Multiple and microemulsions

PESENTED BY,K.SAILAKSHMI,M.PHARMACY,(Pharmaceutics),256213886016.

UNDER THE GUIDENCEOF

Dr . YASMIN BEGUMM.pharm , Ph.d

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CONTENTS

• INTRODUCTION

• MICRO EMULSIONS

TYPES OF MICRO EMULSIONS

DIFFERENCE BETWEEN MICRO AND MACRO

PREPARATION AND CHARACTERISATION

ADVANTAGES

STABILITY STUDIES

USES

• EQUIPMENTS

• MUTIPLE EMULSIONS

TYPES

PREFORMULATION OF DOUBLE EMULSIONS

PREPARATION OF MULTIPLE EMULSIONS

MECHANISMS AND EVALUATION

STABILITY

USES

• CONCLUSION

An emulsion is a thermodynamically unstable system consisting

of atleast two immisible liquid phases one of which is dispersed

as a globules in the other liquid phase stabilised by a third

substance called emulsifying agent

An emulsion is a mixture of two or more

immiscible(unblendable) liquids

Emulsions are a part more general classes of two phase systems

of matter called Colloids

In an emulsion one liquid(the dispersed phase) is dispersed in

the other (the continuos phase)

EMULSION

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MICRO EMULSIONS

DEFINITION: (Danielsson and Lindman)

“ A micro emulsion is a system, of water ,oil and an

amphiphile which is a single optically isotropic and

thermodynamically stable liquid solution.”

In some aspects, micro emulsions can be considered as

small scale versions of emulsions ,i.e , droplet type dispersions

either of oil-in-water (o/w) or of water in oil (w/o) with a size

range in the order of 5-50nm in drop radius.

TYPES OF MICROEMULSIONS

Three types of micro emulsions are most likely to be formed depending on the composition:

• Oil in water micro emulsions wherein oil droplets are dispersed in the continuos aqueous phase

• Water in oil micro emulsions wherein water droplets are dispersed in the continuous oil phase

• Bi-continuous micro emulsions where in micro domains of oil and water are inter dispersed within the system.

In all three types of microemulsions, the interface is stabilized by an appropriate combination of surfactants and/or co-surfactants.

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The term micro emulsion introduced by Schulman and co-works.

The term "micro emulsion" refers to a thermodynamically stable

isotropically clear dispersion of two immiscible liquids, such as oil

and water, stabilized by an interfacial film of surfactant molecules.

A micro emulsion is considered to be a thermodynamically or

kinetically stable liquid dispersion of an oil phase and a water

phase, in combination with a surfactant.

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The key difference between emulsions andmicro emulsions are that the former, whilst they mayexhibit excellent kinetic stability, are fundamentally thermodynamically unstable and will eventually phase separate.

Another important difference concerns their appearance;emulsions are cloudy while micro emulsions are clear or translucent.

In addition, there are distinct differences in their methodof preparation, since emulsions require a large input of energy while micro emulsions do not.

Micro emulsion formation and stability can be explained on the basis of a simplified thermodynamic rationalization.

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Microemulsions and (Macro) emulsions are

Different

Microemulsion

• Thermodynamically Stable

• Droplet size 10 - 100 nm

(transparent)

• High surface area: 200 m2/g

• Ultra Low O/W IFT (10-2 –

10-3 mN/m)

• W/O , O/W and

Bicontinuous types

• Forms at CPP = 1

Macroemulsion

• Kinetically Stable

• 1-10 m (opaque)

• Low surface area: 15 m2/g

• O/W IFT 1-10 mN/m

• W/O or O/W types

• Forms at CPP > or < 1

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PREPARATION OF MICROEMULSION:

Microemulsions were prepared at 27°C by a titration

method.

The drug is be dissolved in the lipophilic part of the microemulsion

i.e. Oil and the water phases can be combined with surfactant and

a cosurfactant is then added at slow rate with gradual stirring until

the system is transparent.

The amount of surfactant and cosurfactant to be added and the

percent of oil phase that can be incorporated shall be determined

with the help of pseudo-ternary phase diagram.

Ultrasonicator can finally be used so to achieve the desired size

range for dispersed globules. It is then be allowed to equilibrate. 9

Oil-in-water microemulsions were prepared by the titrationmethod.

A mixture of fatty acid and oil was added to a caustic solutionto produce a microemulsion, which was then titrated with a cosurfactant, an alcohol, until the system turned clear.

It was found that as the chain length of the surfactant increased, microemulsions with significant transmittances by visible spectrum could be formed with oils of longer chain lengths.

It was also found that different alcohols affected the formationof microemulsions in different ways.

The best results, in terms of the greatest percent transmittance coupled with the widest range of oil (dispersedin water) concentration, were obtained from short or branched alcohols.

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The free energy of microemulsion formation can beconsidered to depend on the extent to which surfactant lowers the surface tension of the oil–water interface andthe change in entropy of the system such that,

DG f = γDA - T DS

where DG f is the free energy of formation,

γ is the surface tension of the oil–waterinterface, DA is the change in interfacial area on

microemulsification, DS is the change in entropy of the system which is

effectively the dispersion entropy,and T is the temperature.

It should be noted that when a microemulsion is formed the change in DA is very large due to the large number of very small droplets formed.

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Though it has been know that several factors determine whether a w/o or o/w system will be formed but in generalit could be summarised that the most likely microemulsionwould be that in which the phase with the smaller volumefraction forms the droplets i.e. internal phase.

The surfactants used to stabilise such systems may be:

(i) Non-ionic

(ii) Zwitterionic

(iii) Cationic

(iv) Anionic surfactants

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Various pharmaceutically acceptable availablethat can be used in microemulsion formulation exicipents are:

Long chain or high molecular weight (>1000) surfactantsinclude

Gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, polyoxyethylene alkyl ethers,

e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters,

e.g., the commercially available Tweens, polyethylene glycols, polyoxyethylene stearates.

The low molecular weight (<1000) surfactants include: Stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, and sorbitan esters.

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Characterization Of Microemulsion

The droplet size, viscosity, density, turbidity, refractive index, phase separation and pH measurements shall be performed to characterize the microemulsion.

The droplet size distribution of microemulsion vesicles canbe determined by either light scattering technique or electron microscopy. This technique has been advocated as the best method for predicting microemulsion stability.

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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

· Rapid and efficient penetration of the drug moiety

· Helpful in taste masking

· Liquid dosage form increases patient compliance.

· Less amount of energy requirement.

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Stability Studies

The physical stability of the microemulsion must be determined under different storage conditions (4, 25 and 40 °C) during 12 months.

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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Uses

Microemulsions have many commercially important uses:

Water-in-oil microemulsions for some dry cleaning processes

Floor polishers and cleaners.

Personal care products

Pesticide formulations

Cutting oils.

Pharmaceutical applications of microemulsionsIncrease bioavailability of drugs poorly soluble in water.

Topical drug delivery systems

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Applications of microemulsions

Microemulsions in enhanced oil recovery

Microemulsions as fuels

Microemulsions as coatings and textile finishing

Microemulsions as lubricants, cutting oils and corrosioninhibitors

Microemulsions in detergency

Microemulsions in cosmetics

Microemulsions in agrochemicals

Microemulsion in pharmaceuticals

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EQUIPMENT USED IN PREPARATION OF

EMULSIONS

COLLOIDAL MILLAPPLICATION:

Product is feed to the operating area of a rotor,

having a speed of 2800 R.P.M by specially

designed feed device. The product is processed

by high sheer, pressure and friction between the

stator and rotor, the angular gap becomes

narrower towards the discharges section. This

processed product continuously leaves the mill

through the drain pipe, if required, it can be re-

circulated.

SALIENT FEATURES

All contact parts can be easily and quickly

dismantled and cleaned.

Machine is designed for continuous operation.

Cylindrical screen for higher output.

Flame proof electrical can be provided at extra

cost. 19

HOMOGENISER

High Speed Homogenizer

Vats & Vessels Homogenizer is used to

homogenize, emulsify, and disperse

material in pharmaceutical, cosmetics,

food, chemical, petrochemical industry, etc.

Working Principle -

High speed mechanical and hydraulic shear

forces are the real key to the success of this

machine. Rotor & stator generates a

shearing action which insures that materials

being processed are subjected to thousands

of shearing actions each minute.

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ROTORSTATOR

High speed rotor operating at close clearance

to stator draws material in from the bottom of

the mixing vessel and subjects it to intense

mixing and shearing action.

The rotor accelerates the product towards the

blades periphery. There it is expelled through

the stator openings into the body of the mix

while undergoing an intensive mechanical and

hydraulic shearing action.

Simultaneously new material is drawn in.

The expelled mixture is deflected by the tank

wall completing the circulation pattern.

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DEFINITION

Multiple emulsions are the emulsion system in which thedispersed phase contain smaller droplets that have the same composition as the external phase.

This is made possible by double emulsification hence thesystems are also called as “double emulsion”.

Like simple emulsions, the multiple emulsions are also considered to be of two

types:

•Oil-in-Water-in-Oil (O/W/O) emulsion system

•Water-in-Oil-in-Water (W/O/W) emulsion system

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O/W/O EMULSION

In O/W/O systems an aqueous phase (hydrophilic)separates internal and external oil phase.

In other words, O/W/O is a system in which water dropletsmay be surrounded in oil phase, which in true encloses oneor more oil droplets.

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W/O/W EMULSION

In W/O/W systems, an organic phase (hydrophobic) separates internal and external aqueous phases.

In other words, W/O/W is a system in which oil droplets maybe surrounded by an aqueous phase, which in turn encloses one or several waterdroplets.

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These systems are the most studied among the multiple emulsions.

The immiscible oil phase, which separates two miscible aqueous phases is known as “liquid membrane” and acts as a different barrier and semi-permeable membrane for the drugs or moieties entrapped in the internal aqueous phase.

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Schematic Diagram of W/O/W & O/W/O

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Pre-Formulation of Double Emulsion

The formulate a double emulsion, it is necessary to

choose, at least, an oil and two surfactants, one low in HLB

and one high in HLB.

In the example mentioned here, we have been working

with span surfactants (HLB<5) and

Tween surfactants (HLB>10) and

with a vegetable oil (caprylic/ capric triglyceride).

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Methods of Preparation

Multiple emulsions are best prepared by

re- emulsification of primary emulsion.

The following are the method of multiple emulsions:

Two Steps Emulsification (Double Emulsification)

Phase Inversion Technique (One Step Technique)

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Two Steps Emulsification

(Double emulsification)

Two steps emulsification methods involve

re-emulsification of primary W/O or O/W emulsion

using a suitable emulsifier agent.

The first step involves, obtaining an ordinary W/O or

O/W primary emulsion wherein an appropriate

emulsifier system is utilized.

In the second step, the freshly prepared W/O or

O/W primary emulsion is re-emulsified with an excess

of aqueous phase or oil phase.

The finally prepared emulsion could be W/O /W or

O/W/O respectively. 30

Two Steps Emulsification

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Modified Two Steps Emulsification

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Phase Inversion Technique

(One Step Technique)

An increase in volume concentration of dispersed phase

may cause an increase in the phase volume ratio, which

subsequently leads the formation of multiple emulsions.

The method typically involves the addition of an aqueous phase

contains the hydrophilic emulsifier

[ Tween 80/sodiumdodecylsulphate (SDS) or Cetyl trimethyl

ammonium salt CTAB)] to an oil phase consisted of liquid

paraffin and containg lipophilic emulsifier (Span80).

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A well-defined volume of oil phase is placed in a vessel of

pin mixer.

An aqueous solution of emulsifier is then introduced

successively to the oilphase in the vessel at a rate of 5 ml/min,

while the pin mixer rotates steadily at 88 rpm at room

temperature. When volume fraction of the aqueous solution

of hydrophilic emulsifier exceeds 0.7, the continuous oil

phase is substituted by the aqueous phase containing a

number of the vesicular globules among the simple oil

droplets, leading to phase inversion and formation of

W/O/W multiple emulsion.

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Phase Inversion Technique

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POSSIBLE MECHANISMS OF DRUG RELEASE

FROM MULTIPLE EMULSIONS

Diffusion mechanism.

Micellar transport.

Thinning of oil membrane.

Rupture of oil phase.

Faciliated diffusion (carrier mediated transport).

Photo -osmotic transport.

Solubilization of internal phase in the oil membrane.

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EVALUATION OF MULTIPLE EMULSIONS

Characterization

Average globule size and size distribution

No.of globules

Percentage drug entrapment

Rheological evaluation

Zeta potential

In-vitro stability studies

In-vitro drug release

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Characterization :

Emulsions are mostly characterized by the size distribution

of the droplet and other physical properities such as dielectric

properities thermal behaviour, rheological properities and other

microscopic and macroscopic observation.

Macroscopic examination:

Primary observations like color, consistency, and

homegeneity are frequently used to ensure type of multiple

emulsions formed (w/o/w or o/w/o) can be validated by dilution

with the external phase.

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• Various other techniques used to characterize emulsions like

coulter counter, freeze-fracture electron microscopy and scanning

electron microscopy and are also used to determine average

globule size and size distribution of multiple emulsions droplets.

Number of globules

• Number of globules per cubic millimeter can be measured using

a haemocytometer cell after approriate dilution of the multiple

emulsions.

• The globules in five groups of 16 small squares (total 80 small

squares) can be counted and the total number of globules in per

cubic mm is calculated using the formula

No . of Globules/mm3 =No . of globules x Dilution x 4000

No . of small squares counted

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Percentage Drug Entrapment:

• Percent entrapment of drug or active moiety in the multiple

emulsion is generally determined using dialysis , centrifugation,

filtration and conductivity measurements.

• However , recently an internal tracer /marker was used to

evaluate the entrapment of an impermeable marker molecule

contained in the inner aqueous phase of w/o/w emulsion.

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The % Entrapment can be calculated using the following

equation :

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Rheology : (Jim et al, 2003)

By increasing the shear rate and shear time the apparent

viscosity increased.

Further shearing caused increase in shear stress of

emulsion and induced phase inversion

Reasons of phase inversion:

Increase in volume fraction of oil droplets by

entrapment of water molecules

Coalescence of oil droplets upon shearing

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Zeta- potential

• The zeta-potential and surface charge can be calculated using

smoluchowski’s equation from the mobility and electrophoretic

velocity of dispersed globules using the zeta-potentiometer.

• The apparatus consists of cylindrically bored micro-

electrophoresis cell equipped with platinum-iridium electrodes

to measure the electrophoretic mobility of the diluted w/o/w

emulsion.

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Zeta-potential was calculated using following formula:

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In vitro stability studies

• Phase separation is a phenomenon by which one phase of

emulsion gets separated due to colescence.

• Percentage phase separation is the volume of phase in

percentage separated from the total volume of emulsion after

storage .

• 20ml of freshly prepared w/o/w emulsion is kept in 25ml of

graduated cylinder and allowed to stand for defined period at

40˚c.

• The volume of separated aqueous phase (V sep) is observed

periodically at regular intervals.

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Percent phase separation is calculated using following

formula:

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In Vitro Drug Release

• The drug released from the aqueous inner phase of a w/o/w

emulsion can be estimated using the conventional dialysis

method using a cellophane tubing.

• Typically, 5ml of (w/o/w) multiple emulsion is placed in the

dialysis tube which is then tied at both ends by thread and

placed in basket (usually 100rpm) and dialyzed against

specified dissolution media (usually 200ml) at 37±1˚C.

•Aliquots were withdrawn at different time intervals and

replaced with fresh dissolution media and estimated using

standard procedure and the data were used to calculate

cumulative drug release profile.

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Fig: Assembly use for invitro drug release.

Stability of Multiple Emulsions

Emulsion stability is a phenomenon, which depends upon theequilibrium between water, oil and surfactant.

Unfortunately multiple emulsions are thermodynamically unstable.

The possible indications of instability includes:

Leakage of the contents from the inner aqueous phase.

Expulsion of internal droplets in external phase.

Constriction or distension of the internal droplets due toosmotic gradient across the oil membrane.

Flocculation of internal aqueous phase and multiple emulsion droplets.

Disruption of oil layer on the surface of internal droplets. Phase separation.

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Methods to Stabilize Multiple

Emulsions The followings are some of the attempt or studies made to restore or strengthen the stability of multiple emulsions :

Liquid crystal stabilized multiple emulsion.

Stabilization in presence of electrolytes.

Stabilization by forming polymeric gel.

Stabilization by interfacial complexation between non- ionic surfactant and macromolecules.

Steric stabilization

Phase-inversion stabilization of W/O/W emulsion

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Fig; Various approaches to stabilize w/o/w multiple emulsion.

A-stabilizing through liquid crystal formation

B-stabilization by interfacial polymerization

C-stabilization by adsorption of electrolyte or adsorption or covalent

anchoring of polymer

D-gelation of either internal or external phase or oil core

Applications in Therapeutics & Cosmetics:

Multiple emulsion systems are finding unlimited

uses because of their vesicular structure with

innermost phase closely similar to that of

liposomal vesicles and the selective permeability

characteristic of liquid membrane.

In cancer therapy.

In herbal drugs.

In taste masking.

In food industry.

In drug over dosage treatment.

In inverse targeting.

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APPLICATIONS

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• Micro emulsion properties are extremely varied. The extreme diversity of their practical applications is one consequence.

One of their disadvantages is the large amount of surfactant required to stabilize them because of the small dispersion size.

Although micro emulsion properties are beginning to be satisfactorily understood, especially the droplet structure, large research domains remain to be clarified.

With evaluation of newer techniques of preparation, stabilization, rheological properties can serves as potential carrier for drugs ,cosmetics ,pharmaceutical agents

CONCLUSION

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Multiple emulsions are complex polydispersed systems

where both oil in water and water in oil emulsion exists

simultaneously which are stabilized by lipophillic and

hydrophilic surfactants respectively.

The ratio of these surfactants is important in achieving

stable multiple emulsions. Among water-in-oil-in-water

(w/o/w) and oil-in-water-in-oil (o/w/o) type multiple

emulsions; the former has wider areas of applications.

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Multiple emulsions have also been employed as intermediate

step in the microencapsulation process and are the systems of

increasing interest for the oral delivery of hydrophilic drugs,

which are unstable in gastrointestinal tract like proteins and

peptides.

With the advancement in techniques for preparation,

stabilization and rheological characterization of multiple

emulsions, it will be able to provide a novel carrier system for

drugs, cosmetics and pharmaceutical

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delivery: novel carrier systems , 1st ed. New Delhi: CBS

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Micro emulsions as drug delivery system,A.N

Lalwani,T.J shah&N.S Parmar-309

Targeted &Controlled Drug delivery vyas/khar-303

Progress in controlled and novel drug delivery system-nk

jain

Advance in controlled &drug delivery A.j khapae&N.K

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page no-745

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6th ed. Page no- 410

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REFERENCES

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