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EMULSIONS.

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An emulsion is essentially a liquid preparation containing a mixture of oil and water that is rendered homogeneous by the addition of an emulsifying agent. The emulsifying agent ensures that the oil phase is finely dispersed throughout the water as minute globules (Figure 4.1). This type of emulsion is termed an ‘oil-inwater’ emulsion. The oily phase (disperse phase) is dispersed through the aqueous phase (continuous phase). Generally all oral dose emulsions tend to be oil-in-water as the oily phase is usually less pleasant to take and more diffi cult to fl avour. ‘Water–in-oil’ emulsions can be formed but these tend to be those withexternal nuses.

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Introduction and overview of emulsions

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The pharmaceutical term ‘emulsion’ is solely used to ndescribe preparations intended for internal use, i.e. via the oral route nof administration. Emulsion formulations for external use are nalways given a different title that refl ects their use, e.g. application, lotion and cream

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Figure 4.1 Illustration of an oil-in-water emulsion..

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British Pharmacopoeia (BP) definition (oral emulsions)

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Oral emulsions are oral liquids containing one or more active ingredients. They are stabilized oil-in-water dispersions, either or both phases of which may contain dissolved solids. Solids may also be suspended in oral emulsions. When issued for use, oral emulsions should be supplied in wide-mouthed bottles.

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Extemporaneous preparation

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In oral emulsions prepared according to the formula and directions given for extemporaneous preparation, the quantity of emulsifying agent specified in individual monographs may be reduced to yield a preparation of suitable consistency provided that by so doing the stability of the preparation is not adversely affected.

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Advantages and disadvantages of emulsions as dosage forms

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Advantages

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–         nUnpalatable oils can be administered in palatable form.

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–         nUnpalatable oil-soluble drugs can be administered in palatable form.

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–         nThe aqueous phase is easily flavoured.

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–         nThe oily sensation is easily removed.

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–         nThe rate of absorption is increased.

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–         nIt is possible to include two incompatible ingredients, one in each phase of the emulsion.

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Disadvantages

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–         nPreparatioeeds to be shaken well before use.

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–         nA measuring device is needed for administration.

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–         nA degree of technical accuracy is needed to measure a dose.

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–         nStorage conditions may affect stability.

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–         nBulky, difficult to transport and prone to container breakages.

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–         nLiable to microbial contamination which can lead to cracking.

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Stability of emulsions

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Emulsions can break down in the following ways:

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–         ncracking

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–         ncreaming

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–         nphase inversion.

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Cracking

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This is the term applied when the disperse phase coalesces and forms a separate layer. Redispersion cannot be achieved by shaking and the preparation is no longer an emulsion. Cracking can occur if the oil turns rancid during storage. The acid formed denatures the emulsifying agent, causing the two phases to separate.

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Creaming

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In creaming, the oil separates out, forming a layer on top of nthe emulsion, but it usually remains in globules so that it can nbe redispersed on shaking (e.g. the cream on the top of a pint of nmilk). This is undesirable as the product appearance is poor and if nthe product is not adequately shaken there is a risk of the npatient obtaining an incorrect dose. Creaming is less likely to occur if nthe viscosity of the continuous phase is increased.

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Phase inversion

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This is the process when an oil-in-water emulsion changes to na water-in-oil emulsion or vice versa. For stability of an nemulsion, the optimum range of concentration of dispersed phase is n30–60% of the total volume. If the disperse phase exceeds this, the stability of the emulsion is questionable. As the concentration of the disperse phase approaches a theoretical maximum of 74% of the total volume, phase inversion is more likely to occur.

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Summary of the problems encountered by emulsions

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Creaming

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Separation of the emulsion into two regions, one containing more of the disperse phase.

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Possible reasons for problem

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–         nlack of stability of the system.

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–         nproduct not homogeneous.

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Can the emulsion be saved?

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The emulsion will reform on shaking.

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Cracking

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The globules of the disperse phase coalesce and there is separation of the disperse phase into a separate layer.

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Possible reasons for problem:

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–         nincompatible emulsifying agent

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–         ndecomposition of the emulsifying agent

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–         nchange of storage temperature.

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Can the emulsion be saved?

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The emulsion will not reform on shaking.

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Phase inversion

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From oil-in-water to water-in-oil or from water-in-oil to oil-in-water.

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Possible reason for problem

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–         namount of disperse phase greater than 74%.

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Can the emulsion be saved?

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The emulsion will not reform on shaking

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General method

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The theory of emulsifi cation is based on the study of the most naturally occurring emulsion, milk. If examined closely, milk will be seen to consist of fatty globules, surrounded by a layer of casein, suspended in water. When a pharmaceutical emulsion is made, the principal considerations are the same. The object is to divide the oily phase completely into minute globules, surround each globule with an envelope of suspending agent (e.g. Acacia BP) and fi nally suspend the globules in the aqueous phase (Figure 4.1). As with other liquid preparations for oral use, emulsions will have in the formulation a vehicle containing added flavouring or colourings as required. nThere is also the need for a preservative, which is usually chloroform, in the form of nDouble Strength Chloroform Water BP. In addition an emulsion will also need an emulsifying agent (or emulgent).

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Continental and dry gum method

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Although emulsions may be made by a variety of methods n(for example, using methylcellulose gum in the preparation of nLiquid ParaffiEmulsion BP: see Example 4.4 below), extemporaneously prepared emulsions for oral administration are usually made nby the continental or dry gum method, where the emulsion is nformed by mixing the emulsifying gum (usually Acacia BP) with the noil which is then mixed with the aqueous phase. The only ndifferences between the continental and dry gum methods are the nproportions of constituents within the primary emulsion (for example, nfixed-oil emulsions made by the continental method would use a ratio nof 4:3:2 rather than 4:2:1 with the dry gum method). Internal emulsions prepared by the dry gum method should contain, in addition to the oil to be nemulsified:

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–         na vehicle

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Freshly boiled and cooled purifi ed water is normally nused because of the increased risk from microbial ncontamination.

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–         na preservative

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This is usually added to the product as Double Strength Chloroform Water BP at 50% of the volume of the vehicle. nIf freshly boiled and cooled purifi ed water is used as the nvehicle, it would be appropriate to manufacture the Double nStrength Chloroform Water BP using freshly boiled and cooled npurified water rather than potable water.

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–         nan emulsifying agent (or emulgent)

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The quantity of emulsifying agent added is determined by nthe type of oil to be emulsifi ed and the quantity of emulsion to nbe prepared

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–         nadditional flavouring if nrequired

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–         nadditional ncolouring if required

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Calculation of the amount of emulsifying agent to be usedin the preparation of an nemulsion

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The amount of emulsifying agent used is dependent on the namount and type of oil to be emulsifi ed. Oils can nbe divided into three categories: fi xed oils, mineral oils and volatile noils.

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Fixed oils

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 Oil: 4 parts by volume

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 Aqueous phase: 2 parts by volume

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 Gum: 1 part by weight

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Mineral oils

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 Oil: 3 parts by volume

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 Aqueous phase: 2 parts by volume

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 Gum: 1 part by weight

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Volatile (aromatic) oils

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 Oil: 2 parts by volume

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 Aqueous phase: 2 parts by volume

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 Gum: 1 part by weight

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These proportions are important when making the primary emulsion, to prevent the emulsion breaking down on dilution nor storage.

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The quantities for primary emulsions (in parts) are summarised in the key points box.

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Wet gum method

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The proportions of oil, water and emulsifying agent for the preparation of the primary emulsion are the same as those used in the dry gum method. The difference is in the method of preparation. Using this method the acacia powder is added to the mortar and then triturated with the water until the gum is dissolved and a mucilage formed. The oil is then nadded to the mucilage drop by drop whilst triturating continuously. Wheearly all the oil has been added the resulting mixture in the mortar may appear a little poor with some of the oil appearing to be absorbed. This can be rectifi ed by the addition of slightly more water. The trituration continues until nall the oil has been added, adding extra small amounts of water wheecessary. When all the oil has been added triturate until a smooth primary emulsion is obtained. In the main, this method has fallen out of favour as it takes much longer than the dry gum method. It should be noted that there is less chance of failure with this method provided the oil is added very slowly and in small quantities. It also means that the reasons for failure when using the dry gum method (outlined above) have been eliminated.

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Clean, dry equipment

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All equipment should be thoroughly cleaned, rinsed with water and carefully dried before use, particularly measures, mortars and pestles.

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Accurate quantities

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Accurate quantities are essential. Check weighing/measuring technique and minimize transference losses; for example, allow oil to drain from measure.

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Have all ingredients ready

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Correct rate of addition is important. Ingredients for the primary emulsion should all be weighed and measured before starting to make the product.

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General method of preparation of an emulsion using the dry gum method

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It is relatively easy for an emulsion to crack, resulting in a failed product. Remember that the key points opposite are critical when preparing emulsions.

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The preparation of an emulsion has two main

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components:

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1. preparation of a concentrate called the primary emulsion

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2. dilution of the concentrate.

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Preparation of the primary emulsion

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1. Measure the oil accurately in a dry measure. Transfer the noil into a large dry porcelain mortar, allowing all the oil to ndrain out.

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2. Measure the quantity of aqueous vehicle required for the primary emulsion. Place this within easy reach.

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3. Weigh the emulsifying agent and place on the oil in the mortar. Mix lightly with the pestle, just suffi cient to ndisperse any lumps. Caution: overmixing generates nheat, which may denature the emulsifying agent and result in a poor nproduct.

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4. Add all of the required aqueous vehicle in none addition. Then mix vigorously, using the pestle with a shearing action in none direction.

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5. When the product becomes white and produces a clicking sound, the primary emulsion has been formed. The product should be a thick, white cream. Increased degree of nwhiteness indicates a better-quality product. Oil globules or slicks nshould not be apparent.

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Dilution of the primary emulsion

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1. Dilute the primary emulsion drop by drop with very small volumes of the remaining aqueous vehicle. Mix carefully nwith the pestle in one direction.

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2. Transfer emulsion to a measure, with rinsings. Add other liquid ingredients if necessary and make up to the final volume.

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Emulsion

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Emulsions are biphasic systems consisting of two immiscible liquids, none of which (the dispersed nphase) is finely subdivided and uniformly dispersed as droplets nthroughout the other phase (the dispersion nmedium).

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Advantages

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1. They can mask the nbitter taste and odor of drugs, nthereby making them more palatable. e.g. castor oil, ncod-liver oil etc.

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2. They can be used to nprolong the release of the drug thereby providing sustained release naction.

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3. Essential nutrients nlike carbohydrates, nfats nand vitamins ncan all be emulsified and can be administered to bed ridden patients as sterile nintravenous emulsions.

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4. Emulsions provide nprotection to drugs which are susceptible to oxidation nor hydrolysis.

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5. Intravenous emulsions nof contrast media have been developed to assist in ndiagnosis.

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6. Emulsions are used nwidely to formulate externally used products like lotions, ncreams, nliniments netc.

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Types Of Emulsions

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1.     nOil in nwater emulsions

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2.     nWater in noil emulsions

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3.     nMultiple nemulsions

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4.     nMicroemulsions n

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DIFFERENCE BETWEEN O/W AND W/O EMULSIONS

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S.No	Oil in water emulsion (o/w)	Water in oil emulsion (w/o)
1.	Water is the dispersion medium and oil is the dispersed phase	Oil is the dispersion medium and water is the dispersed phase
2.	They are non greasy and easily removable from the skin surface	They are greasy and not water washable
3.	They are used externally to provide cooling effect e.g. vanishing cream	They are used externally to prevent evaporation of moisture from the surface of skin e.g. Cold cream
4.	Water soluble drugs are more quickly released from o/w emulsions	Oil soluble drugs are more quickly released from w/o emulsions
5.	They are preferred for formulations meant for internal use as bitter taste of oils can be masked.	They are preferred for formulations meant for external use like creams.
6.	O/W emulsions give a positive conductivity test as water is the external phase which is a good conductor of electricity.	W/O emulsions go not give a positive conductivity test as oil is the external phase which is a poor conductor of electricity.
7.

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Routes of administration of emulsions

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Oral nEmulsions: Generally o/w emulsions are used for internal use as the oil is nmore readily absorbed in a fine state of subdivision through the gastro nintestinal tract and secondly the preparation becomes more palatable when water nforms the continuous phase, as the medicinal oil is enveloped in a thin film of nemulgent which masks the bitter and oily taste of the ndrug like liquid paraffin. Orally emulsions are also used to facilitate the nabsorption of the oil soluble drugs like vitamins A,D, nE and K.

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Example: Liquid Paraffin nOral Emulsion

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Liquid Paraffin 500 nml

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Methyl cellulose 20 n20 ng

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Vanillin n0.5 ng

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Chloroform 2.5 nml

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Benzoic acid solution 20 nml

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Saccharin sodium n0.05 ng

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Purified Water q.s 1000ml

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Uses: Laxative. It acts nas an emollient purgative in chronic constipation especially during pregnancy nand old age.

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Example: Castor oil nEmulsion

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Castor oil 16 nml

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Gum acacia q.s

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Water 80 nml

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Uses: nPurgative

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Example: Cod-Liver oil nEmulsion

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Cod-liver oil 30 nml

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Syrup 12 nml

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Ferric ammonium citrate n4 ng

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Cinnamon water q.s. 90 ml

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Uses: Source of vitamin A nand D. It is used as dietary supplement in infants and children to prevent the noccurance of rickets and to improve nutrition in nundernourished children and patients with rickets.

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Rectal nEmulsions: Enemas are formulated as o/w emulsions.

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Topical nEmulsions: For external use, emulsions may be either o/w or w/o type. Emulsions nfinds the maximum use in topical preparations , both nfor therapeutic and cosmetic use. Therapeutically they are used as carrier for a ndrug. In cosmetic industry o/w emulsions have been used for formulation of moisturing lotions, hand lotions and make up foundation nlotions. When oily layers are desired to prevent moisture loss from the surface nof skin, for barrier action and for cleansing action, then w/o emulsions are nformulated like cold creams.

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Example: Antiseptic ncream

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Cetrimide 1g

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Cetostearyl alcohol n10 ng

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White soft paraffin n10 ng

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Liquid paraffin n29 ng

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Purified water n50 ng

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Uses: Antiseptic cream nfor the treatment of cuts, wounds and nburns.

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Example: Cold nCream

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Liquid paraffin n20 ng

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Hard paraffin n4.5 ng

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Lanette wax 3.5 g

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Glycerine 4.5 g

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Water n17.5 ng

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Propyl paraben 0.1 ng

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Uses: Skin protective and nskin smoothner.

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EMULSIFYING AGENTS

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These are the substances added to an emulsion to prevent the coalescence nof the globules of the dispersed phase. They are also known as emulgents or emulsifiers. These agents have both a nhydrophilic and a lipophilic part in their chemical nstructure. All emulsifying agents concentrate at and are adsorbed onto the noil/water interface to provide a protective barrier around the dispersed ndroplets. In addition to this protective barrier, emulsifiers stabilize the nemulsion by reducing the interfacial tension of the system. Some agents enhance nstability by imparting a charge on the droplet surface thus reducing the nphysical contact between the droplets and decreasing the potential for ncoalescence. Thus these act in three ways:

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1) Formation of a protective barrier

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2) Reduction of interfacial tension

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3) Decreasing the potential for coalescence by forming an electrical ndouble layer

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Interfacial phenomena

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Interfacial phenomena occurs at the limit between two immiscible phases, so-called surface or ninterface. When one phase is fragmented into (small) pieces which are dispersed nin another (continuous) phase, a so-called dispersion or dispersed system is nproduced.

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Emulsifying agents have two fundamental properties. On one hand they ntend to be located preferentially at the interface between a polar and a nonpolar phase. The phenomenon according to which a molecule ncomes from the bulk of a solution to place itself at the interface (with some nspecific orientation) is called adsorption, and is characteristic of many amphiphilic molecules. On the other hand surfactant nmolecules in solution exhibit a tendency to self associate to produce naggregation polymer called micelles, as well as other nstructures.

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All the properties of surfactant solutions come from one of these nfundamental properties.

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Amphiphile

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An amphiphile is a chemical substance that npossesses some affinity for both the polar substances and the apolar ones. Generally speaking these affinities are nreferred to as hydrophilic and lipophilic (or nhydrophobic) respectively since the polar solvents are in most cases aqueous nsolutions and the apolar phases are organic n”oils”.

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Most amphiphilic substances are surfactants, ni.e., substances that are preferentially located at a surface or interface, nwhere the polarity changes drastically within a few angstroms of ndistance.

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Adsorption

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When a surfactant molecule goes to the interface and locates itself nthere with some preferential orientation, it is said that the molecule is nadsorbed. Adsorption is a spontaneous phenomenon which is driven by a reduction nof the energy when the surfactant lyophobic group is nremoved from the solvent, and when one or both affinities are satisfied nrespectively at a surface or at an interface.

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Adsorption is a dynamic phenomenon which is opposed by desorption, i.e., the transfer of a surfactant molecule to a nbulk phase. The adsorption and desorption steps are noften very rapid; as a consequence an adsorption-desorption equilibrium is reached after some time, which ndepends upon the surfactant concentration in the bulk nphase.

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Since the surfactant molecule has a lower free energy when it is nadsorbed at interface than in the solvent bulk phase, the equilibrium is very nmuch displaced toward the adsorbed state. In fact the interface is very rapidly ncovered by a monolayer of surfactant molecules. In such monolayer the molecules nare arranged in some specific pattern which depends upon structural and ngeometrical characteristics.

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Self-Association

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The second fundamental property of surfactant molecules is their ncapability of self-association in aqueous or non aqueous nsolutions.

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The tendency of the surfactant molecules to associate depends upon the nformation of an adsorbed monolayer, which is the first step of surfactant nassociation.

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When the surfactant concentration increases in the aqueous phase, the nsurfactant molecules first saturate the interface, and then accumulate in the nsolution. Each time a new surfactant molecule is added to the solution, the nunfavorable interaction between the surfactant hydrophobic tail and the water nmolecules is increased. At some point the surfactant molecules start aggregating ninto the so-called micelles, a self-association structure in which the nhydrophobic tail is removed from the aqueous environment. The concentration at nwhich the first micelles are formed is called the Critical Micelle nConcentration, which is abbreviated as CMC. The CMC is the concentration at nwhich the factors which favor the formation of the micelle (for instance the nhydrophobic effect) start dominating the effects which oppose nit.

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Micellar solutions are able to solubilize different nkinds of substance, and this capacity of solubilization is one of the most important properties of nthe surfactant solutions. Hydrophobic substances, i.e., oils, can be solubilized inside the micelles core, sometimes in very nsizeable amounts. Some extreme cases are known in which the solubilized oil volume is actually larger than the aqueous nsolvent volume; for such situation to happen, the solution must contain a very nlarge number of micelles and the micelles must be considerably swollen. These nmicelles are no longer spherical, but cigar shaped or hexagonally packed or even ndegraded into lamellar liquid crystals.

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The choice of selection of emulsifying agent plays a very important role nin the formulation of a stable emulsion. No single emulsifying agent possesses nall the properties required for the formulation of a stable emulsion therefore nsometimes blends of emulsifying agents have to be taken.

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CRITERIA FOR THE SELECTION OF EMULSIFYING AGENTS

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An ideal emulsifying agent should posses the following ncharacteristics:

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It should be able to reduce the interfacial tension between the two nimmiscible liquids. It should be physically and chemically stable, inert and ncompatible with the other ingredients of the formulation. It should be ncompletely non irritant and non toxic in the concentrations used. It should be norganoleptically inert i.e. should not impart any ncolour, odour or taste to nthe preparation. It should be able to form a coherent film around the globules nof the dispersed phase and should prevent the coalescence of the droplets of the ndispersed phase. It should be able to produce and maintain the required nviscosity of the preparation.

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CLASSIFICATION OF EMULSIFYING AGENTS

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Emulsifying agents can be classified as:

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1. Natural Emulsifying agents: A large number of emulsifiers are natural nproducts derived from plant or animal tissue. Most of the emulsifiers form nhydrated lyophilic colloids (called hydrocolloids) nthat form multimolecular layers around emulsion ndroplets. Hydrocolloid type emulsifiers have little or no effect on interfacial ntension, but exert a protective colloid effect, reducing the potential for ncoalescence, by:

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· providing a protective sheath around the ndroplets

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· imparting a charge to the dispersed droplets (so that they repel each nother)

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· swelling to increase the viscosity of the system (so that droplets are nless likely to merge)

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Natural emulsifying agents from vegetable sources: These consist of nagents which are carbohydrates and include gums and nmucilaginous substances. Since these substances are of variable chemical ncomposition, these exhibit considerable variation in emulsifying properties. nThey are anionic iature and produce o/w emulsions. They act as primary nemulsifying agents as well as secondary emulsifying agents (emulsion nstabilizers). Since carbohydrates acts a good medium for the growth of nmicroorganism, therefore emulsions prepared using these emulsifying agents have nto be suitable preserved in order to prevent microbial contamination. E.g. tragacanth, acacia, agar, chondrus n(Irish Moss), pectin and starch.

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Gum acacia

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It is generally used in the concentration of 8-15% and gives a stable nand palatable emulsion over the pH range of 2-10. Emulsions tend to cream using nthis as the viscosity is low.

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Tragacanth

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Used in the concentration range of 1-2%. Rarely used now because it nforms thick and coarse emulsions.

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Agar

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Used in the concentration of 2%.  n

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Starch

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Used in concentration of 2-5%. Rarely used because it forms coarse emulsions.

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Pectin

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Used as 1%. Acts as emulsion stabiliserin acacia emulsion.

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Natural emulsifying agents from animal source: The examples include ngelatin, egg yolk and wool fat (anhydrous lanolin). Type A gelatin (Cationic) is generally used for preparing o/w nemulsion while type B gelatin is used for o/w emulsions of pH 8 and above. nLecithin and cholesterol present in egg yolk also act as emulsifying agent. They nshow surface activity and are used for formulating o/w emulsions. However they nare used only for extemporaneous preparation and not for commercial preparation nas it darken and degrade rapidly in unpreserved systems. Wool fat is mainly used nin w/o emulsions meant for external use. They absorb large quantities of water nand form stable w/o emulsions with other oils and fats. Animal derivatives are nmore likely to cause allergic reactions and are subject to microbial growth and nrancidity. Their advantage is their ability to support formation of w/o ncreams.

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Gelatin

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Used in concentration of 1%. Two grades are available-Pharmagol A which nhas an acidic pH and Pharmagol B, which has an nalkaline pH. Emulsions prepared have agreeable taste but are prone to bacterial ncontamination.  Gelatin is used for npreparing o/w emulsions.

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Egg yolk

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It contains lecithin which is a phospholipids acting as an nemulsifier.  Used in concentration nrange of 12-15%. Mainly used for extemporaneous preparation as long term nstability is a problem.  It forms nstable o/w emulsions, which needs to be refrigerated to prolong shelf life. n

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2. Semi-synthetic polysaccharides: Includes mainly cellulose derivatives nlike sodium carboxy methyl cellulose, hydroxyl propyl cellulose and methyl cellulose. They are used for nformulating o/w type of emulsions. They are nontoxic, and are less subject to nmicrobial growth. They primarily act by increasing the viscosity of the system. ne.g., methyl cellulose, hydroxypropyl cellulose and sodium carboxy methyl cellulose.

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Methyl cellulose

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This is non ionic iature and is stable over a wide pH range. It is nmainly used for emulsification of mineral and vegetables oil. Drawback is that nit gets precipitated in the presence of large quantities of nelectrolytes.

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Sodium carboxymethyl ncellulose

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It is anionic iature. Acts as an true nemulsifier and emulsion stabilizer.

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3. Synthetic emulsifying agents: This group contains surface active nagents which act by getting adsorbed at the oil water interface in such a way nthat the hydrophilic polar groups are oriented towards water and lipophillic non polar groups are oriented towards oil, thus nforming a stable film. This film acts as a mechanical barrier and prevents ncoalescence of the globules of the dispersed phase. They are classified naccording to the ionic charge possessed by the molecules of the surfactant e.g., nanionic, cationic, non-ionic and ampholytic.

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Anionic Surfactants: The long anion chain on dissociation imparts nsurface

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activity, while the cation is inactive. These agents nare primarily used for    n

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external preparations and not for internal use as they have an unpleasant nbitter

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taste and irritant action on the intestinal mucosa. e.g., alkali soaps, amine nsoaps,

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metallic soaps, alkyl sulphates and phosphates and nalkyl sulphonates.

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Alkali soaps

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Produce good oil in water emulsions. Unstable at pH below 10 and are nincompatible with acids and polyvalent inorganic and long chain organic cations.

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Amine soaps

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Used for preparing o/w emulsions. Stable to the presence of calcium ions nor changes in pH  n

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Bold text Metallic soaps

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Generally used for formulating w/o emulsions. They are usually insoluble nin water

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Alkyl sulphates and nphosphates

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They form o/w emulsions.

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Alkyl sulponates

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Used mainly as wetting agents and form stable o/w emulsions along with a nsecondary emulsifying agent.

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Cationic surfactants: The positive charge cations produced on dissociation are responsible for nemulsifying properties. They are mainly used in external preparations such as nlotions and creams. Quaternary ammonium compounds such as cetrimide, benzalkonium chloride nand benzethonium chloride are examples of important ncationic surfactants. These compounds besides having good antibacterial activity nare also used in combination with secondary emulsifying agents to produce o/w nemulsions for external application.

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Non-ionic surfactants: They are the class of surfactants widely used as nemulsifying agents. They are extensively used to produce both noil in water and water in oil emulsions for internal as well as external nuse. The emulsions prepared using these surfactants remain stable over a nwide range of pH changes and are not affected by the addition of acids and nelectrolytes. They also show low irritancy as compared to other surfactants. nE.g. glyceryl esters such as glyceryl monostearate, propylene nglycol monostearate, macrogol esters such as polyoxyl nstearates and polyoxyl-castor oil derivatives, sorbitan fatty acid esters such as spans and their polyoxyethylene derivatives such as tweens (polysorbates).

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Ampholytic surfactants: These are the substances whose ionic charge depends on the npH of the system. Below a certain pH, these are cationic while above a defined npH, these are cationic. At intermediate pH these behave as zwitterions. e.g. lecithin.

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4. Finely Divided Solids: This group consists of finely divided solids nhaving balanced hydrophilic lipophillic properties. nThey accumulate at the oil/water interface and form a coherent interfacial film naround the droplets of dispersed phase globules and prevent coalescence. If the solid particles are preferentially wetted by oil, a w/o nemulsion is formed while if wetting is done by water then o/w emulsion is nseen. e.g., bentonite, aluminium magnesium stearate, nattapulgite, colloidal anhydrous silica and hectorite. The emulsions formed using finely divided nsolids are stable and less prone to microbial ncontamination.

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5. Auxillary Emulsifying nAgents

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A variety of fatty acids (e.g., stearic acid), nfatty alcohols (e.g., stearyl or cetyl alcohol), and fatty esters (e.g., glyceryl monostearate) serve to nstabilize creams through their ability to thicken the emulsion. Because these nagents have only weak emulsifying properties, they are always used in ncombination with other emulsifiers.

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n

Selection of Emulsifying Agents using HLB method

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A system was developed in 1949 by William C. Griffin to assist making nsystemic decisions about the amounts and types of surfactants needed in stable nproducts. The system is called the HLB (hydrophile-lipophile balance) system and has an arbitrary nscale of 1 – 18. HLB numbers are experimentally determined for the different nemulsifiers.

n

    HLB RANGE                    nUSE

n

 

n

0-3 Antifoaming agents

n

 

n

4-6 W/O emulsifying agent

n

 

n

7-9 Wetting agents

n

 

n

8-18 O/W emulsifying agent

n

 

n

13-15 Detergents

n

 

n

10-18 Solubilizing nagents

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n

An emulsifier having a low HLB number indicates that the number of nhydrophilic groups present in the molecule is less and it has a lipophillic character. For example, spans generally have low nHLB number and they are also oil soluble. Because of their oil soluble ncharacter, spans cause the oil phase to predominate and form a w/o nemulsion.

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n

A higher HLB number indicate that the emulsifier has a large number of nhydrophilic groups on the molecule and therefore is more hydrophilic in ncharacter. Tweens have higher HLB numbers and they are nalso water soluble. Because of their water soluble character, tweens will cause the water phase to predominate and form an no/w emulsion.

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DISADVANTAGE OF THE HLB SYSTEM

n

 

n

It does not take into account:

n

– the effect of ntemperature

n

– the presence of nadditives

n

– the concentration of nemulsifier

n

 

n

HLB values of some common emulsifying agents

n

Emulsifying Agent : HLB nValue

n

Acacia: 8

n

Polysorbate 20 (Tween 20): 16.7

n

Polysorbate 60: (Tween 60): 14.9

n

Polysorbate 80 (Tween 80): 15

n

Oleic acid: 4.3

n

Sorbitan monolaurate (Span 20): n8.6

n

Sorbitan monolaurate (Span 60): n4.7

n

Sorbitan monolaurate (Span 80): n4.3

n

Tests Used To Identify Emulsion Type

n

Since emulsion (o/w nor w/o) looks the same in appearance with naked eyes, therefore certain tests nhave been developed to differentiate between them. At least two tests should be ndone to reach a conclusive decision about the identity of the nemulsion.

n

 

n

Dilution test

n

In this test the emulsion nis diluted either with oil or water. If the emulsion is o/w ntype and it is diluted with water, it will remain stable as water is nthe dispersion medium but if it is diluted with oil, the emulsion will break as noil and water are not miscible with each other. Oil in water emulsion can easily nbe diluted with an aqueous solvent whereas water in oil emulsion can be diluted nwith a oily liquid.

n

n

Fig: Dilution Testfor oil in water emulsion

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n

n

Fig: Dilution test for nwater in oil emulsion

n

 

n

Conductivity Test

n

This test is based on the nbasic principle that water is a good conductor of electricity. Therefore in case nof o/w nemulsion , this test will be positive as water is the external phase. nIn this test. An assembly consisting of a pair of nelectrodes connected to a lamp is dipped into an emulsion. If the emulsion is no/w type, the lamp glows.

n

n

Fig: Conductivity test nfor oil in water emulsion

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n

n

 

n

Fig: Conductivity test for water in oil emulsion

n

 

n

Dye Solubility Test

n

In this test, when an nemulsion is mixed with a water soluble dye such as amaranth and observed under nthe microscope, nif the continuous phase appears red, then it means that the emulsion is o/w type nas water is the external phase and the dye will dissolve in it to give color but nif the scattered globules appear red and continuous phase colorless, then it is nw/o type. Similarly if an oil soluble dye such as Scarlet red C or Sudan III is nadded to an emulsion and the continuous phase appears red, then it w/o nemulsion.

n

n

Fig: Dye solubility ntest

n

Cobalt Chloride Test

n

When a filter paper nsoaked in cobalt chloride solution is added to an emulsion and dried, it turns nfrom blue to pink, indicating that the emulsion is o/w ntype.

n

Fluorescence Test

n

If an emulsion on nexposure to ultra-violet radiations shows continuous florescence nunder microscope, nthen it is w/o ntype and if it shows only spotty fluorescence, then it is Oil in o/w ntype.

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n

Instabilities In nEmulsions

n

An emulsion is a nthermodynamically unstable preparation so care has to be taken that the chemical nas well as the physical stability of the preparation remains intact throughout nthe shelf life. There should be no appreciable change in the mean particle size nor the size distribution of the droplets of the dispersed phase and secondly ndroplets of the dispersed phase should remain uniformly distributed throughout nthe system. Instabilities seen in emulsion can be grouped nas

n

Creaming

n

An emulsion is said to ncream when the oil or fat rises to the surface, but remains in the form of nglobules, which may be redistributed throughout the dispersion medium by nshaking. An oil of low viscosity tends to cream more readily than one of high nviscosity. Increasing the viscosity of the medium decreases the tendency to ncream. Creaming is a reversible phenomenon which can be corrected by mild nshaking. The factors affecting creaming are best described by stroke’s nlaw

n

V= 2r2 (d1-d2) ng/9η

n

Where V= rate of ncreaming

           r=radius of globules

           d1= density of dispersed phase 

           d2= density of dispersion medium

            g= gravitational constant

η = viscosity of the dispersion medium

n

 

n

The following approaches ncan be used for decreasing Creaming

n

Reduction of globule nsize: nAccording to stroke’s law, rate of creaming is directly nproportional to the size of globules. Bigger is the size of the globules, more nwill be the creaming. Therefore in order to minimize creaming, globule size nshould be reduced by homogenization.

n

Increasing the viscosity nof the continuous phase: Rate of creaming is ninversely proportional to the viscosity of the continuous phase i.e. more the nviscosity of the continuous phase, less will the problem of ncreaming. Therefore to avoid creaming in emulsions, the viscosity of the ncontinuous phase should be increased by adding suitable viscosity enhancers like ngum acacia, tragacanth etc.

n

Cracking

n

Occasionally, it happens nthat an emulsion cracks during preparation, i.e., the primary emulsion does not nbecome white but acquires an oily translucent appearance. In such a case, it is nimpossible to dilute the emulsioucleus with water and the oil separates out. nCracking of emulsion can be due to addition of an incompatible emulsifying nagent, chemical or microbial decomposition of emulsifying agent, addition of nelectrolytes, exposure to increased or reduced temperature or change in npH.

n

Phase Inversion

n

In phase inversion o/w ntype emulsion changes into w/o type and vice versa. It is a physical ninstability. It may be brought about by the addition of an electrolyte or by nchanging the phase volume ratio or by temperature changes. Phase inversion can nbe minimized by using the proper emulsifying agent in adequate concentration, nkeeping the concentration of dispersed phase between 30 to 60 % and by storing nthe emulsion in a cool place.

n

Points to be considered during formulations of nemulsions

n

Stability of the nactive ingredient

n

Stability of the excipients

n

Visual nappearance

n

Color

n

Odor (development of npungent odor/loss of fragrance)

n

Viscosity, extrudability

n

Loss of water and other nvolatile vehicle components

n

Concentration of nemulsifier

n

Order of addition of ningredients

n

Particle size ndistribution of dispersed phases

n

pH

n

Temperature of nemulsification

n

Type of nequipment

n

Method and rate of ncooling

n

Texture, feel upon napplication (stiffness, grittiness, greasiness, tackiness, spreadibility)

n

Microbial ncontamination/sterility (in the unopened container and under conditions of nuse)

n

Release/bioavailability n(percutaneous absorption)

n

Phase distribution, Phase nInversion (homogeneity/phase separation, bleeding

n

Packaging, Labelling And Storage Of Emulsions

n

Depending on the use, nemulsions should be packed in suitable containers. Emulsions meant for oral use nare usually packed in well filled bottles having an air tight closure. Light nsensitive products are packed in amber coloured nbottles. For viscous emulsions, wide mouth bottles should be used. The label on nthe emulsion should mention that these products have to be shaken thoroughly nbefore use. External use products should clearly mention on their label that nthey are meant for external use only. Emulsions should be stored in a cool place nbut refrigeration should be avoided as this low temperature can adversely effect the stability of preparation.

n

 

n

Preservation Of nEmulsions

n

Preservation from nmicroorganisms:

n

It is necessary to npreserve the emulsions from microorganisms nas these can proliferate easily in emulsified systems with high water ncontent, particularly if carbohydrates, nproteins nor steroidal materials are also present.

n

Contamination due to nmicroorganisms can result in problems such as color and odor change, gas nproduction, hydrolysis, pH change and eventually breaking of emulsion. Therefore nis necessary that emulsified systems be adequately preserved. An ideal preservative nshould be nonirritant, nonsensitizing and nontoxic in nthe concentration used. It should be physically as well as chemically compatible nwith other ingredients of the emulsions and with the proposed container of the nproduct. It should not impart any taste, color or odor to the product. It should nbe stable and effective over a wide range of pH and temperature. It should have nhave a wide spectrum of nactivity against a range of bacteria, yeasts and moulds. The selective npreservative should have high water solubility and a low oil/water partition ncoefficient. It should have bactericidal nrather than bacteriostatic nactivity.

n

Examples of antimicrobial npreservatives used to preserve emulsified systems include parahydroxybenzoate esters such as methyl, propyl and butyl parabens, organic nacids such as ascorbic nacid and benzoic nacid, organic mercurials such as phenylmercuric acetate and phenylmercuric nitrate, quarternary ammonium compounds such as cetrimide, cresol derivatives such as chlorocresol and miscellaneous agents such as sodium nbenzoate, chloroform and phenoxyethanol.

n

Preservation from noxidation:

n

Oxidative changes such as nrancidity and spoilage due to atmospheric oxygen and effects of enzymes produced nby micro-organisms is seen in many emulsions containing vegetables and mineral noils and animal fats. Antioxidants ncan be used to prevent the changes occurring due to atmospheric noxygen.

n

Antioxidants are agents nhaving a high affinity for oxygen and compete for it with labile substances in nthe formulation. The ideal antioxidant should be nontoxic, nonirritant, neffective at low concentration under the expected conditions of storage and use, nsoluble in the medium and stable. Antioxidants for use in oral preparation nshould also be odorless and tasteless.

n

Some of the commonly used nantixidants for emulsified systems include alkyl gallate such as ethyl, propyl or ndodecyl gallate, butylated sshydroxyanisole (BHT), nbutylated hydroxytoluene n(BHT)

n

 

n

 

n

Preparation Of Emulsions

n

 

n

Preparation of emulsions depends on the scale at which it is produced. nOn small scale mortar and pestle can be used but its efficiency is limited. To novercome these drawback small electric mixers can be used although care must be nexercised to avoid excessive entrapment of air. For large scale production nmechanical stirrers are used to provide controlled agitation and shearing stress nto produce stable emulsions.

n

 

n

Methods for preparing Emulsions for Internal use

n

The methods commonly used to prepare emulsions can be divided into two ncategories:

n

 

n

Trituration nMethod

n

This method consists of dry gum method and wet gum nmethod.

n

 

n

Dry Gum Method

n

In this method the oil is first triturated with gum with a little amount nof water to form the primary emulsion. The trituration nis continued till a characteristic ‘clicking’ sound is heard and a thick white ncream is formed. Once the primary emulsion is formed, the remaining quantity of nwater is slowly added to form the final emulsion.

n

 

n

Wet Gum Method

n

As the name implies, in this method first gum and water are triturated ntogether to form a mucilage. The required quantity of oil is then added ngradually in small proportions with thorough trituration to form the primary emulsion. Once the primary nemulsion has been formed remaining quantity of water is added to make the final nemulsion.

n

 

n

Bottle Method

n

This method is employed for preparing emulsions containing volatile and nother non-viscous oils. Both dry gum and wet gum methods can be employed for the npreparation. As volatile oils have a low viscosity as compared to fixed oils, nthey require comparatively large quantity of gum for emulsification. In this nmethod, oil or water is first shaken thoroughly and vigorously with the ncalculated amount if gum. Once this has emulsified completely, the second liquid n(either oil or water) is then added all at once and the bottle is again shaken nvigorously to form the primary emulsion. More of water is added in small nportions with constant agitation after each addition to produce the final nvolume.

n

Proportions of.
Type of Oil	Oil	Water	Gum
Fixed Oil	4	2	1
Mineral Oil	3	2	1
Volatile Oil	2	2	1

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n

Table: 1 Proportions of Oil, Water and Gum required for formation of nprimary emulsion

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n

Methods for preparing Emulsions for External use:

n

 

n

Emulsions meant for external application such as creams, lotions and nliniments contain in their formula waxy solids which require melting before nmixing. Such emulsions may be prepared by melting the oily components separately nat 60 0C. nSimilarly in another vessel, the aqueous components are mixed and are warmed ngently to 60 0C. the aqueous nphase is then added to the oily phase at the same temperature and stirred until ncold.

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n

Properties of emulsion

n

PROPERTIES OF EMULSIONS nThe basic properties which should be present in an emulsion include appearance, nfeel, odour, desirable viscosity, consistency, neffectiveness and stability. These properties depends on the ingredients, type nof emulsion, ratio of the two phases, type and quantity of emulsifying agents nand method of emulsification . O/w emulsions will ngenerally have a sheen or matte surface as compared to w/o emulsions which have na shiny or oily surface due to the presence of oil as external phase. W/o emulsions are oily and greasy iature, not easily removable nfrom the surface of the skin whereas o/w emulsions are non greasy and easily nremovable from the skin surface. The viscosity of the emulsions depends ngenerally on the viscosity of the continuous phase. As the ratio of dispersed nphase increases, the viscosity also increases to a point where emulsion starts nloosing its fluidity.

n

 

n

Quality control tests for Emulsions

n

The following are the nquality control tests done for emulsions:

n

1. Determination of nparticle size and particle count: Determination of changes nin the average particle size or the size distribution of droplets is an nimportant parameter used for the evaluation of emulsions. It is performed by noptical microscopy, sedimentation by using Andreasen napparatus and Coulter counter apparatus.

n

2. Determination of nviscosity: Determination of viscosity is done to assess the changes that might ntake place during aging. Emulsions exhibit non-newtonian type of flow characterstics. The viscometers which should be used include ncone and plate viscometers. Capillary and falling sphere type of viscometrs should be avoided. For viscous emulsions, the use nof penetrometer is recommended as it helps in the ndetermination of viscosity with age. In case of o/w emulsions, flocculation of nglobules causes an immediate increase in viscosity. After this change, the nconsistency of the emulsion changes with time. In case of w/o emulsions, , the dispersed phase particles flocculate quite rapidly nresulting in a decrease in viscosity, which stabilizes after 5 to 15 days. As a nrule, a decrease in viscosity with age reflects an increase of particle size due nto coalescence.

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n

3. Determination of phase nseparation: This is another parameter used for assessing the stability of the nformulation. Phase separation may be observed visually or by measuring the nvolume of the separated phases.

n

 

n

4. Determination of electrophoretic properties: Determination of electrophoretic properties like zeta potential is useful for nassessing flocculation since electrical charges on particles influence the rate nof flocculation. O/W emulsion having a fine particle size will exhibit low nresistance but if the particle size increase, then it indicates a sign of oil ndroplet aggregation and instability.

n

 

n

Stability testing

n

Stability of nemulsions is an important parameter for the formulator. Stability testing of nemulsions involves determining stability at long term storage conditions, naccelerated storage conditions, freezing and thawing conditions. Stress nconditions are applied in order to speed up the stability testing. The stress nconditions used for speeding up instability of emulsions ninclude:

n

Centrifugal force Agitational force Aging and temperature The following physical parameters are evaluated to assess the neffect of any of the above stress conditions:

n

–         n· Phase nseparation

n

–         n· nViscosity

n

–         n· Electrophoretic properties

n

–         n· Particle size and nparticle count

n

Particle size and size ndistribution The freeze-thaw cycling technique used to assess emulsions for stress ntesting for stability testing result in increase of particle growth and may indicate future state after long storage. It is of nimportance to study the changes for absolute particle size and particle size ndistribution. It is performed by optical microscopy, sedimentation by using nAndreasen apparatus and Coulter counter apparatus. nNone of these methods are direct methods. However microscopic method allows the nobserver to view the actual particles.

n

Rheological studies Cone and Plate nviscometer with variable shear stress control can be used for evaluating nviscosity of emulsions.

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5.     nFormulation of emulsions n

n

Calculation of the components’ amount of a primary nemulsion

n

The oil’s amount is indicated in the prescription. If there are no indications, then take: 10.0 g of the oil (olive, peach or sunflower) per 100.0 g of the emulsion

n

 

n

The amount of the emulsifier is determined by its ability to emulsify

n

 

n

The amount of water to form a primary emulsion is determined by the emulsifier’s dissolution in water

n

 

n

 

n

To 10.0 g of the oil add:

n

Emulsifier	Water to prepare the primary emulsion
5.0 of gelatose	7.5 ml of water
2.0 of Tween-80	2-3 ml of water
1.0 of methyl cellulose	as 5 % solution – 20.0
0.5 g of sodium carboxymethylcellulose	as 5 % solution – 10.0
5.0 g of starch	as 10 % solution – n50.0

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n

Addition of nmedicinal substances (MSs) to nemulsions

n

MSs nsoluble  in nwater (They can be nused nas concentrated nsolutions.)  dissolve in the portion of water intended for dilution of the primary emulsion. Similarly add nalcoholic solutions, syrups, extracts

n

 

n

MSs nsoluble nin oil dissolve in oil before introducing it into the primary emulsion The namount of an emulsifier is calculated by the weight of the oily solution. (exception – phenylsalycilate (the oily solution does not have the antiseptic naction)

n

 

n

 

n

MSs ninsoluble in water and oil аccording to the rules of suspension’s preparation, add them nas a fine powder thoroughly triturating with the emulsion prepared. If necessary, a nstabilizer is added

n

Formulation of emulsions

n

Rp.: Emulsi olei nPersicorum  n100.0
Coffeini-Natrii benzoatis   n0.5
Misce. Da. nSigna. 1 table-spoon3 times a nday.

n

WCP (reverse side)

n

 

n

n

 

n

Place n20.0 g nof 5 % metylcellulose solution in a porcelain mortar nand triturate thoroughly. Then add 10.0 g of peach oil dropwise while triturating and emulsifying thoroughly. nCollect the mass several times with the celluloid plate from the walls of the nmortar and the pestle. Check the readiness of the primary emulsion and then add nthe purified water ngradually.

n

Since nthe emulsion contains caffeine benzoate sodium, approximately 20-25 ml of the npurified water (or 10 % concentrated solution – 5 ml is used) for its ndissolution is left. Then ndilute the primary emulsion with the remaining amount of water and add the nsolution of caffeine benzoate sodium.

n

WCP (front side)

n

Date                                                          n№ Pr.

n

n

Rp.: Emulsi olei nRicini   n200.0
Camphorae   n          n1.0
Misce. Da. Signa. 1 ntable-spoon 3 times a day.

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n

WCP (reverse side)

n

 

n

n

 

n

Weigh out 20.0 ng of castor oil in a porcelain cup and dissolve n1.0 g of ncamphor, it can be done while heating (to 40°С) on the water bath. Place n4.2 g of ntween-80 nin a mortar, add an oily solution of camphor and mix. Then nadd 5 ml of water dropwise and emulsify until the nprimary emulsion is obtained. The primary emulsion prepared is then diluted by n170.8 ml of the purified water, which is gradually added.

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Rp.: Benzylii nbenzoatis  20.0
Saponis viridis         n2.0
Aquae purificatae  n78 ml
Misce. nDa. Signa. Apply on the nhands.

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n

To prepare this emulsion replace 1.0 ng of the medicinal soap  with the equal amount of nemulsifier Т-2

n

 

n

WCP (front side)

n

Date                                                          n№ Pr.

n

Olei Ricini                            n20.0
Camphorae                           n1.0

n

Tweeni-80                             n4.2

n

Aquae purificatae              n75.8 ml
                           nm_total =    201.0

n

Prepared by:         n(signature)
Checked by:          n(signature)

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Melt 1.0 ng of emulsifier Т-2 in a porcelain cup, pour it into the nwarmed mortar, add 1-2 ml of the hot purified water, mix until a sour cream-like mass is formed. Then add by nportions the remaining amount of hot water with dissolved 1.0 g of the medicinal soap nand mix thoroughly. Then add 20.0 g of benzyl benzoate by portions nwhile continuously stirring.

n

Stratification of the emulsion is possible in 4 days after npreparation; it is easily restored when shaking

n

Emulsion is stable for 2 months.

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