MICROEMULSION

CONTENTS

• INTRODUCTION

• PREPPARATION

• CHARACTERIZATION OF PREPARED
MICROEMULSION

• APPLICATION
 INTRODUCTION

• Modern colloidal drug delivery system

• Micro emulsions are clear,
transparent, thermodynamically
stable dispersions of oil and water,
stabilized by an interfacial film of
surfactant frequently in combination
with a co-surfactant.
• Diameter - 10-140 nm.
 Cont…….
• In this type of system, the two liquids tend to
separate out in two layers.
• And to avoid this, a third substance called as an
emulsifier is added, act by:
– they tend to adsorb at interface, where they can fulfill
their dual affinity with hydrophilic groups located in
aqueous phase and hydrophobic groups in oil or air.
– they reduce the mismatch with solvent through a
specific kind of aggregation process known as
micellization
 HISTORICAL BACKGROUND

• The Microemulsion concept was introduced as

early as 1940s by Hoar and Schulman who
generated a clear single-phase solution by
titrating a milky emulsion with hexanol.
• Schulman and co-worker (1959) subsequently
coined the term microemulsion
• The microemulsion definition provided by
Danielson and Lindman in 1981 will be used as
the point of reference.
• “a microemulsion is a system of water, oil and an
amphiphile which is a single optically isotropic and
thermodynamically stable liquid solution”.
• In particular, in emulsions the average drop size grows
continuously with time so that phase separation
ultimately occurs under gravitational force, i.e., they
are thermodynamically unstable and their formation
requires input of work. The drops of the dispersed
phase are generally large (> 0.1 µm) so that they often
take on a milky, rather than a translucent appearance.
For microemulsions, once the conditions are right,
spontaneous formation occurs
• Microemulsion formation is dependent on surfactant
type and structure.
• If the surfactant is ionic and contains a single
hydrocarbon chain (e.g., sodium dodecylsulphate,
SDS) microemulsions are only formed if a co-
surfactant (e.g., a medium size aliphatic alcohol)
and/or electrolyte (e.g., 0.2 M NaCl) are also present.
• With double chain ionics (e.g., Aerosol-OT) and some
non-ionic surfactants a cosurfactant is not necessary.
• This results from one of the most fundamental
properties of microemulsions, that is, an ultra-low
interfacial tension between the oil and water phases,
 ALTERNATIVE NAMES

• Transparent emulsion

• Swollen micelle

• Micellar solution

• Solubilized oil
 MAJOR GOALS
delivery of hydrophilic as well as lipophilic
drug as drug carriers because of its
improved drug solubilization capacity,
long shelf life,
easy of preparation and
improvement of bioavailability.
EMULSION Vs MICRO EMULSION: Shape

Macro emulsion Micro emulsion

EMULSION Vs MICRO EMULSION: Size
 MACRO EMULSION Vs MICRO EMULSION
FEATURES MACRO EMULSION MICRO EMULSION

DEFINITION Emulsions consist of roughly spherical They constantly evolve between

droplets of one phase dispersed into the various structures ranging from
other droplet like swollen micelles to
bi continuous structure.

DROPLET SIZE 1 – 20 mm. 10 – 100 nm.

APPEARANCE Most emulsions are opaque (white) Microemulsions are transparent

because bulk of their droplets is greater or translucent
than wavelength of light and most oils
have higher refractive indices than water.
FEATURES MACRO EMULSION MICRO EMULSION

PHASES Two One

STABILITY Stable but coalesce finally More thermodynamically stable

than macroemulsions

PREPARATION Require intense agitation for Generally obtained by gentle

their formation. mixing of ingredients.

SURFACTANT 2-3 % Weight 6-8% by weight

CONCENTRATION
MACROEMULSION Vs MICRO
EMULSION
 ADVANTAGES
• These are thermodynamically stable and require minimum energy for
formation.
• Ease of manufacturing and scale-up
• Improved drug solubilization and bioavailability.
• This system is reckoned advantageous because of its wide applications in
colloidal drug delivery systems for the purpose of drug targeting and
controlled release
• The formation of micro emulsion is reversible.  They may become
unstable at low or high temperature but when the temperature returns
to the stability range, the micro emulsion reforms.
• 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.
 DISADVANTAGES
• Use of a large concentration of surfactant and co-
surfactant necessary for stabilizing the nanodroplets.
• Limited solubilizing capacity for high-melting
substances
• The surfactant must be nontoxic for using
pharmaceutical applications
• Micro emulsion stability is influenced by environmental
parameters such as temperature and pH.  These
parameters change upon micro emulsion delivery to
patients.
 Types of micro emulsion
• O/W Microemulsion               
• W/O Microemulsion
• Bi continuous Microemulsion
• Oil in water microemulsions wherein oil droplets are
dispersed in the continuous  aqueous phase
• Water in oil microemulsions wherein water droplets
are dispersed in the continuous oil phase;
• Bi-continuous microemulsions wherein micro domains
of oil and water are inter dispersed within the system.
• In all three types of micro emulsions, the interface is
stabilized by an appropriate combination of
surfactants and/or co-surfactants.
 THEORIES OF MICRO EMULSION

• Interfacial or mixed film theory

• Solubilization Theory
• Thermodynamic theory
 Thermodynamic theory
• The process of formation of oil droplets from a
bulk oil phase is accompanied by an increase in
the interfacial area ∆A, and hence an interfacial
energy ∆G .
• The entropy of dispersion of the droplets is
equal to T ∆ S and hence the free energy of
formation of the system is given by the
expression.
∆G       =    ٧∆A     -  T ∆ S
• When the interfacial tension is made sufficiently low that the
interfacial energy becomes comparable to or even lower than the
entropy of dispersion.
• The free energy of formation of the system becomes zero or
negative.  This explains the thermodynamic stability of micro
emulsions.

• The co-surfactant along with surfactant lower the interfacial tension

to a very small even transient negative value
                                   
• At this value, interface would expand to form fine dispersed droplets.
                            
• Adsorb more surfactant and co-surfactant until their bulk condition is
depleted enough to make interfacial tension positive again

• This process is known as “Spontaneous Emulsification” which forms

the micro emulsion.
 PHASE DIAGRAM
• Phase diagram is a plot showing the condition of
pressure and temperature under which two or more
physical states can exist together in a state of dynamic
equilibrium.
• Micro emulsion consist of three component namely:
– Oil
– Water
– Surfactant and co surfactant
• The concentration of co surfactant is varied.
• So a ternary diagram can be formed
• The surfactant concentration in the electrolyte
solution can be kept constant and the co-
surfactant concentration can be the third
variable.
• This enables us to utilize the conventional
triangular phase diagram plot.
• Temperature variations are then represented by
slices across a parallel-sided triangular prism.
• With high oil concentration surfactant forms reverse micelles capable of
solubilizing water molecules in their hydrophilic interior.

• Continued addition of water in this system may result in the formation of

W/O micro emulsion in which water exists as droplets surrounded and
stabilized by interfacial layer of the surfactant / co-surfactant mixture.

• At a limiting water content, the isotropic clear region changes to a turbid,

birefringent one.

• Upon further dilution with water, a liquid crystalline region may be formed
in which the water is sandwiched between surfactant double layers.

• Finally, as amount of water increases, this lamellar structure will break

down and water will form a continuous phase containing droplets of oil
stabilized by a surfactant / co-surfactant (O/W microemulsions)
• The composition of the three-component systems
are shown as the intersections of the broken lines.
• The ends of the ‘tie-lines’ give the compositions of
the two phases, while the ‘lever rule’ gives the
amounts of each.
• Any change to the system which changes the
hydrophobic balance of the surfactant may enable us
to move from one type of system to another.
• Constant temperature the change of a
surfactant to one with a longer chain length
would take us from left to right in the figure.
• A similar result can be achieved by changing
the polarity of the water phase (by the
addition of short-chain alcohols, for example),
increasing the temperature for a non-ionic
surfactant or increasing the electrolyte
WINSOR I WINSOR II WINSOR III
• At low surfactant concentration, there exist an
equilibria, three phases are referred to as
Winsor phases. They are:
– Winsor I:
– Winsor II:
– Winsor III:
– Winsor IV:
• Phase diagram can be constructed by water titration
method
• Rohit Ramesh Shah [Link] carried work on Preparation and
Evaluation of Aceclofenac Topical Microemulsion.
– The ratios of surfactant to co-surfactants were chosen to be 1:2,
1:1, 2:1, and 4:1, and such mixtures were prepared.
– These mixtures (S/CoS) were mixed with the oil phase to give
the weight ratios of 90:10, 80:20, 70:30, 60:40, 50:50, 40:60,
30:70, 20:80 and 10:90.
– Water was added drop by drop and stirred using a magnetic
stirrer until a homogeneous dispersion or solution was obtained.
– After each addition, the system was examined for the
appearance and flow properties.
– The end point of the titration was the point where the solution
becomes cloudy or turbid.
– The quantity of the aqueous phase required to make the
mixture turbid was noted.
 Formation of Microemulsion
• Micro emulsion is formed wat
er
oil
when
– the interfacial tension at surfa
ctant
the O/W interphase are
brought very low level.
– The interfacial tension
is kept highly flexible and fluid.
 Role of surfactant
• The surfactant used to stabilize the micro emulsion system are:
– Non ionic
– Zwitter ion
– Cationic
– Anionic
• The use of hydrophilic surfactant oil swollen type or oil-in –
water micro emulsions.
• The use of lipophilic surfactant produces water swollen type or
water-in oil micro emulsion
• The combination of ionic and nonionic surfactant , can be very
effective at the extent of microemulsion region
• The change of temperature at the maximum
solubilization is very sensitive to as the
solubilization increases.
• If temperature insensitive three phase system
are produced micro emulsion are stable
against temperature change.
Factors affecting micro emulsion formation

• Packing ratio
• Property of surfactant
• Property of oil phase
• Temperature
• Chain length
• Type and nature of cosurfactant
 Packing ratio
• HLB of surfactant determines the type of micro emulsion through
its influence on packing and film curvature.
• The analysis of film curvature for surfactant association’s leadings to
the formation of micro emulsion.
• Critical packing ratio is given by:
c.p.p= V/(a×l)
where, V-volume of surfactant molecule
a- head group surface area
l- length
 If c.p.p is between 0-1,interface curves towards water(positive)
 If c.p.p is greater than 1, interface curves towards oil(negative)
 If c.p.p is equal to1, then either bicontinuous or lamellar structure.
 Role of surfactants
• Surfactant contains two
group hydrophilic and
lipophilic group.
• Hydrophilic single chain of
surfactant such as ceto methyl
ammonium bromide dissociates
completely in dilute solution and
forms o/w micro emulsion.
• When high concentration of surfactant is used or when the surfactant
is in presence of salt , degree of dissociation of hydrophilic group is
lesser and then resulting solution leads to the formation of w/o
emulsion.
 PROPERTY OF OIL PHASE
• Oil phase also influence curvature by its ability
to penetrate
• Swell the tail group region of the surfactant
monolayer.
• Short chain oil such as alkanes, penetrate the
lipophilic region than long chain oils
• Swelling of tail results into an increased negative
curvature to W/O microemulsion.
 TEMPERATURE
• Temperature plays important role in determining the
effective head group size of nonionic
surfactants.
• At low temperature, they are
hydrophilic and form normal
o/w emulsion.
• At high temperature, they are
lipophilic and form w/o system.
• At an intermediate temperature, ME coexist with excess
water and oil phase and form bicontinous structure.
 THE CHAIN LENGTH, TYPE AND NATURE OF
COSURFACTANT
• Alcohols are widely used as a cosurfactant in
microemulsions.
• Addition of shorter chain co-surfactant 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
• Longer chain co-surfactant favours w/o type by
alcohol swelling more in chain region than head
region.
CHARACTERISATION
 PHASE BEHAVIOUR
– Phase contrast microscopy and freeze fracture
transmission electron microscopy can be used to
differentiate micro emulsions from liquid crystals
and coarse emulsions.
– Clear isotropic one-phase systems are identified as
micro emulsions whereas opaque systems
showing bifringence when viewed by cross
polarized light microscopy may be taken as liquid
crystalline system.
 SIZE AND SHAPE

• Small-angle X-ray scattering (SAXS), small-angle

neutron scattering (SANS), and static as well as
dynamic light scattering
• Transmission Electron Microscopy (TEM) is the most
important technique for the study of microstructures
of micro emulsions because it directly produces
images at high resolution and it can capture any co-
existent structure and micro-structural transitions.
 RHEOLOGY
– Brookfield viscometer
– Change in the rheological characteristics help in
determining the micro emulsion region and its
separation from other related structures like liquid
crystals.
– Bicontinuous micro emulsion are dynamic
structures with continuous fluctuations occurring
between the bicontinuous structure, swollen
reverse micelle, and swollen micelles
 PREDICTION OF TYPE OF EMULSION
• Type – I 
The surfactant is preferentially soluble in water and oil-in-water (O/W) micro
emulsions form (Winsor I).  The surfactant-rich water phase coexists with the oil phase
where surfactant is only present as monomers at small concentration.
• Type – II  
The surfactant is mainly in the oil phase and water-in-oil (W/O) micro emulsions
form.  The surfactant-rich oil phase coexists with the surfactant-poor aqueous phase  
(Winsor II)
• Type – III 
A three-phase system where a surfactant-rich middle-phase coexists with both excess
water and oil surfactant-poor phases (Winsor III or middle-phase micro emulsion).
• Type – IV A
single-phase (isotropic) micellar solution, that forms upon addition of a sufficient
quantity of amphiphile (surfactant plus alcohol)
APPLICATIONS
• Oral drug delivery
• Ocular drug delivery
• Pulmonary drug delivery
• Transdermal drug delivery
• Parenteral drug delivery
• For solubilization of drug
• In biotechnlogy
• others
 Oral drug delivery
• Advantages of microemulsions:
– increased absorption
– improved clinical potency
– decreased drug toxicity
• Ritchel [Link](1990) studied the absorption of
cyclosporine (potent, cyclic endekapeptide).
– Poor bioavailability
– 2 w/o microemulsion-sorbitol ester polyoxyethylene
glycolmonoether. LMW alcohol, fatty ester and water.
• Ritchel [Link](1991) studied the absorption of three
peptides-insulin, vasopressin and cyclosporine in o/w
microemulsion.
• Surjyanarayan Mandal(2010) studied absorption of
atorvastatin by oral route.
– Atorvastatin is a poor water-soluble drug and has a very low
absolute bioavailability (about 5%) due to rapid metabolism in
the gut and liver
– Prepared ME by using various oils (Sunflower oil, Isopropyl
Myristate, soya bean oil, Labrafil M 1944CS, Capmul CMC),
surfactant (Labrafac CC, Tween 60, Cremophor EL, Cremophor
RH 40), and cosurfactants (PEG 400, PEG 600, glycerol, ethanol)
was determined.
• Pradip (2005) [Link]. studied on the bioavailability of
acyclovir.
 Topical drug delivery
• Microemulsions may enhance transdermal drug delivery
primarily by the following effects:
– Micro emulsions can exhibit a high solubilization capacity for
both lipophilic and hydrophilic drugs, thus more drug can be
loaded into the microemulsion, which increases the
concentration gradient across the skin without depletion.
– The reservoir effect of the internal phase maintains a constant
driving force of drug from the external phase to the skin and
prolongs absorption. Since the diffusion of the drug into the
skin only occurs from the external phase of the micro emulsion,
the internal phase continually supplies drug to the external
phase so that it remains saturated with the drug.
• The formulation components may affect skin permeability, i.e.
surfactants, cosurfactants, and oils may act as permeation enhancers
by disrupting the SC lipid organization, thus increasing drug diffusion,
or by increasing the partition of the drug in the skin.
• Chemical enhancers may be incorporated in the microemulsion,
which will also improve dermal and transdermal delivery of drugs.
• The very low interfacial tension required for microemulsion
formation is also responsible for the excellent wetting properties,
which ensures excellent surface contact between the membrane and
the vehicle.
• There is no clear consensus in the literature regarding the influence
of droplet size of the microemulsion on drug permeation.

A recent study by Izquierdo et al. showed no apparent relationship

between droplet size and dermal or transdermal delivery of
tetracaine after 24 h.
• Rohit R Shah(2009) [Link]. topical delivery of
fluconazole, this has poor solubility and
absorption.
Ocular and intranasal drug 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.
• Hasse and keipett(1997) preparaed microemulsion
containing pilocarpine were formulated using
lecithin,PG and PEG 200 as cosurfactant and IPM as
oil [Link] formulation had low viscosity with
refractive index leading to ophthalmic application
• Amrish Kumar(2009) [Link]. formulated
sertraline HCl for intranasal administration
– Nasal cavity has used as alternative route for the
drugs with poor water solubility, susceptible to
acidic or enzymatic degradation and hepatic
metabolism. The objective of the present study
was to improve solubility of sertraline
hydrochloride (STH), formulate microemulsions
containing STH to accomplish rapid onset of action
and to bypass the first-pass metabolism
 Parenteral Drug Delivery
• Parenteral administration (especially via the intravenous
route) of drugs with
– limited solubility is a major problem
– 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. 
• O/w as the carrier for lipophilic drug -IV ,IM and SC
• Keipert [Link].(1989) o/w emulsion as a vector for
FC, Ca antagnoist, steroids.
• Kakutani (1991) [Link] reported the targeting
potential of o/w ME containing lipophilic drug to
RE system.
– Higher PC better will targeting of drug.
• w/o ME –hydrophilic drug prolong the release of
drug by SC and IM.
 Solubilization of drug in ME
• Due to its physiochemical property i.e.
transparency, low viscosity,thermodynamic
stability, high solubility. Can be used for the
delivery of drugs like anti neoplastics,
peptides, steroids, vitamins, LA .
 Conclusion
• Microemulsions are optically isotropic and
thermodynamically stable liquid solutions of
oil, water and amphiphile.
• Microemulsions are readily distinguished from
normal emulsions by their transparency, low
viscosity and more fundamentally their
thermodynamic stability.
• Drug delivery through microemulsions is a
promising area for continued research with
the aim of achieving controlled release with
enhanced bioavailability and for drug targeting
to various sites in the body.