Emulsion (Physical Pharmacy) PDF

# Emulsions ## Emulsions: Definition, Types, Advantages and Disadvantages 1. **Definition:** - An emulsion is a mixture of two or more liquids that are normally immiscible. - An emulsion is a thermodynamically unstable system consisting of two immiscible liquids in which one liquid is dispe...

# Emulsions ## Emulsions: Definition, Types, Advantages and Disadvantages 1. **Definition:** - An emulsion is a mixture of two or more liquids that are normally immiscible. - An emulsion is a thermodynamically unstable system consisting of two immiscible liquids in which one liquid is dispersed as fine globules throughout the other with the help of emulsifying agents. 2. **Types 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 - **TYPES OF EMULSION:** - **Simple emulsions (Macro emulsions):** - Oil-in-water (O/W) - Water-in-oil (W/O) - **Multiple emulsions:** - Oil-in-water-in-oil (O/W/O) - Water-in-oil-in-water (W/O/W) - **Micro emulsions:** - **Nano emulsions:** Thermodynamically stable, optically transparent. ## General Types of Pharmaceutical Emulsions - Lotions - Liniments - Vitamin drops - Creams - Ointments ## Advantages of Emulsions - Mask the unpleasant taste O/W is convenient means of oral administration of water-insoluble liquids. - Oil-soluble drugs can be given parentrally in form of oil-in water emulsion. (e.g. Taxol). - Emulsion can be used for external application in cosmetic and therapeutic Application because of Better and faster absorption. - Sustained-release medication. - Nutritional supplement. - Inert and chemically non-reactive. ## Disadvantages of Emulsions - Emulsions are thermodynamically unstable and have short shelf-life. - Improper formulation of emulsions leads to creaming and cracking of emulsion. - Improper selection of emulsifying agent leads to phase inversion and some times it may also lead to cracking. ## Difference between O/W and W/O Emulsions | Feature | Water in oil Emulsion (w/o) | Oil in water emulsion (o/w) | | :--------------- | :--------------------------------------------------------------- | :---------------------------------------------------------------- | | Dispersion medium | Oil is the dispersion medium and water is the dispersed phase | Water is the dispersion medium and oil is the dispersed phase | | Properties | They are greasy and not water washable | They are non greasy and easily removable from the skin surface | | Uses | They are used externally to prevent evaporation of moisture | They are used externally to provide cooling effect | | Drug release | Oil soluble drugs are more quickly released from w/o emulsions | Water soluble drugs are more quickly released from o/w emulsions | | Formulations | They are preferred for formulations meant for external use | They are preferred for formulations meant for internal use | | Conductivity test | W/O emulsions go not give a positive conductivity test as oil | O/W emulsions give a positive conductivity test | ## Emulsifying Agent 1. **Definition:** - Emulsions are stabilized by adding an emulsifying agent. These agents have both a hydrophilic and a lipophilic part in their chemical structure. - All emulsifying agents get adsorbed onto the Oil : Water interface to provide a protective barrier around the dispersed droplets. - In addition to this protective barrier, emulsifiers stabilize the emulsion by reducing the interfacial tension of the system. 2. **Classification of Emulsifying Agents:** - **1) Chemical structure:** - Synthetic Emulsifying Agents - Natural Emulsifying Agents - Finely Dispersed Solids - Auxiliary Agents - **2) Mechanism of action:** - Monomolecular - Multi-molecular - Solid particle films. ### Synthetic Emulsifying Agents 1. **Anionic: (pH > 8)** - Sodium stearate - Potassium laurate - Sodium dodecyl sulfate - Sodium sulfosuccinate. - Sodium or potassium oleate - Triethanolamine stearate - Sodium lauryl sulfate. 2. **Cationic: (pH 3-7)** - Benzalkonium chloride - Benzethonium chloride - Quaternary ammonium salts 3. **Non lonic (pH 3-10)** - Polyglycol - Fatty acid esters - Lecithin. - Sorbitan esters (Spans) - Polyoxyethylene derivatives of sorbitan esters (Tweens) - Glyceryl esters. ***Cationic and Anionic surfactants are generally limited to use in topical, o/w emulsions*** ### Natural Emulsifying Agents Derived from Plants and Animals: - **Vegetable derivatives:** - Acacia - Tragacanth - Agar - Pectin - Carrageenan - Lecithin - **Animal derivatives:** - Gelatin - Lanolin - Cholesterol ### Finely Divided or Finely Dispersed Solid Particle Emulsifiers - These agents form a particulate layer around dispersed particles. Most will swell in the dispersion medium to increase viscosity. - Most commonly they support the formation of o/w emulsions, but some may support w/o emulsions. - **For Instance:** - Bentonite - Veegum - Hectorite - Magnesium Hydroxide - Aluminum Hydroxide - Magnesium Tri silicate ### Auxiliary Emulsifying Agents - A variety of fatty acids (e.g., stearic acid), fatty alcohols (e.g., stearyl or cetyl alcohol), and fatty esters (e.g., glyceryl monostearate) serve to stabilize emulsions through their ability to thicken the emulsion. - A system was developed to assist in making systemic decisions about the amounts and types of surfactants needed in stable products. The system is called the HLB (hydrophile-lipophile balance) system and has an arbitrary scale of 1 - 18. HLB numbers are experimentally determined for the different emulsifiers. - **Low HLB Indicates?** - Low number of hydrophilic groups on the Molecule thus imparting Lipophilic character. - Spans have low HLB numbers. Because of their oil-soluble character, Spans will cause the oil phase to predominate and form an w/o emulsion. - **High HLB indicates?** - Emulsifier has a large number of hydrophilic groups on the molecule thus imparting hydrophilic Character. - Tweens have higher HLB numbers. Because of their water-soluble character, Tweens will cause the water phase to predominate and form an o/w emulsion. - **HLB value & Application** - 1~3: Anti-foaming agent. - 3~6: W/o emulsifying agents. - 7~9: Wetting agents. - 8~18: O/w emulsifying agents. - 13~15: Detergents. - 15~18: Solubilizing Agents. - **How to Calculate HLB?** - Combinations of emulsifiers can produce more stable emulsions than using a single emulsifier with the same HLB number. - The HLB value of a combination of emulsifiers can be calculated as follows: $HLB = \frac{(Quantity \ of \ surfactant\ 1)(HLB \ surfactant\ 1) + (quantity\ of \ surfactant\ 2)(HLB \ surfactant\ 2)}{quantity \ of \ surfactant\ 1 + quantity\ of\ surfactant\ 2}$ - **Numerical 1:** What is the HLB value of a surfactant system composed of 20 g Span 20 (HLB = 8.6) and 5 g Tween 21 (HLB = 13.3)? $HLB = \frac{(20g)(8.6) + (5g)(13.3)}{(20 g + 5 g)} = 9.54$ ## Classification of emulsifying agents - **Surface active agents (monomolecular film)** - **Hydrophilic colloids (multimolecular film)** - **Finely divided solid particles (Particulate film)** ## Classification of Emulsions Based on Mechanism of Action 1. **Monomolecular film:** To reduce the interfacial tension 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. Adsorbed at oil/water interface to form emulsion 2. **Multimolecular film or Hydrophillic Colloids** 3. **Finely divided solid particles:** They are adsorbed at the interface between two immiscible liquid phases to form Particulate film. ### 2. Hydrophilic Colloids - form multimolecular films - promote O/W - form strong films - may be charge - do not cause appreciable lowering of surface tension - increase in viscosity of dispersion medium ### 3. Finely divided solid particles - form solid particle films - particles are smaller than droplet - particles are wetted by both oil and water - O/W and W/O emulsion can be formed depending on preferential wetting by oil or water. ## Stability of emulsion - There are 2 intermolecular forces which affect the stability of dispersed system. - Van der Waals force is an attractive force, which tends to destabilize the emulsion. - Electrostatic force is a repulsive force, which gives stability to the emulsion. - When the total attractive forces > total repulsive forces, the emulsion is unstable. - When total repulsive forces > total attractive forces, the emulsion is stable. - Often, emulsions are inherently unstable. - The small suspended droplets first coalesce into less stable, larger droplets. This coalescence then continues until the emulsion breaks into two layers. - **A stable emulsion** may be defined as a system in which globues retain their initial character (retain their diameter) and remain uniformly distributed throughout the contineous phase. ### 1.1. Flocculation - On standing, neighbouring globules of the dispersed phase come closer to each other and form colonies in the contineous phase (due to the interaction of attracrive and repulsive forces). - However, the droplets may be redispersed by shaking and may lead to coalescence. - The extent of flocculation depends on: - Globules size distribution - Charge on globules surface - Viscosity of external medium (contineous phase) ### Flocculation and Coalescence - Rehomogenization - Collision and sticking (reaction) - Stir or change chemical conditions - Film rupture - COALESCENCE - FLOCCULATION ### 1.2. Creaming - On standing, creaming is the concentration of globules at the top or bottom of emulsion (due to density differencs between the two phases). - Globules move either upwards (o/w emulsion) or sink downwards (w/o emulsion) leading to creaming. - It can be observed by a differnce in color shade of both layers, and in both cases, emulsion can be easily redispersed by shaking. - As in flocculation, droplets do not coalesce and can be redispersed by gentle shaking. - Creaming **is** however **undesirable** pharmaceutically **beacuse:** - Increased possibility of coalescence of droplets - Creamed emulsion is inelegant - Risk of incorrect dose if not skaken enough. - **Factors affecting creaming** are best described by Stoke's law. - Creaming **can be reduced by:** - Reducing globule size by homogenization - Increasing viscosity of dispersion medium - Reducing the difference in density. ### Physical instability of emulsions - i. Coalescence - iii. Creaming - Good Emulsion - ii. Flocculation - iv. Breaking ### 1.3. Coalescence - Is followed by the creaming stage wherein droplets merge froming larger droplets (irreversible process). This process continues until the emulsion breaks (cracks). - In this process, the emulsifier film around globules is destroyed to a certain extent. - This step is recongized by increased size but reduced number of globules. - Coalescence is observed due to: - Insufficient amount of the emulsifying agent. - Altered partitioning of the emulsifier. - Incompatibilities between emulsifiers. ### 1.4. Cracking (breaking) - It is indicated by complete separation of oil and the aqueous phase. - It is an irreversible process that simple mixing fails to resuspend globules into a uniform emulsion. - In breaking, the protective sheath around globules is completely destroyed. - **Factors that cause emulsion cracking:** - The addition of a chemical that is incompatible with the emulsifier e.g., addition of a cationic surfactant to an emulsion stabilized with an anionic surfactant; addition of electrolytes to emulsion stabilized with opposite ionic surfactants. - Bacterial growth: Protein and polysaccharide emulsifiers are excellent media for bacterial growth. - Temperature fluctuations: Protein emulsfifiers may be denatured and the solubility of non-ionic surfactants change with a rise in temperature (heating above 70C destroys most emulsifiers). Freezing will also crack emulsion because the ice crystals formd distrup the interfacial film around droplets. ### 1.5. Phase inversion - This involves the change of emulsion type from o/w to w/o and viceversa. - When we intend to prepare an o/w emulsion and if the final emulsion turns out to be w/o, it can be termed as a sign of instability. - **Reasons of phase inversion:** - Increasing the dispersed phase concentration above the accepted value: the most suitable range of dispersed phase concentration is 30-60% (o/w 74%, w/o 40%). - Adding substances that alter the solubility of the emulsifier (e.g., precipitation of hydrophilic colloids in the presence of alcohol). - Suppression of ionization for ionic surfactants by adding subbstances with opposite charges (e.g., addition of CaCl₂ into o/w emulsion formed by sodium stearate can be inverted to w/o). - Phase volume ratio. - Temperature of the system: Temperature of o/w makes the emulsifier more hydrophobic and the emulsion may invert to w/o (e.g., temperature-induced breakage of H-bonds of polysorbates, which are responsible for hydrophilicity, will lower HLB value). ### Mechanisms of Emulsion Instability - Phase inversion - Creaming - Sedimentation - Flocculation - Coalescence ## Importance - **1. Improved bioavailability:** Emulsions can enhance the absorption of poorly soluble drugs, increasing their effectiveness. - **2. Enhanced solubility:** Emulsions can solubilize drugs that are insoluble in water, making them easier to administer. - **3. Targeted delivery:** Emulsions can be designed to target specific sites in the body, reducing side effects and improving efficacy - **4. Improved patient compliance:** Emulsions can be formulated to have a pleasant taste or texture, making medications more acceptable to patients. - **5. Increased stability:** Emulsions can protect sensitive drugs from degradation, extending their shelf life. - **6. Reduced toxicity:** Emulsions can reduce the toxicity of certain drugs by encapsulating them in a protective vehicle. - **7. Improved topical delivery:** Emulsions can enhance the delivery of topical drugs through the skin, improving localized treatment. - **8. Parenteral delivery:** Emulsions can be used for injectable drugs, providing a stable and consistent formulation. - **9. Ocular delivery:** Emulsions can be designed for ocular administration, improving the delivery of drugs to the eyes. - **10. Personalized medicine:** Emulsions can be tailored to individual patients' needs, providing a more personalized treatment approach. ## Examples - **1. Mayonnaise:** A stable emulsion of oil, egg yolks, vinegar, and water. - **2. Milk:** A natural emulsion of butterfat globules in water. - **3. Cream:** A mixture of butterfat globules in water, similar to milk but with a higher fat content. - **4. Lotions and creams:** Cosmetic emulsions of oil and water, often with added ingredients like fragrances and preservatives. - **5. Ice cream:** A frozen emulsion of cream, sugar, and flavorings. - **6. Salad dressings:** Emulsions of oil and vinegar - **7. Pharmaceuticals:** Some medications are emulsions, like creams or ointments for skin application. - **8. Food products:** Emulsions are used in many food products, such as: - Margarine - Chocolate - Sauces (e.g., soy sauce, teriyaki sauce) - Beverages (e.g., coffee creamers, fruit smoothies) - **9. Industrial applications:** Emulsions are used in various industrial processes, like: Paints and coatings - Adhesives - Textile finishing - Paper coatings ## Pharmaceutical Emulsions - **Creams:** - Hydrocortisone cream - Clotrimazole cream - Mupirocin cream - **Ointments:** - Petroleum jelly ointment - Zinc oxide ointment - Bacitracin ointment - **Lotions:** - Calamine lotion - Hydrocortisone lotion - **Emulsion injections:** - Liposomal amphotericin B (Fungizone - Vitamin K injection - **Topical emulsions:** - Acne treatments (e.g., benzoyl peroxide, salicylic acid) - Anti-inflammatory creams (e.g., diclofenac, ketoprofen) - Sunscreens (e.g., oxybenzone, avobenzone) - **Oral emulsions:** - Vitamin supplements (e.g., vitamin D, omega-3 fatty acids) - Antacid emulsions (e.g., Gaviscon) - Protein supplements (e.g., whey protein, casein protein) - **Eye drops:** - Timolol (Timoptic) ## THEORIES OF EMULSION - **MANY THEORIES HAVE BEEN ADVANCED TO ACCOUNT FOR THE WAY OR MEANS BY WHICH THE EMULSION IS STABLIZED BY THE EMULSIFIER.** AT THE PRESENT TIME NO THEORY THAT SEEMS TO APPLY UNIVERSALLY TO ALL EMULSIONS. - **1- PLASTIC OR INTERFICIAL FILM THEORY** - **2- SURFACE TENSION THEORY** - **3-INTERFICIAL TENSION THEORY** - **4- ELECTRIC DOUBLE LAYER THEORY** - **5- ΜΟΝΟΜOLCULAR THEORY** - **6- ORIENTED-WEDGE THEORY** - **7- ORIENTED ADSORPTION THEORY** - **8- VISCOSITY THEORY** ### PLASTIC OR INTERFICIAL FILM THEORY - The plastic or interficial film theory places the emulsifying agent at the interface b/w the oil and water, surrounding the droplets of the internal phase as a thin layer of film adsorbed an the surface of drops. - The formation of an o/w or w/o emulsion depends on the degree of stability of the agent in the two phases, with water-soluble agents encouraging o/w emulsions and oil-soluble emulsifer the reverse. ### SURFACE TENSION THEORY - According to surface tension theory of emulsification, the emulsifying agents cause a reduction in the interficial tension of the two immiscible liquids, reducing repellent force b/w the liquids and withdrawing the attraction of liquids for their own molecules. - In this way, the surfactants convert large globules into smallones and avoid small globules from coalescing into large ones ### INTERFACIAL TENSION THEORY - when two immiscible liquids come in contact, the force causing each liquid to resist breakage is known as interfacial tension. when a high interfacial tension existed b/w two liquids emulsification is difficult, and if the tension could be reduced emulcification facilitated. - the explanation that in oil in water dispersion, the interfacial tension is so great that when two globules of dispersed phase approch each other it withdraw the liquid from b/w them, with the result they coalesce. when the interfacial tension is greatly reduced by the addition of emulsifier the globules remain separate ### ELECTRIC DOUBLE LAYER THEORY - The oil globules in a pure oil and pure water emulsion carry a negative charge. The water ionizes so that both hydrogen and hydroxyl ions are present. A second layer of oppositely charged ions forms a layer in the liquid out side the layer of negative ions these two layers of oppositely charged ions are known as helmholtz double layer. They are not confined to emulsion but accompany all boundry phenomena. the electric charge is a factor in all emulsions, even those stablized with emusifying agents.