1. MULTIPLE AND MICROEMULSIONS

2. Emulsion  An emulsion is a thermodynamically unstable system consisting of at least two immiscible liquid phases one of which is dispersed as globules in the other liquid phase stabilized by a third substance called emulsifying agent.  An emulsion is a mixture of two or more immiscible (un bendable) liquids.  Emulsions are part of a more general class of two-phase systems of matter called colloids.  In an emulsion, one liquid w(the dispersed phase) is dispersed in the other (the continuous phase).

3. MICROEMULSION

4. Microemulsion 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 microemulsion is considered to be a thermodynamically or kinetically stable liquid dispersion of an oil phase and a water phase, in combination with a surfactant.

5.  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 wherein micro domains of oil and water are interdispersed within the system.  In all three types of micro emulsions, the interface is stabilized by an appropriate combination of surfactants and/or co-surfactants.

6.  The key difference between emulsions and micro emulsions are that the former, whilst they may exhibit 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 method of preparation, since emulsions require a large input of energy while micro emulsions do not.  Microemulsion formation and stability can be explained on the basis of a simplified thermodynamic rationalization.

7. Preparation Of Microemulsion Micro emulsions were prepared at 27°C by a titration method.  The drug is be dissolved in the lipophilic part of the micro emulsion i.e. Oil and the water phases can be combined with surfactant and a co-surfactant is then added at slow rate with gradual stirring until the system is transparent.  The amount of surfactant and co-surfactant 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.

8.  Oil-in-water micro emulsions were prepared by the titration method.  A mixture of fatty acid and oil was added to a caustic solution to produce a micro emulsion, which was then titrated with a co- surfactant, an alcohol, until the system turned clear.  It was found that as the chain length of the surfactant increased, micro emulsions with significant transmittances by visible spectrum could be formed with oils of longer chain lengths.  It was also found that different alcohols affected the formation of micro emulsions in different ways.  The best results, in terms of the greatest percent transmittance coupled with the widest range of oil (dispersed in water) concentration, were obtained from short or branched alcohols.

9.  The free energy of micro emulsion formation can be considered to depend on the extent to which surfactant lowers the surface tension of the oil–water interface and the 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–water interface, DA is the change in interfacial area on micro emulsification, 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 micro emulsion is formed the change in DA is very large due to the large number of very small droplets formed.

10.  Though it has been know that several factors determine whether a w/o or o/w system will be formed but in general it could be summised that the most likely microemulsion would be that in which the phase with the smaller volume fraction forms the droplets i.e. internal phase.  The surfactants used to stabilize such systems may be: (i) Non-ionic (ii) Zwitterionic (iii) Cationic (iv) Anionic surfactants

11.  Various pharmaceutically acceptable excipients availableexcipients that can be used in microemulsion formulation are:  Long chain or high molecular weight (>1000) surfactants include Gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene Sorbian 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.

12. 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 can be determined by either light scattering technique or electron microscopy. This technique has been advocated as the best method for predicting microemulsion stability.

13. 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.

14. 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.

15. Uses Micro emulsions have many commercially important uses:  Water-in-oil micro emulsions for some dry cleaningdry cleaning processes  Floor polishers and cleaners.polisherscleaners  Personal care products Personal care  Pesticide formulations Pesticide  Cutting oils. Cutting oils  Pharmaceutical applications of micro emulsions Increase bioavailability of drugs poorly soluble in water.  Topical drug delivery systems

16. Applications of microemulsions  Micro emulsions in enhanced oil recovery  Micro emulsions as fuels  Micro emulsions as coatings and textile finishing  Micro emulsions as lubricants, cutting oils and corrosion inhibitors  Micro emulsions in detergency  Micro emulsions in cosmetics  Micro emulsions in agrochemicals  Micro emulsion in pharmaceuticals

17. EQUIPMENT USED IN PREPARATION OF EMULSIONS COLLOIDAL MILL APPLICATION: 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.

18. 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.

19. 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.

20. Multiple Emulsions

21. Definition  Multiple emulsions are the emulsion system in which the dispersed phase contain smaller droplets that have the same composition as the external phase.  This is made possible by double emulsification hence the systems 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

22. 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 droplets may be surrounded in oil phase, which in true encloses one or more oil droplets.

23. 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 may be surrounded by an aqueous phase, which in turn encloses one or several water droplets.

24.  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.

25. Schematic Diagram of W/O/W & O/W/O

26. 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 10) and with a vegetable oil (caprylic/ capric triglyceride).

27. 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)

28. 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.

29. Two Steps Emulsification

30. Modified Two Steps Emulsification

31. 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).

32.  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 oil phase 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.

33. Phase Inversion Technique

34. Stability of Multiple Emulsions  Emulsion stability is a phenomenon, which depends upon the equilibrium 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 to osmotic 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.

35. 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- ionicsurfact and macromolecules. Steric stabilization Phase-inversion stabilization of W/O/W emulsion

36. 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.

37. REFERENCES MARTIN’S PHYSICAL PHARMACY REMINGTON PHARMAINFO.NET JOURNALS

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