Emulsion suitable for intravenous injection Balm Water in

Emulsion suitable for intravenous injection. Balm: Water in oil emulsion Dodecane droplets in a continuous phase of water/glycerol mixture. Emulsions Sodas: Oil in Water emulsion Mayonnaise: Oil in Water emulsion Milk: Oil in Water emulsion

Emulsion – Dispersion of liquid droplets (dispersed phase) of certain size within a second immiscible liquid (continuous phase). Classification of emulsions - Based on dispersed phase Oil in Water (O/W): Oil droplets dispersed in water Water in Oil (W/O): Water droplets dispersed in oil Water in Oil in water (W/O/W): Water in Oil emulsion dispersed in water – multiple emulsion - Based on size of liquid droplets 0. 2 – 50 mm Macroemulsions 0. 01 – 0. 2 mm Microemulsions

Advantages • Administration of Distasteful oil, mask the unpleasant taste • Better and faster absorption • Less irritation to the skin • Sustained release medication • Nutritional supplement • Diagnostic purposes

Emulsions encountered in everyday life! Pesticide Asphalt Skin cream Ice cream Metal cutting oils Margarine Stability of emulsions may be engineered to vary from seconds to years depending on application

Emulsifying Agents Stable dispersions of liquids constituting the dispersed phase, in an immiscible liquid constituting the continuous phase is brought about using emulsifying agents such as Carbohydrates: acacia, tragacanth, agar, chondrus and pectin Proteins: gelatin, egg yolk and casein High mol wt alcohols: stearyl alcohol, cetyl alcohol, glycery monostearate, cholesterol – w/o stabilisers Surfactants: SPAN, TWEEN, organic soaps ( triethanolamine oleate), Non ionic- p. H 3 -10, cationic – 3 -7, anionic- greater than 8

Common Emulsifying Agents Surfactants Anionic – Sodium stearate, Potassium laurate Sodium dodecyl sulfate, Sodium sulfosuccinate Nonionic – Polyglycol, Fatty acid esters, Lecithin Cationic – Quaternary ammonium salts, Finely divided Solids Finely divided solids with amphiphilic properties such as silica and clay, may also act as emulsifying agents Others: bentonite, magnesium hydroxide, Al(OH)3

Tests for Emulsion Type (W/O or O/W emulsions) Based on the Bancroft’s rule, many emulsion properties are governed by the properties of the continuous phase 1. 2. 3. 4. Dye test Dilution test Electrical conductivity measurements Filter paper test

Thermodynamic instability • ∆G=Ὺ. ∆A • Increase in the surface free energy = interfacial tension X increased surface area

Mechanism of emulsification • Monomolecular theory Surfactants • Reduce interfacial tension • Forms a protective film around globule • Ionic surfactant exert repulsion between globules

Mechanism Multimolecular theory • Hydrocolloids form multimolecular physical barrier around globules there by prevent coalescence of oil globules • Acacia, gelatin Solid particle adsorption theory

Physical Instability Creaming: Concentration of globules at the top or bottom of emulsion. Reversible process but leads to breaking Influenced by: Stoke’s equation V = h = d 2 st (ρs–ρo) g t 18ηo -globule size -Viscosity of dispersion medium -Difference in the densities of dispersed and dispersion medium

Creaming of Emulsions Droplets larger than 1 mm may settle preferentially to the top or the bottom under gravitational forces. Creaming is an instability but not as serious as coalescence or breaking of emulsion Probability of creaming can be reduced if a - droplet radius, Δρ - density difference, g - gravitational constant, H - height of the vessel, Creaming can be prevented by homogenization. Also by reducing Δρ, creaming may be prevented.

Creaming can be reduced/prevented by • Reducing the globule size by homogenization • Increasing the viscosity of dispersion medium • Reducing the difference in densities

Coalescence Separation of two phases due to fusion of globules. Also called cracking of emulsion. Irreversible process. Sheath of EA around globules is lost. Creaming leads to breaking- globules comes nearer Breaking of emulsion is observed due to: Insufficient amount of EA Incompatibility between EA Alteration in the properties of EA

Inversion of Emulsions (Phase inversion) O/W W/O 1. 2. 3. The order of addition of the phases W O + emulsifier W/O O W + emulsifier O/W Nature of emulsifier Making the emulsifier more oil soluble tends to produce a W/O emulsion and vice versa. Phase volume ratio Oil/Water ratio W/O emulsion and vice versa

Inversion of Emulsions (Phase inversion) 4. Temperature of the system Temperature of O/W (polyoxyethylenated nonionic surfactant) makes the emulsifier more hydrophobic and the emulsion may invert to W/O. 5. Addition of electrolytes and other additives. Strong electrolytes to O/W (stabilized by ionic surfactants) may invert to W/O Example. Inversion of O/W emulsion (stabilized by sodium cetyl sulfate and cholesterol) to a W/O type upon addition of polyvalent Ca.

W/O vs. O/W emulsions Bancroft's rule Emulsion type depends more on the nature of the emulsifying agent than on the relative proportions of oil or water present or the methodology of preparing emulsion. The phase in which an emulsifier is more soluble constitutes the continuous phase In O/W emulsions – emulsifying agents are more soluble in water than in oil (High HLB surfactants). In W/O emulsions – emulsifying agents are more soluble in oil than in water (Low HLB surfactants).

Emulsions Rate of coalescence – measure of emulsion stability. It depends on: (a) Physical nature of the interfacial surfactant film For Mechanical stability, surfactant films are characterized by strong lateral intermolecular forces and high elasticity Mixed surfactant system preferred over single surfactant. (Lauryl alcohol + Sodium lauryl sulfate: hydrophobic interactions) combination of SPAN and TWEEN

Emulsions (b) Electrical or steric barrier Significant only in O/W emulsions. In case of non-ionic emulsifying agents, charge may arise due to (i) adsorption of ions from the aqueous phase or (ii) contact charging (phase with higher dielectric constant is charged positively) No correlation between droplet charge and emulsion stability in W/O emulsions Steric barrier – dehydration and change in hydrocarbon chain conformation.

Emulsions (c) Viscosity of the continuous phase Higher viscosity reduces the diffusion coefficient Stoke-Einstein’s Equation This results in reduced frequency of collision and therefore lower coalescence. Viscosity may be increased by adding natural or synthetic thickening agents. Further, as the no. of droplets (many emulsion are more stable in concentrated form than when diluted. )

Emulsions (d) Size distribution of droplets Emulsion with a fairly uniform size distribution is more stable than with the same average droplet size but having a wider size distribution (e) Phase volume ratio As volume of dispersed phase stability of emulsion (eventually phase inversion can occur) (f) Temperature , usually emulsion stability Temp affects – Interfacial tension, D, solubility of surfactant, Brownian motion, viscosity of liquid, phases of interfacial film.

Preparation of emulsion Dry gum method Wet gum method Bottle method

Selection of Emulsifiers Correlation between chemical structure of surfactants and their emulsifying power is complicated because (i) Both phases oil and water are of variable compositions. (ii) Surfactant conc. determines emulsifier power as well as the type of emulsion. Basic requirements: 1. Good surface activity 2. Ability to form a condensed interfacial film 3. Appropriate diffusion rate (to interface)

General Guidelines: 1. Type of emulsion determined by the phase in which emulsifier is placed. 2. Emulsifying agents that are preferentially oil soluble form W/O emulsions and vice versa. 3. More polar the oil phase, the more hydrophilic the emulsifier should be. More non-polar the oil phase more lipophilic the emulsifier should be.

General Guidelines 1. HLB method – HLB indicative of emulsification behavior. HLB 3 -6 8 -18 for W/O O/W HLB no. of a surfactant depend on which phase of the final emulsion it will become. Limitation – does not take into account the effect of temperature.

General Guidelines 2. PIT method – At phase inversion temperature, the hydrophilic and lipophilic tendencies are balanced. Phase inversion temperature of an emulsion is determined using equal amounts of oil and aqueous phase + 3 -5% surfactant. For O/W emulsion, emulsifier should yield PIT of 20 -600 C higher than the storage temperature. For W/O emulsion, PIT of 10 -400 C lower than the storage temperature is desired.

General Guidelines 3. Cohesive energy ratio (CER) method Involves matching HLB’s of oil and emulsifying agents; also molecular volumes, shapes and chemical nature. Limitation – necessary information is available only for a limited no. of compounds.