MICROEMULSIONGuided By:

Dr. Tejal Mehta,

Head of Department,

Pharmaceutical Technology & Biopharmaceutics

Prepared By:

Ishani Pandit,

M.Pharm, Sem -1,

Pharmaceutical Technology & Biopharmaceutics

14MPH109.

Content:

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Introduction

History

Basic aspects of Microemulsion

Theories of Microemulsion

Phase behaviour of Microemulsion

Components of Microemulsion

Types of Microemulsiom

Preparation of Microemulsion

Characterization of Microemulsion

Advantages, disadvantages & Applications

Evaluation of Microemulsion

Marketed Preparations

conclusion

Introduction

Microemulsions are thermodynamically stable, optically transparent isotropic mixtures of a biphasic o/w system stabilized with surfactants.

The diameter of droplets in microemulsion may be in the range of 100Å to1000Å.

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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“Microemulsions are dispersions of nanometer-sized droplets ofan immiscible liquid within another liquid. Droplet formation isfacilitated by the addition of surfactants and often also cosurfactants.”

And they can be known as Modern colloidal drug delivery system.

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History

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 Lindmanin 1981 will be used as the point of reference.

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Basic aspects of Microemulsion

Microemulsion are fluid, transparent, thermodynamically stable oiland water system and stabilized by a surfactant usually inconjunction with co-surfactant.

This includes normal micelles, revers micelles, cores and droplets ofwater or oil and for some system like bi-continuous structureneither oil nor water surrounds each other.

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If a co-surfactant is used, it may sometimes be represented at a fixed ratio to surfactant as a single component, and treated as a single “pseudo-component”.

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Comparison between Emulsion & microemulsion

EMULSION

Thermodynamically unstable.

In due time phases it is separate out.

It is cloudy.

Require large input of energy during its preparation. higher cost.

Droplet size > 500 nm

Interfacial tension: high

High viscosity

Stable microstructure

MICROEMULSION Thermodynamically stable.

In due time phases it is not separate out.

It is transparent.

Require low input of energy during its preparation. relatively low cost.

Droplet size 20-200 nm

Interfacial tension: ultra low

Low viscosity with Newtonian behavior.

Dynamic (constantly fluctuating interface)

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Theory of Microemulsion

The understanding of basis for thermodynamic stability of

of microemulsion several thermodynamic theories are

proposed.

In 1975, Ruckenstein and Chi considered the free energy formation of microemulsion to be consisted of three contributions :

Interfacial energy,

Energy of interaction b/w droplets,

Entropy of dispersion.

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The free energy of microemulsion formation can be considered to depend on the extent to which surfactant lowers the surface tension of oil-water interface and the change in entropy of the system such that :

ΔGf = γ ΔA – T ΔS

ΔGf = Free energy formation.

γ = Surface tension of oil-water interface.

ΔA = Change in interfacial area on microemulsion.

ΔS = Change in entropy of system.

T = Temperature.11/21/2014

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Phase Behaviour of Microemulsion

The phase behaviour of simple microemulsion system composing oil, water and surfactant can be studied with the aid of ternary phase diagram.

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WINSOR PHASE :- WI, WII, WIII, WIV

O :- Oil W:- Water

L1:- A single phase region of normal micelles or oil

in water micro emulsion.

L2:- A reverse micelles or water in oil micro

emulsion.

D :- Anisotropic lameller liquid crystalline phase.

μE:- Microemulsion.

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The co-surfactant is also amphiphilic with an affinity for both the oiland aqueous phase.

Eg. Alkyl amine, alkanoic acid, alkanoids, non ionic surfactant,alcohol.

A large no. of drug molecules are also acts as surface active agentby themselves, which influence the phase behaviour.

In this diagram a corner will represent the binary mixture of twocomponents such as surfactant/co-sufactant, water/drug oroil/drug.

At low concentration of surfactant there are certain phases exists inequilibrium. These phases are refered to as WINSOR PHASES.

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A. WINSOR-1 :- With two phases, the lower (o/w) microemulsionphase in equilibrium with excess oil.

B. WINSOR-2 :- With two phases, upper (w/o) microemulsion phasein equilibrium with excess water.

C. WINSOR-3 :- With three phases, middle microemulsion phase(o/w plus w/o, called bio-continuous) in equilibrium with upperexcess oil and lower excess water.

D. WINSOR-4 :- In single phase, with oil, water, and surfactanthomogenously mixed.

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Components of Microemulsion

Oil Phase

• Isopropyl Myristate

• Oleic acid

• Olive oil

• Mineral oil

• Medium chain triglyceride

• Soyabean oil

• Captex 355

• Isopropyl Palmitate

• Sunflower oil

• Safflower oil

Surfactant

• Tween 80

• Tween 40

• Span 40

• Labrafil M1944CS

• Polyoxyethylene-35-ricinoleate

• Brij 58

• CremophorEL

• Lecithin

Co-surfactant

• Propylene glycol

• Ethylene glycol

• Ethanol

• 1-butanol

• Isopropyl alcohol

• PEG 600

• Glycerol

• PEG 400

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Oil Component

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. 11/21/2014

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The main criterion for the selection of oil is that the drug shouldhave high solubility in it.

This will minimize the volume of the formulation to deliver thetherapeutic dose of the drug in an encapsulated form.

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Surfactants

It is to lower the interfacial tension which will ultimately facilitatesdispersion process and provide a flexible around the droplets.

Generally, low HLB (3-6) surfactants are suitable for w/omicroemulsion, whereas high HLB (8-18) are suitable for o/wmicroemulsion.

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Co-surfactants

They allow the interfacial film sufficient flexible to take up differentcurvatures required to form microemulsion over a wide range ofcomposition.

1. Short to medium chain length alcohols (C3-C8) reduce theinterfacial tension and increase the fluidity of the interface.

2. Surfactant having HLB greater than 20 often require the presenceof co-surfactant to reduce their effective HLB to a value within therange required for microemulsion formulation.

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a) By reducing the interfacial tension

b) By increasing the flexibility and fluidity of the interface bypositioning itself between the surfactant tails which alters the solventproperties of both the dispersed and continuous microemulsionphases;

c) By lowering overall viscosity.

d) By being often soluble in both organic and aqueous phases, co-surfactants help solubilise poorlysoluble compounds (e.g., peptides,vitames)

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Types of Microemulsiom

O/W Microemulsion

W/O Microemulsion

Bi continuous Microemulsion

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Preparation of Microemulsion

Drug has to dissolve in to oil phase(lipophilic part) ofmicroemulsion.

Water phase is combined with the surfactant and then cosurfactantis added slowly with constant stirring until the system is becometransparent.

The amount of surfactant and co-surfactant to be added and theparent oil phase that can be incorporated is determined with thehelp of pseudo ternary phase diagram.

Ultrasonicator can finally used to achieve the desired range for thedispersed phase.

It is then allow to equilibrate.11/21/2014

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Gel may be prepared by the addition of the gelling agent to above microemulsion.

Eg. :- Carbomers – Cross linked polyacrylic acid

polymers.

Xanthan gum

Carbomers are widely used as gelling agents.

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Figure shows the pseudo-ternary phase diagram with the area inside the frame assigned on the phase diagram showing the micro-emulsion region. The area outside the frame indicates a turbid region with multiphase systems. It could be noted that the area of micro-emulsion region was considerably large since 1-butanol acted as a co-surfactant and interacted with the surfactant monolayer to increase the flexibility of the interfacial film.

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Characterization

Phase Behaviour

Studies

Scattering Technique

Nuclear Magnetic

Resonance Studies

Electron Microscopic

studies

Interfacial Tension, Electric

Conductivity

Viscosity Measurement

1. Phase Behaviour Studies

This study is very much essential for the determination ofsurfactant by using phase diagram which provide information onthe boundaries of the different phases as the function ofcomposition variables and temperature and more importantstructural organization can also be inferred.

Phase behaviour studies also allow comparison of the efficiency ofthe different surfactant for given application.

In this study, the temperature and pressure remain fixed.

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2. Scattering Technique

In this technique Small Angle X-ray Scattering(SAXS), Small Angle Neutron Scattering(SANS) and static as well as dynamic light scattering are widely applied technique in the study of microemulsion.

In this technique, the intensity of scattered radiation I(q) is maesured as a function of scattering vector q,

q = (4π/λ) sin θ/2

θ = Scattering Angle.

λ = Wavelength of Radiation.

Small Angle X-ray Scattering technique and Static Light Scattering techniques both are used to determine the microemulsion droplet size and shape.

Dynamic Light Scattering is used to analyse the fluctuation in the intensity of scattering by droplets due to Brownian motion.

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3. Nuclear Magnetic Resonance Studies

The structure and dynamics of micro emulsion can be studied byusing nuclear magnetic resonance techniques.

Self diffusion measurements using different tracer techniquegenerally radio labeling. Supply information on the mobility of thecomponents.

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4. Electron Microscopic Studies

Microemulsion has been characterised by some electro microscopic techniques although the high lability of the sample and the possibilities of artifacts electron microscopy used to be considered a misleading techniques in microemulsion studies.

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5. . INTERFACIAL TENSION, ELECTRICAL CONDUCTIVITY AND VISCOSITY MEASUREMENTS

Formation and properties of micro emulsion can be studied by themeasuring of Interfacial Tension. Ultra low values of InterfacialTension are correleated with phase behaviour, particularly theexistance of surfactant phase or middle phase micro emulsion inequilibrium with aqueous and oil phase.

To determine the nature of the continuous phase and to detectphase inversion phenomena the electrical conductivitymeasurement are highly useful.

Viscosity measurements can indicates the presence of rod like orwarm like reverse micelles. It is used to determine thehydrodynamic radius of droplets, as well as interaction b/w dropletsand deviations from spherical shape by fitting the results toappropriate models. 11/21/2014

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Advantages, Disadvantages & Applications of Microemulsion

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Advantages:

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Increase the rate of absorption

Eliminates variability in absorption

Helps solubilize 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 micro-emulsion is not exposed to attack by water and air.

Liquid dosage form increases patient compliance.

Less amount of energy requirement.

Disadvantages:

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

micro-emulsion.

Limited solubilizing capacity for high-melting substances used in the system.

The surfactant should be nontoxic for use in pharmaceutical applications.

Micro-emulsion stability is influenced by environmental parameters such as temperature and pH. These

parameters change as micro-emulsion delivered to patients.

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Applications

Parenteral Administrati

on.

Oral drug delivery.

Topical drug delivery.

Ocular and pulmonary

delivery.

Micro-emulsions in biotechnolo

gy

Parenteral Administration:

In order to attain prolonged release and to administer parenterallylipophilic substances that are not soluble in water, o/wmicroemulsions may be used as carriers.

It is administered by intravenous, intramuscular, or subcutaneousroute.

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Oral Drug Delivery system:

They have short life, conformational stability and biodegradability. So it is very difficult to produce their formulation for oral administration.

Microemulsions extensively studied for protection of biodegradable drugs.

Eg. Proteins and Peptides from biological environment of per-oral route.

In recent time pharmaceutical and biotechnology permit to produced high amount of peptides and proteins.

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Topical drug Delivery System:

The percutaneous route of administration has been extensively studied where the drug transport from microemulsions were recorded usually better than that from other ointments, gels and creams.

Eg. Release of Tetracycline HCl is higher as microemulsion than as gel and cream.

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Occular & Pulmonary Delivery:

For the treatment of eye diseases, drugs are essentially delivered topically. O/W type of microemulsions have been investigated for ocular administration to dissolve poorly soluble drugs, to increase absorption and to attain prolong release profile.

Lecithin-Tween 80 based microemulsions was developed and characterized, which dissolved some poorly soluble drugs such as Atropine, Chloramphenicol and Indomethacin.

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Microemulsion in Biotechnology:

Many enzymatic and bio-catalytic reactions are conducted in pure organic or aqua organic media. Biphasic media also used for these type of reaction. The use of water poor media is relatively advantageous.

Enzymes in low water content and have,

-Increased solubility in nonpolar reactants.

-Possibilities of shifting thermodynamic equilibrium in

favour of condensation.

-Improve thermal conductivity of the enzymes, enabling

reactions to be carried out at higher temperature.11/21/2014

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Other Applications:

Micro-emulsions can improve skin penetration of lycopene.

Micro-emulsion as a vehicle for transdermal permeation of nimesulide

Micro-emulsion in enhanced oil recovery, detergency, cosmetics, agrochemicals, food. Microemulsions in environmental remediation and detoxification.

Micro-emulsions as fuels, as lubricants, cutting oils and corrosion inhibitors, coatings and textile finishing.

Micro-emulsions in microporous media synthesis (micro-emulsion gel technique) Micro-emulsions in analytical applications.

Micro-emulsions as liquid/membranes Novel crystalline colloidal arrays as chemical sensor materials 11/21/2014

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Evaluation of Microemulsion

Parameters Technique used

Phase Behaviour Phase contrast microscopy &freeze fracture TEM

Size and Shape Transmission ElectronMicroscopy(TEM), SEM

Rheology Brookfield viscometer

Conductivity Conductivity meter

Zeta potential Zetasizer

pH pH meter

Drug release studies Franz Diffusion Cells

Physical stability study Ultracentrifuge 11/21/2014

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Different catagories of drugs solubilized in Microemulsion:

Category Drugs

Anti-neoplastics Doxorubicin

Peptide Drug Cyclosporin

Sympatholytic Timolol

Local Anaesthetics Lidocaine, Benzocaine, Tetracaine

Steroids Hydrocortisone, Testosterone

Anxiolytics Diazepam

Vitamins Tocopherol, Ascorbic acid

Anti inflammatory Indomethacin 11/21/2014

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Marketed lipid based and surfactant based formulations

Drug Product Component

Amprenavir Agenerase TPGS, PEG 400, Propylene glycol

Ritonavir Norvir Ethanol, oleic acid, cremophor EL, BHT

Ritonavir/ lopinavir Kaletra Oleic acid, cremophor EL, propylene glycol

Saquinavir Fortovase Medium chain mono-digllycerides, povidone, α-tocopherol

Tipranavir Aptivus Ethanol, Polyoxyl 35 castor oil, propylene glycol, mono-diglycerides of caprylic acid/capric acid

Cyclosporin Neoral Corn oil mono-diglycerides, cremophor RH40, ethanol, propylene glycol, α-tocopherol

Cyclosporin Gengraf Ethanol, PEG, Cremophor EL, polysorbate 80, sorbitanmonooleate

Sirolimus Rapimmune Phosal 50 PG, Polysorbate 80

Doxecalciferol Hectoral Medium chain triglycerides, ethanol, BHA

Progesterone Prometrium Peanut oil, lecithin, glycerin11/21/2014

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Marketed ProductsProprietary

name

Oil Phase (w/v) Emulsifier (w/v) Active

Ingredients

(w/v)

Other

Ingredients

Abbolipid(10%,20%)

Soya oil+saffloweroil (5%/10% each)

3-sn-PC from Egg(0.74% / 1.2%)

--- Glycerol (2.5%)NaOH

Deltalipid (10%, 20%)

Soya oil (10%/20%) Egg Phospholipids (1.2%/1.2%)

--- Glycerol (2.5%)NaOH

Oleic Acid (0.3%)

Intralipid (10/20) Soya oil (10%/20%) 3-sn-PC from Egg yolk

(0.6% / 1.2%)

--- Glycerol (2.5%)NaOH

Intralipid 30 Soya oil 30% 3-sn-PC from Egg yolk (30%)

--- Glycerol (1.67%)NaOH

Lipofundin MCT(10%/20%)

Soya oil + Middle chain Triglycerides(5%/10% each)

Egg Phospholipids(min 68% 3-sn-PC)

(0.8 % / 1.2%)

--- Glycerol (2.5%)NaOH

Sod. Olateα Tocopherol

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Proprietary Name Oil Phase (w/v) Emulsifier (w/v) Active Ingredients

(w/v)

Other Ingredients

Diazepam Lipuro (1%/ 2%)

Soya Oil + Middle Chain Triglycerides

Egg Lecithin Diazepam(1% / 2%)

GlycerolSod. Oleate

NaOH

Disoprivan(1% / 2%)

Soya Oil 3-sn-PC Propofol(1% / 2%)

GlycerolNaOH

Etomidat Lipuro Soya Oil + Middle Chain Triglycerides

Egg Lecithin Etomidate GlycerolSod. Oleate

NaOH

Lipotalon Soya Oil (10%) Egg Phospholipids (1.2%)

Dexamethasone-21-palmitate

(0.4%)

Glycerol

Propofol Abbot 1% Soya Oil Egg Lecithin Propofol (1%) GlycerolNaOH

Stesolid Soya Oil Phospholipidsfrom egg yolk

Diazepam (3%) Glycerol, AcetylatedMonoglycerides, NaOH

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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.

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Thank You

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