2 EmulsionAn emulsion consists of two immiscible liquids one of which is uniformly dispersed through the other as droplets of diameter greater than 0.1 m. The system is stabilized by the presence of emulsifying agent. The particle diameter of the disperse phase extends from 0.1 to 100 m.9/18/2018
18 The HLB or Hydrophilic- Lipophile Balance Each emulsifying agents has a hydrophilic portion (water-loving) and a lipophilic portion (oil-loving) with one or other being more or less predominant and influencingA method indicative of the substances polarity devised and lead to the assigning of an HLB value for each agent. The usual range is between 1 to 20.Materials that are highly polar or hydrophilic have assigned higher numbers than materials that are less polar and were lipophilic.
19 HLB –Hydrophilic Lipophilic Balance HLB is a means of expressing the hydrophilic property of surfactants in figures
20 The HLB System or Hydrophilic-Lipophile Balance Surfactants having an assigned HLB value from 3 to 6 are greatly lipophilic and produce W/O emulsions and those HLB values of from about 8 to 18 produce O/W emulsions.In selecting an Emulsifier for an emulsion, choose one having the same or nearly the same HLB value as the oleaginous phaseExample: Mineral oil has assigned HLB of 4 if a W/O emulsion is desired and a value of 10.5 if O/W emulsion is preparedTherefore, use surfactant SPAN 80 (Sorbitan monoleate) with HLB 4.3 for W/O emulsion and methylcellulose with HLB of 10.5 for O/W.
23 Examples of HLB Values for Selected Emulsifiers PSM (Tween 20)Pluronic FSodium oleatePotassium oleateSodium lauryl sulfate
24 Activity and HLB Value of Surfactants Activity Assigned HLB1. Antifoaming to 32. Emulsifiers (W/O) 3 to 63. Wetting agents 7 to 94. Emulsifiers (O/W) 8 to 185. Solubilizers to 206. Detergents to 15
25 Water in oil emulsifier Oil in water Emulsifiers HLB ValueSignificanceHLB Value123456789101112131415161718UseWater in oil emulsifierOil in water EmulsifiersWetting AgentsDetergentsSolubilizer
26 Emulsifying Agents casein Natural Emulsifying Agents These materials form hydrophilic colloids when added to water and generally produced O/W emulsions. Acacia is most frequently use. Tragacanth and Agar - thickening agents in Acacia emulsified products.These substances produce O/W emulsions. The disadvantage of gelatin is that the emulsion prepared from it are too fluid.Carbohydrates:acacia,tragacanthagar,chondrus,pectinProteinsgelatin,egg yolk,caseinHighMolecularWeightalcoholsThese materials employed primarily as thickening and stabilizing agents for O/W emulsions such as lotion and ointmentsCholesterol may also be employed in externally used emulsion and promote W/O emulsions.stearyl alcohol,cetyl alcohol,glyceryl monostearate
27 Emulsifying Agents Finely Divided Solids These materials generally form O/W emulsions when the insoluble material is added to the aqueous phase if there is greater volume of the aqueous phase than of the oleaginous phaseColloidal clays includingBentonite,Magnesium hydroxideAluminum hydroxideSynthetic(wetting agents), which may be Anionic, Cationic, NonionicAnionic:triethanolamine oleate and sodium lauryl sulfateCationic:benzalkonium chlorideNonionic:sorbitan esters (span); polyethylene glycol 400 monostearate; polyoxyethylene sorbitan esters (Tweens)
28 Qualities Required for Emulsifiers Must be compatible with other ingredients in the formulaMust not interfere with the stability and efficacy of the therapeutic agentMust be stable to microorganismsMust be non-toxicMust possess little or no odor, taste or colorMust promote emulsification and maintain stability of the emulsion for intended shelf-life
29 Pharmaceutical application of emulsions: - Oral, rectal and topical administration of oils and oil-soluble drugs.- The unpleasant taste or odor can be masked by emulsification- The absorption and penetration of medicament are enhanced by emulsification- Intramuscular injections of water-soluble drugs or vaccine to provide slow release.- The use of sterile stable i.v emulsion containing fats, carbohydrates and vitamins as a potential nutrition9/18/2018
31 DIFFERENCE BETWEEN O/W AND W/O EMULSIONS Water in oil emulsion (w/o)Oil in water emulsion (o/w)Oil is the dispersion medium and water is the dispersed phaseWater is the dispersion medium and oil is the dispersed phaseThey are greasy and not water washableThey are non greasy and easily removable from the skin surfaceThey are used externally to prevent evaporation of moisture from the surface of skin e.g. Cold creamThey are used externally to provide cooling effect e.g. vanishing creamOil soluble drugs are more quickly released from w/o emulsionsWater soluble drugs are more quickly released from o/w emulsionsThey are preferred for formulations meant for external use like creams.They are preferred for formulations meant for internal use as bitter taste of oils can be masked.W/O emulsions go not give a positive conductivity test as oil is the external phase which is a poor conductor of electricity.O/W emulsions give a positive conductivity test as water is the external phase which is a good conductor of electricity.9/18/2018
32 Test for identification of emulsion type: Dilution test (miscibility test)Staining test (dye solubility test)Conductivity measurement9/18/2018
34 Dye Solubility TestIn 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 w/o emulsion.9/18/2018
35 Conductivity TestThis test is based on the basic principle that water is a good conductor ofelectricity. Therefore in case of o/w emulsion , this test will be positive aswater is the external phase. In this test. An assembly consisting of a pairof electrodes connected to a lamp is dipped into an emulsion. If the emulsionis o/w type, the lamp glows.9/18/2018
36 Theories of Emulsification 1. Surface Tension Theory2. Oriented-Wedge Theory3. Plastic or Internal Film Theory4. Viscosity Theory
37 Surface Tension Theory A property of liquids in which the exposed surface tends to contract to the smallest possible are. In a spherical drop of liquid there are internal forces that tend to promote the association of the molecule of the substance to resist the distortion of the drop into a less spherical form.
38 Surface Tension Theory The use of substances as emulsifiers and stabilizersResults in the lowering of the interfacial tension of the 2 immiscible liquids, reducing the repellant force between the liquids and diminishing each liquids attraction for its own molecules. These tension lowering substances are referred to as surface active (surfactants) or wetting agents.
39 Oriented-wedge Theory Assumes monomolecular layers of emulsifying agent curved around a droplet of the internal phase of the emulsion.It is based on the presumption that certain emulsifying agents orient themselves about and within a liquid in a manner reflective of their solubility in that particular liquid.An emulsifying agent having a greater hydrophilic character than hydrophobic character will promote an O/w emulsion and a W/O emulsion results through use of more hydrophobic than hydrophilic emulsifiers.
40 Plastic or Interfacial-Film 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.The film prevents the contact and the coalescence of the dispersed phase, the tougher and more pliable (condense) the film, the greater the stability of the emulsion.
41 Viscosity TheoryStates that the viscosity of an emulsion aids emulsification by the mechanical hindrance to coalescence of the globules although it is not the cause of emulsification.
42 Emulsions are Kinetically Stable! Rate of coalescence – measure of emulsion stability.It depends on:Physical nature of the interfacial surfactant filmFor Mechanical stability, surfactant films are characterizedby strong lateral intermolecular forces and high elasticity(Analogous to stable foam bubbles)
43 (b) Electrical or steric barrier Significant only in O/W emulsions.In case of non-ionic emulsifying agents, charge may arise due to(i) adsorption of ions from the aqueous phase or(ii) contact charging (phase with higher dielectric constant is charged positively)No correlation between droplet charge and emulsion stability in W/O emulsionsSteric barrier – dehydration and change in hydrocarbon chain conformation.
44 (c) Viscosity of the continuous phase (many emulsion are more stable in concentrated form than when diluted.)Viscosity may be increased by adding natural or synthetic thickening agents.
45 (d) Size distribution of droplets Emulsion with a fairly uniform size distribution is more stable(e) Phase volume ratioAs volume of dispersed phase stability of emulsion (eventually phase inversion can occur)(f) TemperatureTemperature , usually emulsion stability Temp affects – Interfacial tension, D, solubility of surfactant, viscosity of liquid, phases of interfacial film.
46 Inversion of Emulsions (Phase inversion) O/W W/OThe order of addition of the phasesW O + emulsifier W/OO W + emulsifier O/WNature of emulsifierMaking the emulsifier more oil soluble tends to produce a W/O emulsion and vice versa.Phase volume ratioOil/Water ratio W/O emulsion and vice versa
47 4. Temperature of the system Temperature of O/W makes the emulsifier more hydrophobic and the emulsion may invert to W/O.5. Addition of electrolytes and other additives.Strong electrolytes to O/W (stabilized by ionic surfactants) may invert to W/OExample. Inversion of O/W emulsion (stabilized by sodium cetyl sulfate and cholesterol) to a W/O type upon addition of polyvalent Ca.
48 Phase InversionIn phase inversion o/w type emulsion changes into w/o type and vice versa.It is a physical instability.It may be brought about by the addition of an electrolyte orby changing the phase volume ratio orby temperature changes.Phase inversion can be minimized by using the proper emulsifying agent in adequate concentration,keeping the concentration of dispersed phase between 30 to 60 percentand by storing the emulsion in a cool place.9/18/2018
49 Instabilities In Emulsions An emulsion is a thermodynamically unstable preparation so care has to be taken that the chemical as well as the physical stability of the preparation remains intact throughout the shelf life.There should be no appreciable change in the mean particle size or the size distribution of the droplets of the dispersed phase and secondly droplets of the dispersed phase should remain uniformly distributed throughout the system. Instabilities seen in emulsion can be grouped as:9/18/2018
50 CreamingAn emulsion is said to cream when the oil or fat rises to the surface, but remains in the form of globules, which may be redistributed throughout the dispersion medium by shaking. An oil of low viscosity tends to cream more readily than one of high viscosity. Increasing the viscosity of the medium decreases the tendency to cream. Creaming is a reversible phenomenon which can be corrected by mild shaking.9/18/2018
51 Where V= rate of creaming r=radius of globules The factors affecting creaming are best described by stoke’s law:V= 2r2 (d1-d2) g/9Where V= rate of creamingr=radius of globulesd1= density of dispersed phased2= density of dispersion mediumg= gravitational constant = viscosity of the dispersion medium9/18/2018
52 The following approaches can be used for decreasing Creaming Reduction of globule size: According to stoke’s law, rate of creaming is directly proportional to the size of globules. Bigger is the size of the globules, more will be the creaming. Therefore in order to minimize creaming, globule size should be reduced by homogenization.Increasing the viscosity of the continuous phase: Rate of creaming is inversely proportional to the viscosity of the continuous phase i.e. more the viscosity of the continuous phase, less will the problem of creaming. Therefore to avoid creaming in emulsions, the viscosity of the continuous phase should be increased by adding suitable viscosity enhancers like gum acacia, tragacanth etc.9/18/2018
53 CrackingOccasionally, it happens that an emulsion cracks during preparation, i.e., the primary emulsion does not become white but acquires an oily translucent appearance.In such a case, it is impossible to dilute the emulsion nucleus with water and the oil separates out (irreversible process)Cracking of emulsion can be due to:addition of an incompatible emulsifying agent,chemical or microbial decomposition of emulsifying agent,addition of electrolytes,exposure to increased or reduced temperature or change in pH.9/18/2018
54 Points to be considered during formulations of emulsions Stability of the active ingredientStability of the excipientsVisual appearanceColorOdor (development of pungent odor/loss of fragrance)ViscosityLoss of water and other volatile vehicle componentsConcentration of emulsifierOrder of addition of ingredientsParticle size distribution of dispersed phases9/18/2018
55 Temperature of emulsification Type of equipment pHTemperature of emulsificationType of equipmentMethod and rate of coolingTexture, feel upon application (stiffness, grittiness, greasiness, tackiness, spreadibility)Microbial contamination/sterility (in the unopened container and under conditions of use)Release/bioavailability (percutaneous absorption)Phase distribution, Phase Inversion (homogeneity/phase separation, bleeding9/18/2018
56 Packaging, Labeling and Storage of Emulsions Depending on the use, emulsions should be packed in suitable containers. Emulsions meant for oral use are usually packed in well filled bottles having an air tight closure.Light sensitive products are packed in amber coloured bottles.For viscous emulsions, wide mouth bottles should be used. The label on the emulsion should mention that these products have to be shaken thoroughly before use.External use products should clearly mention on their label that they are meant for external use only.Emulsions should be stored in a cool place but refrigeration should be avoided as this low temperature can adversely effect the stability of preparation.9/18/2018
57 Preservation of Emulsions Preservation from microorganisms:It is necessary to preserve the emulsions from microorganisms as these can proliferate easily in emulsified systems with high water content, particularly if carbohydrates, proteins or steroidal materials are also present.Contamination due to microorganisms can result in problems such as color and odor change, gas production, hydrolysis, pH change and eventually breaking of emulsion.Therefore is necessary that emulsified systems be adequately preserved. An ideal preservative should be nonirritant, nonsensitizing and nontoxic in the concentration used.It should be physically as well as chemically compatible with other ingredients of the emulsions and with the proposed container of the product.It should not impart any taste, color or odor to the product.9/18/2018
58 It should have bactericidal rather than bacteriostatic activity. It should be stable and effective over a wide range of pH and temperature.It should have a wide spectrum of activity against a range of bacteria, yeasts and moulds. The selective preservative should have high water solubility and a low oil/water partition coefficient.It should have bactericidal rather than bacteriostatic activity.9/18/2018
59 parahydroxybenzoate esters such as methyl, propyl and butyl parabens, Examples of antimicrobial preservatives used to preserve emulsified systems includeparahydroxybenzoate esters such as methyl, propyl and butyl parabens,organic acids such as ascorbic acid and benzoic acid,organic mercurials such as phenylmercuric acetate and phenylmercuric nitrate,quarternary ammonium compounds such as cetrimide,cresol derivatives such as chlorocresoland miscellaneous agents such as sodium benzoate, chloroform and phenoxyethano9/18/2018
60 Preservation from oxidation: Oxidative changes such as rancidity and spoilage due to atmospheric oxygen and effects of enzymes produced by micro-organisms is seen in many emulsions containing vegetables and mineral oils and animal fats.Antioxidants can be used to prevent the changes occurring due to atmospheric oxygen.Antioxidants are agents having a high affinity for oxygen and compete for it with labile substances in the formulation.9/18/2018
61 The ideal antioxidant should be: nontoxic, nonirritant, effective at low concentration under the expected conditions of storage and use,soluble in the medium and stable.Antioxidants for use in oral preparation should also be odorless and tasteless.Some of the commonly used antixidants for emulsified systems include alkyl gallate such as ethyl, propyl or dodecyl gallate, butylated hydroxyanisole (BHT), butylated hydroxytoluene (BHT)9/18/2018
63 Preparation of Emulsions Preparation of emulsions depends on the scale at which it is produced.On small scale mortar and pestle can be used but its efficiency is limited. To overcome these drawback small electric mixers can be used although care must be exercised to avoid excessive entrapment of air.For large scale production mechanical stirrers are usedto provide controlled agitation and shearing stressto produce stable emulsions.9/18/2018
64 This method consists of dry gum method and wet gum method. The methods commonly used to prepare emulsions can be divided into two categories:A- Trituration MethodThis method consists of dry gum method and wet gum method.1- Dry Gum MethodIn this method the oil is first triturated with gum with a little amount of water to form the primary emulsion. The trituration is continued till a characteristic ‘clicking’ sound is heard and a thick white cream is formed. Once the primary emulsion is formed, the remaining quantity of water is slowly added to form the final emulsion.9/18/2018
65 2- Wet Gum MethodAs the name implies, in this method first gum and water are triturated together to form a mucilage. The required quantity of oil is then added gradually in small proportions with thorough trituration to form the primary emulsion.Once the primary emulsion has been formed remaining quantity of water is added to make the final emulsion.9/18/2018
66 B- Bottle MethodThis method is employed for preparing emulsions containing volatile and other non-viscous oils. Both dry gum and wet gum methods can be employed for the preparation.As volatile oils have a low viscosity as compared to fixed oils, they require comparatively large quantity of gum for emulsification.In this method, oil or water is first shaken thoroughly and vigorously with the calculated amount of gum. Once this has emulsified completely, the second liquid (either oil or water) is then added all at once and the bottle is again shaken vigorously to form the primary emulsion. More of water is added in small portions with constant agitation after each addition to produce the final volume.9/18/2018
67 Methods for preparing Emulsions for External use: Emulsions meant for external application such as creams, lotions and liniments contain in their formula waxy solids which require melting before mixing.Such emulsions may be prepared by melting the oily components separately at 60 0C.Similarly in another vessel, the aqueous components are mixed and are warmed gently to 60 0C.The aqueous phase is then added to the oily phase at the same temperature and stirred until cold.9/18/2018
68 Table: 1 Proportions of Oil, Water and Gum required for formation of primary emulsion' Type of Oil124Fixed Oil3Mineral OilVolatile Oil9/18/2018
69 Emulsifying Agents are the substances added to an emulsion to prevent the coalescence of the globules of the dispersed phase.They are also known as emulgents or emulsifiers.They act by reducing the interfacial tension between the two phases and forming a stable interfacial film.The choice of selection of emulsifying agent plays a very important role in the formulation of a stable emulsion.No single emulsifying agent possesses all the properties required for the formulation of a stable emulsion therefore sometimes Mixture of emulsifying agents have to be taken.9/18/2018
70 Criteria For The Selection of Emulsifying Agents An ideal emulsifying agent should posses the following characteristics:It should be able to reduce the interfacial tension between the two immiscible liquids.It should be physically and chemically stable , inert and compatible with the other ingredients of the formulation.It should be non irritant and non toxic in the conc., used.It should be organoleptically inert i.e. should not impart any color , odour or taste to the preparation.It should be able to produce and maintain the required viscosity of the preparation.It should be able to form a coherent film around the globules of the dispersed phase and should prevent the coalescence of the droplet of the dispersed phase.9/18/2018
71 1-Natural emulsifying agents from vegetable sources These consist of agents which are carbohydrates and include gums and mucilaginous substances. Since these substances are of variable chemical composition,these exhibit considerable variation in emulsifying properties. They are anionic in nature and produce o/w emulsions. They act as primary emulsifying agents as well as secondary emulsifying agents (emulsion stabilizers).Since carbohydrates acts a good medium for the growth of microorganism, therefore emulsions prepared using these emulsifying agents have to be suitable preserved in order to prevent microbial contamination.E.g. tragacanth, acacia, agar, pectin and starch.9/18/2018
72 2-Natural emulsifying agents from animal source The examples include gelatin, egg yolk and wool fat (anhydrous lanolin). Type A gelatin (Cationic) is generally used for preparing o/w emulsion while type B gelatin is used for o/w emulsions of pH 8 and above. Lecithin and cholesterol present in egg yolk also act as emulsifying agent. They show surface activity and are used for formulating o/w emulsions. However they are used only for extemporaneous preparation and not for commercial preparation as it darken and degrade rapidly in unpreserved systems. Wool fat is mainly used in w/o emulsions meant for external use. They absorb large quantities of water and form stable w/o emulsions with other oils and fats.9/18/2018
73 3- Semi-synthetic polysaccharides Includes mainly cellulose derivatives like sodium carboxy methyl cellulose, hydroxyl propyl cellulose and methyl cellulose.They are used for formulating o/w type of emulsions.They primarily act by increasing the viscosity of the system. e.g., methyl cellulose, hydroxypropyl cellulose and sodium carboxy methyl cellulose.9/18/2018
74 4- Synthetic emulsifying agents This group contains surface active agents which act by getting adsorbed at the oil water interface in such a way that the hydrophilic polar groups are oriented towards water and lipophillic non polar groups are oriented towards oil, thus forming a stable film.This film acts as a mechanical barrier and prevents coalescence of the globules of the dispersed phase.They are classified according to the ionic charge possessed by the molecules of the surfactant e.g., anionic, cationic, non-ionic and ampholytic.9/18/2018
75 4.1. Anionic SurfactantsThe long anion chain on dissociation imparts surface activity, while the cation is inactive.These agents are primarily used for external preparations and not for internal use as they have an unpleasant bitter taste and irritant action on the intestinal mucosa.e.g., alkali soaps, amine soaps, metallic soaps, alkyl sulphates and phosphates and alkyl sulphonates.9/18/2018
76 4.2. Cationic surfactantsThe positive charge cations produced on dissociation are responsible for emulsifying properties.They are mainly used in external preparations such as lotions and creams.Quaternary ammonium compounds such as cetrimide, benzalkonium chloride and benzethonium chloride are examples of important cationic surfactants.These compounds besides having good antibacterial activity are also used in combination with secondary emulsifying agents to produce o/w emulsions for external application.9/18/2018
77 4.3. Non-ionic surfactants They are the class of surfactants widely used as emulsifying agents.They are extensively used to produce both o/w and w/o emulsions for internal as well as external use. The emulsions prepared using these surfactants remain stable over a wide range of pH changes and are not affected by the addition of acids and electrolytes.They also show low irritancy as compared to other surfactants.E.g. glyceryl esters such as glyceryl monostearate, propylene glycol monostearate, macrogol esters such as polyoxyl stearates and polyoxyl-castor oil derivatives, sorbitan fatty acid esters such as spans and their polyoxyethylene derivatives such as tweens (polysorbates).9/18/2018
78 5- Finely Divided Solids This group consist of finely divided solids having balanced hydrophilic lipophillic properties.They accumulate at the oil/water interface and form a coherent interfacial film around the droplets of dispersed phase globules and prevent coalescence.If the solid particles are preferentially wetted by oil, a w/o emulsion is formed while if wetting is done by water then o/w emulsion is seen.e.g., bentonite, aluminium magnesium stearate, attapulgite, colloidal anhydrous silica and hectorite. The emulsions formed using finely divided solids are stable and less prone to microbial contamination.9/18/2018
79 Quality control tests for Emulsions The following are the quality control tests done for emulsions:1. Determination of particle size and particle count: Determination of changes in the average particle size or the size distribution of droplets is an important parameter used for the evaluation of emulsions. It is performed by optical microscopy, sedimentation by using Andreasen apparatus and Coulter counter apparatus.2. Determination of viscosity: Determination of viscosity is done to assess the changes that might take place during aging. Emulsions exhibit non-newtonian type of flow characterstics.The viscometers which should be used include cone and plate viscometers.9/18/2018
80 3. Determination of phase separation: This is another parameter used for assessing the stability of the formulation.Phase separation may be observed visually or by measuring the volume of the separated phases.4. Determination of electrophoretic properties: Determination of electrophoretic properties like zeta potential is useful for assessing flocculation since electrical charges on particles influence the rate of flocculation.O/W emulsion having a fine particle size will exhibit low resistance but if the particle size increase, then it indicates a sign of oil droplet aggregation and instability.9/18/2018
81 Stability testingStability of emulsions is an important parameter for the formulator.Stability testing of emulsions involves determining stability at long term storage conditions, accelerated storage conditions, freezing and thawing conditions. Stress conditions are applied in order to speed up the stability testing.The stress conditions used for speeding up instability of emulsions include:Centrifugal force, Agitational force, Aging and temperatureThe following physical parameters are evaluated to assess the effect of any of the above stress conditions:Phase separationViscosityElectrophoretic propertiesParticle size and particle count9/18/2018