Microemulsion and Self Emulsification System

SEMINAR ON
MICROEMUSION
&
SELF EMUSIFICATION SYSTEM

• Guided by: • Prepared by:
– Mrs. Vaishali thakkar – Bhavesh Maktarpara
– M.Pharm. 1st sem
Pharmaceutics

Anand Pharmacy College, ANAND 1

Microemulsion
• Microemulsions are thermodynamically stable
dispersions of oil and water stabilized by a
surfactant and, in many cases, also a
cosurfactant.
• Microemulsions can have characteristic
properties such as ultralow interfacial tension,
large interfacial area and capacity to solubilize
both aqueous and oil-soluble compounds.


“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.”


Theories of Microemulsion Formation**
• Historically, three approaches have been used to explain microemulsion
formation and stability. They are as follows-
1. Interfacial or mixed film theories.
2. Solubilization theories.
3. Thermodynamic treatments.
• The free energy of microemulsion formation can be considered to depend
on the extent to which surfactant lowers the surface tension of the oil water
interface and change in entropy of the system such that,
Gf = γ a - T S
• Where,
– Gf = free energy of formation
– A = change in interfacial area of microemulsion
– S = change in entropy of the system
– T = temperature
– γ = surface tension of oil water interphase
• It should be noted that when a microemulsion is formed the change in A is
very large due to the large number of very small droplets formed.
• In order for a microemulsion to be formed (transient) negative value of was
required, it is recognized that while value of is positive at all times, it is very
small and it is offset by the entropic component.

• The dominant favorable entropic contribution is very large
dispersion entropy arising from the mixing of one phase in
the other in the form of large number 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 achieved when
large reductions in surface tension are accompanied by
significant favorable entropic change.
• In such cases, microemulsion is spontaneous and the
resulting dispersion is thermodynamically stable.

1. Schulman J.H, Stoeckenius, W., Prince, L.M, J. Phys. Chem., 63, 1677-1680. (1959).
Mechanism of formation and structure o f microemulsions by electron Microscopy .
2. Prince L.M, J. Colloid Interface Sci., 23,165-173 (1967). A theory of aqueous emulsions
I.Negative interfacial tension at the oil/water interface

Types of microemulsion systems*
• According to Winsor, there are four types of microemulsion phases
exists in equilibria, these phases are referred as Winsor phases
• They are,
Winsor I: With two phases, the lower (o/w)
microemulsion phases in equilibrium with the upper excess oil.
Winsor II: With two phases, the upper (w/o)
microemulsion phase microemulsion phases in equilibrium with lower
excess water.
Winsor III: With three phases, middle
microemulsion phase (o/w plus w/o, called bi continous) in
equilibrium with upper excess oil and lower excess water.
Winsor IV: In single phase, with oil, water and
surfactant homogenously mixed.

*Aboofazeli R, LawrenceM.J, Int. J. Pharm., 93,161-175 (1993). Investigations into the formation and
characterization of phospholipid microemulsions. I. Pseudo-ternary phase diagrams of systems containing
water-lecithin-alcohol-isopropyl myristate.
* Hasse A, Keipert, S, Eur. J. Pharm. Biopharm., 430, 179-183 (1997). Development and characterization of
microemulsions for ocular application.

• 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.

– 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
reflected by the numerous publications and patents being granted
on these systems. Anand Pharmacy College, ANAND 8

Component of Microemulsion System
• 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.
• The emphasis is, excipients should be generally regarded as safe
(GRAS)[


Main three components
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.


Oil Component
• 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.


Surfactants
• 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).


Co surfactants
• 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.


Preparation of Microemulsion
• Following are the different methods are used
for the preparation of microemulsion*:
1. Phase titration method
2. Phase inversion method


Phase titration method
• 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. Anand Pharmacy College, ANAND 15

• 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.


Phase inversion method
• 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 at higher temperatures (transitional phase inversion).

• 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 locus.

• 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.

Characterization Of Microemulsion

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.


The droplet size
• 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.


Phase analysis and viscosity measurement
• 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.


In Vitro Drug Permeation Studies
• 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 used.

– 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.


In Vivo Studies
• 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.

• 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.


• 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’. Anand Pharmacy College, ANAND 28

• 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.


Application of microemulsion in delivery of drug

• 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.

• 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.

• 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.

• 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 improve patient compliance.

• 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


• 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.

Self Emulsification Drug Delivery
System


• SEDDSs are isotropic mixtures of oils and surfactants,
sometimes containing cosolvents, and can be used for the
design of formulations in order to improve the oral absorption
of highly lipophilic compounds.

• SEDDSs emulsify spontaneously to produce fine oil-in-water
emulsions when introduced into an aqueous phase under
gentle agitation.

• SEDDS can be orally administered in soft or hard gelatine
capsules and form fine, relatively stable oil-in-water
emulsions upon aqueous dilution.

• Self-emulsifying formulations spread readily in the
gastrointestinal (GI) tract, and the digestive motility of
the stomach and the intestine provide the agitation
necessary for selfemulsification.
• These systems advantageously present the drug in
dissolved form and the small droplet size provides a
large interfacial area for the drug absorption.
• SEDDSs typically produce emulsions with a droplet size
between 100–300 nm while self-microemulsifying drug
delivery systems (SMEDDSs) form transparent
microemulsions with a droplet size of less than 50 nm.


• Composition of SEDDSs
– The self-emulsifying process is depends on:
• The nature of the oil–surfactant pair
• The surfactant concentration
• The temperature at which self-emulsification occurs.


• Oils
– Oils can solubilize the lipophilic drug in a specific
amount. It is the most important excipient because it
can facilitate self-emulsification and increase the
fraction of lipophilic drug transported via the
intestinal lymphatic system, thereby increasing
absorption from the GI tract.
– Long-chain triglyceride and medium-chain triglyceride
oils
– Modified or hydrolyzed vegetable oils have
contributed widely to the success of SEDDSs owing to
their formulation and physiological advantages


• Surfactant
– Nonionic surfactants with high hydrophilic–
lipophilic balance (HLB) values are used in
formulation of SEDDSs (e.g., Tween, Labrasol,
Labrafac CM 10, Cremophore, etc.).
– The usual surfactant strength ranges between 30–
60% w/w of the formulation in order to form a
stable SEDDS.


• Cosolvents
– Cosolvents like diehylene glycol monoethyle ether
(transcutol), propylene glycol, polyethylene glycol,
polyoxyethylene, propylene carbonate,
tetrahydrofurfuryl alcohol polyethylene glycol
ether (Glycofurol), etc., may help to dissolve large
amounts of hydrophilic surfactants or the
hydrophobic drug in the lipid base.
– These solvents sometimes play the role of the
cosurfactant in the microemulsion systems.


Formulation of SEDDSs
• The following should be considered in the
formulation of a SEDDS:
– The solubility of the drug in different oil,
surfactants and cosolvents.
– The selection of oil, surfactant and cosolvent
based on the solubility of the drug and the
preparation of the phase diagram.
– The preparation of SEDDS formulation by
dissolving the drug in a mix of oil, surfactant and
cosolvent.


• The addition of a drug to a SEDDS is critical
because the drug interferes with the self-
emulsification process to a certain extent, which
leads to a change in the optimal oil–surfactant
ratio.
• So, the design of an optimal SEDDS requires
preformulation-solubility and phase-diagram
studies. In the case of prolonged SEDDS,
formulation is made by adding the polymer or
gelling agent


Mechanism of self-emulsification
• According to Reiss, self-emulsification occurs
when the entropy change that favors
dispersion is greater than the energy required
to increase the surface area of the dispersion.

Where,
DG is the free energy associated with the process
N is the number of droplets
R is radius of droplet
S is interfacial tension


Characterization of SEDDSs
• The primary means of self-emulsification assessment is visual
evaluation. The efficiency of self-emulsification could be
estimated by determining the rate of emulsification, droplet-
size distribution and turbidity measurements.
• Visual assessment. This may provide important information
about the self-emulsifying and microemulsifying property of the
mixture and about the resulting dispersion.
• Turbidity Measurement. This is to identify efficient self-
emulsification by establishing whether the dispersion reaches
equilibrium rapidly and in a reproducible time.


• Droplet Size.
– This is a crucial factor in self-emulsification performance because it
determines the rate and extent of drug release as well as the stability of
the emulsion.
– Photon correlation spectroscopy, microscopic techniques or a Coulter
Nano sizer are mainly used for the determination of the emulsion droplet
size.
– The reduction of the droplet size to values below 50 μm leads to the
formation of SMEDDSs, which are stable, isotropic and clear o/w
dispersions.
• Zeta potential measurement.
– This is used to identify the charge of the droplets. In conventional SEDDSs,
the charge on an oil droplet is negative due to presence of free fatty acids.
• Determination of emulsification time.
– Self-emulsification time, dispersibility, appearance and flowability was
observed and scored according to techniques described in H. Shen et al.
used for the grading of Anand Pharmacy College, ANAND
formulations. 47

References
• Microemulsions- Potential Carrier for Improved Drug Delivery
INTERNATIONALE PHARMACEUTICA SCIENCIA April-June 2011 Vol. 1 Issue 2
http://www.ipharmsciencia.com ISSN 2231-5896 ©2011 IPS, Sajal Kumar
Jha1*, Sanjay Dey1, Roopa Karki2
• N.H. Shah et al., "Self-emulsifying drug delivery systems (SEDDS) with
polyglycolyzed glycerides for improving in vitro dissolution and oral absorption
of lipophilic drugs," Int. J. Pharm. 106, 15–23 (1994).
• J.R. Crison and G.L. Amidon, "Method and formulation for increasing the
bioavailability of poorly water-soluble drugs," US Patent No. 5,993,858, issued
November 30, 1999.
• P.P. Constantinides, "Lipid microemulsions for improving drug dissolution and
oral absorption: physical and biopharmaceutical aspects," Pharm. Res. 12,
1561–72 (1995).
• N. Gursoy et al., "Excipient effects on in vitro cytotoxicity of a novel paclitaxel
selfemulsifying drug delivery system," J. Pharm. Sci. 92, 2420–2427 (2003).


Microemulsion and Self Emulsification System

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