Pharmaceutics I - Theoretical (Suez Canal University, 2021/2022) PDF

SUEZ CANAL UNIVERSITY FACULTY OF PHARMACY DEPARTMMENT OF PHARMACEUTICS & INDUSTRIAL PHARMACY Dosage forms I (PT303) FOR SECOND YEAR STUDENTS 2021/2022 Liquid Dosage Forms An understanding of the properties of solutions, the factors that affect solubility and the process of dissolution is essential because of the importance of solutions in so many areas of pharmaceutical formulation. In general, the solvent is present in the greater amount, but there are several exceptions. For example, Syrup BP contains 66.7% w/w of sucrose as the solute in 33.3% w/w of water as the solvent. Advantages and Disadvantages of Solutions as an Oral Dosage Form Advantages 1. Liquids are easier to swallow than solids and are therefore particularly acceptable for paediatric and geriatric use. 2. A drug must usually be in solution before it can be absorbed. If it is administered in the form of a solution, the drug is immediately available for absorption. Therefore, the therapeutic response is faster than if using a solid dosage form, which must first disintegrate in order to allow the drug to dissolve in the gastrointestinal fluid before absorption can begin. Even if the drug should precipitate from solution in the acid conditions of the stomach, it will be in a sufficiently wetted and finely divided state to allow rapid absorption to occur. 3. A solution is a homogenous system and therefore the drug will be uniformly distributed throughout the preparation. In suspension or emulsion formulations uneven dosage can occur as a result of phase separation on storage. 4. Some drugs, including aspirin and potassium chloride, can irritate and damage the gastric mucosa, particularly if localized in one area, as often occurs after the ingestion of a solid dosage form. Irritation is reduced by the administration of a solution of a drug because of the immediate dilution by the gastric contents. Disadvantages 1 1. Liquids are bulky and therefore inconvenient to transport and store. If the container should break the whole of the product is immediately and irretrievably lost. 2. The stability of ingredients in aqueous solution is often poorer than if formulated as a tablet or capsule, particularly if they are susceptible to hydrolysis. The shelf-life of a liquid dosage form is often much shorter than that of the corresponding solid preparation. Not only is the stability of the drug important, but also that of other excipients, such as surfactants, preservatives, flavours and colours. The chemical stability of some ingredients can, however, be improved by the use of a mixed solvent system. 3. Solutions often provide suitable media for the growth of microorganisms and may therefore require the incorporation of a preservative. 4. Most liquid preparations are designed so that the normal dosage of the drug is present in 5 mL, or a multiple of 5 mL, of product. Accurate dosage depends on the ability of the patient to use a 5 mL spoon or a volumetric dropper. 5. The taste of a drug, which is usually unpleasant, is always more pronounced when in solution than in a solid form. Solutions can, however, easily be sweetened and flavoured to make them more palatable. Choice of Solvent A- Aqueous solutions Water is the solvent most widely used as a vehicle for pharmaceutical products, because of its physiological compatibility and lack of toxicity. It possesses a high dielectric constant, which is essential for ensuring the dissolution of a wide range of ionisable materials. In some cases this property may be an advantage, but the lack of selectivity can be responsible for aqueous solutions containing unwanted substances such as inorganic salts and organic impurities. This is one reason why water is rarely used for the extraction of active constituents from vegetable sources. Types of pharmaceutical water Purified Water BP, which has been freshly boiled and cooled immediately before use to destroy any vegetative microorganisms that might be present. Purified Water must, however, be used on all occasions where the presence of salts - often dissolved in potable water - is undesirable. Purified Water is normally prepared by the distillation or deionization of potable water, or by the process of reverse osmosis. Water for Injections must be used for the formulation of parenteral solutions and is obtained by sterilizing pyrogen-free distilled water immediately after its collection. For the formulation of aqueous solutions of drugs, such as phenobarbitone sodium or aminophylline, which are sensitive to the presence of carbon dioxide, Water for Injections 2 free from carbon dioxide must be used. Similarly, drugs which are liable to oxidation, such as apomorphine and ergotamine maleate, require Water for Injections BP free from dissolved air to be used. These are both obtained from apyrogenic distilled water in the same way as before, but are then boiled for at least 10 minutes, cooled, sealed in their containers while excluding air, and then sterilized by autoclaving. Approaches to the improvement of aqueous solubility Although water is very widely used for inclusion in pharmaceutical preparations, it may not be possible to ensure complete solution of all ingredients at all normal storage temperatures. Strongly ionized materials are likely to be freely soluble in water over a wide pH range. Similarly, weak acids and bases should be adequately soluble at favourable pHs. Even if in solution, it is still important to ensure that the concentration of any material is not close to its limit of solubility, as precipitation may occur if the product is cooled or if any evaporation of the vehicle should occur. For unionized drugs or for weak electrolytes at a pH that is unfavourable for extensive ionization, one or more of the following methods should be used to improve aqueous solubility. 1- Cosolvency The solubility of a weak electrolyte or non-polar compound in water can be achieved by the addition of another solvent that is both miscible with water and in which the compound is also soluble. Vehicles used in combination to increase the solubility of a drug are called cosolvents, and often the solubility in this mixed system is greater than can be predicted from the material's solubility in each individual solvent. The choice of suitable cosolvents is somewhat limited for pharmaceutical use because of possible toxicity and irritancy, particularly if required for oral or parenteral use. Ideally, suitable blends should possess values of dielectric constant between 25 and 80. The most widely used system that will cover this range is a water/ethanol blend. Other suitable solvents for use with water include sorbitol, glycerol, propylene glycol and syrup. For example, a blend of propylene glycol and water is used to improve the solubility of co-trimoxazole, and paracetamol is formulated as an elixir by the use of alcohol, propylene glycol and syrup. 2- pH control 3 A large number of drugs are either weak acids or weak bases, and therefore their solubilities in water can be influenced by the pH of the system. A quantitative application of the Henderson-Hasselbalch equation will enable the solubility of such a drug in water at a given pH to be determined, provided its pKa and the solubility of its unionized species are known. The solubility of a weak base can be increased by lowering the pH of its solution, whereas the solubility of a weak acid is improved by an increase in pH. In controlling the solubility of a drug in this way, it must be ensured that the chosen pH does not conflict with other product requirements. For example, the chemical stability of a drug may also depend on pH, and in many cases the pH of optimum solubility does not coincide with the pH of optimum stability. This may also be true for other ingredients, especially colours, preservatives and flavours. Often a compromise must be reached during formulation to ensure that the stability and solubility of all ingredients, physiological compatibility and bioavailability are all adequate for the product's intended purpose. It must be appreciated that maximum solubility may best be achieved by a judicious balance between pH control and concentration of cosolvent, and can be determined, as before, by the Henderson-Hasselbalch equation, substituting the new values both for pKa and for the molar solubilities of the unionized species. 3- Solubilization The solubility of a drug that is normally insoluble or poorly soluble in water can often be improved by the addition of a surface-active agent (SAA). These molecules form different types of micelles, ranging from simple spherical structures to more complex liposomes and liquid crystals. This phenomenon of micellar solubilization has been widely used for the formulation of solutions of poorly soluble drugs. In aqueous systems, non-polar molecules will dissolve in the interior of the micelle, which consists of the lipophilic hydrocarbon moiety. The amount of surfactant to be used for this purpose must be carefully controlled. A large excess is undesirable because of cost, possible toxicity. Excessive amounts may also reduce the bioavailability of a drug if it is strongly adsorbed within the micelle. The surfactant chosen must be non-toxic and non-irritant. Examples include the solubilization of fat-soluble vitamins such as phytomenadione using polysorbates. This enables their inclusion with water-soluble vitamins in the same aqueous- based formulation. 4 The solubilization of iodine to produce iodophores is achieved by the use of macrogol ethers. These products exhibit several advantages over simple iodine solutions, including an improved chemical stability, reduced loss of active agent due to sublimation, less corrosion of surgical instruments and, in some cases, enhanced activity. The solubility of phenolic compounds such as cresol and chloroxylenol, which are normally soluble in water up to 2% and 0.03% respectively, can be improved by solubilization with soaps. Lysol contains 50% cresol in an aqueous system by the use of the potassium soaps of oleic, linoleic and linolenic acids. It is also important to ensure that the formulation chosen does not lie too close to a phase boundary, as the positions of these can depend on the storage temperature of the product. In general the degree of solubilization of a drug increases as the temperature increases. Alternatives to the use of surface-active agents as solubilizing agents include the cyclodextrins. This range of compounds is based on a series of glucopyranose units that form cyclical structures resembling hollow cylinders. As the inside surface of the ring is hydrophobic, owing to the presence of -CH2 groups, drugs that are poorly soluble in water can be accommodated here. The outer part of the structure is hydrophilic and therefore freely soluble in water. There are three natural cyclodextrins, the α,  and γ forms, the ring structures of which are composed of 6, 7 and 8 glucopyranose units, respectively, as well as an expanding series of derivatives. Poorly soluble drugs of appropriate size slot into the interior of these structures, forming soluble inclusion complexes, usually with one 'host' molecule per cyclodextrin molecule. 4- Complexation In some cases it may be possible to interact with a poorly soluble drug with a soluble material to form a soluble intermolecular complex. As most complexes are macromolecular, however, they tend to be inactive, being unable to cross lipid membranes. 5 It is therefore essential that complex formation is easily reversible, so that the free drug is released during or before contact with biological fluids. It is not easy to predict whether a given drug will complex with a particular compound to improve solubility. Many complexes are not water soluble and may, in fact, be better suited for the prolonged release of the drug. Several well known examples are in general use, however, and include the complexation of iodine with a 10-15% solution of polyvinylpyrrolidone(PVP) to improve the aqueous solubility of the active agent. 5- Chemical modification As a last resort, chemical modification of a drug may be necessary in order to produce a water-soluble derivative. Examples include the synthesis of the sodium phosphate salts of hydrocortisone, prednisolone and betamethasone. There are many examples of poorly soluble acids and bases being converted to a salt form to increase water solubility. B- Non-aqueous solutions If it is not possible to ensure complete solution of the ingredients at all storage temperatures, or if the drug is unstable in aqueous systems it may be necessary to use an alternative, non- aqueous solvent. The use of non-aqueous systems may also have other advantages. For example, the intramuscular injection of solutions of drugs in oils is often used for depot therapy, and some drugs are specifically synthesized to improve their oil solubilities. The propionate and benzoate esters of testosterone and estradiol, respectively, are good examples of this. It is essential that, in choosing a suitable solvent, its toxicity, irritancy and sensitizing potential are taken into account, as well as its flammability, cost, stability and compatibility with other excipients. It will be obvious that there is a greater choice of solvents available for inclusion into products for external application than those for internal use, and that for parenteral products the choice is limited even further. The following is a classification of non-aqueous solvents in pharmaceutical preparations. 1- Fixed oils of vegetable origin These are non-volatile oils that consist mainly of fatty acid esters of glycerol. Almond oil, for example, which consists of glycerides mainly of oleic acid, is used as a solvent for oily phenol injections. 6 Olive oil, sesame oil, maize oil, cottonseed oil, soya oil and castor oil are all suitable for parenteral use, the latter also being used as the solvent in miconazole eye drops Oils tend to be unpleasant to use externally, however, unless presented as an emulsion. Arachis oil is one of the few examples and is used as the solvent in Methyl Salicylate Liniment. 2- Alcohols Ethyl alcohol is the most widely used solvent in this class, particularly for external application, where its rapid evaporation after application to the skin imparts a cooling effect to such products as salicylic acid lotion. If required for external use then industrial methylated spirit (IMS), which is free from excise duty, is usually included rather than the more expensive ethanol. Because industrial methylated spirit contains 5% methyl alcohol as a denaturant it is rendered too toxic for internal use. An alcohol possessing similar properties is isopropyl alcohol, which is used externally as a solvent for diclophane. Its main advantage is that it is less likely to be abused than ethanol and that denaturation is not necessary. 3- Polyhydric alcohols Alcohols containing two hydroxyl groups per molecule are known as glycols, but because of their toxicity they are rarely used internally. One important exception to this is propylene glycol. Injection, and some formulations of Diazepam Injection, Co-trimoxazole Intravenous Infusion and as the diluent for both Chloramphenicol Ear Drops and some brands of hydrocortisone ear drops, and in many preparations for oral use. The lower molecular weight polyethylene glycols (PEG) or macrogols which is often used in conjunction with water or glycerol as a cosolvent. PEG400, for example, is used as a solvent in clotrimazole topical solution. They are also widely used as cosolvents with alcohol or water, although their main use is in the formulation of water-miscible ointment bases. 4- Dimethylsulphoxide (DMSO) This is a highly polar compound and is thought to aid the penetration of drugs through the skin. Although used mainly as a solvent for veterinary drugs, it is used as a carrier for idoxuridine, an antiviral agent, for application to human skin. 7 5- Ethyl ether This material is widely used for the extraction of crude drugs, but because of its own therapeutic activity it is not used for the preparation of formulations for internal use. It is, however, used as a cosolvent with alcohol in some collodions. 6- Miscellaneous solvents A- Isopropyl myristate and isopropyl palmitate are used as solvents for external use, particularly in cosmetics, where their low viscosity and lack of greasiness make them pleasant to use. B- Xylene is present in some ear drops for human use to dissolve ear wax. Other Formulation Additives 1- Buffers These are materials which, when dissolved in a solvent, will enable the solution to resist any change in pH should an acid or an alkali be added. The choice of suitable buffer depends on the pH and buffering capacity required. It must be compatible with other excipients and have a low toxicity. Most pharmaceutically acceptable buffering systems are based on carbonates, citrates, gluconates, lactates, phosphates or tartrates As the pH of most body fluids is 7.4, products such as injections, eye drops and nasal drops should, in theory, be buffered at this value to avoid irritation. Many body fluids themselves, however, have a buffering capacity and, when formulating low volume intravenous injections or eye drops, a wider pH range can be tolerated. This is potentially useful should a compromise be necessary when choosing a pH that is physiologically acceptable for a drug whose optimum stability, solubility and/or bioavailability may depend on different pHs. 2- Isotonicity modifiers Solutions for injection, for application to mucous membranes, and large-volume solutions for ophthalmic use must be made iso-osmotic with tissue fluid to avoid pain and irritation. The most widely used isotonicity modifiers are dextrose and sodium chloride. Isotonicity adjustments can only be made after the addition of all other ingredients, because each ingredient will contribute to the overall osmotic pressure of a solution. 3- Viscosity enhancement It may be difficult for aqueous-based topical solutions to remain in place on the skin or in the eyes for any significant time because of their low viscosities. 8 To counteract this effect, low concentrations of gelling agents can be used to increase the apparent viscosity of the product. Examples include povidone, Hydroxyethylcellulose (HEC) and carbomer. 4- Preservatives When choosing a suitable preservative, it must be ensured that: a. Adsorption of the preservative onto the container from the product does not occur, and b. Its efficiency is not impaired by the pH of the solution or by interactions with other ingredients. For example, many of the widely used parahydroxybenzoic acid esters can be adsorbed into the micelles of some non-ionic surfactants and, although their presence can be detected by chemical analysis, they are in fact unable to exert their 5- Reducing agents and antioxidants The decomposition of pharmaceutical products by oxidation can be controlled by the addition of reducing agents such as sodium metabisulphite, or antioxidants such as butylated hydroxyanisole or butylated hydroxytoluene. 6- Sweetening agents Low molecular weight carbohydrates, and in particular sucrose, are traditionally the most widely used sweetening agents. Sucrose has the advantage of being colourless, very soluble in water, stable over a pH range of about 4-8 and, by increasing the viscosity of fluid preparations, will impart to them a pleasant texture in the mouth. It will mask the tastes of both salty and bitter drugs and has a soothing effect on the membranes of the throat. For this reason, despite its cariogenic properties, sucrose is particularly useful as a vehicle for antitussive preparations. Polyhydric alcohols such as sorbitol, mannitol and, to a lesser extent glycerol, also possess sweetening power and can be included in preparations for diabetic use, where sucrose is undesirable. Artificial sweeteners can be used in conjunction with sugars and alcohols to enhance the degree of sweetness, or on their own in formulations for patients who must restrict their sugar intake. They are also termed intense sweeteners because, weight for weight, they are hundreds and even thousands of times sweeter than sucrose and are therefore rarely required at a concentration greater than about 0.2%. Only about six artificial sweeteners are permitted for oral use within the European Union, the most widely used being the sodium or calcium salts of saccharin (E954). Both exhibit 9 high water solubility and are chemically and physically stable over a wide pH range. Less widely used is aspartame (E951). The main disadvantage of all artificial sweeteners is their tendency to impart a bitter or metallic aftertaste, and they are therefore often formulated with sugars to mask this. 7- Flavours and perfumes The simple use of sweetening agents may not be sufficient to render palatable a product containing a drug with a particularly unpleasant taste. In many cases, therefore, a flavouring agent can be included. This is particularly useful in paediatric formulation to ensure patient compliance. The inclusion of flavours has the additional advantage of enabling the easy identification of liquid products. Flavouring and perfuming agents can be obtained from either natural or synthetic sources. Natural products include fruit juices, aromatic oils such as peppermint and lemon, herbs and spices, and distilled fractions of these. Artificial perfumes and flavours are of purely synthetic origin, often having no natural counterpart. They tend to be cheaper, more readily available and more stable than natural products. They are usually available as alcoholic or aqueous solutions or as powders. 8- Colours Once a suitable flavour has been chosen, it is often useful to include a colour associated with that flavour in order to improve the attractiveness of the product. Another reason for the inclusion of colours is to enable easy product identification, for example, to differentiate 10 between the many types of antiseptic solution used in hospitals for the disinfection of skin, instruments, syringes etc. TYPES OF PREPARATION This section attempts to give an overview of the types of pharmaceutical solution available. 1- Liquids for cutaneous application Lotions, liniments, paints and collodions a- Lotions Can be formulated as solutions, and are designed to be applied to the skin without friction. They may contain humectants, so that moisture is retained on the skin after application of the product, or alcohol, which evaporates quickly, imparting a cooling effect and leaving the skin dry. b- Liniments, Are intended for massage into the skin and can contain such ingredients as methyl salicylate or camphor as counterirritants. are often termed c- paints, Liquids for application to the skin or mucous membranes in small amounts and are usually applied with a small brush. The solvent is normally alcohol, acetone or ether, which evaporates quickly leaving a film on the skin that contains the active agent. A viscosity modifier such as glycerol is often added to ensure prolonged contact with the skin. d- Collodions Are similar preparations which, after evaporation of the solvent, leave a tough, flexible film that will seal small cuts or hold a drug in intimate contact with the skin. The film former is usually pyroxylin (nitrocellulose) in an alcohol/ether or alcohol/acetone solvent blend. Often a plasticizer such as castor oil and an adherent such as colophony resin are included. 2- Ear preparations Also known as otic or aural products, these are simple solutions of drugs in either water, glycerol, propylene glycol or alcohol/water mixtures for local use, and include antibiotics, antiseptics, cleansing solutions and wax softeners. They are applied to the external auditory canal as drops, sprays or washes. 3- Eye preparations These are small-volume sterile liquids designed to be instilled on to the eyeball or within the conjunctival sac for a local effect. 4- Irrigations Irrigations are sterile, large-volume aqueous-based solutions for the cleansing of body cavities and wounds. They should be made isotonic with tissue fluid. 5- Mouthwashes and gargles 11 Aqueous solutions for the prevention and treatment of mouth and throat infections can contain antiseptics, analgesics and/or astringents. They are usually diluted with warm water before use. 6- Nasal products These are formulated as small-volume solutions in an aqueous vehicle, oils being no longer used for nasal administration. Because the buffering capacity of nasal mucus is low, formulation at a pH of 6.8 is necessary. Nasal drops should also be made isotonic with nasal secretions using sodium chloride, and viscosity can also be modified using cellulose derivatives if necessary. 12 Oral liquids This is a general term used to describe a solution, suspension or emulsion in which the active ingredient is dissolved or dispersed in a suitable liquid vehicle. 1- Elixirs Elixirs are clear, sweetened, hydroalcoholic solutions intended for oral use, and are usually flavoured to enhance their palatability. Elixirs are either; 1- Non-medicated and are employed as vehicles. 2- Medicated which contain medicinal substances and have a therapeutic effect Elixirs differ from syrups in that: 1. Less sweet. 2. Less effective in masking the taste of medicinal substances. 3. Less viscous. They have the following advantages: 1- Able to maintain water-soluble and alcohol-soluble components in solution. 2- More stable and easier in preparation than syrups. 2- Mixtures and draughts Mixtures are usually aqueous preparations that can be in the form of either a solution or a suspension. Most preparations of this type are manufactured on a small scale as required, and are allocated a shelf-life of a few weeks before dispensing. Doses are usually given in multiples of 5 mL using a metric medicine spoon. A draught is a mixture of which only one or two large doses of about 50 mL are given, although smaller doses are often necessary for children. Rectal preparations Enems Aqueous or oily solutions, as well as emulsions and suspensions, are available for the rectal administration of medicaments for cleansing, diagnostic or therapeutic reasons. Intermediate products 1- Aromatic waters and spirits 13 There are many pharmaceutical solutions that are designed for use during the manufacture of other preparations and which are rarely administered themselves. Aromatic waters, for example, are aqueous solutions of volatile materials and are used mainly for their flavouring properties. Examples include peppermint water and anise water, which also have carminative properties, and chloroform water, which also acts as a preservative. They are usually manufactured as concentrated waters and are then diluted, traditionally 1:40 in the final preparation. Spirits are also alcoholic solutions but of volatile materials, which are mainly used as flavouring agents. 2- Extracts, infusions and tinctures Infusions, extracts and tinctures are terms used for concentrated solutions of active principles from animal or vegetable sources. Infusions are prepared by extracting the drug using 25% alcohol, but without the application of heat. Traditionally these preparations are then diluted 1:10 in the final product. Extracts are similar products that are then concentrated by evaporation. Tinctures are alcoholic extracts of drugs but are relatively weak compared with extracts. 3- Syrups Syrups are concentrated solutions of sucrose or other sugars to which medicaments or flavourings are often added. For example, Codeine Phosphate Syrup is used as a cough suppressant and Orange Syrup contains dried bitter orange peel as a flavouring agent. Although syrups are used in the manufacture of other preparations, such as mixtures or elixirs, they can also be administered as products in their own right, the high concentrations of sugars imparting a sweetening effect. As syrups can contain up to 85% of sugars, they are capable of resisting bacterial growth by virtue of their osmotic effect. Syrups can contain lower concentrations of sugars but will often include sufficient of a polyhydric alcohol such as sorbitol, glycerol or propylene glycol in order to maintain a high osmotic gradient. In addition, by acting as cosolvents they will help to prevent crystallization and to maintain solubility of all ingredients. It is possible, however, in a closed container, for surface dilution of a syrup to take place. This occurs as a result of solvent evaporation that condenses on the upper internal surfaces of the container and then flows back on to the surface of the product, thereby producing a 14 diluted layer which provides an ideal medium for the growth of certain microorganisms. For this reason syrups often contain additional preservatives. A further problem with the storage and use of syrups involves the crystallization of the sugar within the screw cap used to seal the containers, thereby preventing its release. This can be avoided by the addition of the polyhydric alcohols previously mentioned, or by the inclusion of invert syrup, which is a mixture of glucose and fructose. STABILITY OF SOLUTIONS Both the chemical and the physical stability of solutions in their intended containers are important. A solution must retain its initial clarity, colour, odour, taste and viscosity over its allocated shelf-life. Clarity can easily be assessed by visual examination or by a measurement of its optical density after agitation. Colour too may be assessed both visually and spectrophotometrically. The stability of flavours and perfumes is perhaps more difficult to assess. Although chromatographic methods are used with varying success to quantify these properties, MANUFACTURE OF SOLUTIONS For both small- and large-scale manufacture of solutions the only equipment necessary is suitable mixing vessels, a means of agitation and a nitration system to ensure clarity of the final solution. During manufacture, the solute is simply added to the solvent in a mixing vessel and stirring is continued until dissolution is complete. If the solute is more soluble at elevated temperatures it may be advantageous to apply heat to the vessel, particularly if the dissolution rate is normally slow. Care must be taken, however, should any volatile or thermolabile materials be present. Size reduction of solid materials to increase their surface areas should also speed up the process of solution. Solutes present in low concentrations, particularly dyes, are often predissolved in a small volume of the solvent and then added to the bulk. Volatile materials such as flavours and perfumes are, where possible, added at the end of a process and after any cooling, to reduce loss by evaporation. Finally, it must be ensured that significant amounts of any of the materials are not irreversibly adsorbed on to the filtration medium used for final clarification. 15 Disperse systems Colloids A disperse system defined as a system in which one substance, the disperse phase, is dispersed as particles throughout another, the dispersion medium. A disperse system consists essentially of one component, the disperse phase, dispersed as particles or droplets throughout another component, the continuous phase. By definition, dispersions in which the size of the dispersed particles is within the range 10- 9 m (1 nm) to about 10-6 m (1 μm) are termed colloidal. The essential character common to all disperse systems is the large area to volume ratio for the particles involved, for example, when a cube of 1 cm edge is subdivided into cubes of 100 nm edge there is a 105 increase in surface area and associated free energy. This free energy will be decreased if the particles aggregated or coalesce because of the reduction in interfacial area that accompanies such aggregation. Since any system will tend to react spontaneously to decrease its free energy to a minimum it follows that disperse system are often unstable, the particles aggregating rather than remaining in contact with the dispersion medium. However, the upper size limit is often extended to include emulsions and suspensions, which are very polydisperse systems in which the droplet size frequently exceeds 1 um but which show many of the properties of colloidal systems. Pharmaceutical Applications 1- The efficiency of certain substances, used in pharmaceutical preparations, may be increased if colloidal forms are used since these have large surface area. Thus, for example a- The adsorption of toxins from the gastrointestinal tract by kaolin b- The rate of neutralization of excess acid in the stomach by aluminium hydroxide may be increased if these compounds are used in the colloidal form. 2- In the purification of proteins, use is made of the changes in the solubility of colloidal materials with alteration of pH and addition of electrolyte. 3- The protective ability of hydrophilic colloids is used to prevent the coagulation of hydrophobic particles such as colloidal gold stabilized by gelatine. Hydrophilic sols are viscous and used in retarding the sedimentation of particles in pharmaceutical suspensions. 4- Blood plasma substitutes such as dextrin, polyvinylpyrrolidine (PVP) and gelatine are hydrophilic colloid which exert an osmotic pressure similar to that of plasma and are thus to restore or maintain blood volume. 16 5- Iron-dextrin complexes form non-ionic hydrophilic sols suitable for injection for the treatment of anaemia. Colloids can be broadly classified as those that are 1- Lyophobic (solvent-hating) 2- Lyophilic (solvent-liking). When the solvent is water the terms hydrophobic and hydrophilic are used. Surfactant molecules tend to associate in water into aggregates called micelles, and these constitute hydrophilic colloidal dispersions. Proteins and gums also form lyophilic colloidal systems because of a similar affinity between the dispersed particles and the continuous phase. On the other hand, dispersions of oil droplets in water or water droplets in oil are examples of lyophobic dispersions. It is because of the subdivision of matter in colloidal systems that they have special properties. A common feature of these systems is a large surface-to-volume ratio of the dispersed particles. As a consequence there is a tendency for the particles to associate to reduce their surface area. Preparation and purification of colloidal systems 1- Lyophilic colloids The affinity of lyophilic colloids for the dispersion medium leads to the spontaneous formation of colloidal dispersions. For example, acacia, tragacanth, and methylcellulose readily disperse in water. This simple method of dispersion is a general one for the formation of lyophilic colloids. 2- Lyophobic colloids The preparative methods for lyophobic colloids may be divided into those methods that involve the breakdown of larger particles into particles of colloidal dimensions (dispersion methods) and those in which the colloidal particles are formed by the aggregation of smaller particles such as molecules (condensation methods). A- Dispersion methods Colloid mills These cause the dispersion of coarse material by shearing in a narrow gap between a static cone (the stator) and a rapidly rotating cone (the rotor). Ultrasonic treatment The passage of ultrasonic waves through a dispersion medium produces alternating regions of cavitation and compression in the medium. The cavities collapse with great force and cause the breakdown of coarse particles dispersed in the liquid. 17 B- Condensation methods These involve the rapid production of supersaturated solutions of the colloidal material under conditions in which it is deposited in the dispersion medium as colloidal particles and not as a precipitate. The supersaturation is often obtained by means of a chemical reaction that results in the formation of the colloidal material. For example, colloidal silver iodide may be obtained by reacting together dilute solutions of silver nitrate and potassium iodide; and ferric chloride boiled with an excess of water produces colloidal hydrated ferric oxide. A change of solvent may also cause the production of colloidal particles by condensation methods. If a saturated solution of sulphur in acetone is poured slowly into hot water the acetone vaporizes, leaving a colloidal dispersion of sulphur. A similar dispersion Dialysis: Colloidal particles are not retained by conventional filter papers but are too large to diffuse through the pores of membranes such as those made from regenerated cellulose products, e.g. collodion and cellophane. The smaller particles in solution are able to pass through these membranes. Use is made of this difference in diffusibility to separate micromolecular impurities from colloidal dispersions. The process is known as dialysis. Pharmaceutical application of dialysis - These include the use of membrane filters, artificial membranes as Models for the diffusion of drugs through natural membranes, - In this study of drug/protein binding and - As a principle of haemodialysis where small molecular weight impurities from the body are removed by passage through a membrane. Ultrafiltration: By applying pressure (or suction) the solvent and small particles may be forced across a membrane but the larger colloidal particles are retained. This process is referred to as ultrafiltration. It is possible to prepare membrane filters with a known pore size, and the use of these allows the particle size of a colloid to be determined Electrodialysis An electric potential may be used to increase the rate of movement of ionic impurities through a dialysing membrane and so provide a more rapid means of purification. The concentration of charged colloidal particles at one side and at the base of the membrane is termed electrodecantation. 18 Pharmaceutical applications of dialysis Dialysis is the basis of a method - haemodialysis – whereby small molecular weight impurities from the body are removed by passage through a membrane. Other applications involving dialysis include the use of membranes for filtration, and as models for the diffusion of drugs through natural membranes. Properties of colloids A- Kinetic properties 1- Brownian motion Colloidal particles are subject to random collisions with the molecules of the dispersion medium, with the result that each particle pursues an irregular and complicated zigzag path. If the particles (up to about 2 um diameter) are observed under a microscope or the light scattered by colloidal particles is viewed using an ultramicroscope, an erratic motion is seen. This movement is referred to as Brownian motion. 2- Diffusion As a result of Brownian motion colloidal particles spontaneously diffuse from a region of higher concentration to one of lower concentration. The rate of diffusion is expressed by Pick's first law where dm is the mass of substance diffusing in time dt across an area A under the influence of a concentration gradient dC/dx (the minus sign denotes that diffusion takes place in the direction of decreasing concentration). D is the diffusion coefficient and has the dimensions of area per unit time. 3- Sedimentation Consider a spherical particle of radius a and density σ falling in a liquid of density p and viscosity η. The velocity v of sedimentation is given by Stokes' law: where g is acceleration due to gravity. If the particles are subjected only to the force of gravity, then as a result of Brownian motion, the lower size limit of particles obeying this Equation is about 0.5 μm. A stronger force than 19 gravity is therefore needed for colloidal particles to sediment, and use is made of a high- speed centrifuge, usually termed an ultracentrifuge, which can produce a force of about 106g. 4- Osmotic pressure The determination of molecular weights of dissolved substances from colligative properties such as the depression of freezing point or the elevation of boiling point is a standard procedure. However, of the available methods only osmotic pressure has a practical value in the study of colloidal particles because of the magnitude of the changes in the properties. However, the usefulness of osmotic pressure measurement is limited to a molecular weight range of about 104-106; below 104 the membrane may be permeable to the molecules under consideration and above 106 the osmotic pressure will be too small to permit accurate measurement. If a solution and a solvent are separated by a semipermeable membrane the tendency to equalize chemical potentials (and hence concentrations) on either side of the membrane results in a net diffusion of solvent across the membrane. The pressure necessary to balance this osmotic flow is termed the osmotic pressure. 5- Viscosity Viscosity is an expression of the resistance to flow of a system under an applied stress. B- Optical properties 1- Light scattering When a beam of light is passed through a colloidal sol some of the light may be absorbed, some is scattered and the remainder is transmitted undisturbed through the sample. Because of the scattered light the sol appears turbid: this is known as the Tyndall effect. Light scattering measurements are of great value for estimating particle size, shape and interactions, particularly of dissolved macromolecular materials, as the turbidity depends on the size (molecular weight) of the colloidal material involved. As most colloids show very low turbidities, instead of measuring the transmitted light (which may differ only marginally from the incident beam), it is more convenient and accurate to measure the scattered light, at an angle (usually 90°) relative to the incident beam. The turbidity can then be calculated from the intensity of the scattered light, provided the dimensions of the particle are small compared to the wavelength of the incident light. Light-scattering measurements are particularly suitable for finding the size of the micelles of surface active agents and for the study of proteins and natural and synthetic polymers. 20 2- Ultra-microscopy Colloidal particles are too small to be seen with an optical microscope. Light scattering is made use of in the ultramicroscope, in which a cell containing the colloid is viewed against a dark background at rightangles to an intense beam of incident light. The particles, which exhibit Brownian motion, appear as spots of light against the dark background. The ultramicroscope is used in the technique of microelectrophoresis for measuring particle charge. 3- Electron microscopy The electron microscope, capable of giving actual pictures of the particles, is used to observe the size, shape and structure of colloidal particles. The success of the electron microscope is due to its high resolving power, defined in terms of d, the smallest distance by which two objects can be separated yet remain distinguishable. The smaller the wavelength of the radiation used the smaller is d and the greater the resolving power. Electrical properties 1- Electrical properties of interfaces Most surfaces acquire a surface electric charge when brought into contact with an aqueous medium, the principal charging mechanisms being as follows. a- Ion dissolution Ionic substances can acquire a surface charge by virtue of unequal dissolution of the oppositely charged ions of which they are composed. For example, the particles of silver iodide in a solution with excess [I-] will carry a negative charge, but the charge will be positive if excess [Ag+] is present. Because the concentrations of Ag+ and I- determine the electric potential at the particle surface, they are termed potential determining ions. In a similar way H+ and OH- are potential determining ions for metal oxides and hydroxides such as magnesium and aluminium hydroxides. b- Ionization Here the charge is controlled by the ionization of surface groupings; examples include the model system of polystyrene latex, which frequently has carboxylic acid groupings at the 21 surface which ionize to give negatively charged particles. In a similar way acidic drugs such as ibuprofen and nalidixic acid also acquire a negative charge. Amino acids and proteins acquire their charge mainly through the ionization of carboxyl and amino groups to give –COO- and NH3+ ions. The ionization of these groups and hence the net molecular charge depends on the pH of the system. At a pH below the pK, of the COO- group the protein will be positively charged because of the protonation of this group, - COO- > COOH, and the ionization of the amino group -NH2 —> -NH3+, which has a much higher p/C,; whereas at higher pH, where the amino group is no longer ionized, the net charge on the molecule is now negative because of the ionization of the carboxyl group. At a certain definite pH, specific for each individual protein, the total number of positive charges will equal the total number of negative charges and the net charge will be zero. This pH is termed the isoelectric point of the protein and the protein exists as its zwitterion. c- Ion adsorption A net surface charge can be acquired by the unequal adsorption of oppositely charged ions. Surfaces in water are more often negatively charged than positively charged, because cations are generally more hydrated than anions. Consequently, the former have the greater tendency to reside in the bulk aqueous medium, whereas the smaller, less hydrated and more polarizing anions have a greater tendency to reside at the particle surface; Surface-active agents are strongly adsorbed and have a pronounced influence on the surface charge, imparting either a positive or negative charge depending on their ionic character. 2- The electrical double layer Consider a solid charged surface in contact with an aqueous solution containing positive and negative ions. The surface charge influences the distribution of ions in the aqueous medium; ions of opposite charge to that of the surface, termed counter-ions are attracted towards the surface; ions of like charge, termed co-ions, are repelled away from the surface. However, the distribution of the ions will also be affected by thermal agitation, which will tend to redisperse the ions in solution. The result is the formation of an electrical double layer, made up of the charged surface and a neutralizing excess of counter-ions over co-ions (the system must be electrically neutral) distributed in a diffuse manner in the aqueous medium. The theory of the electric double layer deals with this distribution of ions and hence with the magnitude of the electric potentials that occur in the locality of the charged surface. 22 The double layer is divided into two parts Fig., the inner, which may include adsorbed ions and the diffuse part where ions are distributed as influenced by electrical forces and random thermal motion. The two parts of the double layer are separated by a plane, the Stern plane, at about a hydrated ion radius from the surface: thus counter-ions may be held at the surface by electrostatic attraction, and the centre of these hydrated ions forms the Stern plane. Electrokinetic phenomena This is the general description applied to the phenomena that arise when attempts are made to shear off the mobile part of the electrical double layer from a charged surface. There are four such phenomena: electrophoresis, sedimentation potential, streaming potential and electro-osmosis, all of which may be used to measure the zeta potential, but electrophoresis is the easiest to use and has the greatest pharmaceutical application. a- Electrophoresis The movement of a charged particle (plus attached ions) relative to a stationary liquid under the influence of an applied electric field is termed electrophoresis. When the movement of the particles is observed with a microscope, or the movement of light spots scattered by particles too small to be observed with the microscope is observed using an ultramicroscope, this constitutes microelectrophoresis. A microscope equipped with an eyepiece graticule is used and the speed of movement of the particle under the influence of a known electric field is measured. b- Sedimentation potential the reverse of electrophoresis, is the electric field created when particles sediment; 23 c- Streaming potentia, the electric field created when liquid is made to flow along a stationary charged surface, e.g. a glass tube or a packed powder bed; and d- electroosmosis, the opposite of streaming potential, the movement of liquid relative to a stationary charged surface, e.g. a glass tube, by an applied electric field. Physical stability of colloidal systems In colloidal dispersions, frequent encounters between the particles occur as a result of Brownian movement. Whether these collisions result in permanent contact of the particles (coagulation), which leads eventually to the destruction of the colloidal system as the large aggregates formed sediment out, or temporary contact (flocculation), or whether the particles rebound and remain freely dispersed (a stable colloidal system), depends on the forces of interaction between the particles. These forces can be divided into three groups: electrical forces of repulsion, forces of attraction, and forces arising from solvation. An understanding of the first two explains the stability of lyophobic systems, and all three must be considered in a discussion of the stability of lyophilic dispersions. Before considering the interaction of these forces it is necessary to define the terms aggregation, coagulation and flocculation, as used in colloid science. Aggregation is a general term signifying the collection of particles into groups. Coagulation signifies that the particles are closely aggregated and difficult to redisperse Flocculation the aggregates have an open structure in which the particles remain a small distance apart from one another 24 Suspensions A pharmaceutical suspension is a coarse dispersion in which insoluble particles, generally greater than 1 μm in diameter, are dispersed in a liquid medium, usually aqueous. An aqueous suspension is a useful formulation system for administering an insoluble or poorly soluble drug. The large surface area of dispersed drug ensures a high availability for dissolution and hence absorption. Aqueous suspensions may also be used for parenteral and ophthalmic use, and provide a suitable form for the applications of dermatological materials to the skin. An acceptable suspension possesses certain desirable qualities, among which are the following: 1. the suspended material should not settle too rapidly; 2. the particles that do settle to the bottom of the container must not form a hard cake 3. should be readily dispersed into a uniform mixture when the container is shaken; 4. must not be too viscous to pour freely from the bottle or to flow through a syringe needle. The physical stability of a pharmaceutical suspension may be defined as the condition in which the particles do not aggregate and in which they remain uniformly distributed throughout the dispersion. As this ideal situation is seldom realized it is appropriate to add that if the particles do settle they should be easily resuspended by a moderate amount of agitation. The major difference between a pharmaceutical suspension and a colloidal dispersion is one of size of the dispersed particles, with the relatively large particles of a suspension liable to sedimentation owing to gravitational forces. Apart from this, suspensions show most of the properties of colloidal systems. Controlled flocculation A suspension in which all the particles remain discrete would, be considered to be stable. However, with pharmaceutical suspensions, in which the solid particles are very much coarser, such a system would sediment because of the size of the particles. The electrical repulsive forces between the particles allow them to slip past one another to form a close- packed arrangement at the bottom of the container, with the small particles filling the voids between the larger ones. The supernatant liquid may remain cloudy after sedimentation owing to the presence of colloidal particles that remain dispersed. Those particles lowermost in the sediment are gradually pressed together by the weight of the ones above. The repulsive barrier is thus overcome, allowing the particles to pack closely together. Physical bonding, leading to 'cake' or 'clay' formation, may then occur owing to the formation of bridges 25 between the particles resulting from crystal growth and hydration effects, forces greater than agitation usually being required to disperse the sediment. Coagulation in the primary minimum, resulting from a reduction in the zeta potential to a point where attractive forces predominate, thus produces coarse compact masses with a 'curdled' appearance, which may not be readily dispersed. On the other hand, particles flocculated in the secondary minimum form a loosely bonded structure, called a flocculate or floe. A suspension consisting of particles in this state is said to be flocculated. Although sedimentation of flocculated suspensions is fairly rapid, a loosely packed, high- volume sediment is obtained in which the floes retain their structure and the particles are easily resuspended. The supernatant liquid is clear because the colloidal particles are trapped within the floes and sediment with them. Secondary minimum flocculation is therefore a desirable state for a pharmaceutical suspension. Particles greater than 1 μm radius should, unless highly charged, show a sufficiently deep secondary minimum for flocculation to occur because the attractive force between particles, FA, depends on particle size. Other factors contributing to secondary minimum flocculation are shape (asymmetric particles, especially those that are elongated, being more satisfactory than spherical ones) and concentration. The rate of flocculation depends on the number of particles present, so that the greater the number of particles the more collisions there will be and the more flocculation is likely to occur. However, it may be necessary, as with highly charged particles, to control the depth of the secondary minimum to induce a satisfactory flocculation state. This can be achieved by the addition of electrolytes or ionic surface-active agents that reduce the zeta potential and hence FR. The production of a satisfactory secondary minimum leading to floe formation in this manner is termed controlled flocculation. A convenient parameter for assessing a suspension is the sedimentation volume ratio, F, which is defined as the ratio of the final settled volume Fu to the original volume F0. The ratio F gives a measure of the aggregated deflocculated state of a suspension and may usefully be plotted, together with the measured zeta potential, against concentration of additive, enabling an assessment of the state of the dispersion. The appearance of the supernatant liquid should be noted and the redispersibility of the suspension evaluated. Steric stabilization of suspensions Pharmaceutical suspensions may be stabilized against coagulation in the absence of a charge on the particles by the use of naturally occurring gums such as tragacanth, and synthetic materials such as non-ionic surfactants and cellulose polymers, may be used to produce satisfactory suspensions. These materials may increase the viscosity of the aqueous vehicle and thus slow the rate of sedimentation of the particles, but they will also form adsorbed 26 layers around the particles so that the approach of their surfaces and aggregation to the coagulated state is hindered. Repulsive forces arise as the adsorbed layers interpenetrate and, as explained above, these have an enthalpic component owing to the release of water of solvation from the polymer chains, and an entropic component due to movement restriction. Wetting problems One of the problems encountered in dispersing solid materials in water is that the powder may not be readily wetted. This may be due to entrapped air or to the fact that the solid surface is hydrophobic. The wettability of a powder may be described in terms of the contact angle. For a liquid to wet a powder completely there should be a decrease in the surface free energy as a result of the immersion process. Once the particle is submerged in the liquid, the process of spreading wetting becomes important. In most cases where water is involved the reduction of contact angle may only be achieved by reducing the magnitude of contact angle by the use of a wetting agent. Rheological properties of suspensions Flocculated suspensions tend to exhibit plastic or pseudoplastic flow, depending on concentration, whereas concentrated deflocculated dispersions tend to be dilatant. This means that the apparent viscosity of flocculated suspensions is relatively high when the applied shearing stress is low, but it decreases as the applied stress increases and the attractive forces producing the flocculation are overcome. Conversely, the apparent viscosity of a concentrated deflocculated suspension is low at low shearing stress, but increases as the applied stress increases. This effect is due to the electrical repulsion that occurs when the charged particles are forced close together, causing the particles to rebound and creating voids into which the liquid flows, leaving other parts of the dispersion dry. In addition to the rheological problems associated with particle charge, the sedimentation behaviour is also of course influenced by the rheological properties of the liquid continuous phase. Pharmaceutical Applications of Suspensions Suspensions can be used as oral dosage forms, applied topically to the skin or mucous membrane surfaces, or given parenterally by injection. Suspensions as oral drug delivery systems 1. Many people have difficulty in swallowing solid dosage forms and therefore require the drug to be dispersed in a liquid. Some materials are required to be present in the gastrointestinal tract in a finely divided form, and their formulation as suspensions will provide the desired high surface area. 27 2. Solids such as kaolin, magnesium carbonate and magnesium trisilicate, for example, are used for the adsorption of toxins, or to neutralize excess acidity. 3. The taste of most drugs is more noticeable if it is in solution rather than in an insoluble form. Paracetamol is available both in solution as Paediatric Paracetamol Oral Solution and also as a suspension. The latter is more palatable, and therefore particularly suitable for children. For the same reason chloramphenicol mixtures can be formulated as suspensions containing the insoluble chloramphenicol palmitate. Suspensions for topical administration 1. They can be fluid preparations, such as Calamine Lotion, which are designed to leave a light deposit of the active agent on the skin after quick evaporation of the dispersion medium. 2. Some suspensions, such as pastes, are semisolid in consistency and contain high concentrations of powders dispersed - usually - in a paraffin base. 3. It may also be possible to suspend a powdered drug in an emulsion base, as in Zinc Cream. Suspensions for parenteral use and inhalation therapy 1. By varying the size of the dispersed particles of active agent, the duration of activity can be controlled. The absorption rate of the drug into the bloodstream will then depend simply on its rate of dissolution. 2. If the drug is suspended in a fixed oil such as arachis or sesame, the product will remain after injection in the form of an oil globule, thereby presenting to the tissue fluid a small surface area from which the partitioning of drug can occur. The release of drug suspended in an aqueous vehicle will be faster, as some diffusion of the product will occur along muscle fibres and become miscible with tissue fluid. This will present a larger surface area from which the drug can be released. 3. Vaccines for the induction of immunity are often formulated as dispersions of killed microorganisms, as in Cholera Vaccine, or of the constituent toxoids adsorbed on to a substrate of aluminium hydroxide or phosphate, as in Adsorbed Diphtheria and Tetanus Vaccine. Thus a prolonged antigenic stimulus is provided, resulting in a high antibody titre. 4. Some X-ray contrast media are also formulated in this way. Barium sulphate, for the examination of the alimentary tract, is available as a suspension for either oral or rectal administration,. 5. The adsorptive properties of fine powders are also used in the formulation of some inhalations. The volatile components of menthol and eucalyptus oil would be lost from solution very rapidly during use, whereas a more prolonged release is obtained if the two active agents are adsorbed on to light magnesium carbonate prior to the preparation of a suspension. 28 Solubility and stability considerations If the drug is insoluble or poorly soluble in a suitable solvent, then formulation as a suspension is usually required. Some eye drops, notably Hydrocortisone Acetate and Neomycin Eye Drops, are formulated as suspensions because of the poor solubility of hydrocortisone in a suitable solvent. The degradation of a drug in the presence of water may also preclude its use as an aqueous solution. In this case it may be possible to synthesize an insoluble derivative that can then be formulated as a suspension. For example, oxytetracycline hydrochloride is used in solid dosage forms, but in aqueous solution would rapidly hydrolyse. A stable liquid dosage form has been made by suspending the insoluble calcium salt in a suitable aqueous vehicle. Prolonged contact between the solid drug particles and the dispersion medium can be considerably reduced by preparing the suspension immediately prior to issue to the patient. Amoxicillin, for example, is provided by the manufacturer as the trihydrate salt mixed with the other powdered or granulated ingredients. The pharmacist then makes the product up to volume with water immediately before issue to the patient, allocating a shelf-life of 14 days at a temperature at or below 25°C. A drug that degrades in the presence of water may alternatively be suspended in a non- aqueous vehicle. Fractionated coconut oil is used as the vehicle for some formulations of antibiotics for oral use, and in some countries tetracycline hydrochloride is dispersed in a similar base for ophthalmic use. FORMULATION OF SUSPENSIONS Particle size control It is first necessary to ensure that the drug to be suspended is of a fine particle size prior to formulation. This is to ensure a slow rate of sedimentation of the suspended particles. Large particles, if greater than about 5 /μm diameter, will also impart a gritty texture to the product, and may cause irritation if injected or instilled into the eyes. The ease of administration of a parenteral suspension may depend upon particle size and shape, and it is quite possible to block a hypodermic needle with particles over about 25 μm diameter, particularly if they are acicular in shape rather than isodiametric. A particular particle size range may also be chosen in order to control the rate of dissolution of the drug and hence its bioavailability. Even though the particle size of a drug may be small when the suspension is first manufactured, there is always a degree of crystal growth that occurs on storage, particularly if temperature fluctuations occur. This is because the solubility of the drug may increase as the temperature rises, but on cooling, the drug will crystallize out. This is a particular problem with slightly soluble drugs such as paracetamol. If the drug is polydispersed, then the very small crystals of less than 1 μm diameter will exhibit a greater solubility than the larger ones. Over a period of time the small crystals will become even smaller, whereas the 29 diameters of the larger particles will increase. It is therefore advantageous to use a suspended drug of a narrow size range. The inclusion of surface-active agents or polymeric colloids, which adsorb on to the surface of each particle, may also help to prevent crystal growth. Different polymorphic forms of a drug may exhibit different solubilities, the metastable state being the most soluble. Conversion of the metastable form, in solution, to the less soluble stable state, and its subsequent precipitation, will lead to changes in particle size. The use of wetting agents Some insoluble solids may be easily wetted by water and will disperse readily throughout the aqueous phase with only minimal agitation. Most, however, will exhibit varying degrees of hydrophobicity and will not be easily wetted. Some particles will form large porous clumps within the liquid, whereas others remain on the surface and become attached to the upper part of the container. The foam produced on shaking will be slow to subside because of the stabilizing effect of the small particles at the liquid/air interface. To ensure adequate wetting, the interfacial tension between the solid and the liquid must be reduced so that the adsorbed air is displaced from the solid surfaces by the liquid. The particles will then disperse readily throughout the liquid, particularly if an intense shearing action is used during mixing. If a series of suspensions is prepared, each containing one of a range of concentrations of wetting agent, then the concentration to choose will be the lowest that provides adequate wetting. The following is a discussion of the most widely used wetting agents for pharmaceutical products. Surface-active agents possessing an HLB value between about 7 and 9 would be suitable for use as wetting agents. The hydrocarbon chains would be adsorbed by the hydrophobic particle surfaces, whereas the polar groups project into the aqueous medium and become hydrated. Wetting of the solid occurs as a result of a fall both in interfacial tension between the solid and the liquid and, to a lesser extent, between the liquid and air. Most surfactants are used at concentrations of up to about 0.1% as wetting agents and include, for oral use, the polysorbates (Tweens) and sorbitan esters (Spans). For external application, sodium lauryl sulphate, sodium dioctylsulphosuccinate and quillaia extract can also be used. The choice of surfactant for parenteral administration is obviously more limited, the main ones used being the polysorbates, some of the poloxamers (polyoxyethylene/polyoxypropylene copolymers) and lecithin. Disadvantages in the use of this type of wetting agent include excessive foaming and the possible formation of a deflocculated system, which may not be required. 30 Hydrophilic colloids These materials include acacia, bentonite, tragacanth, alginates, xanthan gum and cellulose derivatives, and will behave as protective colloids by coating the solid hydrophobic particles with a multimolecular layer. This will impart a hydrophilic character to the solid and so promote wetting. These materials are also used as suspending agents and may, like surfactants, produce a deflocculated system, particularly if used at low concentrations. Solvents Materials such as alcohol, glycerol and glycols, which are water miscible, will reduce the liquid/air interfacial tension. The solvent will penetrate the loose agglomerates of powder displacing the air from the pores of the individual particles, so enabling wetting to occur by the dispersion medium. Flocculated and deflocculated systems Having incorporated a suitable wetting agent, it is then necessary to determine whether the suspension is flocculated or deflocculated and to decide which state is preferable. Whether or not a suspension is flocculated or deflocculated depends on the relative magnitudes of the forces of repulsion and attraction between the particles. In a deflocculated system the dispersed particles remain as discrete units and, because the rate of sedimentation depends on the size of each unit, settling will be slow. The supernatant of a deflocculated system will continue to remain cloudy for an appreciable time after shaking, due to the very slow settling rate of the smallest particles in the product, even after the larger ones have sedimented. The repulsive forces between individual particles allow them to slip past each other as they sediment. The slow rate of settling prevents the entrapment of liquid within the sediment, which thus becomes compacted and can be very difficult to redisperse. This phenomenon is also called caking or claying, and is the most serious of all the physical stability problems encountered in suspension formulation. The aggregation of particles in a flocculated system will lead to a much more rapid rate of sedimentation or subsidence because each unit is composed of many individual particles and is therefore larger. The rate of settling will also depend on the porosity of the aggregate, because if it is porous the dispersion medium can flow through, as well as around, each aggregate or floccule as it sediments. The nature of the sediment of a flocculated system is also quite different from that of a deflocculated one. The structure of each aggregate is retained after sedimentation, thus entrapping a large amount of the liquid phase. aggregation in the primary minimum will produce compact floccules, whereas a secondary minimum effect will produce loose floccules of higher porosity. Whichever occurs, the 31 volume of the final sediment will still be large and will easily be redispersed by moderate agitation. In a flocculated system the supernatant quickly becomes clear, as the large floes that settle rapidly are composed of particles of all sizes. In summary, deflocculated systems have the advantage of a slow sedimentation rate, thereby enabling a uniform dose to be taken from the container, but when settling does occur the sediment is compacted and difficult to redisperse. Flocculated systems form loose sediments which are easily redispersible, but the sedimentation rate is fast and there is a danger of an inaccurate dose being administered; also, the product will look inelegant. Controlled flocculation A deflocculated system with a sufficiently high viscosity to prevent sedimentation would be an ideal formulation. It cannot be guaranteed, however, that the system would remain homogenous during the entire shelf-life of the product. Usually a compromise is reached in 32 which the suspension is partially flocculated to enable adequate redispersion if necessary, and viscosity is controlled so that the sedimentation rate is at a minimum. The next stage of the formulation process, after the addition of the wetting agent, is to ensure that the product exhibits the correct degree of flocculation. Underflocculation will give those undesirable properties that are associated with deflocculated systems. An overflocculated product will look inelegant and, to minimize settling, the viscosity of the product may have to be so high that any necessary redispersion would be difficult. Controlled flocculation is usually achieved by a combination of particle size control, the use of electrolytes to control zeta potential, and the addition of polymers to enable crosslinking to occur between particles. Some polymers have the advantage of becoming ionized in an aqueous solution, and can therefore act both electrostatically and sterically. These materials are also termed polyelectrolytes. Flocculating agents In many cases, after the incorporation of a non-ionic wetting agent a suspension will be found to be deflocculated, either because of the reduction in solid/liquid interfacial tension, or because of the hydrated hydrophilic layer around each particle forming a mechanical barrier to aggregation. The use of an ionic surfactant to wet the solid could produce either a flocculated or a deflocculated system, depending on any charge already present on the particles. If particles are of opposite charge to that of the surfactant then neutralization will occur. If a high charge density is imparted to the suspended particles then deflocculation will be the result. If it is necessary for the suspension to be converted from a deflocculated to a partially flocculated state, this may be achieved by the addition of electrolytes, surfactants and/or hydrophilic polymers. Electrolytes The addition of an inorganic electrolyte to an aqueous suspension will alter the zeta potential of the dispersed particles and, if this value is lowered sufficiently, flocculation may occur. The Schultz-Hardy rule shows that the ability of an electrolyte to flocculate hydrophobic particles depends on the valency of its counter-ions. Although they are more efficient, trivalent ions are less widely used than mono- or divalent electrolytes because they are generally more toxic. If hydrophilic polymers, which are usually negatively charged, are included in the formulation they may be precipitated by the presence of trivalent ions. The most widely used electrolytes include the sodium salts of acetates, phosphates and citrates, and the concentration chosen will be that which produces the desired degree of flocculation. Care must be taken not to add excessive electrolyte or charge reversal may occur on each particle, so forming, once again, a deflocculated system. 33 Surfactants Ionic surface-active agents may also cause flocculation by neutralizing the charge on each particle, thus resulting in a deflocculated system. Non-ionic surfactants will, of course, have a negligible effect on the charge density of a particle but may, because of their linear configurations, adsorb on to more than one particle, thereby forming a loose flocculated structure. Polymeric flocculating agents Starch, alginates, cellulose derivatives, tragacanth, carbomers and silicates are examples of polymers that can be used to control flocculation. Their linear branched-chain molecules form a gel-like network within the system and become adsorbed on to the surfaces of the dispersed particles, thus holding them in a flocculated state. Although some settling can occur, the sedimentation volume is large, and usually remains so for a considerable period. Care must be taken to ensure that, during manufacture, blending is not excessive as this may inhibit the crosslinking between adjacent particles and result in the adsorption of each molecule of polymer on to one particle only. If this should occur then a deflocculated system may result, because the formation of the hydrophilic barrier around each particle will inhibit aggregation. A high concentration of polymer may have a similar effect if the whole surface of each particle is coated. It is essential that areas on each suspended particle remain free from adsorbate, so that crosslinking can recur after the product is sheared. Further details of the use of polymers can be found in the next section. Rheology of suspensions An ideal pharmaceutical suspension would exhibit a high apparent viscosity at low rates of shear so that, on storage, the suspended particles would either settle very slowly or, preferably, remain permanently suspended. At higher rates of shear, such as those caused by moderate shaking of the product, the apparent viscosity should fall sufficiently for the product to be poured easily from its container. The product, if for external use, should then spread easily without excessive dragging, but should not be so fluid that it runs off the skin surface. If intended for injection, the product should pass easily through a hypodermic needle with only moderate pressure applied to the syringe plunger. It would then be important for the initial high apparent viscosity to be reformed after a short time to maintain adequate physical stability. A flocculated system partly fulfils these criteria. In such a system pseudoplastic or plastic behaviour is exhibited as the structure progressively breaks down under shear. The product then shows the time-dependent reversibility of this loss of structure, which is termed thixotropy. 34 A deflocculated system, however, would exhibit newtonian behaviour owing to the absence of such structures and may even, if high concentrations of disperse phase are present, exhibit dilatancy. Although a flocculated system may exhibit some thixotropy and plasticity, unless a high concentration of disperse phase is present it may not be sufficient to prevent rapid settling, particularly if a surfactant or an electrolyte is present as a flocculating agent. In these cases suspending agents may be used to increase the apparent viscosity of the system. Suitable materials are the hydrophilic polymers discussed above. These exert their effect by entrapping the solid dispersed particles within their gel-like network, so preventing sedimentation. At low concentrations many suspending agents can be used to control flocculation, and it must be realized that if large quantities are to be used to enhance viscosity the degree of flocculation may also be altered. Viscosity modifiers The following materials are those most widely used for the modification of suspension viscosity. Polysaccharides Acacia This natural material is often used as a suspending agent for extemporaneously prepared suspensions. Acacia is not a good thickening agent and its value as a suspending agent is largely due to its action as a protective colloid. It is therefore useful for preparations containing tinctures of resinous materials that precipitate on addition to water. It is essential to ensure that any precipitated resin is well coated by the protective colloid before any electrolyt (which should be well diluted) is added. Acacia is not very effective for dense powders, and for these it is often combined with other thickeners such as tragacanth, starch and sucrose in compound tragacanth powder. Unfortunately, acacia mucilage becomes acidic on storage as a result of enzyme activity, and it also contains an oxidase enzyme which may cause deterioration of active agents that are susceptible to oxidation. This enzyme can, however, be inactivated by heat. Because of the stickiness of acacia it is rarely used in preparations for external use. Tragacanth This product will form viscous aqueous solutions. Its thixotropic and pseudoplastic properties make it a better thickening agent than acacia and it can be used both for internal and external products. Like acacia it is mainly, though not exclusively, used for the extemporaneous preparation of suspensions with a short shelf-life. 35 Tragacanth is stable over a pH range of 4-7.5 but takes several days to hydrate fully after dispersion in water. The maximum viscosity of its dispersions is not, therefore, achieved until after this time, and can also be affected by heating. There are several grades of this material and only the best quality is suitable for use as a pharmaceutical suspending agent. Alginates Alginic acid, a polymer of D-mannuronic acid, is prepared from kelp, and its salts have suspending properties similar to those of tragacanth. Alginate mucilages must not be heated above 60°C as depolymerization occurs, with a consequent loss in viscosity. They are most viscous immediately after preparation, after which there is a fall to a fairly constant value after about 24 hours. Alginates exhibit a maximum viscosity over a pH range of 5-9, and at low pH the acid is precipitated. Sodium alginate (Manucol) is the most widely used material in this class but it is, of course, anionic and will be incompatible with cationic materials and with heavy metals. The addition of calcium chloride to a sodium alginate dispersion will produce calcium alginate, which has a much higher viscosity. Several different viscosity grades are commercially available. Starch Starch is rarely used on its own as a suspending agent but is one of the constituents of compound tragacanth powder, and it can also be used with carmellose sodium. Sodium starch glycollate (Explotab, Primojel), a derivative of potato starch, has also been evaluated for its use in the extemporaneous preparation of suspensions. Xanthan gum (Keltrol) This is an anionic heteropolysaccharide produced by the action of Xanthomonas campestris on corn sugars. It is very soluble in cold water and is one of the most widely used thickening agents for the extemporaneous preparation of suspensions for oral use. It is used in concentrations up to about 2% and is stable over a wide pH range. Water-soluble celluloses Several cellulose derivatives are available that will disperse in water to produce viscous colloidal solutions suitable for use as suspending agents. Methylcellulose (Celacol, Methocel) 36 This is a semisynthetic polysaccharide of the general formula: where x represents the degree of substitution, usually about 0.7, which in turn affects its solubility. The viscosity of its solution depends on the value of n, which represents the degree of polymerization. The numerical suffix gives an indication of the viscosity of a 2% solution. For example sodium carboxymethylcellulose 50 at a concentration of 2% will have a viscosity of 50 mPa s. Hydroxyethylcellulose (Natrosol) This compound has hydroxyethyl instead of methyl groups attached to the cellulose chain and is also available in different viscosity grades. It has the advantage of being soluble in both hot and cold water and will not gel on heating. Otherwise it exhibits the same properties as methylcellulose. Carmellose sodium (sodium carboxymethylcellulose) This material can be represented by: dispersions. They can be used both internally and externally at concentrations of up to about 5%, and are stable over a pH range of 3.5-11. Veegurn/water dispersions will exhibit thixotropy and plasticity with a high yield value, but the presence of salts can alter these rheological properties because of the flocculating effect of their positively charged counter-ions. Some grades, however, have a higher resistance to flocculation than others. This material is often combined with organic thickening agents such as sodium carboxymethylcellulose or xanthan gum to improve yield values and degree of thixotropy, and to control flocculation. Hydroxyethylcellulose (Natrosol) This material produces clear solutions in both hot and cold water, which are stable over a pH range of about 5-10. Being anionic, this material is incompatible with polyvalent cations and the acid will be precipitated at low pHs. Heat sterilization of either the powder or its mucilage will reduce the viscosity, and this must be taken into account during formulation. It is widely used at concentrations of up to 1 % in products for oral, parenteral or external use. Microcrystalline cellulose This material consists of crystals of colloidal dimensions which disperse readily in water (but are not soluble) to produce thixotropic gels. It is a widely used suspending agent and the rheological properties of its dispersions can often be improved by the incorporation of additional hydrocolloid, in particular carboxymethylcellulose, methylcellulose and hydroxypropylmethylcellulose. These will aid dispersion and also stabilize the product against the flocculating effects of added electrolyte. 37 Hydrated silicates There are three important materials within this classification, namely bentonite, magnesium aluminium silicate and hectorite, and they belong to a group called the montmorillonite clays. They hydrate readily, absorbing up to 12 times their weight of water, particularly at elevated temperatures. The gels formed are thixotropic and therefore have useful suspending properties. As with most naturally occurring materials they may be contaminated with spores, and this must be borne in mind when considering a sterilization process and choosing a preservative system. Bentonite This has the general formula:It is used at concentrations of up to 2 or 3% in preparations for external use, such as calamine lotion. As this product may contain pathogenic spores it should be sterilized before use. Magnesium aluminium silicate (Veegum) Also known as attapulgite, this is available as insoluble flakes that disperse and swell readily in water by absorbing the aqueous phase into its crystal lattice. Several grades are available, differing in their particle size, their acid demand and the viscosity of their and is produced by the methylation of cellulose. Several grades are available, depending on their degree of methylation and on the chain length. The longer the chain, the more viscous is its solution. For example, a 2% solution of methylcellulose 20 exhibits an apparent viscosity of 20 millipascal seconds (mPa s) and methylcellulose 4500 has value of 4500 mPa s at 2% concentration. Because these products are more soluble in cold water than in hot, they are often dispersed in warm water and then, on cooling with constant stirring, a clear or opalescent viscous solution is produced. Methylcelluloses are non-ionic and therefore stable over a pH range of 3-11, and are compatible with many ionic additives. When these dispersions are heated, the methylcellulose molecules become progressively dehydrated and eventually gel at about 50°C; on cooling the original form is regained. Hectorite This material is similar to bentonite and can be used at concentrations of 1-2% for external use. It is also possible to obtain synthetic hectorites (Laponite) that do not exhibit the batch variability or level of microbial contamination associated with natural products, and which can also be used internally. As with other clays it is often advantageous to include an organic gum to modify its rheological properties. 38 This material is a totally synthetic copolymer of acrylic acid and allyl sucrose. It is used at concentrations of up to 0.5%, mainly for external application, although some grades can be taken internally. When dispersed in water it forms acidic, low-viscosity solutions which, when adjusted to a pH of between 6 and 11, become highly viscous. Colloidal silicon dioxide (Aerosil) When dispersed in water this finely divided product will aggregate, forming a three- dimensional network. It can be used at concentrations of up to 4% for external use, but has also been used for thickening non-aqueous suspensions. example, many small water droplets can be enclosed within larger oil droplets, which are themselves then dispersed in water. This gives a water-in-oil-in-water (w/o/w) emulsion. The alternative o/w/o emulsion is also possible. If the dispersed globules are of colloidal dimensions (1 nm to 1 [Am diameter) the preparation, which is quite often transparent or translucent, is called a microemulsion. This type has similar properties to a micellar system and will therefore exhibit the properties of hydrophobic colloids. As the size of the dispersed droplets increases more of the characteristics of coarse dispersions will be exhibited 39 Emulsion INTRODUCTION. An emulsion may be defined as two immiscible liquids, one of which is finely subdivided and uniformly distributed as droplets (the dispersed phase) throughout the other (the dispersion medium or continuous phase). The system is stabilized by the presence of an emulsifying agent. The dispersed liquid or internal phase usually consists of globules of diameters down to 0.1μm which are distributed within the external or continuous phase. TYPES OF EMULSION Pharmaceutical emulsions usually consist of a mixture of an aqueous phase with various oils and/or waxes. If the oil droplets are dispersed throughout the aqueous phase the emulsion is termed oil-in-water (o/w). A system in which the water is dispersed throughout the oil is a water-in-oil (w/o) emulsion. It is also possible to form multiple emulsions. For example, many small water droplets can be enclosed within larger oil droplets, which are themselves then dispersed in water. This gives a water-in-oil-in-water (w/o/w) emulsion. The alternative o/w/o emulsion is also possible. If the dispersed globules are of colloidal dimensions (1 nm to 1 μm diameter) the preparation, which is quite often transparent or translucent, is called a microemulsion. This type has similar properties to a micellar system and will therefore exhibit the properties of hydrophobic colloids. Tests for identification of emulsion type Several simple methods are available for distinguishing between o/w and w/o emulsions. The most common of these involve: 1. Miscibility tests The emulsion will only be miscible with liquids that are miscible with its continuous phase; oil-in-water emulsions are miscible with water but immiscible with oil; however; water-in- oil emulsions are miscible with oil but not with water. 2. Conductivity measurements Systems with aqueous continuous phases will readily conduct electricity, whereas systems with oily continuous phases will not; o/w emulsion water being the continuous phase, will conduct electricity throughout the system. Two electrode, when placed in such a preparation with a battery and suitable light source connected in series, will cause the lamp to glow. In contrast, a preparation in which oil is the continuous phase will not conduct electricity. The lamp will not glow or will only flicker spasmodically. 40 3. Staining tests Water-soluble and oil-soluble dyes are used, one of which will dissolve in, and color the continuous phase. Incorporation of an oil-soluble dye and microscopic examination of o/w emulsion shows paler color than w/o one, but the colored globules on colorless background have been observed; however; colorless globules against a colored background is observed in w/o type. Advantage of emulsion 1. Objectionable taste of certain medicinal agent is masked, when these agents are prepared in emulsion dosage form. 2. The penetration and spreading of emulsion constituents is increased when administered in emulsion form. 3. Medicaments, such as antiseptics are found to be more efficacious in o/w emulsions. 4. Locally the absorption and penetration of medicaments may be controlled by proper selection of emulsion type. 5. Emulsions, especially w/o type have a greater emollient effect when applied externally. 6. O/W emulsions applied externally to the skin may be readily washed off the skin and the clothing, since water is external phase PHYSICAL PROPERTIES OF WELL FORMULATED EMULSIONS  The product must remain sufficiently homogenous for at least the period between shaking the container and removing the required amount.  The creaming produced on storage, if any, must be easily redispersed by moderate agitation of the container.  The product may be required to be thickened in order to reduce the rate of creaming of oil globules. The resulting viscosity must not be so high that removal of the product from the container and transfer to the site of application are difficult.  The dispersed globules should be small and uniformly sized in order to give a elegant product. THEORY OF EMULSION STABILIZATION Interfacial films When two immiscible liquids, e.g. liquid paraffin and water, are shaken together a temporary emulsion will be formed. The subdivision of one of the phases into small globules results in a large increase in surface area and hence the interfacial free energy of the system. The system is thus thermodynamically unstable, which results first in the dispersed phase being in the form of spherical droplets (the shape of minimum surface area for a given volume), and secondly in coalescence of these droplets, causing phase separation, the state of minimum surface free energy. 41 The adsorption of a surface-active agent at the globule interface will lower the o/w interfacial tension, the process of emulsification will be made easier and the stability may be enhanced. However, if a surface-active agent such as sodium dodecyl sulphate is used, the emulsion, after standing for a short while, will still separate out into its constituent phases. On the other hand, substances such as acacia, which are only slightly surface active, produce stable emulsions. Acacia forms a strong viscous interfacial film around the globules, and it is thought that the characteristics of the interfacial film are most important in considering the stability of emulsions. A mixture of an oil-soluble alcohol such as cholesterol and a surface-active agent such as sodium cetyl (hexadecyl) sulphate was able to form a stable complex condensed film at the oil/water interface. This film was of high viscosity, sufficiently flexible to permit distortion of the droplets, resisted rupture, and gave an interfacial tension lower than that produced by either component alone. The emulsion produced was stable, the charge arising from the sodium cetyl sulphate contributing to the stability, as described for lyophobic colloidal dispersions. For complex formation at the interface the correct 'shape' of molecule is necessary. In practice, the oil-soluble and water-soluble components are dissolved in the appropriate phases and when the two phases are mixed the complex is formed at the interface. Alternatively, an emulsifying wax may be used consisting of a blend of the two components. The wax is dispersed in the oil phase and the aqueous phase is added at the same temperature. This principle is also applied with the non-ionic emulsifying agents. For example, mixtures of sorbitan mono-oleate and polyoxyethylene sorbitan esters (e.g. polysorbate 80) have good emulsifying properties. Non-ionic surfactants are widely used in the production of stable emulsions and have the advantages over ionic surfactants of being less toxic and less sensitive to electrolytes and pH variation. These emulsifying agents are not charged and there is no electrical repulsive force contributing to stability. It is likely, however, that these substances, sterically stabilize the emulsions. Hydrophilic colloids as emulsion stabilizers A number of hydrophilic colloids are used as emulsifying agents in pharmacy. These include proteins (gelatin, casein) and polysaccharides (acacia, cellulose derivatives and alginates). These materials, which generally exhibit little surface activity, adsorb at the oil/water interface and form multilayers. Such multilayers have viscoelastic properties, resist rupture and presumably form mechanical barriers to coalescence. However, some of these substance have chemical groups that ionize, e.g. acacia consists of salts of arabic acid, and proteins contain both amino and carboxylic acid groupings, thus providing electrostatic repulsion as an additional barrier to coalescence. Most cellulose derivatives are not charged. There is evidence, however, from studies on solid suspensions, that these substances sterically stabilize and it would appear probable that there will be a similar effect with emulsions. 42 Solid particles in emulsion stabilization Emulsions may be stabilized by finely divided solid particles if they are preferentially wetted by one phase and possess sufficient adhesion for one another so that they form a film around the dispersed droplets. Solid particles will remain at the interface as long as a stable contact angle, θ, is formed by the liquid/liquid interface and the solid surf ace. The particles must also be of sufficiently low mass for gravitational forces not to affect the equilibrium. If the solid is preferentially wetted by one of the phases, then more particles can be accommodated at the interface if the interface is convex towards that phase. In other words, the liquid whose contact angle (measured through the liquid) is less than 90° will form the continuous phase as shown in Figure. Aluminium and magnesium hydroxides and clays such as bentonite are preferentially wetted by water and thus stabilize o/w emulsions, e.g. liquid paraffin and magnesium hydroxide emulsion. Carbon black and talc are more readily wetted by oils and stabilize w/o emulsions. Emulsion stabilization using solid particles.(a) Preferential wetting of solid by water, leading to an o/w emulsion; (b) preferential wetting of solid by oil, leading to a w/o emulsion. FORMULATION OF EMULSIONS Because of the very wide range of emulsifying agents available, considerable experience is required to choose the best emulgent system for a particular product. The final choice will depend to a large extent on the properties and use of the final product and the other materials required to be present. Choice of emulsion type The decision as to whether an o/w or a w/o emulsion is to be formulated will eliminate many unsuitable emulsifying systems. Fats or oils for oral administration, either as medicaments in their own right or as vehicles for

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