Emulsions Presented by: Rabbia Saleem Pharm-D, MPhil Mohi-ud-Din Institute of Pharmaceutical Sciences (MIIPS) 2 Dispersion System • Biphasic liquid preparations, containing 2- immiscible liquids one of which is dispersed as minute globules into others. • Size of dispersed liquid is 0.25-25μm. • Emulsifying agent required to make stable emulsion. • Various tests adopt to confirm type of emulsion. • Biphasic liquid dosage form of medicament in which finely divided solid particles are dispersed in a liquid. • Suspended solids have size range of 0.5-5microns. • Suspending agent required to make stable suspension. • No tests to confirm type of suspension. Suspensions Emulsions Introduction An emulsion is a heterogeneous, thermodynamically unstable and biphasic system containing two immiscible liquid phases, one of which is dispersed as globules in other phase and the system is stabilized by the presence of emulsifying agent. Phases in Emulsion: The dispersed liquid is known as the Internal or Discontinuous phase. The droplet phase is called “dispersed phase or internal phase”. whereas the dispersion medium is known as the External or Continuous phase The liquid in which droplets are dispersed is called the “external or continuous phase”. 3 Types of Emulsions Based on dispersed phase 1. Oil in water (O/W): Oil droplets dispersed in water. i.e. creams like moisturizers, vanishing creams and topical steroid products. 2. Water in oil (W/O): Water droplets dispersed in oil. i.e. sunscreens and cold creams. 3. Multiple emulsion (O/W/O, W/O/W): Polydispersed systems where both oil in water and water in oil emulsion exists simultaneously. Based on size of liquid droplets 1. Macroemulsions: O/W or W/O (0.2-50 mm) 2. Microemulsions: Thermodynamically stable (10-100 nm) 3. Nanoemulsions: Thermodynamically unstable (20-500 nm) 4 Difference between O/W & W/O Emulsions 5 Oil in water emulsion • Water is the dispersion medium and oil is the dispersed phase. • Water soluble drugs are more quickly released from o/w emulsions. • They are preferred for formulations meant for internal use as bitter taste of oils can be masked. • They are non greasy and easily removable from the skin surface. • They are used externally to provide cooling effect e.g. vanishing cream. • O/W emulsions give a positive conductivity test as water is the external phase which is a good conductor of electricity. Water in oil emulsion • Oil is the dispersion medium and water is the dispersed phase. • Oil soluble drugs are more quickly released from w/o emulsions. • They are preferred for formulations meant for external use like creams. • They are greasy and not water washable. • They are used externally to prevent evaporation of moisture from the surface of skin e.g. Cold cream. • W/O emulsions go not give a positive conductivity test as oil is the external phase which is a poor conductor of electricity. Multiple Emulsion • It is a dynamic hetero complex type of emulsion system in which oil-in-water or water-in-oil emulsions are dispersed in another liquid medium. • In this way an oil-in-water-in-oil (O/W/O) emulsion consists of very small droplets of oil dispersed in the water globules of a water-in-oil emulsion and a water-in-oil-in-water (W/O/W) emulsion consists of droplets of water dispersed in the oil phase of an oil-in-water emulsion. • Their pharmaceutical applications include taste masking, adjuvant vaccines, an immobilization of enzymes and sorbent reservoir of overdose treatments, and sometimes for the augmentation of external skin or dermal absorption. • Multiple emulsions have been formulated as cosmetics, such as skin moisturizer. • Prolonged release can also be obtained by means of multiple emulsions. • Thermodynamically instable. 6 Theories of Emulsification Theories of emulsification explain the action of emulsifying agents in stabilizing emulsions. It is the surface or more accurately the interface between the two immiscible liquids that plays the foremost role. Emulsifying agents affect the interface in such a way to obtain stable emulsions. There are several theories proposed to explain the action of emulsifying agents in stabilizing emulsions. Among these theories, some may be applied to specific emulsifying agents under certain conditions like pH of the phases of system, and nature and proportion of the internal and external phases. The most well-known theories include:- 1. Surface tension theory 2. Oriented wedge theory 3. Interfacial film theory 1. SURFACE TENSION THEORY Molecules in a liquid are attracted equally on all sides by surrounding molecules; however, at surface, there is inward attraction of molecules due to imbalance attractive forces. Due to this attraction, a stress or tension is produced known as “ surface tension” . When two immiscible liquids come in contact, the force causing each liquid to resist breakage is known as “ interfacial tension” In accordance to surface tension theory of emulsification, emulsifying agents cause a reduction in interfacial tension of the two immiscible liquids, reducing repellent force b/w liquids and withdrawing the attraction of liquids for their own molecules. In this way, the surfactants convert large globules into small ones and avoid small globules from coalescing into large ones. 7 2. ORIENTED WEDGE THEORY According to this theory, mono molecular layers of emulsifying agents are curved around a droplet of internal phase of the emulsion. It is based on presumption that certain emulsifying agents orient themselves about and within a liquid in a manner reflective of their solubility in that particular liquid. The oil or non-polar ends of the emulsifying agents turn towards the oil and the polar ends towards the polar liquid. This theory indicates that if the non-polar end of the emulsifying agent is smaller (having a greater hydrophilic than hydrophobic character), the emulsion will be o/w and if the polar end is smaller (more hydrophobic) the emulsion will be w/o. However, this theory could not explain the formation of type of emulsion. 3. PLASTIC/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 the coalescence of dispersed phase. The formation of an o/w or w/o emulsion depends on the degree of solubility of the agent in two phases, with water -soluble agents encouraging o/w emulsions and vice versa. 8 A. Emulsifier molecules oriented at interface. Dotted lines indicate the large volume occupied by polar head due to formation of hydrated complex. B. Shows that close packing of molecules ‘ fits’ this curvature. Formulation of Emulsion Selection of an emulsifying agent: An agent used for stabilizing an emulsion is known as emulsifying agent, stabilizing agent for emulsion, emulsifier, emulgent. The ideal emulsifying agent is organoleptically inert, physicochemically stable, non-toxic, non-irritant and able to produce stable emulsions at low concentrations. The efficiency of an emulsifying agent is related to its chemical structure, solubility, pH and physical properties. Classification of emulsifiers: Synthetic emulsifying agents They act as “surface active agents”. They are very effective at lowering interfacial tension between oil and water phases because molecules possess both hydrophilic and hydrophobic properties. Form protective “monomolecular film”, thus prevents coalescence of droplets. i.e. Polysorbate, Sodium lauryl sulphate, Benzalkonium chloride etc. Further classified as; a. Anionic emulsifying agents b. Cationic emulsifying agents c. Amphoteric emulsifying agents d. Non-ionic emulsifying agents 9 Semi synthetic and natural emulsifying agents Also known as “Hydrocolloid Emulsifying Agents”. Provide a protective sheath (Multi-molecular films) around droplets making them highly resistant to coalescence. They swell to increase viscosity of the system (so that droplets are less likely to merge). i.e. Semi synthetic:- methyl cellulose, hydroxypropyl cellulose and sodium carboxy methyl cellulose. Natural:- Plant origin → Polysaccharides (acacia, tragacanth, agar, pectin, lecithin) Animal origin → Proteins ( Gelatin), lecithin, cholesterol, wool, fat, egg yolk. Finely divided solid emulsifying agents These are emulsifiers, that form “particulate films” around dispersed droplets, producing emulsions that are coarse- grained but have considerable physical stability. i.e. Bentonite and magnesium aluminum silicate. 10 Classification of emulsifying agents on the basis of charged groups 11 Hydrophilic-Lipophilic Balance (HLB) Griffin (1954) introduced a very useful system for the classification of surfactants on the basis of their solubility in water. The numerical values in this system is known as hydrophilic-lipophilic balance. The HLB value can be used to predict the surfactant properties of a molecule (either it is hydrophilic or lipophilic). The usual range in between 1-20. HLB number increases with increasing hydrophilicity and HLB decreases with increasing lipophilicity Surfactants with an HLB value between 3–6, greatly lipophilic include: glycerol ester, propylene glycol, polyglycerol esters, and sorbitol fatty acid esters. Surfactants with HLB values between 8–16, greatly hydrophilic include: proteins, phospholipids, potassium and sodium salts and alginates. 12 Methods of Emulsion Preparation 13 1. Extemporaneous Methods 2. Large Scale Methods “EXTEMPORANEOUS METHODS” Emulsification process can be carried out by following methods; A. Trituration Method:- This method consists of dry gum method and wet gum method. 1. 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. a. Triturate emulsifier (usually acacia) + oil. b. Add water. c. Triturate and form primary emulsion. d. Add remaining quantity of water. 2. English or wet gum method By this method, same proportions of oil, water and gum are used as in the continental or dry gum method but the order of mixing is different. a. Triturate gum (acacia)+ water. b. Add oil and form primary emulsion. c. Add remaining quantity of water. B. Bottle or Forbes Bottle Method:- a. It is useful for preparation of emulsions from volatile oils & oleaginous substances of low viscosities. b. Powdered acacia is placed in a dry bottle, two parts of oil are added and the mixture is thoroughly shaken in the container. c. A volume of water approximately equal to that of oil is then added in portions and the mixture is shaken after each addition. d. When all water has been added, primary emulsion has formed may be diluted to the proper volume with water or an aqueous solution of other formulative agents. 14 C. Auxiliary Method:- 1. An emulsion prepared by either wet gum or dry gum method can generally be increase in the quality by passing it through a hand homogenizer. 2. In this apparatus, the pumping action of the handle forces emulsion through a very small orifice that reduces the globules of the internal phase to about 5 μm and sometimes less. 3. The hand homogenizer is less efficient in reducing the particle size of very thick emulsions, and it should not be employed for emulsions containing a high proportion of solid matter because of possible damage to the valve. D. In-Situ Soap Method:- • The two types of soaps developed by this method are 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 simply by mixing equal volumes of the oil and limewater. • Because oil phase is the external phase, this formulation is ideal where occlusion and skin softening are desired, such as for itchy, dry skin or sunburned skin. • A typical example of this emulsion is calamine liniment. 15 “LARGE SCALE METHODS” Commercially, emulsions are prepared in large volume mixing tanks and refined and stabilized by passage through a colloid mill or homogenizer Physical parameters affecting the droplet size distribution, viscosity, and stability of emulsion: a. Location of the emulsifier b. Method of incorporation of the phases c. The temperature of each phase d. The rates of addition e. The rate of cooling after mixing of the phases considerably Energy may be supplied into the system in the form of: a. Heat b. Homogenization c. Agitation Heat: 1. Emulsification by vaporization; (emulsions prepared by passing vapor of a liquid into external phase that contains emulsifier, also known as condensation method) 2. Emulsification by phase inversion; (Firstly, emulsion is prepared at higher temperature, then upon cooling phase inversion occurs and a stable inversion with finely divided internal phase is produced) 3. Low energy emulsification; (all of internal but only a portion of external phase is heated, then after emulsification, the remainder external phase is added to emulsion concentrate. Good emulsions are manufactured by this method with controlled variables like emulsification temperature, mixing time and intensity, method of blending and amount of external phase during emulsification) 16 17 Phase Inversion Example Equipment for emulsification (Agitation) 1. Mechanical stirrers 2. Propeller typed mixers a. Turbine mixers b. Homogenizers 3. Colloid mills 4. Ultrasonifiers Ultrasonic Emulsifiers 18 Turbine mixer Homogenizer Stability of Emulsions Emulsion is considered to be physically unstable if; a. The internal or dispersed phase upon standing tends to form aggregates of globules. b. Large globules or aggregates of globules rise to the top or fall to the bottom of the emulsion to form a concentrated layer of the internal phase. c. If all or part of the liquid of the internal phase separates and forms a distinct layer on top or bottom of the emulsion as a result of the coalescing of globules of the internal phase. I: Coalescence and Breaking Coalescence is the process by which two or more droplets or particles merge during contact to form a single daughter droplet or particle. If there is no coalescence of internal phase emulsion will remain stable. Dispersed phase totally separated from the dispersion medium. II: Creaming It may be the upward movement of dispersed globules to form a thick layer at the surface of emulsion. It can be redistributed upon mild shaking or stirring. 19 III: Flocculation It is a process in which is a process wherein colloids come out of suspension in the form of floc or flake. It could be reversible or irreversible. IV: Phase Inversion It means internal phase is inverted to external phase i.e W/O emulsion is changed to O/W emulsion or vice versa. By keeping concentration of disperse phase in between 30-60 % phase inversion can be minimized. 20