Lecture (6) Emulsions PDF

Lecture (6) Dr. Ahmed Y. Kira Lecturer of Pharmaceutics and Pharmaceutical Technology  Definition Emulsions are biphasic heterogeneous systems consisting of two immiscible phases, one of which (the dispersed phase) is uniformly distributed as droplets througho...

Lecture (6) Dr. Ahmed Y. Kira Lecturer of Pharmaceutics and Pharmaceutical Technology  Definition Emulsions are biphasic heterogeneous systems consisting of two immiscible phases, one of which (the dispersed phase) is uniformly distributed as droplets throughout the other (the dispersion medium). Surfactant An emulsion is stabilized by the addition of an emulsifying agent. The emulsifying agent ensures that the droplets (dispersed phase) is finely dispersed throughout the dispersion medium as small globules.  Types (O/W) 1. Oil in water (O/W) emulsions: The oil (internal or dispersed) phase is dispersed as droplets throughout the water (external or continuous phase or dispersion medium). 2. Water in oil (W/O) emulsions: The internal (W/O) phase is composed of water droplets and the external phase is oil.  O/W emulsion W/O emulsion Oil is the dispersed phase and water is the Water is the dispersed phase and oil is the dispersion medium. dispersion medium. They are nongreasy and easily washed from They are greasy and not easily washed by the skin surface. water. They are used externally to provide a They are used externally to prevent cooling effect, for example, vanishing evaporation of moisture from the surface of cream. skin, for example, cold cream. Water-soluble drugs are more quickly Oil-soluble drugs are more quickly released released from O/W emulsions. from W/O emulsions. They are preferred for oral formulations as They are preferred for topical preparations the taste of oils can be masked. such as creams.  Types 3. Microemulsions They are Clear dispersions of water, oil, surfactants, and co- surfactants. The disperse phase globules are very small, ranging in diameter from 10 to 200 nm. Emulsion These emulsions appear as transparent solutions and are more stable physically as compared to ordinary emulsions. Also, compared to ordinary emulsion, microemulsions form upon simple mixing of the components and do not require the high shear conditions generally used in the formation of ordinary emulsions. Microemulsion 4. Self-emulsifying systems These are anhydrous products that when added to excess of water form emulsions spontaneously without requiring too much agitation. Following their oral administration, these systems rapidly disperse in GIT fluids, yielding microemulsions containing the solubilized drug. These systems are known as self-emulsifying drug delivery systems (SEDDS). Oral administration Circulation 5. Complex emulsions (multiple emulsions) They have been developed to delay the release of an active ingredient. W/O/W In these types of emulsions three phases are present, the emulsion has the form of w/o/w or o/w/o. In these emulsions, any drug present in the innermost layer phase must now cross two- phase boundaries to reach the external continuous phase. O/W/O  Advantages 1. The taste of oils can be masked; unpalatable oils can be administered in a palatable form. 2. The aqueous phase is easily flavored. 3. Enhance the bioavailability of poorly soluble drugs. 4. It is possible to include two incompatible ingredients, one in each phase of the emulsion. 5. Sometimes O/W emulsions of nutritive oils and fats are administered intravenously to patients who are unable to ingest food in the normal way. 6. Pharmaceutical emulsions may be prepared as liquids or semisolids (Cream).  Disadvantages 1. Calculation of primary emulsion formulae are needed for the manufacture of stable emulsions. 2. A measuring device is needed for administration. 3. Emulsions require shaking before use to ensure uniformity of dose. 4. Transportation and storage challenges. 5. Microbial contamination of emulsions can lead to emulsion breaking.  Identification of emulsion type The tests that can be performed to distinguish between O/W and W/O emulsions are given below: 1.Dilution test 2.Dye solubility test 3.Conductivity test  Dilution Test or Miscibility Test Dilute the emulsion with water or oil O/W W/O When diluted with water, emulsion is When diluted with oil, emulsion is stable stable When diluted with oil, breaking When diluted with water, breaking occurs occurs  Dye Solubility Test or Staining Test An oil-soluble dye (scarlet red) or water-soluble dye (amaranth) is added to the emulsion and observed under a microscope. O/W W/O Water-soluble dye: Water-soluble dye: Continuous phase is colored Disperse phase is colored disperse phase is colorless. continuous phase is colorless. Oil-soluble dye: Oil-soluble dye: Disperse phase is colored Continuous phase is colored continuous phase is colorless. disperse phase is colorless.  Conductivity Test Immerse a pair of electrodes in the emulsion and connect them to a bulb. O/W W/O emulsions give a positive emulsions give a negative conductivity test since the conductivity test since the external phase is water, which is a external phase is oil, which is a good conductor of electricity. poor conductor of electricity  Formulation of emulsions 1. Choice of Emulsion Type (according to the intended use) Fats or oils for oral administration are formulated as O/W emulsions. Emulsions for intravenous administration must also be of O/W type. Intramuscular injections can be formulated as W/O products if a water- soluble drug is required for depot therapy. Semisolid emulsions (Creams) for external application can be of O/W or W/O type. (For example, vanishing cream or cold cream)  Formulation of emulsions 2. Choice of Oil Phase In many instances, the oil phase of an emulsion is the active agent and its concentration in the product is predetermined. For example, castor oil, cod liver oil and arachis oil are medicaments formulated as emulsions for oral administration. Cottonseed oil, soya bean oil and sunflower oil are used in parenteral emulsions. liquid paraffin is externally applied oils.  Formulation of emulsions 3. Choice of Emulsifying Agent (Emulgent, Emulsifier) Emulsifying agents are the substances added to an emulsion to prevent the aggregation of the globules of the dispersed phase. These agents have both a hydrophilic and a lipophilic part in their structure. Emulsifying agents act in three ways; 1. Formation of a protective barrier. 2. Reduction of interfacial tension. 3. Decreasing the potential for aggregation by imparting a charge on the droplet surface (Cationic or Anionic Emulsifiers). Hydrophilic Lipophilic Balance (HLB) The HLB system is based on the balance between the hydrophilic and lipophilic portions of the surfactant. Each surfactant is allocated a HLB number, which represents the relative proportions of its lipophilic and hydrophilic portions. The values are assigned from 1 to 20 and are an indication of the polarity of the substances. Emulgents with higher numbers (8–18) indicate hydrophilic properties and produce O/W emulsions, whereas those with lower numbers (3–6) indicate lipophilic properties and produce W/O emulsions.  Emulsifying agents' classification 1. Natural emulsifying agents They are hydro-colloids, that form a protective multi-molecular layers around oil droplets. A- from vegetable source: as acacia - tragacanth- pectin. B- from animal source: such as gelatin. They are nontoxic and relatively inexpensive. However, They readily support microorganism growth. 2. Finely divided solid They form a coherent film (solid particle film) which prevents adhesion of the dispersed globules. For example: Bentonite and Mg(OH)2  3. Synthetic emulsifying agents: These are further classified into the following types: (a) Anionic emulsifying agents (b) Cationic emulsifying agents Soaps Quaternary ammonium compounds Monovalent soaps (Alkali soaps) Divalent soaps (Metallic soaps) Amine soaps Sulfated compounds (c) Nonionic emulsifying agents glycerol esters Sorbitan esters (a) Anionic emulsifying agents They are salts of long chain fatty acids such as Lauric, oleic, and stearic acid: Fatty acid + alkali → soap Soaps Monovalent soaps (Alkali soaps) E.g., sodium and potassium stearate. Used For external use Divalent soaps (Metallic soaps) E.g., Magnesium and calcium soaps Amine soaps E.g., Tri-ethanol amine oleate is less alkaline, less irritating soap. Sulfated compounds E.g., Sodium lauryl sulphate (SLS) (b) Cationic emulsifying agents They bear a positive charge on them, for example, quaternary ammonium compounds. They have emulgent properties apart from their preservative properties Examples are benzalkonium chloride, and Cetyl trimethylammonium bromide (cetrimide). Cetrimide Benzalkonium chloride (c) Nonionic emulsifying agents They do not ionize in aqueous solutions. The Span emulsion prepared is stable over a wide range of pH. Examples Spans ( Sorbitan fatty acid ester) Tweens (Poly oxyethylene Sorbitan fatty acid ester) Glyceryl monostearate(glycerol esters ) Tween Advantages: 1. Low toxicity so suitable for oral and parenteral administration. 2. High degree of compatibility. Glyceryl monostearate  Theories of emulsification 1-Mono-molecular adsorption: Surfactants reduce the interfacial tension, because of their adsorption at the oil-water interface to form monomolecular films that surround the dispersed droplets and prevent coalescence between two droplets as they approach each other. 2-Multi-molecular adsorption: Hydrophilic colloids such as acacia, form strong multi-molecular films around the droplets and render them highly resist to coalescence. Moreover, any hydrocolloid not adsorbed at the interface increases the viscosity of the continuous aqueous phase; this enhances emulsion stability. 3-Solid particle adsorption: Finely divided solid particles such as magnesium hydroxide, that are wetted to some degree by both oil and water can acts as emulsifying agents 1-Mono-molecular adsorption 2-Multi-molecular adsorption 3-Solid particle adsorption Surfactants Hydrophilic colloids Finely divided solid particles  Additives 1. Preservatives: preservative should have a low oil–water partition coefficient. Examples, parabens, organic acids such as benzoic acid, quaternary ammonium compounds such as cetrimide. 2. Antioxidants: Some oils are liable to degradation by oxidation. So, oil soluble antioxidant is added. Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT),and Tocopherol (Vit. E). 3. Emulsifying agent (emulgent): The quantity of emulsifying agent added is determined by the type of oil and the quantity of emulsion to be prepared. 4. Flavoring agent: This is used to increase the palatability of the final preparation. Examples are pineapple, orange, chocolate and mint flavors. 5. Humectant: The aim of humectants; to reduce the evaporation of water either from: the packaged product when the closure is opened or from the surface of skin after application. E.G.; Propylene glycol and Glycerol.  Preparation of emulsions The preparation of an emulsion involves two stages: 1. Preparation of the primary emulsion. 2. Dilution of the primary emulsion. Type of Oil Examples Oil water Gum acacia Fixed Oil Castor oil, Olive oil, and cod liver oil 4 2 1 Mineral Oil Liquid Paraffin 3 2 1 Volatile Oil Cinnamon oil, Peppermint oil 2 2 1 Note: Gum is the emulsifying agent or emulgent. These proportions are important when making the primary emulsion to prevent the breaking down of emulsion on dilution or storage.  preparation of emulsions There are two methods used in the preparation of emulsions: 1. Trituration method 2. Bottle or Forbes method Dry gum or Continental method Wet gum or English method 1. Trituration method Dry gum or Continental method In this method the emulsifying agent (usually acacia) is triturated with the oil in a perfectly dry porcelain mortar. The amount of water required for the primary emulsion is added in small portions with continuous trituration. Trituration is continued in one direction until the primary emulsion is creamy white and a cracking sound is produced by the movement of the pestle. The emulsion is then made up to volume with the remaining water. 1. Trituration method Wet gum or English method In this method the emulsifying agent is triturated with Water to form mucilage. The amount of oil required for the primary emulsion is added in small portions with continuous trituration. Trituration is continued in one direction until the primary emulsion is formed, cracking sound is produced by the movement of the pestle. The emulsion is then made up to volume with the remaining water.  For instance, since alcohol has a precipitating action on gums such as acacia, alcohol or any solution Other additives that Any substance that containing alcohol should are soluble or miscible may interfere with not be added directly to with external phase the stability of the the primary emulsion, added to the primary emulsifying agent, since the total alcoholic emulsion. should be added as concentration of the near last as is mixture would be greater practically possible. at that point. So, it would be added after other diluents had been previously added.  2. Bottle or Forbes method This method is employed for preparing emulsions containing volatile and non-viscous oils. Both dry gum and wet gum methods can be employed for the preparation. This method is not suitable for viscous oils as they cannot be thoroughly agitated in the bottle when mixed with the emulgent. When the intended dispersed phase is a mixture of fixed oil and volatile oil, the dry gum method is generally employed.  2. Bottle or Forbes method The oil (dry) or water (wet) is first shaken vigorously with the calculated amount of gum. Once this has emulsified completely, the second liquid (water or oil) is then added all at once and the bottle is again shaken vigorously to form the primary emulsion. More water is added in small portions, with constant shaking after each addition, to produce the final volume.  Instability of Emulsions Instabilities in emulsion can be grouped as follows: 1. Flocculation and Creaming 2. Coalescence and Breaking 3. Phase inversion Breaking Instability of emulsion can be caused by the following: Addition of emulsifying agents of the opposite type. Gums, are insoluble in alcohol and if alcohol is added to emulsions prepared with these materials, the emulgent is precipitated and Breaking occurs. Decomposition of the emulsifying agent due to microbial action or when oil turning rancid during storage. Addition of common solvent. in which both the disperse and continuous phases are soluble forms a one-phase system and destroys the emulsion. Change of storage temperature. 1. Flocculation and Creaming Flocculation: The small spheres of dispersed phase join together to form clumps or flocs which rise or settle in the emulsion. Creaming: it is a concentration of the downward creaming Of W/O Emulsion floccules of the internal phase formed upward (upward creaming) or downward layer (downward creaming) according to the density of internal phase. It is not a serious instability problem as It is a temporary or reversible process, a uniform dispersion can be reobtained by shaking the emulsion. However, there may be coalescence of droplets as they are present close to each other. Therefore, the emulsion may eventually break. Based on Stoke’s equation, the rate of creaming in an emulsion can be decreased by: 1. Decreasing the diameter of the dispersed globules, This can be achieved by the use of a homogenizer. 2. Decreasing density differences between the two phases. Creaming can be prevented if the densities of the two phases are identical. 3. Increasing the viscosity of the external phase by adding thickeners like tragacanth.  2. Coalescence and Breaking Coalescence is the process by which emulsified particles merge and fuse with each other to form large particles. Breaking: The globules of the disperse phase coalesce together and separates completely from the continuous phase. Redispersion cannot be achieved by shaking and the preparation is no longer an emulsion. Breaking of Emulsion Differences between creaming and breaking Creaming Breaking Definition Formation of a downward or Complete separation of the upward layer of flocculated dispersed phase from the dispersed globules. continuous phase. Reverersability Reversible Irreversible The Emulsifying film Intact destroyed Internal phase globules Floccules, no fusion (no Coalescence ( complete coalescence) fusion) 3. Phase inversion This is the process when W/O emulsion changes to a O/W emulsion or vice versa. It may be brought about by: 1- The addition of a substance that alters the solubility of the emulsifying agent may cause reversal of the phases. 2- Increasing the internal phase volume > 60%. 3- Temperature changes Phase inversion can be minimized by using the proper emulsifying agent in adequate concentration, keeping the concentration of dispersed phase between 30% and 60% and storing the emulsion in a cool place.  Labeling and storage Labeling The label on the emulsion should mention that these products have to be shaken thoroughly before use. Topical products should clearly mention on their label that they are meant for external use only. Storage Emulsions should be stored in a cool place as it can decrease creaming. Note: Temperature rise decreases the viscosity of the continuous phase and increases the number of collisions between the globules. Freezing must be avoided since ice may separate and cause breaking by exerting pressure on the globules.  Pharmaceutical applications O/W emulsion are preferred for oral formulations as the taste of Oral oils can be masked. Due to small globule size, the medicinal agent gets absorbed faster. Essential nutrients (fats and vitamins) are emulsified O/W and given to bed ridden patients by iv infusion. Parenteral Depot injections : W/O emulsions are used for IM depot injection of water-soluble drugs. O/W creams are more acceptable as water washable bases for cosmetic purposes. Topical W/O creams are used for treatment of dry skin.  Thank You Any questions ? Pharmaceutics Department Faculty of Pharmacy Delta University for Science and Technology