Emulsions PDF

EMULSIONS Prof Thiru Govender Discipline of Pharmaceutical Sciences Definition Two immiscible liquids, one of which is finely subdivided and uniformly distributed as droplets throughout the other. The system is stabilized by the presence of an emulsifying agent. Emulsion Ty...

EMULSIONS Prof Thiru Govender Discipline of Pharmaceutical Sciences Definition Two immiscible liquids, one of which is finely subdivided and uniformly distributed as droplets throughout the other. The system is stabilized by the presence of an emulsifying agent. Emulsion Types Pharmaceutical emulsions → mixtures of an aqueous phase with various oils and/or waxes: — o/w: oil droplets dispersed throughout the aqueous phase — w/o: water is dispersed throughout the oil phase — w/o/w: water droplet enclosed in larger oil droplet which itself dispersed in water Test for Identification of Emulsion Type ž To distinguish between o/w and w/o emulsion, the following are done: — Miscibility tests with oil or water → emulsion is miscible with liquids that are miscible with its continuous phase. — Conductivity measurements → systems with aqueous continuous phases will readily conduct electricity whilst systems with oily continuous phases will not. — Staining tests → water soluble and oil soluble dyes are used, 1of which will dissolve in and colour the continuous phase. Choice of Emulsion Type ž Fats or oils for oral use → used either as medicaments or as vehicles for oil soluble drugs can be formulated as oil in water emulsions. (Are pleasant to take - flavour in aqueous phase masks the unpleasant taste). ž Emulsions for IV administration → must be o/w type (IM injection can be formulated as w/o products if H2O soluble drug required for depot therapy). ž Emulsions are most widely used for external application. ž Semi solid emulsions include creams, lotions, liniments. ž Both o/w and w/o types are available — o/w: Used for Topical use of H2O soluble drug for local effect. Is easily washed from skin. — w/o: Used for Occlusive effect - hydrating upper layers of stratum corneum. Useful for cleansing skin of oil soluble dirt. Moisturizing creams to prevent moisture loss from skin - formulated as w/o emulsion. Emulsion Consistency ž Ideally, emulsions should exhibit rheological properties of plasticity/ pseudoplasticity and thixotropy. ž NB that these products flow freely during agitation, pouring from the container or injecting through needle. Therefore, high rates of shear and lower apparent viscosity is required. ž For externally applied product -can have range of emulsion consistencies. Several ways to control rheological properties: 1. Volume Concentration of Dispersed Phase: — As [ ] of dispersed phase ↑, viscosity of product ↑ — dispersed phase [ ] must not exceed 60% → since phase inversion may occur. 2. Particle Size of Dispersed Phase — Possible to ↑ viscosity by ↓ mean globule diameter by homogenization 3. Viscosity of Continuous Phase — Direct relationship between viscosity of emulsion and viscosity of continuous phase. 4. Viscosity of Dispersed Phase — Doubtful whether it effects viscosity.  Choice of Oil Phase Often oil phase of emulsion is the active agent. Therefore [ ] in product is predetermined e.g. liquid paraffin, castor oil, cod liver oil and arachis oil are examples of medicaments used as emulsions for oral administration. Then & Now ž Oils also used as a carrier for active agent – may affect viscosity of product and transport of active e.g. liquid paraffin. ž Can be used with other hydrocarbons e.g. hard paraffin, soft paraffin and light liquid paraffin to control consistency. Product must be spread easily but sufficiently viscous to form coherent film over skin. ž Film forming properties further modified by including waxes e.g. beeswax, carnauba wax or higher fatty alcohols. ž Fixed oils of vegetable origin also used e.g. arachis, sesame, cotton seed and maize oils.  Emulsifying Agents ž Selection is NB to facilitate actual emulsification during manufacture and also to ensure emulsion stability during shelf life of product. Emulsifier prevents separation. ž Exert emulsifying ability by forming an adsorbed film around the dispersed droplets between the two phases. Choice of Emulsifying Agent ž Choice depends on emulsifying ability, route of administration and also toxicity. ž Approved emulsifiers include naturally occurring materials and semi-synthetic derivatives e.g. polysaccharides, glycerol esters, cellulose ethers, sorbitan esters and polysorbates. — less nontoxic, non irritant than anionic and cationic ones. ž Ionic emulsifying agents should not be used orally due to GI irritant effect and laxative effect. Examples 1. Synthetic & semisynthetic surface active agents ž Anionic surfactants — → Amine soaps(triethanol amine), alkali metal and ammonium soaps (sodium stearate) ž Cationic surfactants — → Cetrimide ž Nonionic surfactants — → Polyethylene glycols ž Amphoteric surfactants — → Lecithin 2. Naturally occurring materials & their derivatives ž (disadvantage: batch to batch variation and susceptible to bacterial/ mould growth) — → polysaccharides, beeswax, wool fat (lanolin) 3. Finely divided solids — → Bentonite and colloidal silicon dioxide Formulation by the HLB Method Hydrophile-lipophile balance (HLB) Useful method for calculating quantities of emulgents necessary to form physically stable emulsion. * if a mixture of oils, fats waxes is used in a formulation, the total HLB can be calculated. Example of o/w emulsion: Liquid paraffin 35% Wool fat 1% OILS Cetyl alcohol 1% Emulsifier system 5% Water to 100% Total % of oil = 37%, therefore proportion of each = Liquid paraffin 35/37 X 100 = 94.6% Wool fat 1/ 37 X 100 = 2.7% Cetyl alcohol 1/37 X 100 = 2.7%  Standard values The total required HLB number: found in references Liquid paraffin (12) 94.6/ 100 x 12 = 11.4 Wool fat (10) 2.7/ 100 x 10 = 0.3 Cetyl alcohol (15) 2.7/ 100 x 15 = 0.4 12.1 Therefore requires emulgent with HLB value of 12 for stable emulsion. Can use blends.  e.g. assume a blend of sorbitan mon-oleate (HLB 4.3) and polyoxyethylene sorbitan monoleate (HLB 15) is used to provide HLB of 12, amount required are as follows: Let A = % [ ] of the hydrophilic and B = % [ ] of the hydrophobic surfactants required to give a blend having an HLB value of x, then: A = 100 (X - HLB of B) and B = 100 – A HLB of A – HLB of B Therefore, A = 100 (12.1 - 4.3) = 72.9% 15 - 4.3 B = 100 - 72.9 = 27.1% Since the total % of emulgent blend = 5%, then % of each emulsifier = Sorbiton mono-oleate = 5 x 27.1/100 = 1.36% Polyoxyethylene sorbitan Mono-oleate = 5 – 1.36 = 3.64% The formula for the o/w emulsion now becomes: Liquid paraffin 35% Wool fat 1% Cetyl alcohol 1% Sorbiton mono-oleate 1.36% Polyoxyethylene sorbitan Mono-oleate 3.64% Water to 100%  Other Formulation Additives Antioxidants Efficiency of antioxidant in product depends on: - Compatibility with other ingredients - Oil/water partition coefficient - Extent of solubilization within micelles - Sorption onto container ž Choice / concentration of antioxidant determined by testing effectiveness in the final product e.g. butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) Humectants Added to reduce the evaporation of water from packaged product when closure is removed or from surface of skin e.g. propylene glycol, glycerol and sorbitol Preservatives Desirable features of preservatives for use in emulsions 1. Wide spectrum of activity against all bacteria, yeasts and moulds. 2. Must have bactericidal rather than bacteriostatic activity. 3. Freedom from toxic, irritant or sensitizing activity. 4. High water solubility.  5. Stability and effectiveness over a wide pH range and temperature. 6. Compatibility with other ingredients within container. 7. Retention of activity in the presence of large numbers of microorganisms. Examples of preservatives: — Organic acids and their salts e.g. benzoic acid. — Also chlorocresol, parahydroxybenzoic acid, phenylmercuric nitrate. Stability of Emulsions Stable when dispersed globules retain their initial character and remain uniformly distributed throughout the continuous phase. 1. Creaming and its Avoidance — Is separation of emulsion into two regions one of which is richer in the disperse phase than the other. — Uniform dispersion can be re-obtained simply by shaking the emulsion. — Still not desirable because emulsion is inelegant, risk of incorrect dosage if not shaken properly. To avoid creaming: — Produce emulsion of small droplet size: efficient emulsifying agent not only stabilize emulsion but also gives fine globule size. — ↑ viscosity of the continuous phase. — Many auxiliary emulsifying agents e.g. methylcellulose ↑ viscosity and ↓ mobility of dispersed droplets in o/w emulsion. — Reduce density difference between the 2 phases. — Control disperse phase concentration. — A higher disperse phase [ ] would result in hindrance of movement of the droplets and therefore ↓ rate of creaming. However > 60%- phase inversion occurs 2. Flocculation prevention — Involves aggregation of dispersed globules into loose clusters within the emulsion. Individual droplets retain their identities but each cluster behaves as a single unit. — Flocculation precedes coalescence, but redispersion achieved by shaking. — High charge density on droplets can ↓ flocculation. 3. Coalescence — Resisted by presence of mechanically strong adsorbed layers of emulsifier around each globule.  Manufacture of Emulsions Simple blending of oil and water phases with suitable emulgent system is sufficient. Blending: Mortar and Pestle or Turbine mixer – for intense shearing Homogeniser can be used to ↓ globule size further. Dispersed phase is added to continuous phase. Other ingredients dissolved prior to mixing, in phase which they are soluble.  Oily ingredients (solid/semisolid) must be melted. Aqueous phase → is heated to same temperature as oil phase to avoid premature solidification of oil phase by cold H2O before emulsification has taken place. Because of ↑ kinetic motion of emulgent molecules at oil/water interface → must continue stirring during cooling to avoid demulsification. Volatile ingredients (flavours/perfumes) → added after emulsion has cooled.  Stability Testing of Emulsions Macroscopic examination: Physical stability can be assessed by examining degree of creaming/ coalescence. Determined by calculating ratio of volume of the creamed or separated part of emulsion and total volume & comparing these values for different products. Globule Size Analysis: Size can ↑ with time -due to coalescence. Technique used for size measurement = Coulter counter/ Laser diffraction sizing.  Viscosity Changes: Variation in globule size, orientation or migration of emulsifier over period of time may be detected by change in apparent viscosity. Rheometers used to measure viscosity. pH, colour, taste & odour to be assessed. Assay of active by HPLC.