EMULSIONS Karunya Kandimalla, Ph.D. Karunya.kandmalla@famu.edu 228 Dyson Pharmacy Building

A thermodynamically unstable system consisting of at least two immiscible liquid phases- an oil phase (dispersed phase) and a liquid phase (continuous phase) stabilized by an emulsifying agent. Emulsified systems could range from lotions of low viscosity to ointments, creams which are semi-solids Particle diameter 0.1- 10um In some cases 0.01-100um 2 Types o/w and w/o Medicinal emulsions are mostly o/w type Butter, salad dressings etc. are w/o emulsions

Determination of Emulsion Type   Methylene Blue or Brilliant blue FCF may be dusted on surface of an emulsion In case of o/w emulsion- dye will dissolve and uniformly diffuse through the water  In case of w/o emulsion- particles of dye will lie in clumps on the surface Dilute the emulsion with water  If emulsion mixes freely with water- o/w type Electrodes connected to external electric source and immersed in the emulsion  If the external phase is water, a current will pass through the emulsion and can be made to deflect the voltmeter reading. If oil is the continuous phase-no current flow

Emulsion Preparation Continental or Dry Gum Method   Continental or Dry Gum Method In continental method, emulsifying agent is mixed with the oil before addition of water English or Wet gum Method In English method, emulsifying agent is added to the water to form a mucilage and then the oil is slowly incorporated. Forbes Bottle Method Bottle method is reserved for volatile oils and is variation of continental method.  

Classification of Emulsifying Agents Natural- Animal origin wool fat. Egg yolk, gelatin, cholesterol, pectin, chondrus Plant origin- Acacia, Tracaganth. All these are hydrophilic colloids and form o/w emulsions. Tracaganth and agar are used as thickening agents. Gelatin, egg yolk and casein are protein in nature but emulsions (o/w) formed by them are too fluid in nature. These form monomolecular(lecithin, cholesterol) and multimolecular films(acacia, gelatin).   Synthetic Emulsifying Agents Surface active agents: can be anionic, cationic, non-ionic. These agents contain both hydrophilic and lipophilic groups with the lipophilic portion of the molecule accounting for the surface activity of the molecule. Anionic-lipophilic portion is negatively charged, sodium stearate, sodium lauryl sulphate Cationic- lipophilic portion is positively charged, Benzalkonium chloride Non-ionic- these agents do not ionize E.g. Sorbitan Fatty acid esters (Spans), Polyoxyethylene sorbitan fatty acid esters (Tweens) High molecular weight alcohols like stearyl alcohol, cetyl alcohol and glyceryl monostearate. These are mostly used as thickening agents and stabilizers for o/w emulsions. Cholesterol may also be used and promotes w/o emulsions. Finely divided solids such as colloidal clays including Bentonite, magnesium hydroxide and aluminium hydroxide. These form o/w emulsions.

Mechanisms of emulsion formation Formation of Monomolecular films Oil droplets are surrounded by a coherent monolayer of the surfactant which prevents coalescence. If the emulsifier is ionized, the presence of strong charge may lead to repulsion in droplets and hence increasing stability. Formation of Multimolecular films Formation of Solid particle films

THEORIES OF EMULSIFICATION  SURFACE TENSION THEORY  A drop of liquid forms a spherical shape which gives it the smallest surface area per unit volume Coalescence: 2 drops come together to form a bigger drop- gives lesser surface area. Also called surface tension at air-liquid interface   Surface Tension- Force that has to be applied parallel to the surface of liquid to counterbalance exactly the internal inward forces that tend to pull the molecule together. When there are two immiscible liquids-it is called interfacial tension Interfacial Tension: Lowering interfacial tension is one way to decrease the free surface energy associated with the formation of droplets. Assuming the droplets are spherical, ΔF= 6 γV D V= volume of the dispersed phase in ml, d is the mean diameter of the particles. γ = interfacial tension It is desirable that: The surface tension be reduced below 10dynes/cm by the emulsifier and Be absorbed quickly around the dispersed drops as a condensed non-adherent film that will prevent coalescence.

Oriented Wedge theory:   This theory deals with formation of monomolecular layers of emulsifying agent curved around a droplet of the internal phase of the emulsion Example: In a system containing 2 immiscible liquids, emulsifying agent would be preferentially soluble in one of the phases and would be embedded in that phase. Hence an emulsifying agent having a greater hydrophilic character will promote o/w emulsion and vice-versa. Sodium oleate is dispersed in water and not oil. It forms a film which is wetted by water than by oil. This leads the film to curve so that it encloses globules of oil in water. Sodium Oleate Zinc Oleate

Bancroft Rule: The phase (oil or water) in which the emulsifier is the more soluble tends to be the external phase of the emulsion. –

Example Solubility Emulsion type Acacia Water O/W Gelatin Na stearate Ca stearate oil W/O Tween 80 Span 80

- The diameter of the dispersed particles is 100A – 1000A Microemulsions -        Appear as clear transparent solutions -        However, they represent a state intermediate between thermodynamically stable solubilized solutions and ordinary emulsions, which are relatively unstable.      Microemulsions are O/W or W/O systems which are stabilized with addition of surfactants -         The diameter of the dispersed particles is 100A – 1000A -         Hydrophilic surfactants may be used to produce O/W emulsions of oils like vitamin A, D, E. o      HLB = 15-18 Ex. Polysorbate 60 -         I.V. administration of emulsions o      Droplets are taken up by the cells of the reticuloendothelial system in particular macrophages. The rate of clearance increases as droplet size increases or surface charge increases. o      Therefore, emulsions stabilized by a non-ionic surfactant (zero surface charge) were cleared more slowly than droplets stabilized by negative surfactants.

Multiple Emulsions -        Dispersed phase in these emulsions contain even smaller droplets that are miscible with the continuous phase.   -        Thus, emulsions of O/W/O, W/O/W may be formed -        In these systems, both hydrophobic and hydrophilic emulsifiers are used o     O/W/O – are formed better by lipophilic, nonionic surfactants using gum acacia-emulsified simple systems o     W/O/W – are formed better by nonionic surfactants in a two-stage emulsification procedure. -        Potential uses include: o     Prolonged action o     Taste-masking o     More effective dosage forms o     Improved stability o     Parenteral preparations o     Enzyme entrapment o     Separate two incompatible hydrophilic substances.

Theory of Sedimentation   Stoke’s Law is used to explain velocity of sedimentation V= d2 (ps-po)g 18o V= terminal velocity in cm/sec d= diameter of particles in cm Ps and Po= densities of dispersed phase and dispersion medium o= viscosity of dispersion medium in poise concentration of solids should be between 2g-0.5g/100ml In case of concentrated preparations, stokes equation can be modified as : v’= v∊n v’= rate of fall at the interface in cm/sec v= velocity of sedimentation as per stokes law ∊= initial porosity of the system Exponent n= measure of the hindering of the system

Creaming of Emulsions Stability of Emulsions Physical and chemical stability of Emulsions is very important.Physical stability issue with emulsions are very important. Some of these are:  1.   The upward or downward movement of dispersed droplets which is also termed as creaming or sedimentation. 2.   The aggregation or coalescence of the dispersed droplets to reform the separate bulk phases. In aggregation dispersed droplets come together but do not fuse. Coalescence is the complete fusion of droplets. 3. Miscellaneous Physical and chemical change 4.   Inversion of emulsion in which o/w emulsion becomes w/o and vice-versa  Creaming of Emulsions

Creaming is called the upward movement of dispersed droplets relative to the continuous phase. Sedimentation Is the reverse process. If the density of the internal phase is less than that of the external phase, upward creaming and vice versa.

How to Overcome Creaming If there is no coalescence, it is a reversible process. Several techniques are:   A.     Reduction of particle size by homogenization. In most cases particle size cannot be reduced below 0.1um. B.     Raise the viscosity of the external phase. The limitation here is that the viscosity should not be increased so much that the emulsion is not pourable. Various agents used here are, methylcellulose, tracaganth or sodium alginate. C.     By lowering the density difference between the internal phase and external phase to be minimal (Stokes Law). D.     Sometimes molds, yeasts, bacteria can bring about decomposition of emulsifying agent of an emulsion. Hence preservatives like methyl Paraben or Propyl Paraben should be incorporated in emulsion system. To use a combination of emulsifiers which allow a more elastic interfacial film which can resist emulsion breakage. Also when emulsifiers re mixed in certain concentrations, Liquid crystals are formed which have greater stability against coalescence.

Inversion of Emulsions   Inversion can be brought about by the addition of an electrolyte or by changing the phase-volume ratio. Example: o/w emulsion with sodium stearate as the emulsifier can be inverted by adding calcium chloride because calcium stearate formed is a lipophillic emulsifier and favors the formation of w/o emulsion. To avoid inversion, the volume of the dispersed phase should not exceed 50% of the total volume of emulsion. Most stable medicinal emulsions are formed with a volume ratio of 50 parts oil and 50 parts water. If one attempts to incorporate more than 74% of the oil in a o/w emulsion, it will lead to coalescence and the emulsion will break.

Radiopague agents for diagnostic purposes Applications of Emulsions Radiopague agents for diagnostic purposes Intravenous nutrition (maintenance of debilitated patients)- Intralipid, Nutralipid. Fluorocarbon Emulsions- fluorocarbons have high capacities for dissolving gases like O2 and CO2 and serve as blood substitutes for a short period of time Sustained release emulsions – W/O emulsions used in administration of vaccines (Freund’s Adjuvants). Administering water insoluble liquids orally as O/W emulsion to reduce unpleasant taste, increase absorption e.g. oil soluble vitamins. 6. Pharmaceutical and cosmetic products for external use, e.g. dermatological and cosmetic lotions and creams.