University of Sulaimani School of Pharmacy Dept. of Pharmaceutics Third level - Second semester Coarse dispersion, emulsions 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 1 Outlines • Introduction • Theories and mechanisms • Emulsifying agents • HLB system • Methods of emulsion preparation • Microemulsion • Stability of emulsions • Common features and differences 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 2 Introduction • An emulsion is a dispersion in which the dispersed phase is composed of small globules of a liquid distributed throughout a vehicle in which it is immiscible. • Depending on external and internal phase, emulsions are either water in oil (w/o) or oil in water (o/w) type. • The third phase of an emulsion is the emulsifying agent • Can we dilute emulsion? water Emulsifier W/O O/W Oil 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 3 Introduction cont. • Based on the constituents and the intended application, liquid emulsions may be employed orally, topically (sometime semisolid), or parenterally. • Advantages of emulsion • Preparation of relatively stable and homogeneous mixtures of two immiscible liquids • The o/w type permits palatable administration of distasteful oil. • The reduced particle size of the oil globules may render the oil more digestible and more readily absorbed 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 4 Outlines • Introduction • Theories and mechanisms • Emulsifying agents • HLB system • Methods of emulsion preparation • Microemulsion • Stability of emulsions • Common features and differences 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 5 Theories and mechanisms 1. Surface tension theory • All liquids have a tendency to assume a shape having the minimal surface area exposed i.e. sphere. • If two or more drops of the same liquid come into contact with one another, making one larger drop having a smaller surface area i.e. coalescence . • ΔG = γ * ΔΑ • The force causing each liquid to resist breaking up into smaller particles is called interfacial tension. 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 6 Theories and mechanisms cont. • Substances that reduce this resistance (encourage a liquid to break up into smaller drops or particles) is called surface-active (surfactant) or wetting agents. 2. The oriented-wedge theory • It assumes monomolecular layers of emulsifying agent curved around a droplet of the internal phase of the emulsion. • The phase in which the emulsifying agent is more soluble will become the continuous or external phase • An emulsifying agent having a greater hydrophilic than hydrophobic character will promote an o/w emulsion. 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 7 Theories and mechanisms cont. Film type Example Mechanism A. Monomolecular Synthetic like, • The film is flexible. Potassium laurate • They lower the interfacial tension, and thus Tween contributes to stability of emulsion. B. Multimolecular Natural like • The film is strong and rigid film formed Acacia, Gelatine • The Interfacial tension is not reduced. C. Solid particles Bentonite • Film formed by solid particles that are small in size Magnesium hydroxide compared to the dispersed droplet. • Particles must be wetted by both phases to some extent. 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 8 Outlines • Introduction • Theories and mechanisms • Emulsifying agents • HLB system • Methods of emulsion preparation • Microemulsion • Stability of emulsions • Common features and differences 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 9 Emulsifying agents • Features of emulsifying agents • The emulsifying agent must be compatible with the other ingredients • It should be stable • It should be non toxic and possess a little color, odor, and taste. • It should be surface active and decrease interfacial tension • It should be effective in a fairly low concentration 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 10 Emulsifying agents 1. Carbohydrate materials like acacia, tragacanth, agar, and pectin generally produce o/w emulsions. • Tragacanth and agar are commonly employed as thickening agents in acacia- emulsified products • Needs addition of 0.2% of benzoic acid. 2. High molecular weight alcohols, such as stearyl alcohol, cetyl alcohol, and glyceryl monostearate. • Usually they are used externally • Cholesterol is used to promote w/o emulsions. 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 11 Emulsifying agents cont. 3. Wetting agents, which may be anionic, cationic, or nonionic • These agents contain both hydrophilic and lipophilic groups • Anionic emulsifiers include various monovalent, polyvalent, like sodium lauryl sulfate • Benzalkonium chloride is an example for cationic emulsifier • Agents of the nonionic type include the sorbitan esters and the polyoxyethylene derivatives, • Cationic surfactants are effective over pH range of 3 to 7, and anionic surfactants require a pH greater than 8. 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 12 Emulsifying agents cont. 4. Finely divided solids such as colloidal clays, including bentonite, magnesium hydroxide, and aluminum hydroxide • Inversion • Is changing of emulsion from o/w to w/o as a result of increased internal phase. • Maximum limit of the internal phase is 75%. 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 13 Outlines • Introduction • Theories and mechanisms • Emulsifying agents • HLB system • Methods of emulsion preparation • Microemulsion • Stability of emulsions • Common features and differences 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 14 HLB system • Emulsifying agent has a hydrophilic portion and a lipophilic portion, predominance of each portion is influence the type of emulsion. • Emulsifying agent could be categorized on the base of their hydrophilic-liphophilic balance HLB system. • The usual range is between 1 and 20. • Higher polarity → higher the value • Agents with HLB value of 3 to 6 are greatly lipophilic and produce w/o emulsions • Agents with HLB values of about 8 to 18 produce o/w emulsions. 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 15 HLB system cont. Emulsifier HLB value 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 16 Outlines • Introduction • Theories and mechanisms • Emulsifying agents • HLB system • Methods of emulsion preparation • Microemulsion • Stability of emulsions • Common features and differences 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 17 Methods of emulsion preparation • On a small scale, emulsions may be prepared using porcelain mortar and pestle. • The product may be rendered finer by passage through a colloid mill. 1. Continental or dry gum method Ratios of Oil: Water: Emulsifier Fixed oils except liquid Linseed oil, liquid Emulsifying agent petrolatum and linseed oil petrolatum and volatile oils Acacia 4:2:1 3:2:1 or 2:2:1 Tragacanth 40:20:1 30:20:1 or 20:20:1 • The acacia or other o/w emulsifier is triturated with the oil in a dry porcelain (better than glass) mortar until thoroughly mixed. • After oil-gum mixing, the two parts of water are added all at once, and the mixture is triturated immediately → primary emulsion produces a crackling sound (3 min). • Solution of other ingredients is added into the primary emulsion. 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 18 Methods of emulsion preparation cont. 2. English or wet gum method • Same proportions of oil, water, and gum are used as in dry gum method. • The order of mixing is different. • water+acacia trituration → add oil slowly. 3. Bottle method • It is used for volatile oils or less viscous oils. • (1 acacia+ 2 oil)→ shaking in a capped bottle. Then adding water equal to the oil. Auxiliary • Homogenizer → 5 μm 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 19 Methods of emulsion preparation cont. 4. In situ soap method • This method includes calcium soaps and soft soaps. • Calcium soaps are w/o emulsions that contain certain vegetable oils, such as oleic acid, in combination with limewater (Calcium Hydroxide Solution, USP). • They are prepared by mixing equal volumes of the oil and limewater. 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 20 Outlines • Introduction • Theories and mechanisms • Emulsifying agents • HLB system • Methods of emulsion preparation • Microemulsion • Stability of emulsions • Common features and differences 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 21 Microemulsion • They are thermodynamically stable, optically transparent mixtures of a biphasic o/w system stabilized with surfactants. • Droplet size 10-100 nm. • The surfactant is commonly called solubilizing agent. • Advantages • More rapid and efficient oral absorption of drugs • Enhanced transdermal drug delivery through increased diffusion into the skin. • Development of artificial red blood cells and targeting of cytotoxic drugs to cancer cells 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 22 Outlines • Introduction • Theories and mechanisms • Emulsifying agents • HLB system • Methods of emulsion preparation • Microemulsion • Stability of emulsions • Common features and differences 4/30/2017 Pharmaceutical Compounding, Dr. rer. nat. Rebaz Ali 23 Stability of emulsions • Freezing and excessive heat coarsen an emulsion and sometimes break it. • Fungistatic preservatives, commonly combinations of methylparaben