a bicontinuous microemulsion may result, figure 1.4. In all three types of
microemulsions, the interface is stabilized by an appropriate combination of surfactants
and/or co-surfactants. The mixture of oil, water and surfactants is able to form a wide variety
of structures and phases depending upon the proportions of the components. The flexibility of
the surfactant film is an important factor in this regard. A flexible surfactant film will enable
the existence of several different structures like droplet like shapes, aggregates and
bicontinuous structures, and therefore broaden the range of microemulsion existence. A very
rigid surfactant film will not enable existence of bicontinuous structures which will impede
the range of existence. Besides microemulsions, structural examinations can reveal the
existence of regular emulsions, anisotropic crystalline hexagonal or cubic phases, and
lamellar structures depending on the ratio of the components. The internal structure of a
microemulsion vehicle is very important for the diffusivity of the phases, and thereby also for
the diffusion of a drug in the respective phases. Researchers have been trying zealously to
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understand the complicated phase behaviour and the various microstructures encountered in
the microemulsion systems.

Figure 1.3 Structure of Microemulsion9

Figure 1.4

Schematic representation of the three most commonly encountered

microemulsion microstructures9
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1.2.3 Differences between Emulsions and Microemulsions9

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1.2.4 Advantages and Disadvantages of Microemulsion8,9
Advantages of Microemulsion as Oral Drug Vehicle:1.

Increases the rate of absorption.

2.

Eliminates intersubject and intrasubject variability in absorption.

3.

Helps to solubilize lipophilic drug.

4.

Provides a aqueous dosage form for water insoluble drugs.

5.

Thermodynamically stable system, so for long time they can remain stable without
any type of aggregation or creaming.

6.

Releases drug in controlled fashion.

7.

Minimizes first pass metabolism.

8.

Increases bioavailability.

9.

Helpful in taste masking.

10.

Provides protection from hydrolysis and oxidation as drug in oil phase in O/W
microemulsion is not exposed to attack by water and air.

11.

Ease of preparation due to spontaneous formation.

12.

Scale up process is also easy.

Disadvantages (limitations) of Microemulsion as Oral Drug Vehicle:

1.

Use of a large concentration of surfactant and co-surfactant necessary for stabilizing

the nanodroplets.

2.

Limited solubilizing capacity for high-melting substances.

3.

The surfactant must be nontoxic for using pharmaceutical applications.

4.

Microemulsion stability is influenced by environmental parameters such as

temperature and pH. These parameters change upon microemulsion delivery to
patients.

5.

For unique dosage preparation in gelatin capsules, it may produce softening or

hardening effect on capsule shell, so for long term storage it is undesirable.

1.2.5 Biopharmaceutical Aspects

The ability of lipids to enhance the bioavailability of poorly water-soluble drugs has been
comprehensively reviewed and though incompletely understood. The currently accepted view
is that lipids may enhance bioavailability via a number of potential mechanisms, including10:
a)

Alterations (reduction) in gastric transit, thereby slowing delivery to the absorption

site and increasing the time available for dissolution.
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b)

Increases in effective lumenal drug solubility: The presence of lipids in the GI tract
stimulates an increase in the secretion of bile salts (BS) and endogenous biliary lipids
including phospholipid (PL) and cholesterol (CH), leading to the formation of
BS/PL/CH intestinal mixed micelles and an increase in the solubilisation capacity of
the GI tract. However, intercalation of administered (exogenous) lipids into these BS
structures either directly (if sufficiently polar), or secondary to digestion, leads to
swelling of the micellar structures and a further increase in solubilization capacity.

c)

Stimulation of intestinal lymphatic transport: For highly lipophilic drugs, lipids may
enhance the extent of lymphatic transport and increase bioavailability directly or
indirectly via a reduction in first-pass metabolism, figure 1.5.

d)

Changes in the biochemical barrier function of the GI tract: It is clear that certain
lipids and surfactants may attenuate the activity of intestinal efflux transporters, as
indicated by the p-glycoprotein efflux pump, and may also reduce the extent of
enterocyte-based metabolism.

e)

Changes in the physical barrier function of the GI tract: Various combinations of

lipids, lipid digestion products and surfactants have been shown to have permeability
enhancing properties.

Results of study for intestinal lymphatic transport of halofantrine shows the significant effect
that small amounts of lipid present within a single lipid-based dose form can have on the
transport of a lymphatically transported drug administered in the fasted state. The reported
data have implications with regard to (a) the recruitment of the lymphatics as an absorption
pathway after fasted administration of a lipid-based formulation, (b) altered drug delivery
profiles as lymphatically transported drugs access the mesenteric lymphatics and associated
lymph nodes and then empty into the systemic circulation at the junction of the left
subclavian vein and the jugular vein, (c) possible changes in the pharmacokinetics and
systemic clearance of lipophilic drugs, (d) the potential stimulation of lymphatic transport
when a lipophilic drug is ingested in a partial-prandial state (e.g., as a consequence of the
presence of a small amount of dietary lipid from a snack or previously consumed meal), and
(e) safety assessment of lipophilic new drug candidates, which are often administered in
conjunction with lipids and/or lipidic excipients to enhance drug exposure.5

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Figure 1.5

Potential mechanisms for absorption enhancement for lipid based

Formulation11

1.2.6 Marketed Lipid- based and Surfactant-based Drug Formulation

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Table 1.2 Marketed lipid based formulations12

1.2.7 Theories and Thermodynamics of Microemulsion Formulations9,13

Historically, three different approaches have been proposed to explain microemulsion
formation and the stability aspects13.
(i) Interfacial or mixed film theories,
(ii) Solubilization theories and
(iii) Thermodynamic treatments.
The important features of the microemulsion are thermodynamic stability, optical
transparency, large overall interfacial area (about 100 m2 /ml), variety of structures, low
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interfacial tension and increased solubilization of oil/water dispersed phase. Microemulsion
requires more surfactant than emulsion to stabilize a large overall interfacial area.
The interfacial tension between the oil and water can be lowered by the addition and
adsorption of surfactant. When the surfactant concentration is increased further, if lowers the
interfacial tension till CMC (Critical Micelle Concentration). The micellar formation
commences beyond this concentration of surfactant. This negative interfacial tension leads to
a simultaneous and spontaneous increase in the area of the interface.
The large interfacial area formed may divide itself into a large number of closed shells
around small droplets of either oil in water or water in oil and further decrease the free energy
of the system. In many cases, the interfacial tension is not yet ultra low when the CMC is
reached.
It has been studied and observed by Schulman and workers that the addition of a cosurfactant
(medium sized alcohol or amine) to the system results in virtually zero interfacial tension.
The further addition of a surfactant (where, interfacial tension () is zero) leads to negative
interfacial tension.
1.2.7.1 Interfacial/Mixed Film Theories:
The relatively large entropy of mixing of droplets and continuous medium explains the
spontaneous formation of microemulsion. Schulman emphasized the importance of the
interfacial film. They considered that the spontaneous formation of microemulsion droplets
was due to the formation of a complex film at the oil-water interface by the surfactant and cosurfactant. This caused a reduction in oil-water interfacial tension to very low values (from
close to zero to negative) which is represented by following equation.
i= o/w-i -----------------------(1)
Where,
o/w = Oil-water interfacial tension without the film present
i = Spreading pressure
i =Interfacial tension
Mechanism of curvature of a duplex film:
The interfacial film should be curved to form small droplets to explain both the stability of
the system and bending of the interface. A flat duplex film would be under stress because of
the difference in tension and spreading of pressure on either side ofit. Reduction of this
tension gradient by equalizing the two surface tensions is the driving force for the film
curvature. Both sides of the interface expand spontaneously with penetration of oil and co
surfactant until the pressures become equal. The side with higher tension would be concave
and would envelop the liquid on that side, making it an internal phase. It is generally easier to
expand the oil side of an interface than the waterside and hence W/O microemulsion can be
formed easily than O/W microemulsion.

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1.2.7.2 Solubilization Theories:Shinoda et al. considered microemulsion to be thermodynamically stable monophasic
solution of water-swollen (W/O) or oil swollen (O/W) spherical micelles. Rance and Friberg
illustrated the relationship between reverse micelles and W/O microemulsion with the help of
phase diagrams. The inverse micelle region of ternary system i.e. water, pentanol and sodium
dodecyl sulphate (SDS) is composed of water solubilized reverse micelles of SDS in
pentanol. Addition of O-xylene up to 50% gives rise to transparent W/O region containing a
maximum of 28% water with 5 % pentanol and 6% surfactant (i.e. microemulsions). The
quaternary phase diagram constructed on adding p-xylene shows relationship of these areas to
the isotropic inverse micellar phase. These four component systems could be prepared by
adding hydrocarbon directly to the inverse micellar phase by titration. Thus the system
mainly consists of swollen inverse micelle rather than small emulsion droplets.
1.2.7.3 Thermodynamic Theories
This theory explains the formation of microemulsion even in the absence of co surfactant.
The free energy of microemulsion formation can be considered to depend on the extent to
which surfactant lowers the surface tension of the oilwater interface and the change in
entropy of the system such that,
Gm =G1+G2+G3- TS-----------------------(2)
Gm = free energy change for microemulsion formation
G1 = free energy change due to increase in total surface area
G2 = free energy change due to interaction between droplets
G3 = free energy change due to adsorption of surfactant at the oil/water interface
from bulk oil or water
S = increase in entropy due to dispersion of oil as droplets
In other way, we can write it as,
Gf = A-TS-----------------------(3),
Where,

Gf = Free energy of formulation

= Surface tension of the oil-water interface
A = Change in surface area on microemulsification
S = Change in entropy of the system
T = Temperature

Thermodynamic theory takes into account entropy of droplets and thermal fluctuations at the
interface as important parameters leading to interfacial bending instability. Originally
workers proposed that in order for a microemulsion to be formed a negative value of was
required, it is now recognized that while value of 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
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large numbers of small droplets. However, there are also expected to be favorable entropic
contributions arising from other dynamic processes such as surfactant diffusion in the
interfacial layer and monomer-micelle surfactant exchange. Thus a negative free energy of
formation is achiever when large reductions in surface tension are accompanied by significant
favorable entropic change. In such cases, microemulsification is spontaneous and the
resulting dispersion is thermodynamically stable. Later it was shown that accumulation of the
surfactant and co-surfactant at the interface results in a decrease in chemical potential
generating an additional negative free energy change called as dilution effect. This theory
explained the role of co-surfactant and salt in a microemulsion formed with ionic surfactants.
The co-surfactant produces an additional dilution effect and decreases interfacial tension
further. The addition of salts to system containing ionic surfactants causes similar effects by
shielding the electric field produced by the adsorbed ionic surfactant the adsorption of large
amount of surfactant.
1.2.8 Formulation of Microemulsions
Pharmaceutical acceptability of excipients and the toxicity issues of the components used
makes the selection of excipients really critical. There is a great restriction as which
excipients to be used. Early studies revealed that the microemulsion formulation is specific to
the nature of the oil/surfactant pair, the surfactant concentration and oil/surfactant ratio, the
concentration and nature of co-surfactant and surfactant/co-surfactant ratio and the
temperature. These important discoveries were further supported by the fact that only very
specific combinations of pharmaceutical excipients led to efficient systems.14,15
The main components of microemulsion system are:
1) Oil phase
2) Primary surfactant
3) Secondary surfactant (co-surfactant)
4) Co-Solvent
1.2.8.1 Oil phase
The oil represents one of the most important excipients in the formulation not only because it
can solubilize the required dose of the lipophilic drug, it can increase the fraction of lipophilic
drug transported via the intestinal lymphatic system, thereby increasing absorption from the
GI tract depending on the molecular nature of the triglyceride.16
The oil component influences curvature by its ability to penetrate and hence swell the tail
group region of the surfactant monolayer. Short chain oils penetrate the tail group region to a
greater extent than long chain alkanes, and hence swell this region to a greater extent,
resulting in increased negative curvature (and reduced effective HLB). Saturated (for
example, lauric, myristic and capric acid) and unsaturated fatty acids (for example, oleic acid,
linoleic acid and linolenic acid) have penetration enhancing property of their own and they
have been studied since a long time. Fatty acid esters such as ethyl or methyl esters of lauric,
myristic and oleic acid have also been employed as the oil phase. Lipophilic drugs are
preferably solubilized in o/w microemulsions. The main criterion for selecting the oil phase is
that the drug should have high solubility in it. This will minimize the volume of the
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formulation to deliver the therapeutic dose of the drug in an encapsulated form.1 Examples
are given in table 1.3.
1.2.8.2 Surfactants
The surfactant chosen must be able to lower the interfacial tension to a very small value
which facilitates dispersion process during the preparation of the microemulsion and provide
a flexible film that can readily deform around the droplets and be of the appropriate lipophilic
character to provide the correct curvature at the interfacial region.17
Surfactants used to stabilize microemulsion system may be:
(i) non-ionic,
(ii) zwitterionic,
(iii) cationic, or
(iv) anionic surfactants.
The surfactant used in microemulsion formation could be ionic or nonionic, which
determines the stabilizing interactions of the hydrophilic end of the surfactant with the
aqueous phase. Thus, while a nonionic surfactant is stabilized by dipole and hydrogen bond
interactions with the hydration layer of water on its hydrophilic surface, an ionic surfactant is
additionally stabilized by the electrical double layer. Thus, the effect of salt concentration on
the stability of an emulsion or a microemulsion is more profound in the case of ionic
surfactant than nonionic surfactants. However for pharmaceutical applications, ionic
surfactants are not preferred due to toxicological concerns.17 Non-ionic surfactants are
generally considered to be acceptable for oral ingestion, and the emergence of several
successful marketed products has given the industry confidence in lipid-based products. The
oral and intravenous LD50 values for most non-ionic surfactants are in excess of 50 g/Kg and
5 g/Kg respectively, so 1 g surfactant in a formulation is well-tolerated for uses in acute oral
drug Administration.
Non-ionic surfactants in commercially available solubilized oral formulations include
polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH
40), polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), d--tocopherol polyethylene
glycol 1000 succinate (TPGS), Solutol HS-15, sorbitan monooleate (Span 80), polyoxyl 40
stearate, and various polyglycolyzed glycerides including Labrafil M-1944CS, Labrafil M2125CS, Labrasol, Gellucire 44/14, etc.18
It is generally accepted that low HLB (3-6) surfactants are favoured for the formulation of
w/o microemulsion, whereas surfactants with high HLB (8-18) are preferred for the
formation of o/w microemulsion. Surfactants having HLB greater than 20 often require the
presence of co-surfactants to reduce their effective HLB to a value within the range required
for microemulsion formation.1 Examples are given in table 1.3.
1.2.8.3 Co-surfactants
In most cases, single-chain surfactants alone are unable to reduce the o/w interfacial tension
sufficiently to enable a microemulsion to form. The presence of co-surfactants allows the
interfacial film sufficient flexibility to take up different curvatures required to form
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microemulsion over a wide range of composition. If a single surfactant film is desired, the
lipophilic chains of the surfactant should be sufficiently short, or contain fluidizing groups
(e.g. unsaturated bonds). Short to medium chain length alcohols (C3-C8) are commonly
added as co surfactants which further reduce the interfacial tension and increase the fluidity
of the interface.1 Examples are given in table 1.3.
Typical co-surfactants are short chain alcohols (ethanol to butanol), glycols such as propylene
glycol, medium chain alcohols, amines or acids. The role of co-surfactant is to destroy liquid
crystalline or gel structures that form in place of a microemulsion phase and co-surfactant
free microemulsion in most system cannot be made except at high temperature.19
The role of a co-surfactant is as following19:
1)

Increase the fluidity of the interface.

2)

Destroy liquid crystalline or gel structure which would prevent the formation of
microemulsion. 3) Adjust HLB value and spontaneous curvature of the interface by
changing surfactant partitioning characteristic.

1.2.8.4 Co-solvents
The production of an optimum microemulsion requires relatively high concentrations
(generally more than 30% w/w) of surfactants. Organic solvents such as, ethanol, propylene
glycol (PG), and polyethylene glycol (PEG) are suitable for oral delivery, and they enable the
dissolution of large quantities of either the hydrophilic surfactant or the drug in the lipid base.
These solvents can even act as co-surfactants in microemulsion systems.1
Table 1.3 Some commonly used components for Microemulsions12

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1.2.9 Factors Affecting Formation and Phase Behavior of Microemulsions
1.2.9.1 Factor affecting formation of Microemulsion system8,20
The formation of oil or water swollen microemulsion depends on the packing ratio, property
of surfactant, oil phase, temperature, the chain length, type and nature of co-surfactant.
Packing ratio: The HLB (Hydrophilic Lipophilic Balance) of surfactant determines the type
of microemulsion through its influence on molecular packing and film curvature. The
analysis of film curvature for surfactant associations leading to microemulsion formation has
been explained by Israclachvili et al (1976) and Mitchell and Ninham (1977) in terms of
packing ratio, also called as critical packing parameter.
Critical Packing Parameter (CPP) = v/a * l ----------------------(4)
Where,
v is the partial molar volume of the hydrophobic portion of the surfactant, a is the optimal
head group area and l is the length of the surfactant tail.
If CPP has value between 0 and 1 interface curves towards water (positive curvature) and o/w
systems are favoured but when CPP is greater than 1, interface curves spontaneously towards
oil (negative curvature) so w/o microemulsions are favoured. At zero curvature, when the
HLB is balanced (p is equivalent to 1), then either bi continuous or lamellar structures may
form according to the rigidity of the film (zero curvature).
Property of Surfactant, Oil Phase and Temperature:
The type of microemulsion depends on the nature of surfactant. Surfactant contains
hydrophilic head group and lipophilic tail group. The areas of these groups, which are a
measure of the differential tendency of water to swell head group and oil to swell the tail
area, are important for specific formulation when estimating the surfactant HLB in a
particular system. When a high concentration of the surfactant is used or when the surfactant
is in presence of salt, degree of dissociation of polar groups becomes lesser and resulting
system may be w/o type. Diluting with water may increase dissociation and leads to an o/w
system. Ionic surfactants are strongly influenced by temperature. It mainly causes increased
surfactant counter-ion dissociation. The oil component also influences curvature by its ability
to penetrate and hence swell the tail group region of the surfactant monolayer. Short chains
oils penetrate the lipophilic group region to a great extent and results in increased negative
curvature. Temperature is extremely important in determining the effective head group size
of nonionic surfactants. At low temperature, they are hydrophilic and form normal o/w
system. At higher temperature, they are lipophilic and form w/o systems. At an intermediate
temperature, microemulsion coexists with excess water and oil phases and forms
bicontinuous structure.
The Chain Length, Type and Nature of Co-Surfactant:
Alcohols are widely used as a co-surfactant in microemulsions. Addition of shorter chain cosurfactant gives positive curvature effect as alcohol swells the head region more than tail
region so, it becomes more hydrophilic and o/w type is favoured, while longer chain cosurfactant favours w/o type w/o type by alcohol swelling more in chain region than head
region.
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1.2.9.2 Factor Affecting Phase Behavior8,13
Salinity
At low salinity, the droplet size of o/w microemulsion increases. This corresponds to increase
in the solubilization of oil. As salinity further increases, the system becomes bi- continuous
over an intermediate salinity range. Increase in salinity leads to formation of continuous
microemulsion with reduction in globule size. Further increase in salinity ultimately results in
complete phase transition.
Alcohol concentration
Increasing the concentration of low molecular weight alcohol as a co surfactant leads to the
phase transition from w/o to bi continuous and ultimately to o/w type microemulsion. Exactly
opposite phase transition is noticed in case of high molecular weight alcohol.
Surfactant Hydrophobic Chain Length
The increase in length of hydrophobic chain length of the surfactant shows the change of o/w
microemulsion to w/o via bi continuous phase.
pH
Change in pH influences the microemulsions containing pH sensitive surfactants. This effect
is more pronounced in case of acidic or alkaline surfactants. Carboxylic acids and amines
change the phase behaviour from w/o to o/w by increasing the pH.
Nature of Oil
Increase in the aromaticity of oil leads to phase transition from o/w to w/o and is opposite to
that of increase in the oil alkane carbon number.
Ionic Strength
As the ionic strength increases the system passes from o/w microemulsion in equilibrium
with excess oil to the middle phase and finally to w/o microemulsion in equilibrium with
excess water.
1.2.10 Methods for Microemulsion Formulation1
1.2.10.1 Phase Titration Method (Water Titration Method)
Microemulsions are prepared by the spontaneous emulsification method (phase titration
method) and can be depicted with the help of phase diagrams. Construction of phase diagram
is a useful approach to study the complex series of interactions that can occur when different
components are mixed. Microemulsions are formed along with various association structures
(including emulsion, micelles, lamellar, hexagonal, cubic, and various gels and oily
dispersion) depending on the chemical composition and concentration of each component.
The understanding of their phase equilibria and demarcation of the phase boundaries are
essential aspects of the study. As quaternary phase diagram (four component system) is time
consuming and difficult to interpret, pseudo ternary phase diagram is often constructed to
find the different zones including microemulsion zone, in which each corner of the diagram
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represents 100% of the particular component, figure 1.6. The region can be separated into
w/o or o/w microemulsion 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.

Figure 1.6

Pseudoternary phase diagram of oil, water and surfactant showing

microemulsion region1

1.2.10.2 Phase inversion method

Phase inversion of microemulsions occurs upon addition of excess of the dispersed phase or
in response to temperature. During phase inversion drastic physical changes occur including
changes in particle size that can affect drug release both in vivo and in vitro. These methods
make use of changing the spontaneous curvature of the surfactant. For non-ionic surfactants,
this can be achieved by changing the temperature of the system, forcing a transition from an
o/w microemulsion at low temperatures to a w/o microemulsion at higher temperatures
(transitional phase inversion). During cooling, the system crosses a point of zero spontaneous
curvature and minimal surface tension, promoting the formation of finely dispersed oil
droplets. This method is referred to as phase inversion temperature (PIT) method. Instead of
the temperature, other parameters such as salt concentration or pH value may be considered
as well instead of the temperature alone.
Additionally, 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 continuous oil phase. 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. Short-chain surfactants form flexible monolayers
at the o/w interface resulting in a bicontinuous microemulsion at the inversion point.
1.2.11 Construction of Phase Diagram21,22
When water, oil and surfactants are mixed, microemulsion is only one of the association
structures. Preparation of a stable, isotropic homogeneous, transparent, non toxic
microemulsion requires consideration of a number of variables. Construction of phase
diagrams reduces a number of trials and labour. Phase diagrams help to find the
microemulsion region in ternary or quaternary system and also help to determine the
minimum amount of surfactant for microemulsion formation.
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Ternary Systems
Pseudo-ternary phase diagrams of oil, water, and co-surfactant/surfactants mixtures are
constructed at fixed cosurfactant/surfactant weight ratios.
Phase diagrams are obtained by mixing of the ingredients, which shall be pre-weighed into
glass vials and titrated with water and stirred well at room temperature. Formation of
monophasic/ biphasic system is confirmed by visual inspection. In case turbidity appears
followed by a phase separation, the samples shall be considered as biphasic. In case
monophasic, clear and transparent mixtures are visualized after stirring, the samples shall be
marked as points in the phase diagram. The area covered by these points is considered as the
microemulsion region of existence.
Figure 1.7 shows hypothetical pseudo-ternary diagram at constant surfactant to co-surfactant
ratio. It also shows that single phase or multiphase regions of microemulsion domains are
near the centre of diagram in areas containing large amounts of surfactant that is toxic. The
phase behavior of surfactants, which form microemulsion in absence of co-surfactant, can be
completely represented by ternary diagram.

Figure 1.7 Pseudo Ternary Phase Diagram21

Winsors Phase Diagram
Winsor (1954) reported the relationship between the phase behaviour of amphiphiles oilwater and nature of the different components of ternary system.

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Figure 1.8 Ternary Phase Diagram Of Winsor Phase (WI, WII, WIII, WIV)22
L1

= A single phase region of normal micelles or oil in water microemulsion

L2

= reverse micelles or water in oil microemulsion

= anisotropic lamellar liquid crystalline phase

= represents for microemulsion

Winsor I
The microemulsion composition corresponding to Winsor I is characterized by two phase, the
lower oil/water (O/W) microemulsion phase in equilibrium with excess oil.
Winsor II
The microemulsion composition corresponding to Winsor II is characterized by very low
interfacial tension and maximal solubilization of oil and water for a given quantity of
surfactant. Since, in this phase, microemulsion coexists with both excess phases, no one can
distinguish the dispersed phase from the continuous phase.
Winsor III
This phase comprises of three phases, middle microemulsion phase (O/W plus W/O, called
bicontinuous) in equilibrium with upper excess oil and lower water.
Winsor IV
Microemulsions can be distinguished from the micelles by its inner core swollen with oil.
The microemulsion structure depends on the chemical composition, temperature and
concentration of the constituents. Different surfactants stabilize different microstructures due
to aggregation. This aggregation phenomenon leads to a system with minimum free energy
and thermodynamic stability. Even though the spherical micelles are considered to have
minimal water-hydrocarbon contact area for a given volume, the inter micellar free energy
and the impossibility of the existence of voids in the hydrophobic region leads to other
amphiphillic assemblies like cylinders and planes. They are organized in the form of liquid
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crystalline phases or liquid isotropic phases. A wide variety of surfactant molecules obeys the
geometric rules embodied in the packing parameter.
Methods for Constructing Phase Diagram
Quaternary phase diagrams should be constructed to define the extent and nature of the
microemulsion regions and surrounding regions. Several methods can be used to achieve the
same. In one of the methods, a large number of samples of different composition must be
prepared. The microemulsion region is identified by its isotropic nature and low viscosity.
Other regions can be identified by their characteristic optical structure (Shinoda and Friberg,
1986). These diagrams are complicated and time consuming to prepare. In another method,
microemulsion region can be located by titration method. At a constant ratio of S/CoS,
various combinations of oil and S/CoS are produced. The water is added dropwise. After the
addition of each drop, the mixture is stirred and examined through a polarized filter. The
appearance (transparency, opalescence and isotropy) is recorded along with the number of
phases. Thus, an appropriate delineation of the boundaries can be obtained in which it is
possible to refine through the production of compositions point-by point beginning with the
four basic components. The original method for construction of phase diagram developed by
Bowcott and Schulman (1955) can be used for preparation of microemulsion. In this method
adding the oil surfactant mixture to some of the aqueous phase in a temperature controlled
container with agitation makes a coarse macro emulsion as a first step, which is then titrated
with cosurfactant until clarity is obtained and then diluted with water to give a microemulsion
of the desired concentration.
1.2.12 Characterization of Microemulsions9
Microemulsions have been characterized using a wide variety of techniques. The
characterization of microemulsions is a difficult task due to their complexity, variety of
structures and components involved in these systems, as well as the limitations associated
with each technique but such knowledge is essential for their successful commercial
exploitation. Therefore, complementary studies using a combination of techniques are usually
required to obtain a comprehensive view of the physicochemical properties and structure of
microemulsions. At the macroscopic level viscosity, conductivity and dielectric methods
provides useful information.
(A) Phase Behavior Studies
Phase behavior studies are essential for the study of surfactant system determined by using
phase diagram that provide information on the boundaries of the different phases as a
function of composition variables and temperatures, and, more important, structural
organization can be also inferred. Phase behaviour studies also allow comparison of the
efficiency of different surfactants for a given application. In the phase behaviour studies,
simple measurement and equipments are required. The boundaries of one-phase region can be
assessed easily by visual observation of samples of known composition. The main drawback
is long equilibrium time required for multiphase region, especially if liquid crystalline phase
is involved.
Other useful means and ways of representing the phase behaviour are to keep the
concentration of one component or the ratio of two components constant. As the number of
components increases, the number of experiments needed to define the complete phase
behaviour becomes extraordinary large and the representation of phase behaviour becomes
extremely complex. One approach to characterize these multicomponent systems is by means
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of pseudo-ternary diagrams that combine more than one component in the vertices of the
ternary diagram.24
(B) Scattering Techniques for Microemulsions Characterization
Small-angle X-ray scattering (SAXS), small-angle neutron scattering (SANS), and static as
well as dynamic light scattering are widely applied techniques in the study of
microemulsions. These methods are very valuable for obtaining quantitative informations on
the size, shape and dynamics of the components. The major drawback of this technique is the
dilution of the sample required for the reduction of interparticular interaction. This dilution
can modify the structure and the composition of the pseudophases. Nevertheless, successful
determinations have been carried out using a dilution technique that maintains the identity of
droplets. Small-angle X-ray scattering techniques have been used to obtain information on
droplet size and shape.25
Static light scattering techniques have also been widely used to determine microemulsion
droplet size and shape. In these experiments the intensity of scattered light is generally
measured at various angles and for different concentrations of microemulsion droplets.
Dynamic light scattering, which is also referred as photon correlation spectroscopy (PCS), is
used to analyse the fluctuations in the intensity of scattering by the droplets due to Brownian
motion. The self-correlation is measured that gives information on dynamics of the system.26
(C) Nuclear Magnetic Resonance Studies
The structure and dynamics of microemulsions can be studied by using nuclear magnetic
resonance techniques. Self-diffusion measurements using different tracer techniques,
generally radio labeling, supply information on the mobility of the components. The Fourier
transform pulsed-gradient spin-echo (FT-PGSE) technique uses the magnetic gradient on the
samples and it allows simultaneous and rapid determination of the self-diffusion coefficients
(in the range of 10-9 to 10-12 m2s-1), of many components.27
(D) Interfacial Tension
The formation and the properties of microemulsion can be studied by measuring the
interfacial tension. Ultra low values of interfacial tension are correlated with phase behaviour,
particularly the existence of surfactant phase or middle-phase microemulsions in equilibrium
with aqueous and oil phases. Spinning-drop apparatus can be used to measure the ultra low
interfacial tension. Interfacial tensions are derived form the measurement of the shape of a
drop of the low-density phase, rotating it in cylindrical capillary filled with high-density
phase.28
(E) Viscosity Measurements
Viscosity measurements can indicate the presence of rod-like or worm-like reverse micelle.
Viscosity measurements as a function of volume fraction have been used to determine the
hydrodynamic radius of droplets, as well as interaction between droplets and deviations from
spherical shape by fitting the results to appropriate models (e.g. for microemulsions showing
Newtonian behaviour, Einsteins equation for the relative viscosity can be used to calculate
the hydrodynamic volume of the particles).29

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(F) Simple tests
Dye Solubilization
A water soluble dye is solubilized within the aqueous phase of the W/O globule but is
dispersible in the O/W globule.A oil soluble dye is solubilized within the oil phase of the
O/W globule but is dispersible in the W/O globule.
Dilutability Test
O/W microemulsions are dilutable with water whereas W/O are not and undergo phase
inversion into O/W microemulsion.
Conductance Measurement
O/W microemulsion where the external phase is water are highly conducting whereas W/O
are not, since water is the internal or dispersal phase. To determine the nature of the
continuous phase and to detect phase inversion phenomena, the electrical conductivity
measurements are highly useful. A sharp increase in conductivity in certain W/O
microemulsion systems was observed at low volume fractions and such behaviour was
interpreted as an indication of a percolative behaviour or exchange of ions between droplets
before the formation of bicontinuous structures. 37 Dielectric measurements are a powerful
means of probing both structural and dynamic features of microemulsion systems.
(H) Electron Microscope Characterization
Transmission Electron Microscopy (TEM) is the most important technique for the study of
microstructures of microemulsions because it directly produces images at high resolution and
it can capture any co-existent structure and micro-structural transitions.31
There are two variations of the TEM technique for fluid samples.
1.

The cryo-TEM analyses in which samples are directly visualized after fast freeze and
freeze fructose in the cold microscope.

2.

The Freeze Fracture TEM technique in which a replica of the specimen is images
under RT conditions.

Stability Studies
The stability of the microemulsion has been assessed by conducting long term stability study
and accelerated stability studies. In long term stability study, the system is kept at room
temperature, refrigeration temperature (4-8 C) and elevated temperature (502 C). Over the
time period, microemulsion systems are evaluated for their size, zeta potential, assay, pH,
viscosity and conductivity. On long term study, the activation energy for the system and shelf
life of the system may be calculated as like other conventional delivery system. Accelerated
stability studies are the essential tools to study the thermodynamic stability of
microemulsions. It can be done by centrifugation, heating/cooling cycle and freeze/thaw
cycles.53

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1.2.13 Pharmaceutical Applications of Microemulsions9
Parenteral Delivery

Parenteral administration (especially via the intravenous route) of drugs with limited
solubility is a major problem in industry because of the extremely low amount of drug
actually delivered to a targeted site. Microemulsion formulations have distinct advantages
over macroemulsion 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. The literature contains the details of the many microemulsion systems,
few of these can be used for the parenteral delivery because the toxicity of the surfactant and
parenteral use. An alternative approach was taken by Von Corsewant and Thoren in which
C3-C4 alcohols were replaced with parenterally acceptable co-surfactants, polyethylene
glycol (400) / polyethylene glycol (660) 12-hydroxystearate / ethanol, while maintaining a
flexible surfactant film and spontaneous curvature near zero to obtain and almost balanced
middle phase microemulsion. The middle phase structure was preferred in this application,
because it has been able to incorporate large volumes of oil and water with a minimal
concentration of surfactant.32
Oral Delivery
Microemulsion formulations offer the several benefits over conventional oral formulation for
oral administration including increased absorption, improved clinical potency and decreased
drug toxicity. Therefore, microemulsion have been reported to be ideal delivery of drugs such
as steroids, hormones, diuretic and antibiotics. The microemulsion droplets dispersed in the
gastrointestinal tract provide large surface area and promote a rapid release of dissolved form
of the drug substance and/or mixed micelles containing drug substance, and they may be also
responsible for transporting the drug through the unstirred water layer to the gastrointestinal
membrane for absorption. In addition to the enhanced dissolution of drugs, another factor
contributing to the increasing bioavailability is that lymphatic transport is responsible for a
portion of the entire drug uptake as well. The lipid composition of system may be related to
facilitate the extent of lymphatic drug transport by stimulating lipoprotein formation and
intestinal lymphatic liquid flux.
Pharmaceutical drugs of peptides and proteins are highly potent and specific in their
physiological functions. However, most are difficult to administer orally. With on oral
bioavailability in conventional (i.e. non-microemulsion based) formulation of less than 10%,
they are usually not therapeutically active by oral administration. Because of their low oral
bioavailability, most protein drugs are only available as parenteral formulations. However,
peptide drugs have an extremely short biological half life when administered parenterally, so
require multiple dosing.33A microemulsion formulation of cyclosporine, named Neoral has
been introduced to replace Sandimmune, a crude oil-in-water emulsion of cyclosporine
formulation. Neoral is formulated with a finer dispersion, giving it a more rapid and
predictable absorption and less inter and intra patient variability.34
Topical Delivery

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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 affected area of the skin
or eyes. Both O/W and W/O microemulsions have been evaluated in a hairless mouse model
for the delivery of prostaglandin E1. The microemulsions were based on oleic acid or
Gelucire 44/14 as the oil phase and were stabilized by a mixture of Labrasol (C8 and C10
polyglycolysed glycerides) and Plurol Oleique CC 497 as surfactant. Although enhanced
delivery rates were observed in the case of the o/w microemulsion, the authors concluded that
the penetration rates were inadequate for practical use from either system. The use of
lecithin/IPP/water microemulsion for the transdermal transport of indomethacin and
diclofenac has also been reported. Fourier transform infra red (FTIR) spectroscopy and
differential scanning calorimetry (DSC) showed the IPP organogel had disrupted the lipid
organisation in human stratum corneum after a 1 day incubation.36
Ocular and Pulmonary Delivery
For the treatment of eye diseases, drugs are essentially delivered topically. O/W
microemulsions have been investigated for ocular administration, to dissolve poorly soluble
drugs, to increase absorption and to attain prolong release profile. The microemulsions
containing pilocarpine were formulated using lecithin, propylene glycol and PEG 200 as cosurfactant and IPM as the oil phase. The formulations were of low viscosity with a refractive
index lending to ophthalmologic applications. The formation of a water-in-HFA propellent
microemulsion stabilized by fluorocarbon non-ionic surfactant and intended for pulmonary
delivery has been described.37
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 pure apolar
media causes the denaturation of biocatalysts. The use of water-proof media is relatively
advantageous. Enzymes in low water content display and have
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.

Many enzymes, including lipases, esterases, dehydrogenases and oxidases often function in
the cells in microenvironments that are hydrophobic in nature. In biological systems many
enzymes operate at the interface between hydrophobic and hydrophilic domains and these
usually interfaces are stabilized by polar lipids and other natural amphiphiles. Enzymatic
catalysis in microemulsions has been used for a variety of reactions, such as synthesis of
esters, peptides and sugar acetals transesterification, various hydrolysis reactions and steroid
transformation. The most widely used class of enzymes in microemulsion-based reactions is
of lipases.38
Intranasal Drug Delivery
The nasal route is one of the most permeable and highly vascularized site for drug
administration ensuring rapid absorption and onset of therapeutic action. Microemulsion has
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generated considerable amount of interest as a potential drug delivery system for nasal
delivery of drugs. The viscosity of microemulsions can be tailored as per the need of
application or in some instances through incorporation of specific gelling agents such as a
carbopol or gelatin.The dispersal of drug as a solution in nano sized droplets enhances the
rate of dissolution into contacting aqueous phase and results in increase in the drug
bioavavilability. In addition, the presence of surfactant and in some cases co-surfactant, for
example medium chain triglycerdes in many cases serve to increase membrane permeability
thereby increasing the drug uptake.
Intranasal administration of microemulsion based systems help in overcoming the first pass
hepatic metabolism of labile drugs, thereby assist in improving the therapeutic levels of drug
at the site of action and enhance bio availability of drugs. Bhanushali and Bajaj, (2007)
reported improved brain targeting and higher brain uptake of Sumatriptan following
intranasal administration of mucoadhesive microemulsion formulations of the drug.39
SUMMARY
Microemulsions are powerful formulation tools for poorly soluble APIs, both for the oral
and topical administration routes. The availability of efficient, non toxic surfactants and cosurfactant now makes them a very attractive and feasible option to overcome the
bioavailability problems frequently encountered in the development of modern drugs.
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