EMULSIONS.

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 uses.

Introduction and overview of emulsions

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

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

British Pharmacopoeia (BP) definition (oral emulsions)

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.

Extemporaneous preparation

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.

Advantages and disadvantages of emulsions as dosage forms

Advantages

- Unpalatable oils can be administered in palatable form.

- Unpalatable oil-soluble drugs can be administered in palatable form.

- The aqueous phase is easily flavoured.

- The oily sensation is easily removed.

- The rate of absorption is increased.

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

Disadvantages

- Preparation needs to be shaken well before use.

- A measuring device is needed for administration.

- A degree of technical accuracy is needed to measure a dose.

- Storage conditions may affect stability.

- Bulky, difficult to transport and prone to container breakages.

- Liable to microbial contamination which can lead to cracking.

Stability of emulsions

Emulsions can break down in the following ways:

- cracking

- creaming

- phase inversion.

Cracking

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.

Creaming

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

Phase inversion

This is the process when an oil-in-water emulsion changes to a water-in-oil emulsion or vice versa. For stability of an emulsion, the optimum range of concentration of dispersed phase is 30–60% 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.

Summary of the problems encountered by emulsions

Creaming

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

Possible reasons for problem

- lack of stability of the system.

- product not homogeneous.

Can the emulsion be saved?

The emulsion will reform on shaking.

Cracking

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

Possible reasons for problem:

- incompatible emulsifying agent

- decomposition of the emulsifying agent

- change of storage temperature.

Can the emulsion be saved?

The emulsion will not reform on shaking.

Phase inversion

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

Possible reason for problem

- amount of disperse phase greater than 74%.

Can the emulsion be saved?

The emulsion will not reform on shaking

General method

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. There is also the need for a preservative, which is usually chloroform, in the form of Double Strength Chloroform Water BP. In addition an emulsion will also need an emulsifying agent (or emulgent).

Continental and dry gum method

Although emulsions may be made by a variety of methods (for example, using methylcellulose gum in the preparation of Liquid Paraffi n Emulsion BP: see Example 4.4 below), extemporaneously prepared emulsions for oral administration are usually made by the continental or dry gum method, where the emulsion is formed by mixing the emulsifying gum (usually Acacia BP) with the oil which is then mixed with the aqueous phase. The only differences between the continental and dry gum methods are the proportions of constituents within the primary emulsion (for example, fixed-oil emulsions made by the continental method would use a ratio of 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 emulsified:

- a vehicle

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

- a preservative

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

- an emulsifying agent (or emulgent)

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

- additional flavouring if required

- additional colouring if required

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

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

Fixed oils

Oil: 4 parts by volume

Aqueous phase: 2 parts by volume

Gum: 1 part by weight

Mineral oils

Oil: 3 parts by volume

Aqueous phase: 2 parts by volume

Gum: 1 part by weight

Volatile (aromatic) oils

Oil: 2 parts by volume

Aqueous phase: 2 parts by volume

Gum: 1 part by weight

These proportions are important when making the primary emulsion, to prevent the emulsion breaking down on dilution or storage.

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

Wet gum method

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 added to the mucilage drop by drop whilst triturating continuously. When nearly 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 all the oil has been added, adding extra small amounts of water when necessary. 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.

Clean, dry equipment

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

Accurate quantities

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

Have all ingredients ready

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

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

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.

The preparation of an emulsion has two main

components:

1. preparation of a concentrate called the primary emulsion

2. dilution of the concentrate.

Preparation of the primary emulsion

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

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

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

4. Add all of the required aqueous vehicle in one addition. Then mix vigorously, using the pestle with a shearing action in one direction.

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 whiteness indicates a better-quality product. Oil globules or slicks should not be apparent.

Dilution of the primary emulsion

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

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

Emulsion

Emulsions are biphasic systems consisting of two immiscible liquids, one of which (the dispersed phase) is finely subdivided and uniformly dispersed as droplets throughout the other phase (the dispersion medium).

Advantages

1. They can mask the bitter taste and odor of drugs, thereby making them more palatable. e.g. castor oil, cod-liver oil etc.

2. They can be used to prolong the release of the drug thereby providing sustained release action.

3. Essential nutrients like carbohydrates, fats and vitamins can all be emulsified and can be administered to bed ridden patients as sterile intravenous emulsions.

4. Emulsions provide protection to drugs which are susceptible to oxidation or hydrolysis.

5. Intravenous emulsions of contrast media have been developed to assist in diagnosis.

6. Emulsions are used widely to formulate externally used products like lotions, creams, liniments etc.

Types Of Emulsions

1. Oil in water emulsions

2. Water in oil emulsions

3. Multiple emulsions

4. Microemulsions

DIFFERENCE BETWEEN O/W AND W/O EMULSIONS

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.

Routes of administration of emulsions

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

Example: Liquid Paraffin Oral Emulsion

Liquid Paraffin 500 ml

Methyl cellulose 20 20 g

Vanillin 0.5 g

Chloroform 2.5 ml

Benzoic acid solution 20 ml

Saccharin sodium 0.05 g

Purified Water q.s 1000ml

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

Example: Castor oil Emulsion

Castor oil 16 ml

Gum acacia q.s

Water 80 ml

Uses: Purgative

Example: Cod-Liver oil Emulsion

Cod-liver oil 30 ml

Syrup 12 ml

Ferric ammonium citrate 4 g

Cinnamon water q.s. 90 ml

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

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

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

Example: Antiseptic cream

Cetrimide 1g

Cetostearyl alcohol 10 g

White soft paraffin 10 g

Liquid paraffin 29 g

Purified water 50 g

Uses: Antiseptic cream for the treatment of cuts, wounds and burns.

Example: Cold Cream

Liquid paraffin 20 g

Hard paraffin 4.5 g

Lanette wax 3.5 g

Glycerine 4.5 g

Water 17.5 g

Propyl paraben 0.1 g

Uses: Skin protective and skin smoothner.

EMULSIFYING AGENTS

These 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. These agents have both a hydrophilic and a lipophilic part in their chemical structure. All emulsifying agents concentrate at and are adsorbed onto the oil/water interface to provide a protective barrier around the dispersed droplets. In addition to this protective barrier, emulsifiers stabilize the emulsion by reducing the interfacial tension of the system. Some agents enhance stability by imparting a charge on the droplet surface thus reducing the physical contact between the droplets and decreasing the potential for coalescence. Thus these act in three ways:

1) Formation of a protective barrier

2) Reduction of interfacial tension

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

Interfacial phenomena

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

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

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

Amphiphile

An amphiphile is a chemical substance that possesses some affinity for both the polar substances and the apolar ones. Generally speaking these affinities are referred to as hydrophilic and lipophilic (or hydrophobic) respectively since the polar solvents are in most cases aqueous solutions and the apolar phases are organic "oils".

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

Adsorption

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

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

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

Self-Association

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

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

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

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

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 blends of emulsifying agents have to be taken.

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 completely non irritant and non toxic in the concentrations used. It should be organoleptically inert i.e. should not impart any colour, odour or taste to 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 droplets of the dispersed phase. It should be able to produce and maintain the required viscosity of the preparation.

CLASSIFICATION OF EMULSIFYING AGENTS

Emulsifying agents can be classified as:

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

· providing a protective sheath around the droplets

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

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

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, chondrus (Irish Moss), pectin and starch.

Gum acacia

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

Tragacanth

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

Agar

Used in the concentration of 2%.

Starch

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

Pectin

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

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. Animal derivatives are more likely to cause allergic reactions and are subject to microbial growth and rancidity. Their advantage is their ability to support formation of w/o creams.

Gelatin

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

Egg yolk

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

2. 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 are nontoxic, and are less subject to microbial growth. They primarily act by increasing the viscosity of the system. e.g., methyl cellulose, hydroxypropyl cellulose and sodium carboxy methyl cellulose.

Methyl cellulose

This is non ionic in nature and is stable over a wide pH range. It is mainly used for emulsification of mineral and vegetables oil. Drawback is that it gets precipitated in the presence of large quantities of electrolytes.

Sodium carboxymethyl cellulose

It is anionic in nature. Acts as an true emulsifier and emulsion stabilizer.

3. 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.

Anionic Surfactants: The 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.

Alkali soaps

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

Amine soaps

Used for preparing o/w emulsions. Stable to the presence of calcium ions or changes in pH

Bold text Metallic soaps

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

Alkyl sulphates and phosphates

They form o/w emulsions.

Alkyl sulponates

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

Cationic surfactants: The 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.

Non-ionic surfactants: They are the class of surfactants widely used as emulsifying agents. They are extensively used to produce both oil in water and water in oil 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).

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

4. Finely Divided Solids: This group consists 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.

5. Auxillary Emulsifying Agents

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

Selection of Emulsifying Agents using HLB method

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

HLB RANGE USE

0-3 Antifoaming agents

4-6 W/O emulsifying agent

7-9 Wetting agents

8-18 O/W emulsifying agent

13-15 Detergents

10-18 Solubilizing agents

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

A higher HLB number indicate that the emulsifier has a large number of hydrophilic groups on the molecule and therefore is more hydrophilic in character. Tweens have higher HLB numbers and they are also water soluble. Because of their water soluble character, tweens will cause the water phase to predominate and form an o/w emulsion.

DISADVANTAGE OF THE HLB SYSTEM

It does not take into account:

- the effect of temperature

- the presence of additives

- the concentration of emulsifier

HLB values of some common emulsifying agents

Emulsifying Agent : HLB Value

Acacia: 8

Polysorbate 20 (Tween 20): 16.7

Polysorbate 60: (Tween 60): 14.9

Polysorbate 80 (Tween 80): 15

Oleic acid: 4.3

Sorbitan monolaurate (Span 20): 8.6

Sorbitan monolaurate (Span 60): 4.7

Sorbitan monolaurate (Span 80): 4.3

Tests Used To Identify Emulsion Type

Since emulsion (o/w or w/o) looks the same in appearance with naked eyes, therefore certain tests have been developed to differentiate between them. At least two tests should be done to reach a conclusive decision about the identity of the emulsion.

Dilution test

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

Fig: Dilution Testfor oil in water emulsion

Fig: Dilution test for water in oil emulsion

Conductivity Test

This test is based on the basic principle that water is a good conductor of electricity. Therefore in case of o/w emulsion , this test will be positive as water is the external phase. In this test. An assembly consisting of a pair of electrodes connected to a lamp is dipped into an emulsion. If the emulsion is o/w type, the lamp glows.

Fig: Conductivity test for oil in water emulsion

Fig: Conductivity test for water in oil emulsion

Dye Solubility Test

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

Fig: Dye solubility test

Cobalt Chloride Test

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

Fluorescence Test

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

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

Creaming

An 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. The factors affecting creaming are best described by stroke’s law

V= 2r2 (d1-d2) g/9η

Where V= rate of creaming

 r=radius of globules
 d1= density of dispersed phase 
 d2= density of dispersion medium
 g= gravitational constant
η = viscosity of the dispersion medium

The following approaches can be used for decreasing Creaming

Reduction of globule size: According to stroke’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.

Cracking

Occasionally, 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. 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.

Phase Inversion

In 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 or by changing the phase volume ratio or by 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 % and by storing the emulsion in a cool place.

Points to be considered during formulations of emulsions

Stability of the active ingredient

Stability of the excipients

Visual appearance

Color

Odor (development of pungent odor/loss of fragrance)

Viscosity, extrudability

Loss of water and other volatile vehicle components

Concentration of emulsifier

Order of addition of ingredients

Particle size distribution of dispersed phases

pH

Temperature of emulsification

Type of equipment

Method and rate of cooling

Texture, 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, bleeding

Packaging, Labelling 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.

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. It should be stable and effective over a wide range of pH and temperature. It should have 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.

Examples of antimicrobial preservatives used to preserve emulsified systems include parahydroxybenzoate 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 chlorocresol and miscellaneous agents such as sodium benzoate, chloroform and phenoxyethanol.

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. 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 sshydroxyanisole (BHT), butylated hydroxytoluene (BHT)

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 used to provide controlled agitation and shearing stress to produce stable emulsions.

Methods for preparing Emulsions for Internal use

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

Trituration Method

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

Dry Gum Method

In 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.

Wet Gum Method

As 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.

Bottle Method

This 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 if 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.

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

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

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.

Properties of emulsion

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

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. Capillary and falling sphere type of viscometrs should be avoided. For viscous emulsions, the use of penetrometer is recommended as it helps in the determination of viscosity with age. In case of o/w emulsions, flocculation of globules causes an immediate increase in viscosity. After this change, the consistency of the emulsion changes with time. In case of w/o emulsions, , the dispersed phase particles flocculate quite rapidly resulting in a decrease in viscosity, which stabilizes after 5 to 15 days. As a rule, a decrease in viscosity with age reflects an increase of particle size due to coalescence.

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.

Stability testing

Stability 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 temperature The following physical parameters are evaluated to assess the effect of any of the above stress conditions:

- · Phase separation

- · Viscosity

- · Electrophoretic properties

- · Particle size and particle count

Particle size and size distribution The freeze-thaw cycling technique used to assess emulsions for stress testing for stability testing result in increase of particle growth and may indicate future state after long storage. It is of importance to study the changes for absolute particle size and particle size distribution. It is performed by optical microscopy, sedimentation by using Andreasen apparatus and Coulter counter apparatus. None of these methods are direct methods. However microscopic method allows the observer to view the actual particles.

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

5. Formulation of emulsions

Calculation of the components’ amount of a primary emulsion

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

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

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

To 10.0 g of the oil add:

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 – 50.0

Addition of medicinal substances (MSs) to emulsions

MSs soluble in water (They can be used as concentrated solutions.) dissolve in the portion of water intended for dilution of the primary emulsion. Similarly add alcoholic solutions, syrups, extracts

MSs soluble in oil dissolve in oil before introducing it into the primary emulsion The amount of an emulsifier is calculated by the weight of the oily solution. (exception - phenylsalycilate (the oily solution does not have the antiseptic action)

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

Formulation of emulsions

Rp.: Emulsi olei Persicorum 100.0
Coffeini-Natrii benzoatis 0.5
Misce. Da. Signa. 1 table-spoon3 times a day.

WCP (reverse side)

(as an emulsifier – solution of Methylcellulose 5 %)

Peach oil: 100.0 / 10 = 10.0

Solution of МС 5 %: 10.0 х 2 = 20.0
(to prepare the primary emulsion water is not required)
Purified water for dilution of the primary emulsion:
100.0 – (10.0 + 20.0) = 70 ml

Place 20.0 g of 5 % metylcellulose solution in a porcelain mortar and triturate thoroughly. Then add 10.0 g of peach oil dropwise while triturating and emulsifying thoroughly. Collect the mass several times with the celluloid plate from the walls of the mortar and the pestle. Check the readiness of the primary emulsion and then add the purified water gradually.

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

WCP (front side)

Date № Pr.

Sol. Methylcellulosae 5 % 20.0
Olei Persicorum 10.0
Aq. purificatae 70 ml
Coffeini-natrii benzoatis 0.5
m_total = 100.5
Prepared by: (signature)
Checked by: (signature)

Rp.: Emulsi olei Ricini 200.0
Camphorae 1.0
Misce. Da. Signa. 1 table-spoon 3 times a day.

WCP (reverse side)

(as an emulsifier – Tween-80)

Peach oil: 200.0 / 10 = 20.0

Oil phase: 20.0 + 1.0 = 21.0

Tween-80: 21.0 / 5 = 4.2
Water for preparing the primary emulsion: 2.0 g ----- 2–3 ml

4.2 g ------ x

x » 5 ml
Water for diluting the primary emulsion:
201.0 – (21.0 + 4.2 + 5.0) = 170.8 ml

Weigh out 20.0 g of castor oil in a porcelain cup and dissolve 1.0 g of camphor, it can be done while heating (to 40°С) on the water bath. Place 4.2 g of tween-80 in a mortar, add an oily solution of camphor and mix. Then add 5 ml of water dropwise and emulsify until the primary emulsion is obtained. The primary emulsion prepared is then diluted by 170.8 ml of the purified water, which is gradually added.

Rp.: Benzylii benzoatis 20.0
Saponis viridis 2.0
Aquae purificatae 78 ml
Misce. Da. Signa. Apply on the hands.

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

WCP (front side)

Date № Pr.

Olei Ricini 20.0
Camphorae 1.0

Tweeni-80 4.2

Aquae purificatae 75.8 ml
m_total = 201.0

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

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

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

Emulsion is stable for 2 months.