Pharmaceutical Emulsions

**Emulsions** They are biphasic liquid preparation of atleast two immiscible liquids in which one is dispersed into another via addition of emulsifying agent. OR.... An emulsion is a dispersion in which the dispersed phase is composed of small globules of a liquid distributed throughout a vehicle...

**Emulsions** They are biphasic liquid preparation of atleast two immiscible liquids in which one is dispersed into another via addition of emulsifying agent. OR.... 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. **Emulsions** are **thermodynamically unstable** and the droplets tend to coalesce over sufficiently long periods of time. **Types**: In emulsion terminology, the dispersed phase is the *internal phase*, and the dispersion medium is the *external* or *continuous phase*. Emulsions with an oleaginous internal phase and an aqueous external phase are *oil-in-water* (o/w) emulsions e.g. Mayonnaise stabilized by lecithin, milk. While the emulsions having an aqueous internal phase and an oleaginous external phase are termed *water in-oil* (w/o) emulsions e.g. butter. - In an emulsion the external phase is continuous, so an o/w emulsion may be diluted with water or an aqueous preparation and a w/o emulsion, with an oleaginous or oil-miscible liquid. - To prepare a stable emulsion, a third phase, an *emulsifying agent*, is necessary. - Depending on nature and quantities of ingredients, the viscosity of emulsions can vary greatly from liquids to semisolids. - Based on the constituents and the intended application, liquid emulsions may be employed orally, topically, or parenterally; semisolid emulsions are used topically. - Many pharmaceutical preparations that are actually emulsions are not classified as such because they fit better in other pharmaceutical categories. For example; certain lotions, liniments, creams, ointments, and commercial vitamin drops. **Purpose of emulsions** - Emulsification enables to prepare relatively stable and homogeneous mixtures of two immiscible liquids and permits administration of a liquid drug in the form of minute globules rather than in bulk. - It enhances pallativeness for orally administered emulsions, by dispersing globules in a sweetened, flavored vehicle. - The reduced particle size of the oil globules may render the oil more digestible and more readily absorbed, or for increased efficacy, e.g. increased efficacy of mineral oil as a cathartic when emulsified. - Emulsions to be applied to the skin may be o/w or w/o, depending on such factors as the nature of the therapeutic agents, the desirability for an emollient or tissue-softening effect, and the condition of the skin. - Skin irritating drugs can be made less irritating if emulsified in internal phase, where it cannot make contact to the skin surface directly. - On the unbroken skin, a w/o emulsion can usually be applied more evenly, because the skin is covered with a thin film of sebum (oily secretion from sebaceous glands), and this surface is more readily wetted by oil than by water. A w/o emulsion is also more softening to the skin, because it resists drying of skin and also not easily removal by water. - If fast removal of preparation is desired from the skin with water, an o/w emulsion is preferred. - To enhance absorption through the skin (percutaneous absorption) due to reduced particle size of internal phase. **Emulsifying agents** The selected emulsifying agent must fulfil the following criteria: - Must be compatible with the other ingredients and must not interfere with the stability or efficacy of the therapeutic agent. - It should be stable and not deteriorate in the preparation and should be nontoxic with respect to its intended use and the amount to be consumed by the patient. - It should possess little or no organoleptic effects such as odor, taste, or color. - It must be capable to promote emulsification and to maintain the emulsion stability for the intended shelf life. Various types of materials have been used as emulsifying agents. Classified as below. **[Synthetic emulsifiers]** - **Anionic (-ve):** Sod, pot and ammonium salts of lauric acid and oleic acid and form o/w emulsion. Calcium and magnesium salts of fatty acids form w/o type. They act as emulsifier better at pH 10. - **Cationic (+ve):** They have bactericidal activity and act at 4-6 pH, making them suitable for skin. They are weak emulsifiers so used with auxiliary emulsifiers. E.g. Cetrimide (quaternary ammonium salt). - **Non-ionic emulsifiers:** They are not effected by pH and has hydrophilic-lipophilic balance within molecule. They act at 3-10 pH range. E.g. sorbitan esters (spans), glyceryl esters, tweens. **[Hydrocolloids]** 1. **Naturally occurring:** These materials form hydrophilic colloids which when added to water and generally produce o/w emulsions. E.g. Acacia. The tragacanth and agar are used as thickening agents in acacia-emulsified products. Protein substances, such as gelatin, egg yolk, and casein (in milk) produce o/w emulsions. Cholesterol promote w/o emulsions while lecithin (due to hydrophilicity) promotes o/w. 2. **Semisynthetic agents: Cellulose derivative like methylcellulose, hydroxyl-propyl-methylcellulose, sodium carboxymethylcellulose.** 3. **Synthetic agents: sodium lauryl sulphate, polyvinyl alcohol, PEG, acrylic acid.** **[Finely divided particles]** These are colloidal clays of mineral source and form a thick film around droplets. E.g. veegum (Al-Mg silicate) and bentonite (Al-phyllosilicate). For o/w; bentonite is dispersed in water to form **magma** (insoluble aq-susp of inorganics) and then oil is added slowly. In case of w/o type, it is dispersed in oil followed by addition of water. Other examples are aluminum hydroxide, mag-trisilicate. **[Axillary emulsifiers]** They are not capable to make stable emulsion but used with other types. They mainly act as thickening agents and help in stability of emulsion. E.g. cetyl alcohol, stearyl alcohol, glyceryl monstearate. **The HLB system** - Each emulsifying agent has a hydrophilic portion and a lipophilic portion, with one or the other being more or less predominant and influencing the type of emulsion. The emulsifying or surface-active agents may be categorized on the basis of their chemical makeup according to their hydrophilic--lipophilic balance, or HLB. - By this method, each agent has an HLB value or number indicating the polarity. Although the numbers have been assigned up to about 40, the usual range is between 1 and 20. - Materials that are polar or hydrophilic have been assigned higher numbers (8 to 18) producing o/w. The materials that are less polar and more lipophilic has HLB value of 3 to 6 producing w/o emulsions. - In the HLB system, in addition to the emulsifying agents, values are assigned to oils and oil like substances also, and for the emulsion those emulsifying agents are selected which have similar or nearer HLB value as the oleaginous phase of the intended emulsion. For example, mineral oil has an assigned HLB value of 4 if an w/o emulsion is desired, and a value of 10.5 if an o/w emulsion is to be prepared. - Therefore, to prepare a stable emulsion, the emulsifying agent selected should have an HLB value similar to the mineral oil, depending on the type of emulsion desired. When needed, two or more emulsifiers may be combined to achieve the proper HLB value. **Theories of emulsification** Many theories have been published to explain how emulsifying agents promote emulsification and maintain the stability of the emulsion. Although certain of these theories apply rather specifically to certain types of emulsifying agents and to certain conditions (e.g., the pH of the phases of the system and the nature and relative proportions of the internal and external phases), to describe the preparation and stability of emulsions. The most prevalent theories are the ***surface tension theory*, the *oriented-wedge theory*, and the *plastic* or *interfacial film theory.*** a. ***Surface tension theory:*** - All liquids have a tendency to assume a shape having the minimal surface area exposed. For a drop of a liquid, that shape is the sphere. It possesses internal forces that tend to promote association of the molecules to resist distortion of the sphere. - If two or more drops of the same liquid come into contact with one another, the tendency is for them to join or to *coalesce*, making one larger drop having a smaller surface area than the total surface area of the collective individual drops. - This tendency of liquids may be measured quantitatively, and when the surrounding of the liquid is air, it is referred to as the **liquid's surface tension.** When two insoluble and immiscible liquid comes in contact, this force develop a resistance in each liquid to break into smaller particles, this force is called **interfacial tension**. - Substances that reduce this resistance encourage a liquid to break up into smaller drops or particles are called *surface active* (surfactant) or *wetting agents*. - According to the *surface tension theory* of emulsification, the use of these substances as emulsifiers and stabilizers lowers the interfacial tension of the two immiscible liquids, reducing the repellent forces between the liquids and minimizing each liquid's attraction for its own molecules. b. ***Oriented-wedge* theory:** - It assumes that monomolecular layers of emulsifying agent are curved around a droplet of the internal phase, and orient themselves between the liquids in a manner according to their solubilities. - Emulsifying agents has both hydrophilic and hydrophobic ends and if added to a system of two immiscible liquids, it become soluble in one phase more and embed more deeply than the other. - Depending on the shape and size of the molecules, their partial solubility characteristics in either phases, they orient into a wedge shape around the globules. - Generally, an emulsifying agent having a greater hydrophilic character will promote an o/w emulsion, and with more lipophilic character will form w/o emulsion. - The broader end of wedge will go into continuous phase and narrow will be towards dispersed phase. c. ***Plastic* or *interfacial film theory:*** - This theory Places the emulsifying agent at the interface between the oil and water, surrounding the droplets of the internal phase as a thin layer of film adsorbed on the surface of the drops. This film prevents contact and coalescing of the dispersed phase. - The tougher and more flexible the film, the greater the stability of the emulsion. Naturally, enough of the film forming material must be available to coat the entire surface of each droplet. - The formation of an o/w or a w/o emulsion depends on the degree of solubility of emulsifying agent in the two phases. Water-soluble agents encourage o/w emulsions and oil-soluble emulsifiers the reverse. **Methods of emulsion preparation** - **On a small scale**, as in the laboratory or pharmacy, emulsions may be prepared using a dry Wedgwood or porcelain mortar and pestle, a mechanical blender or mixer, such as milkshake mixer, a hand homogenizer or a simple prescription bottle. - **On a large scale**, large mixing tanks may be used to form the emulsion through the action of a high-speed impeller. As desired, the product can be made finer by passage through a colloidal mill, in which the particles are pumped forcefully between the small gap separating a high-speed rotor and the stator, or by passage through a large homogenizer, in which the liquid is forced under great pressure through a small valve opening. - Emulsions, are prepared by three methods. They are the *continental* or *dry gum method*, the *English* or *wet gum method*, and the *bottle* or *Forbes bottle method*. In the first method, the emulsifying agent (usually acacia) is mixed with the oil before the addition of water, that is, dry gum. In the second method, the emulsifying agent is added to the water to form a mucilage, and then the oil is slowly incorporated to form the emulsion, that is, wet gum. The bottle method is reserved for volatile oils or less viscous oils and is a subtype of the dry gum method. a. **Continental or dry gum method** - The continental method is also referred to as the 4:2:1 method because for every 4 parts by volume of oil, 2 parts of water and 1 part of gum are added in preparing the initial or ***primary emulsion***. For instance, if 40 mL of oil is to be emulsified, 20 mL of water and 10 g of gum would be employed in the primary emulsion, with any additional water or other formulation ingredients added afterward. - In this method, the acacia or other o/w emulsifier is levigated with the oil in a perfectly dry Wedgwood or porcelain mortar until thoroughly mixed. A mortar with a rough rather produce more uniform grinding and reduction of the globule size than smooth inner surface. - A glass mortar is too smooth to produce the proper reduction of the internal phase. - After the oil and gum have been mixed, the two parts of water are added all at once, and the mixture is triturated immediately, rapidly, and continuously until the primary emulsion is creamy white and produces a crackling sound to the movement of the pestle. - Other soluble liquid ingredients are added into the primary emulsion. Solid substances such as preservatives, stabilizers, colorants, and any flavoring material are dissolved in a small volume of water (assuming water is the external phase) and added as a solution to the primary emulsion. - Any substance that might interfere with the stability of the emulsion or the emulsifying agent are added in last. For instance, alcohol has a precipitating action on gums such as acacia, thus no alcohol or solution containing alcohol should be added directly to the primary emulsion, - The dry gum method can almost be guaranteed to produce an acceptable emulsion. Sometimes, however, the amount of acacia must be adjusted upward to ensure that an emulsion can be produced. For example, volatile oils, liquid petrolatum (mineral oil), and linseed oil usually require a 3:2:1 or 2:2:1 ratio for adequate preparation. b. **English or wet gum method** - By this method, the same proportions of oil, water, and gum are used as in the continental or dry gum method, but the order of mixing is different, and the proportion of ingredients may be varied during the preparation of the primary emulsion. - Generally, a mucilage of the gum is prepared by triturating acacia with twice its weight of water in a mortar. The oil is then added slowly in portions, and mixed to emulsify the oil. - After all of the oil has been added the mixture is thoroughly mixed for several minutes to ensure uniformity. Other formulative materials are added, and the emulsion is brought to volume with water. c. **Bottle or Forbes bottle method** - This method is suitable for extemporaneous preparation of emulsions from volatile oils or low viscous oleaginous substances. - Powdered acacia is placed in a dry bottle, two parts of oil are added, and the mixture is thoroughly shaken in the capped container. - A volume of water approximately equal to that of the oil is then added in portions and the mixture is thoroughly shaken after each addition. The primary emulsion thus formed may be diluted to the proper volume with water or an aqueous solution of other formulative agents. - This method is not suited for viscous oils because they cannot be thoroughly agitated in the bottle when mixed with the emulsifying agent. - When the intended dispersed phase is a mixture of fixed oil and volatile oil, the dry gum method is appropriate.. **Identification test for emulsion:** 1. **Dilution test:** To identify w/o or o/w type. If water is added to w/o the additive will not mix and form a separate layer. If added to o/w type than dilution of emulsion will occur. 2. **Conductivity test:** The o/w will show more conductivity as compared to the w/o using electrodes connected to a lamp and battery, so the type of emulsion can be identified. 3. **Dye solubility test:** It is conducted using dyes soluble in continuous phase. Such as in case of o/w emulsion, the addition of water-soluble dye will stain the continuous phase. This can be observed microscopically. If it doesn't stain the continuous phase then we have to go for oil soluble dye. **Stability of emulsion:** The phenomenon related to the physical stability of emulsions are; 1. **Creaming and sedimentation:** Both results in the breaking of emulsion. Creaming is the upward movement of dispersed phase, while sedimentation is the downward movement. They both depends on the relative densities of continuous phase and dispersed phase and temperature. High and freezing temperatures results in cracking of emulsion 2. **Aggregation and coalescence:** In aggregation the dispersed phase come closer and make loose flocs but not fuse, while in coalescence there is fusion of droplets leading to phase separation of immiscible liquids. Aggregates are easily reversible, while in coalescence the dispersed phase presents as a single drop. Aggregation depends on the electrical potential on the droplet, they might come closer but will not fuse due to elasticity and cohesiveness of interfacial film of emulsifiers. Coalescence depends on the structural properties of the interfacial film, i.e. if interfacial film around droplet breaks or rupture will result in fusion of droplets. 3. **Inversion:** Conversion of o/w to w/o or vice versa, due to either addition of electrolyte, or changing ratio of disperse phase to dispersion medium. E.g., addition of calcium chloride to an o/w emulsion, stabilized with sodium stearate will result in calcium stearate, which favors w/o type. Other includes addition of excessive inner phase or heating the emulsion. \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--