Pharmaceutical Emulsion PDF

Pharmaceutical Emulsion  Definition Pharmaceutical Emulsion  A thermodynamically unstable system consisting of two immiscible liquid phases, one of which is dispersed as globules (disperse...

Pharmaceutical Emulsion  Definition Pharmaceutical Emulsion  A thermodynamically unstable system consisting of two immiscible liquid phases, one of which is dispersed as globules (dispersed phase) in the other liquid phase (continuous phase), stabilized by the presence of an emulsifying agent.  The dispersed or internal phase usually consists of globules of diameters down to 0.1μm  Emulsified systems range from lotions of relatively low viscosity, to ointments and creams, which are semisolid in nature.  1-They can mask the bitter taste and odor of drugs, by this means making them more palatable. Advantages of Emulsion e.g. castor oil, cod-liver oil etc. 2-They can be used to prolong the release of the drug thus providing sustained release action. 3- Essential nutrients like carbohydrates, fats and vitamins can all be emulsified and can be administered to bed ridden patients as sterile intravenous emulsions. 4-Emulsions provide protection to drugs which are susceptible to oxidation or hydrolysis takes place. 5- Intravenous emulsions of contrast media have been developed to assist in diagnosis. 6-Emulsions are used widely to formulate externally used products like lotions, creams, liniments etc. Types of emulsion 1-Oil in water emulsion 2- Water in oil emulsion 3- Multiple emulsion 4- Microemulsion  1- Oil in water emulsion (o/w) 2- Water in oil emulsion (w/o) When the oil phase is dispersed as globules throughout an aqueous continuous phase, the When the oil phase serves as the continuous system is referred to as an oil-in water (o/w) phase, the emulsion is termed water-in-oil emulsion. (w/o) emulsion.  4- Microemulsion These consist of homogeneous transparent 3- Multiple emulsion systems of low viscosity which contain a high percentage of both oil and water and Types of emulsions, a small water droplet high concentrations of emulsifier mixture. can be enclosed in larger oil droplet which The dispersed globules are of colloidal is itself dispersed in water. dimensions (1 nm to 1 μm diameter). The alternative o/w/o emulsion is also Microemulsions form spontaneously when possible. the components are mixed in the appropriate ratios and are thermodynamically stable. Tests for identification of emulsion type 1. Miscibility tests 2. Conductivity measurements 3. Cocl2 filter paper test 4. Staining test 5. Fluorescence Test 1. Miscibility tests  In this test the emulsion is diluted either with oil or water. If the emulsion is o/w type and it is diluted with water, it will remain stable as water is the dispersion medium but if it is diluted with oil, the emulsion will break as oil and water are not miscible with each other.  o/w emulsion can easily be diluted with an aqueous solvent whereas water in oil emulsion can be diluted with an oily liquid. 2. Conductivity measurements This test is based on the basic principle that water is a good conductor of electricity. Therefore in case of o/w emulsion this test will be positive as water is the external phase. In this test an assembly consisting of a pair of electrodes connected to a lamp is dipped into an emulsion. If the emulsion is o/w type, the lamp glows. 3. Dye tests In this test, when an emulsion is mixed with a water-soluble dye such as amaranth and observed under the microscope, if the continuous phase appears red, then it means that the emulsion is o/w type as water is the external phase and the dye will dissolve in it to give color but if the scattered globules appear red and continuous phase colorless, then it is w/o type. Similarly, if an oil soluble dye such as Scarlet red C or Sudan III is added to an emulsion and the continuous phase appears red, then it is w/o emulsion. 4. CoCl2/filter paper test Filter paper impregnated with CoCl2 and dried (blue) changes to pink when o/w emulsion is added 5. Fluorescence test If an emulsion on exposure to ultra-violet radiations shows continuous florescence under microscope, then it is w/o type and if it shows only spotty fluorescence, then it is o/w type. Formulation of emulsion Choice of Choice of oily Choice of aqueous emulsion type phase phase Choice of Other formulation Emulsion consistency emulsifying agent additives Choice of emulsion type Oral administration: (O/W) Fats or oils, either as medicaments, or as vehicles for The emulsion type depends upon the route of oil-soluble drugs, are formulated as o/w emulsions. in this form administration and whether it will be applied they are pleasant to be taken. internally or externally Intravenous administration : (o/w) Intramuscular injections: (w/o) Mainly for depot therapy External application Creams can be formulated as o/w or w/o: Creams of O/W emulsion type have the following characters: They are used for local effect. They don’t have greasy texture. They are pleasant to be used and easily washed from the skin surface. Creams of W/O emulsion type have the following characters: They have an occlusive effect by hydrating the upper layers of th stratum corneum. They are useful for cleansing the skin of oil-soluble dirt. They can be formulated as moisturizing creams as they prevent moisture loss from the skin. Choice of oil phase 1. Oil can act as an active ingredient 2. Carrier for active agent in emulsions 1- Oil phase is the active agent When the Oil phase is the active agent, its concentration in the product should be predetermined Examples of medicaments Liquid paraffin, castor oil, cod liver and arachis oil are examples of medicaments which are formulated as emulsion for oral administration. Cottonseed oil, soya bean oil and safflower oil are formulated as emulsion for intravenous feeding because of their high calorific value. 2-Oils are used as carriers in case of many emulsions for external applications Liquid paraffin Both soft paraffin and light liquid paraffin can be used individually or in combination with each other (blend). Silicone oils (silicone-based barrier cream) Have water-repellent properties, which permit the formulation of o/w products. Fixed oils (arachis, sesame, cottonseed and maize oils) They are Protein rich and contain useful vitamins and minerals. They can be used orally because of their lack of toxicity They can be used both internally and externally as vehicles. Choice of aqueous phase In addition to water, the aqueous phase may contain water soluble drugs, preservatives, coloring and flavoring agents. Distilled water or deionized water is often used in emulsion preparation, since calcium and magnesium ions of hard water may have adverse effect on the stability of some emulsion especially whose containing soaps as emulsifying agent. Emulsion consistency A w/o preparation will have a greasy texture and often exhibits a higher apparent viscosity than emulsions o/w. This fact is often used to convey a feeling of richness to many cosmetic formulations. A o/w emulsions will, however, feel less greasy or sticky on application to the skin, will be absorbed more readily because of their lower oil content, and can be more easily washed from the skin surface.  For an externally applied product a wide range of emulsion consistencies can be tolerated Emulsion of Low viscosity Examples Emulsions of high apparent viscosity Examples lotions and liniments can be formulated that are dispensed from a flexible plastic container via a nozzle on to the skin for painful or inflamed skin conditions. For external use are termed creams and are of a semisolid consistency. Disadvantage They are usually packed into collapsible plastic or Their tendency to cream easily, especially if aluminum tubes, although large volumes or very high- formulated with a low oil concentration. viscosity products are often packed into glass or It is rarely possible to formulate low-viscosity w/o plastic jars. products because of the consistency of the oil phase.  Choice of Emulsifying Agents depend on: 1- Emulsifying ability 2- Route of administration NB: Most of non-ionic, having a tendency to be less irritant and less toxic than their anionic, and particularly their cationic counterparts. Cationic surfactants in general are toxic even at lower concentrations. The emulgent cetrimide is limited to externally used preparations, where its antiseptic properties are of use.  The naturally occurring materials and their semi-synthetic derivatives, such as the polysaccharides, as well as glycerol esters, cellulose ethers, sorbitan esters and polysorbates would be suitable for internally used pharmaceutical emulsions. The concentrations of ionic emulsifying agents necessary for emulsification will be irritant to the gastrointestinal tract and have a laxative effect, and should not be used for oral emulsions. Parenteral use it must be realized that only certain types of non-ionic material are suitable. These include lecithin, polysorbate 80, methylcellulose, gelatin and serum albumin. Theory of emulsion stabilization When two immiscible liquids, e.g. liquid paraffin and water, are shaken together a temporary emulsion will be formed. The subdivision of one of the phases into small globules results in a large increase in surface area and hence the interfacial free energy of the system. The system is thus thermodynamically unstable. The liquids separate rapidly into two defined layers Emulsifying agents are needed to decrease the surface tension and to stabilize the droplets  Classification of emulsifying agents 1.Surface active agents (monomolecular film)  Many theories explain how emulsifying agents 2.Hydrophilic colloids act in promoting emulsification. (multimolecular film)  No universal theory for emulsification. 3. Finely divided solid particles  Each emulsifying agent depends for its action on different principle to achieve a stable (Particulate film) product. 1- Monomolecular adsorption They reduce interfacial tension because of their adsorption at the oil/water interface to form Surface free energy (W ) monomolecular films. W= γo/w x Δ A Since we must retain a high surface area for the dispersed phase, so any reduction in γo/w, Where: will reduce the surface free energy and hence the tendency for coalescence. γo/w = interfacial tension Δ A = surface area  The dispersed droplets are surrounded by a coherent monolayer (film) that helps to prevent coalescence between two droplets as they approach one another. The presence of a surface charge, cause repulsion between adjacent particles. Surface active agents can Produce both (W/O) and (O/W) emulsions Rule of Bancroft The type of the emulsion is a function of the relative solubility of the surfactant, the phase in which it is more soluble being the continuous phase. The following example of an o/w emulsion will show this. Liquid paraffin 35% Wool fat 1% Cetyl alcohol 1% Emulsifier system 5% Water to 100% The total percentage of oil phase is 37% and the proportion of each is: Liquid paraffin 35/37 x 100 = 94.6% Wool fat 1/37 x 100 = 2.7% Cetyl alcohol 1/37 x 100 = 2.7% The total required HLB number is obtained as follows: Liquid paraffin (HLB 12) 94.6/100 x 12 = 11.4 Wool fat (HLB 10) 2.7/100x10= 0.3 Cetyl alcohol (HLB 15) 2.7/100x15= 0.4 Total required HLB = 12.1 2- Multimolecular adsorption and film formation Hydrated lyophilic colloids Mechanism: 1- Providing a protective sheath around the droplets imparting a charge to the dispersed droplets (so that they repel each other). 2-Swelling to increase the viscosity of the system (so that droplets are less liable to join together). Since hydrocolloids form multilayer films around the droplets are always hydrophilic, they tend to promote the formation of o/w emulsions only. Classification of hydrocolloids 1. Vegetable derivatives. (acacia, tragacanth, agar, pectin, lecithin) 2. Animal derivatives. (gelatin, lanolin, cholesterol) 3. Semi-synthetic agents. (methylcellulose, carboxymethylcellulose) 4. Synthetic agents. (carbomers, PEG and acrylic acid) 3- Finely divided solid particles Examples (Solid particle adsorption) Bentonite (Al2O3.4SiO2.H2O) They are wetted to some degree by both oil and water can act as emulsifying agents. Veegum (Magnesium Aluminum Silicate) This results from their being concentrated at the interface, where they produce a particulate film around the Hectorite dispersed droplets to prevent coalescence. Magnesium hydroxide Aluminum hydroxide Magnesium trisilicate Auxiliary emulsifying agents A variety of fatty acids serve to stabilize emulsions through their ability to thicken the emulsion. Because these agents have only weak emulsifying properties, they are always use in combination with other emulsifiers. Examples Fatty acids (e.g., stearic acid) Fatty alcohols (e.g., stearyl or cetyl alcohol) Fatty esters (e.g., glyceryl monostearate) Other formulation additives Humectants Buffers Glycerol, polyethylene glycol and propylene glycol are examples of suitable humectants that The inclusion of buffers may be necessary to can be incorporated to an emulsion formulation maintain chemical stability, control tonicity or in order to reduce the evaporation of the ensure physiological compatibility. water, either from the packaged product when the closure is removed or from the surface of the skin after application. Density modifiers Antioxidants If the disperse and continuous phases both The efficiency of an antioxidant in a product have the same densities, then sedimentation or will depend on many factors, including its creaming will not occur. compatibility with other ingredients, its Minor modifications to the aqueous phase of an oil/water partition coefficient, the extent of emulsion by incorporating sucrose, dextrose, its solubilization within micelles of the glycerol or propylene glycol can be achieved, but emulgent, and its sorption on to the container this can only be possible over a small temperature and its closure. range. Methods of emulsion preparation 1- Small Scale a-Dry gum method Dry gum method is used to prepare the initial or primary emulsion from oil, water, and a hydrocolloid or "gum" type emulsifier (usually acacia). B-Wet gum method (English method) In this method, the proportions of oil, water, and emulsifier are the same (4:2:1), but the order and techniques of mixing are different. C-Bottle method This method may be used to prepare emulsions of volatile oils, or oleaginous substances of very low viscosities. D-Auxiliary method An emulsion prepared by other methods can also usually be improved by passing it through a hand homogenizer, which forces the emulsion through a very small orifice, reducing the dispersed droplet size to about 5 microns or less. Dry gum method The primary emulsion, or emulsion nucleus, is formed from 4 parts oil, 2 parts water, and 1 part emulsifier. In a mortar, the 1-part gum (e.g., acacia) is levigated with the 4 parts oil until the powder is thoroughly wetted; the 2 parts water are added all at once, and the mixture is continually triturated until the primary emulsion formed is creamy white. Additional water or aqueous solutions may be incorporated after the primary emulsion is formed. Solid substances (e.g., active ingredients, preservatives, color, flavors) are generally dissolved and added as a solution to the primary emulsion. Oil soluble substance, in small amounts, may be incorporated directly into the primary emulsion. Any substance which might reduce the physical stability of the emulsion, such as alcohol (which may precipitate the gum) should be added as near to the end of the process as possible to avoid breaking the emulsion. When all agents have been incorporated, the emulsion should be transferred to a calibrated vessel, brought to final volume with water, then homogenized or blended to ensure uniform distribution of ingredients. Wet gum method (English method) In this method, the proportions of oil, water, and emulsifier are the same (4:2:1), but the order and techniques of mixing are different. The 1-part gum is triturated with 2 parts water to form mucilage; then the 4 parts oil is added slowly, in portions, while triturating. After all the oil is added, the mixture is triturated for several minutes to form the primary emulsion. Then other ingredients may be added as in the continental method. Bottle method This method may be used to prepare emulsions of volatile oils, or oleaginous substances of very low viscosities. One-part powdered acacia (or other gum) is placed in a dry bottle and four parts oil are added. The bottle is capped and thoroughly shaken. To this, the required volume of water is added all at once, and the mixture is shaken thoroughly until the primary emulsion forms. It is important to minimize the initial amount of time the gum and oil are mixed.  2- Large Scale Turbine mixer For large scale production, it requires very powerful rate of shearing to produce very small globule sizes. Examples of equipment High speed impellers a- High speed impellers b-Turbine mixer c- Homogenizer d- Ultrasonic vibrations e- Colloid mills Homogenizer Colloid mill Quality control tests for emulsions 2. Determination of viscosity To assess the changes that might take place during aging. Emulsions exhibit non-newtonian type of flow characteristics. The viscometers which should be used include cone and plate viscometers. Capillary and falling sphere type of visacometrs should be avoided. 3. Determination of phase separation Phase separation may be observed visually or by measuring the volume of the separated phases. 4. Determination of electrophoretic properties 1. Determination of particle size and particle count Determination of electrophoretic properties like zeta potential is useful for assessing flocculation since electrical Determination of changes in the average particle size charges on particles influence the rate of flocculation. or the size distribution of droplets is an important O/W emulsion having a fine particle size will exhibit low parameter used for the evaluation of emulsions. resistance but if the particle size increase, then it Performed by optical microscopy, sedimentation by indicates a sign of oil droplet aggregation and instability. Coulter counter apparatus. Stability of emulsion Stability problems of emulsion may be due to physical, chemical, microbiological factors, or adverse storage conditions. Physical instability The stability of an emulsion is characterized by the absence of coalescence of the internal phase, the absence of creaming, and maintenance of elegance with respect to appearance, odor, color, and other physical properties. An emulsion becomes physically unstable due to: 1- Creaming 2- Breaking 3- Coalescence 4- Phase inversion Creaming and sedimentation Creaming is the upward movement of dispersed droplets relative to the continuous phase. While sedimentation, the reverse process, is the downward movement of particles. These processes take place due to the density differences in the two phases and can be reversed by shaking. Creaming is undesirable, because a creamed emulsion increases the possibility of coalescence due to the close nearness of the globules in the cream. The rate of creaming is decreased by: 1- Production of an emulsion of small droplet size. Which depends on: Method of manufacture Efficiency of emulsifier (product of fine globule size) homogenization of emulsion decrease globule size. \ 2- Increase in the viscosity of the continuous phase. This is done by: Addition of auxiliary emulsifying agents (hydrophilic colloids). Inclusion of methylcellulose Addition of soft paraffin. Storage of the product at a low temperature 3- Reduction density difference between two phases. (Impossible to be achieved). Breaking, coalescence and aggregation Breaking and Creaming Creaming is different from breaking, since creaming is a reversible process, whereas breaking is irreversible. When breaking occurs, simple mixing fails to resuspend the globules in a stable emulsified form, since the film surrounding the particles has been destroyed and the oil tends to coalesce. Coalescence Coalescence is the process by which emulsified particles merge with each other to form large particles. The major factor preventing coalescence is the mechanical strength of the interfacial barrier. Formation of a thick interfacial film is essential for minimal coalescence. Aggregation or flocculation Aggregation, the dispersed droplets come together but do not fuse. Aggregation is to some extent reversible. Phase inversion An emulsion is said to invert when it changes from an o/w to a w/o emulsion or vice versa. Inversion can occur by: 1- Changing the phase volume ratio. The incorporation of excessive amounts of disperse phase> 60%, may cause cracking or phase inversion. 2- Any additive that alters the HLB of the emulsifier may alter the emulsion type. For example, an o/w emulsion stabilized with sodium stearate can be inverted to an w/o emulsion by adding calcium chloride to form calcium stearate 3-Emulsions stabilized with non-ionic emulsifying agents may invert on heating. (Its HLB is altered). Chemical instability Chemical instability can cause the coalescence of emulsion. 1- Chemical incompatibility of ionic emulsifying agents with the cationic active drugs or with the other emulsion ingredients. 2- The presence of electrolyte, which may influence the stability of emulsion by Reducing the energy of interaction between adjacent globules Salting out effect, the high concentration of electrolytes cause the emulsifiers to be slipped from their hydrated layers, causing precipitation of emulsion. Phase inversion. For example, o/w emulsion stabilized with sodium stearate can be inverted to an w/o emulsion by adding calcium chloride to form calcium stearate. 3-Changes in pH cause breaking of emulsions The emulsion stabilized by soap must be prepared in alkaline pH because acidic pH causes the liberation of free fatty acid of the soap. 4-Precipitation of Emulsifying agents By addition of materials in which they are insoluble. (Precipitation of hydrophilic colloids by the addition of alcohol). 5-Oxidation by atmospheric oxygen or by action of micro-organisms It may lead to rancidity of oil which cause unpleasant odour and taste. Oxidation of microbiological origin is controlled by the use of antimicrobial preservatives and the use of reducing agents (antioxidants). Microbiological contamination Microbiological contamination causes the following physicochemical adverse effects Gas production Color and odour changes Hydrolysis of fats and oils pH changes in the aqueous phase Breaking of the emulsion Sources of contamination Emulsifying agents from natural sources Deionized water, distilled water, if incorrectly stored after collection Propagation of microbial growth in O/W emulsion Adverse storage conditions a-High temperature It may cause one of the following Increase the rate of creaming due to the decrease in the viscosity of continues phase by increasing the temperature. Increase the kinetic motion of dispersed droplets and emulsifying agent which lead to increase the number of collisions between globules, which cause coalescence and cracking of emulsion Coagulation of Certain macromolecular emulsifier. b- Freezing It may cause one of the following: Destruction of adsorbed film of emulgent. Dissolved electrolyte may concentrate in the unfrozen water thus affecting the charge density on the globules. Precipitation of Certain emulsifying agents.  Stability tests of emulsion 1-Macroscopic examination The emulsion is examined for the occurrence of creaming or coalescence over time and the ratio volume of creamed part, and the total volume of emulsion is calculated 2-Globule size analysis The increase in the globules size accompanied with decrease in globules numbers with time indicates coalescence. This is done by using Coulter counter (electronic particle counting devices) or laser diffraction. 3-Viscosity changes Any variation in globule size or globule number or in the emulsifier over time may be detected by a change in apparent viscosity.