3. • Microemulsions are thermodynamically stable
dispersions of oil and water stabilized by a surfactant
and, in many cases, also a cosurfactant. Diameter -
10-140 nm.
Microemulsions can have characteristic
properties such as ultralow interfacial
tension, large interfacial area and capacity to
solubilize both aqueous and oil-soluble
compounds.
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4. “Microemulsions are dispersions of
nanometer-sized droplets of an immiscible
liquid within another liquid. Droplet formation
is facilitated by the addition of surfactants and
often also co surfactants.”
And they can be known as Modern
colloidal drug delivery system.
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5. 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.
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Vadodara 4/21/2012 5
6. Transparent emulsion
Swollen micelle
Micellar solution
Solubilized oil
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7. Macro emulsion Micro emulsion
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9. FEATURES MACRO EMULSION MICRO EMULSION
DEFINITION Emulsions consist of roughly They constantly evolve
spherical droplets of one phase between various structures
dispersed into the other ranging from droplet like
swollen micelles to bi
continuous structure.
DROPLET 1 – 20 mm. 10 – 100 nm.
SIZE
APPEARANCE Most emulsions are opaque (white) Microemulsions are
because bulk of their droplets is transparent or translucent
greater than wavelength of light
and most oils have higher refractive
indices than water.
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10. FEATURES MACRO EMULSION MICRO EMULSION
PHASES Two One
STABILITY Stable but coalesce finally More thermodynamically
stable than
macroemulsions
PREPARATION Require intense agitation Generally obtained by
for their formation. gentle mixing of
ingredients.
SURFACTANT 2-3 % Weight 6-8% by weight
CONCENTRATION
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Vadodara 4/21/2012 10
11. O/W Microemulsion
W/O Microemulsion
Bi continuous Microemulsion
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12. Advantages Of Microemulsion Over Other Dosage Forms
◦ Increase the rate of absorption
◦ Eliminates variability in absorption
◦ Helps solublize lipophilic drug
◦ Provides a aqueous dosage form for water insoluble drugs
◦ Increases bioavailability
◦ Various routes like tropical, oral and intravenous can be used
to deliver the product
◦ Rapid and efficient penetration of the drug moiety
◦ Helpful in taste masking
◦ Provides protection from hydrolysis and oxidation as drug in
oil phase in O/W microemulsion is not exposed to attack by
water and air.
◦ Liquid dosage form increases patient compliance.
◦ Less amount of energy requirement.
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13. ◦ Aesthetically appealing products can be formulated as
trans- parent o/w or w/o dispersions called
microemulsions.
◦ These versatile systems are currently of great
technological and scientific interest to the researchers
because of their potential to incorporate a wide range of
drug molecules (hydrophilic and hydrophobic) due to the
presence of both lipophilic and hydrophilic domains.
◦ These adaptable delivery systems provide protection
against oxidation, enzymatic hydrolysis and improve the
solubilization of lipophilic drugs and hence enhance
their bioavailability. In addition to oral and intravenous
delivery, they are amenable for sustained and targeted
delivery through ophthalmic, dental, pulmonary, vaginal
and topical routes.
◦ Microemulsions are experiencing a very active
development as reflectedofby the numerous publications
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14. A large number of oils and surfactant are available but
their use in the microemulsion formulation is restricted
due to their toxicity, irritation potential and unclear
mechanism of action.
Oils and surfactant which will be used for the
formulation of microemulsion should be biocompatible,
non-toxic, clinically acceptable, and use emulsifiers in
an appropriate concentration range that will result in
mild and non-aggressive microemulsion.
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15. 1. Oil phase
2. Surfactant
3. Aqueous Component
If a cosurfactant is used, it may sometimes be represented
at a fixed ratio to surfactant as a single component, and
treated as a single "pseudo-component".
The relative amounts of these three components can be
represented in a ternary phase diagram.
Gibbs phase diagrams can be used to show the influence
of changes in the volume fractions of the different phases
on the phase behavior of the system.
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16. The oil component influences curvature by its ability to penetrate
and swell the tail group region of the surfactant monolayer.
As compare to long chain alkanes, short chain oil penetrate the
tail group region to a greater extent and resulting in increased
negative curvature (and reduced effective HLB).
Following are the different oil are mainly used for the
formulation of microemulsion:
1. Saturated fatty acid-lauric acid, myristic acid,capric acid
2. Unsaturated fatty acid-oleic acid, linoleic acid,linolenic acid
3. Fatty acid ester-ethyl or methyl esters of lauric, myristic and
oleic acid.
The main criterion for the selection of oil is that the drug should
have high solubility in it.
This will minimize the volume of the formulation to deliver the
therapeutic dose of the drug in an encapsulated form.
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17. The role of surfactant in the formulation of microemulsion is to
lower the interfacial tension which will ultimately facilitates
dispersion process during the preparation of microemulsion and
provide a flexible around the droplets.
The surfactant should have appropriate lipophilic character to
provide the correct curvature at the interfacial region.
Generally, low HLB surfactants are suitable for w/o
microemulsion, whereas high HLB (>12) are suitable for o/w
microemulsion.
Following are the different surfactants are mainly used for
microemulsion-
◦ Polysorbate (Tween 80 and Tween 20), Lauromacrogol 300, Lecithins,
Decyl polyglucoside (Labrafil M 1944 LS), Polyglyceryl-6-dioleate (Plurol
Oleique), Dioctyl sodium sulfosuccinate (Aersol OT), PEG-8 caprylic/capril
glyceride (Labrasol).
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18. Cosurfactants are mainly used in microemulsion formulation for
following reasons:
They allow the interfacial film sufficient flexible to take up
different curvatures required to form microemulsion over a wide
range of composition.
1. Short to medium chain length alcohols (C3-C8) reduce the
interfacial tension and increase the fluidity of the interface.
2. Surfactant having HLB greater than 20 often require the presence
of cosurfactant to reduce their effective HLB to a value within the
range required for microemulsion formulation.
Following are the different cosurfactant mainly used for
microemulsion:
◦ sorbitan monoleate, sorbitan monosterate, propylene glycol, propylene
glycol monocaprylate (Capryol 90), 2-(2-ethoxyethoxy)ethanol (Transcutol)
and ethanol.
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Vadodara 4/21/2012 18
20. Packing ratio
Property of surfactant
Property of oil phase
Temperature
Chain length
Type and nature of cosurfactant
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21. Following are the different methods are used
for the preparation of microemulsion*:
1. Phase titration method
2. Phase inversion method
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22. Microemulsions are prepared by the spontaneous
emulsification method (phase titration method) and
can be portrayed with the help of phase diagram.
As quaternary phase diagram (four component system)
is time consuming and difficult to interpret, pseudo
ternary phase diagram is constructed to find out the
different zones including microemulsion zone, in which
each corner of the diagram represents 100% of the
particular components.
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.
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24. 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.
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25. Phase inversion of microemulsion is carried out 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 ultimately
affect drug release both in vitro and in vivo.
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
temperature to a w/o microemulsion ofat higher temperatures
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Vadodara 4/21/2012 25
26. During cooling, the system crosses a point zero
spontaneous curvature and minimal surface tension,
promoting the formation of finely dispersed oil droplets.
Apart from temperature, salt concentration or pH value
may also be considered.
A transition in the radius of curvature can be obtained by
changing the water volume fraction.
Initially water droplets are formed in a continuous oil
phase by successively adding water into oil. 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
Babaria Institute of pharmacy,
locus.
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27. Many examples of microemulsion based
formulations are now on the market ;
◦ Among them, the performances of microemulsions
are well demonstrated in the reformulation of
Cyclosporin A by Novartis into a microemulsion
based formulation marketed under the trade mark
Neoral®
this has increased the bioavailability nearly by
a factor 2.
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28. 1. The droplet size,
2. viscosity,
3. density,
4. turbidity,
5. refractive index,
6. phase separation and
7. pH measurements shall be performed to
characterize the microemulsion.
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29. The droplet size distribution of
microemulsion vesicles can be determined
by either light scattering technique or
electron microscopy.
This technique has been advocated as the
best method for predicting microemulsion
stability.
◦ Dynamic light-scattering measurements.
The DLS measurements are taken at 90° in a dynamic
light-scattering spectrophotometer which uses a neon
laser of wavelength 632 nm. The data processing is done
in the built-in computer with the instrument.
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30. Polydispersity
◦ Studied using Abbe refractometer.
Phase analysis
◦ To determine the type if microemulsion that has formed
the phase system (o/w or w/o) of the microemulsions is
determined by measuring the electrical conductivity
using a conductometer.
· Viscosity measurement
◦ The viscosity of microemulsions of several compositions
can be measured at different shear rates at different
temperatures using Brookfield type rotary viscometer.
◦ The sample room of the instrument must be maintained
at 37 ± 0.2°C by a themobath, and the samples for the
measurement are to be immersed in it before testing.
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31. Determination of permeability coefficient and flux
◦ Excised human cadaver skin from the abdomen can be
obtained from dead who have undergone postmortem not
more than 5 days ago in the hospital. The skin is stored at
4C and the epidermis separated.
◦ The skin is first immersed in purified water at 60C for 2
min and the epidermis then peeled off.
◦ Dried skin samples can be kept at -20C for later use.
◦ Alternatively the full thickness dorsal skin of male hairless
mice may be used.
◦ The skin shall be excised, washed with normal saline and
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32. ◦ The passive permeability of
lipophilic drug through the
skin is investigated using
Franz diffusion cells with
known effective diffusional
area.
◦ The hydrated skin samples
are used. The receiver
compartment may contain a
complexing agent like
cyclodextrin in the receiver
phase, which shall increase
the solubility and allows the
maintenance of sink
conditions in the
experiments.
◦ Samples are withdrawn at
regular interval and analyzed
for amount of drug released.
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33. Bioavailability studies: Skin bioavailability of topical
applied microemulsion on rats
◦ Male Sprague–Dawley rats (400–500 g), need to be
anesthetized (15 mg/kg pentobarbital sodium i.p.) and
placed on their back.
◦ The hair on abdominal skin shall be trimmed off and then
bathed gently with distilled water.
◦ Anesthesia should be maintained with 0.1-ml pentobarbital
(15 mg/ml) along the experiment.
◦ Microemulsions must be applied on the skin surface (1.8
cm2) and glued to the skin by a silicon rubber.
◦ After 10, 30 and 60 min of in vivo study, the rats shall be
killed by aspiration of ethyl ether.
◦ The drug exposed skin areas shall be swabbed three to four
times with three layers of gauze pads, then bathed for 30 s
with running water, wiped carefully, tape-stripped (X10
strips) and harvested from the animals.
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34. Determination of residual drug remaining in
the skin on tropical administration.
◦ The skin in the above permeation studies can be
used to determine the amount of drug in the
skin. The skin cleaned with gauze soaked in
0.05% solution of sodium lauryl sulfate and shall
bathed with distilled water.
◦ The permeation area shall be cut and weighed
and drug content can be determined in the clear
solution obtained after extracting with a suitable
solvent and centrifuging.
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35. Pharmacological Studies
◦ Therapeutic effectiveness can be evaluated for the specific
pharmacological action that the drug purports to show as
per stated guidelines.
Estimation Of Skin Irritancy
◦ As the formulation is intended for dermal application skin
irritancy should be tested.
◦ The dorsal area of the trunk is shaved with clippers 24
hours before the experiment.
◦ The skin shall be scarred with a lancet. 0.5 ml of product is
applied and then covered with gauze and a polyethylene
film and fixed with hypoallergenic adhesive bandage.
◦ The test be removed after 24 hours and the exposed skin is
graded for formation of edema and erythema.
◦ Scoring is repeated a 72 hours later.
◦ Based on the scoring the formulation shall be graded as
„non-irritant‟,
„irritant‟ and
„highly irritant‟.
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36. Stability Studies
◦ The physical stability of the microemulsion must
be determined under different storage conditions
(4, 25 and 40 °C) during 12 months.
◦ Depending on different regulatory agency
requirement it‟ll vary according to them.
◦ Fresh preparations as well as those that have
been kept under various stress conditions for
extended period of time is subjected to droplet
size distribution analysis.
◦ Effect of surfactant and their concentration on
size of droplet is also be studied.
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37. APPLICATIONS
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38. Oral drug delivery
Ocular drug delivery
Pulmonary drug delivery
Transdermal drug delivery
Parenteral drug delivery
For solubilization of drug
Nasal delivery
Drug targeting
In biotechnlogy
others
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39. Oral delivery
◦ Microemulsions have the potential to enhance the
solubilization of poorly soluble drugs (particularly BCS
class II or class IV) and overcome the dissolution
related bioavailability problems.
◦ These systems have been protecting the incorporated
drugs against oxidation, enzymatic degradation and
enhance membrane permeability.
◦ Presently, Sandimmune Neoral(R) (Cyclosporine A),
Fortovase(R) (Saquinavir), Norvir(R) (Ritonavir) etc. are
the commercially available microemulsion
formulations.
◦ Microemulsion formulation can be potentially useful
to improve the oral bioavailability of poorly water
soluble drugs by enhancing their solubility in
gastrointestinal fluid. Babaria Institute of pharmacy,
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40. Parenteral delivery
◦ The formulation of parenteral dosage form of
lipophilic and hydrophilic drugs has proven to be
difficult.
◦ O/w microemulsions are beneficial in the parenteral
delivery of sparingly soluble drugs where the
administration of suspension is not required.
◦ They provide a means of obtaining relatively high
concentration of these drugs which usually requires
frequent administration.
◦ Other advantages are that they exhibit a higher
physical stability in plasma than liposome‟s or other
vehicles and the internal oil phase is more resistant
against drug leaching.
◦ Several sparingly soluble drugs have been formulated
into o/w microemulsion for parenteral delivery.
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41. Topical delivery
◦ 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 areas of the skin or eyes.
◦ Now a day, there have been a number of studies in the
area of drug penetration into the skin.
◦ They are able to incorporate both hydrophilic (5-
flurouracil, apomorphine hydrochloride,
diphenhydramine hydrochloride, tetracaine
hydrochloride, methotrexate) and lipophilic drugs
(estradiol, finasteride, ketoprofen, meloxicam,
felodipine, triptolide) and enhance their permeation.
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42. Ophthalmic delivery
◦ Low corneal bioavailability and lack of efficiency in the
posterior segment of ocular tissue are some of the
serious problem of conventional systems.
◦ Recent research has been focused on the development
of new and more effective delivery systems.
◦ Microemulsions have emerged as a promising dosage
form for ocular use.
◦ Chloramphenicol, an antibiotic used in the treatment of
trachoma and keratitis, in the common eye drops
hydrolyzes easily.
◦ Fialho et al. studied microemulsion based
dexamethasone eye drops which showed better
tolerability and higher bioavailability. The formulation
showed greater penetration in the eye which allowed the
possibility of decreasing dosing frequency and thereby
Babaria Institute of pharmacy,
improve patient compliance. Vadodara 4/21/2012 42
43. Nasal delivery
◦ Recently, microemulsions are being studied as a
delivery system to enhance uptake of drug through
nasal mucosa.
◦ In addition with mucoadhesive polymer helps in
prolonging residence time on the mucosa.
◦ Lianly et al. investigated the effect of diazepam on the
emergency treatment of status epilepticus.
◦ They found that the nasal absorption of diazepam
fairly rapid at 2 mg kg-1 dose with maximum drug
plasma concentration reached within 2-3 min
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Vadodara 4/21/2012 43
44. Drug targeting
◦ Drug targeting to the different tissues has evolved
asthe most desirable goal of drug delivery.
◦ By altering pharmacokinetics and biodistribution of
drugs and restricting their action to the targeted
tissue increased drug efficacy with concomitant
reduction of their toxic effects can be achieved.
◦ Shiokawa et al. reported a novel microemulsion
formulation for tumor targeting of lipophilic
antitumor antibiotic aclainomycin A (ACM).
◦ They reported that a folate-linked microemulsion is
feasible for tumour targeted ACM delivery.
◦ They also reported that folate modification with a
sufficiently long PEG chain on emulsions is an
effective way of targeting emulsion to tumour cells.
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Vadodara 4/21/2012 44
45. 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.
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Vadodara 4/21/2012 45
