Taibah University College of Health Sciences

Department of Pharmacy

Pharmaceutics II
PHR 206

College of Health Sciences

2009 2010

TOC

Table of Contents
1. MIXTURES..................................................................................................................... 3 Definition: .................................................................................................................... 3 Advantages: ................................................................................................................. 3 Containers for mixtures: ............................................................................................. 3 Classification: .............................................................................................................. 4 Class 1: Simple mixtures containing soluble substances only .......................................... 4 Class 2: Mixtures containing diffusible solids .................................................................. 4 Class 3: Mixtures containing indiffusible solids ............................................................... 5 Class 4: Mixtures containing precipitate forming liquids ................................................. 6 Class 5: Mixtures containing slightly-soluble liquids or solids ........................................ 7 Class 6: Effervescent mixtures.......................................................................................... 8 Class 7: Miscellaneous mixtures ....................................................................................... 9 o o o o o Protective effect of gums on colloidal precipitates: ................................................ 14 Stock solutions:.......................................................................................................... 14 Stock mixtures: .......................................................................................................... 15 Suspending Agents .................................................................................................... 16 Polysaccharides ...................................................................................................... 16 Water-soluble celluloses ......................................................................................... 18 Hydrated silicates ................................................................................................... 20 Carbomers (carboxypolymethylene) ....................................................................... 22 Colloidal silicon dioxide (Aerosil) .......................................................................... 22

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Mixtures

1. MIXTURES Definition: Liquid medicine for internal use of which several doses are contained in one bottle. Advantages: 1. They are more quickly effective than, for example, tablets, which require previous disintegration-in the body before absorption can begin. 2. Certain substances can only be given in liquid form, the character of the remedy, or the large dose, makes administration in any other from inconvenient, e. g. castor oil, liquid paraffin, ammonium acetate solution. 3. The usefulness of some substances is largely dependent upon administration in a diffused form. For example, light kaolin is used to adsorb toxic substances in the gut, the great surface area of the fine powder giving Maximum adsorbent effect. 4. Certain chemical substances, e. g. potassium iodide and potassium bromide, may cause pain if taken in the dry state as a powder or tablet. Containers for mixtures: o Plain white bottles should be used for preference. The bottle selected should then be fitted with a cork. This fitting should be done before the medicine is put into the bottle, so that unsuitable corks may be returned to stock for later use. The ideal fit should leave about two thirds of the cork projecting from the neck of the bottle, to ensure easy removal. A white label indicating the dose is affixed on the bottle.

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Mixtures

Classification: Class 1. Simple mixtures containing soluble substances only. Class 2. Mixtures containing diffusible solids. Class 3. Mixtures containing indiffusible solids. Class 4. Mixtures containing precipitate forming liquids. Class 5. Mixtures containing slightly soluble liquids or solids. Class 6. Effervescent mixtures. Class 7. Miscellaneous mixtures. Class 1: Simple mixtures containing soluble substances only Mixtures containing soluble substances such as sodium citrate, potassium citrate, magnesium sulphate, sodium sulphate and ephedrine hydrochloride are prepared by dissolving the solid in a portion of the vehicle which may be water or aromatic water as chloroform water or an infusion as infusion of senege or a decoction as decoction of ammi visnaga and straining the prepared solution. The other liquid ingredients (spirit, syrup, tincture, extract) are then added and the mixture completed with the vehicle to volume. Class 2: Mixtures containing diffusible solids Diffusible solids are those which do not dissolve in water, but may be mixed therewith so that, upon shaking, the powder is evenly diffused throughout the liquid for sufficient time to ensure uniform distribution in each dose. Examples of diffusible solids include: Rhubarb powder, aromatic chalk powder, compound rhubarb powder, bismuth subnitrate compound bismuth powder, compound kaolin powder,, compound liquorice powder, compound magnesium trisilicate powder, light kaolin, light and heavy magnesium oxide, light and heavy magnesium
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Mixtures

trisilicate, phenolphthalein, quinine sulphate, and compound jalap powder are diffusible insoluble . Diffusible substance when introduced into mixtures requires no suspending agents. The presence of air in the interstices of many powders, particularly those of vegetable origin, causes some of the powder to float on the water. To prevent this tendency, make a smooth cream first, by adding only a small quantity of vehicle, and then-diluting. Class 3: Mixtures containing indiffusible solids A solid is regarded as indiffusible when it will not remain evenly distributed in the vehicle long enough to ensure uniformly of the measured dose. The vehicle must, therefore, be increased in viscosity, and it should be noticed that the viscosity required to hold a given powder in suspension for a stated period is independent of the quantity of the powder. Therefore, the amount of suspending agent required depends upon the volume of the mixture. Examples of insoluble indiffusible solids include: Acetylsalicylic acid (aspirin) benzoic acid, bismuth oxychloride, bismuth salicylate, calomel, chlorbutol, phenacetin, phenobarbitone, prepared chalk, quinidine sulphate, Quinine salicylate, Salicylic acid, salol, succinylsulphathiazole, sulphadimidine, acetanilide, and resins of guaiacum, Jalap, podophyllum and scammony. All of these solids require a suspending agent when prescribed in mixtures Suspending agents:

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Mixtures

There are many suspending agents which can be used. The best suspending agents for general use are: 1. Compound powder of tragacanth: 2% w/v 2. Powder of tragacanth: 6.25% to 6.32% w/v 3. Powder of acacia 6% to 10% w/v 4. Mucilage of tragacanth; 1/4 the volume of the mixture. 5. Mucilage of acacia: 1/4 the volume of the mixture. For bismuth salts in mixtures, the suspending agents that can be used are compound powder of tragacanth, powder of tragacanth and mucilage of tragacanth, but not powder of acacia or mucilage of acacia because they tend to form Cement - like mass at the bottom of the bottle. Class 4: Mixtures containing precipitate forming liquids Certain liquid preparations contain resinous matter, when mixed with water, the resin is precipitated and may adhere to the sides of the bottle, or form a clotted precipitates which will not rediffuse upon shaking. This happens particularly when salts are present. Resins of scammony, podophyllum, jalap, guaiacum are insoluble and form indiffusible masses, particularly when salts are present. Resinous tinctures and extracts as ammoniated tinctures of guaiacum, and of quinine, compound tincture of benzoin, liquid extract of hydrastis, tinctures of asafetida, of tolu and of podophyllum when mixed with water, the resin is precipitated and may adhere to the bottle to form a clotted precipitate, which will not rediffuse upon shaking. A suspending agent must be added such as compound powder of tragacanth ( 2% w/v) or mucilage of tragacanth (25% w/v).
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Tinctures of cubebs, of jalap and of myrrh when added to water, their resins precipitated in a diffusible state, and thus they do not need a suspending agent except when salts are present in appreciable proportions. If the mixture contains other tinctures or spirits, they are mixed with the resinous tinctures first before adding to water or to the vehicle. The suspending agent is added before adding the precipitate forming liquids. Class 5: Mixtures containing slightly-soluble liquids or solids 1. Slightly soluble liquids The insoluble portion of slightly soluble liquids is not readily diffusible, and a suspending agent is therefore necessary. Compound tragacanth powder (2% w/v) and tragacanth mucilage (25% v/v) are used for this purpose. Examples: Creosote is soluble (1 in 150), guaiacol (1 in 80),

paraldehyde (1 in 9), and amyl nitrite (almost insoluble). Alcohol, alcoholic tinctures, spirits and extracts facilitate their solution if present in favorable proportions. 2. Slightly soluble solids: The insoluble portion of slightly soluble solids is diffusible and if presented in the form of a fine powder, it requires no suspending agent. Examples of substances commonly prescribed in a quantity greater than will dissolve: Borax (1 in 20) boric acid (1 in 20), caffeine citrate (1 in 32) calcium lactate (1 in 20) and potassium chlorate (1 in 14).

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Mixtures

Class 6: Effervescent mixtures An effervescent mixture is one containing a recently prepared salt by combining an acid (citric, tartaric) and a bicarbonates or carbonate ( K, Na or NH4 ) at the time of dispensing and producing by this means a mixture charged with carbon dioxide. The substance that produces the effervescence may be added last without powdering. Effervescent preparations are more agreeable to the taste when slightly acid, and thus it is better to arrange for a slight excess of the acid. Examples: 1.Limonade purgative E.P. (Magnesium citrate). 2. Effervescent mixture. Effervescent mixture E.P. Solution no. 1

Sodium bicarbonate Simple syrup Distilled water to Solution no. 2

40 g 170 ml 1000 ml

Citric acid Simple syrup Spirit of lemon Distilled water to

33 g 170 ml 10 ml 1000 ml
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The two solutions are freshly prepared in separate bottles. Class 7: Miscellaneous mixtures 1. Mixtures containing small doses of potent medicaments: Substances like hyoscine hydrodromide, arsenic trioxide and "strychnine hydrochloride require great care in dispensing the volume to be used. 2. Use of official solutions to obtain small doses: The pharmacopoeia includes few solutions of potent substances, e.g. Arsenical solution, containing 1% w/v of arsenic trioxide, adrenaline solution containing 0.1 % w/v of adrenaline, and morphine hydrochloride solution, containing, ,1% w/v of morphine hydrochloride. These are convenient unsuitable cases where fractions of a mg. are required.

3. Calcium lactate mixtures: Samples of calcium lactate differ in the extent of solubility. This causes a variation in the appearance of a mixture; sometimes it may be clear and sometimes there may be a diffused powder. Some commercial specimens have the objectionable odour of sour milk to an undesirable extent. When freshly made, this odour is not so apparent, and solubility is also good. Calcium carbonate and lactic acid are allowed to interact and boiled together for about 20 minutes in order to hydrolyze any lactide present in lactic acid to form lactic acid which will react with calcium carbonate.

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4. Other forms of mixtures: a. DROUGHT o A draught is a liquid medicine which is usually ordered in from one to three doses sent in a separate bottle. b. LINCTUSES o Linctuses are viscous preparations usually containing medicaments having a local action on the mucous membrane of the throat and are usually prescribed for the relief of cough. o The vehicle is some mucilaginous syrupy or viscous substance. They are sipped or swallowed slowly without dilution in orders that they may have a prolonged action. o It usually consists of a simple solution of the active agent in a high concentration of sucrose often with other sweetening agents. o This type of products, which is also designed to be administered in multiples of 5 ml should be sipped slowly and do not diluted beforehand. o The syrup content has a demulcent action on the mucous membranes of the throat. o For diabetic use the sucrose is usually replaced by sorbitol and /or synthetic sweeteners. o Examples are Codeine Linctus in sucrose syrup PC (11 th ed) & Diabetic Codeine Linctus in sorbitol solution, PC (11 th ed).

c. ELIXIRS o Elixirs are clear, pleasantly flavored, sweetened hydroalcoholic liquids intended for oral use. o The main ingredients in elixirs are ethanol and water but glycerin, sorbitol propylene glycol, flavoring agent, preservatives, and syrups
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often are used in the preparation of the final product. The solvents are often used to increase the solubility of the drug substance in the dosage form. o Elixirs are more fluid than syrups, due to the use of less viscous ingredients such as alcohol and the minimal use of viscosityimproving agents such as sucrose. o They are used as flavors and vehicles for drug substances (e.g. aromatic elixir USP). o Examples of medicated elixirs: Dexamethasone elixir USP Phenobarbital elixir USP o Occasionally, certain adverse effects (e.g., mucosal erosions) may be eliminated or reduced if the active drug (e.g. potassium chloride) is administered in elixir rather than in a solid dosage form. o The distinction between some of the medicated syrups and elixirs is not always clear however elixir must contain alcohol. o Elixirs also may contain glycerin and syrup. These may be added to increase the solubility of the medicinal agent, for sweetening purposes or to decrease the pharmacological effects of the alcohol. Some elixirs contain propylene glycol. Claims have been made for this solvent as a satisfactory substitute for both glycerin and alcohol. o An elixir may contain both water- and alcohol-soluble ingredients. If such is the case, the following procedure is indicated: Dissolve the water-soluble ingredients in part of the water. Add and solubilize the sucrose in the aqueous solution. Prepare alcoholic solution containing the other ingredients. Add the aqueous phase to the alcoholic solution, filter, and make to volume with water.

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Sucrose increases viscosity and decreases the solubilizing properties of water and so must be added after primary solution has been affected. A high alcoholic content is maintained during preparation by adding the aqueous phase to the alcoholic solution. o Elixirs that contain therapeutically active compounds are known as medicated elixirs. Phenobarbital elixir is considered a medicated elixir.

Phenobarbital Orange oil Amaranth solution Alcohol Glycerin Syrup Purified water, q.s. Sig.: Phenobarbital elixir.

4.00 g 0.75 ml 10.00 ml 150.00 ml 450.00 ml 150.00 ml 1000.00 ml

In preparing Phenobarbital elixir, the Phenobarbital and the orange oil are dissolved in alcohol. The remaining ingredients are then added, and the solution is adjusted to final volume by the addition of water. If all the ingredients were mixed and the Phenobarbital was added last, the Phenobarbital would dissolve with difficulty. The 15% alcohol in the Phenobarbital elixir is not sufficient to maintain the Phenobarbital in solution. It is the aqueous

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alcohol and glycerin solution that maintains the drug in solution. The addition of aqueous solutions to Phenobarbital elixir may cause precipitation of the Phenobarbital. o Incompatibilities: Because elixirs contain alcohol, incompatibilities of this solvent are an important consideration during formulation. Alcohol precipitates tragacanth, acacia, and agar from aqueous solutions. If an aqueous solution is added to an elixir, a partial precipitation of alcohol soluble ingredients may occur. This is due to reduced alcoholic content of the final preparation.

d. DROPS o A mixture is designated Drops when it is ordered in doses of less than one teaspoonful. Drops may be remedies given in their original form without dilution. Sometimes the remedy decomposes in aqueous media. Tincture of strophanthus contains the active principle strophanthin, a glycoside which is readily hydrolyzed by water to Strophanthidin which is inactive. To avoid this, it is prescribed generally in an alcoholic medium sometimes with compound tincture of cardamom. o Care must be taken to note the considerable difference between drops and minims. The weight of the minim of water is always constant while the weight of drop is variable with different substances. One minim approximately gives three drops of alcohol, five drops of chloroform, two and a half drops of tincture of belladonna, tincture of digitalis and tincture of opium.

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o Drops are usually sent out in bottles, accompanied by a standard dropper or a measure graduated in minims.

Protective effect of gums on colloidal precipitates: o The addition of an electrolyte, e.g. potassium bromide, and magnesium sulphate to certain colloidal solutions (e.g. resins) cause rapid agglomeration of the particles, with the formation of large visible particles, the colloid is then said to be precipitated. With other colloidal solutions, e.g. a solution of acacia or tragacanth no such precipitation takes place. o A solution of acacia is a protective colloid, i.e. not only is it stable with electrolytes, but it also prevents precipitation of other colloids when an electrolyte is added thereto. o The protective effect maybe explained by saying that the colloidal particles of acacia surround the particles of the other colloid, forming an effective barrier against the electrolyte. Stock solutions: o It is quicker to measure a liquid than to weigh a solid, hence stable soluble salts in frequent use are often made into solutions of known strength. o A common strength for very soluble substances is 1 in 3, meaning that 1 gram contained in 3 milliliters of solution. Less soluble substances are necessarily stocked in weaker solutions, e.g. 1 in 6 or 1 in 8. o It must be remembered, however, that measuring is less accurate than weighing and great care must be taken to ensure a satisfactory degree of accuracy.
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Stock mixtures: o These are mixtures prepared in bulk, to enable small volumes to be dispensed quickly when required.

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Suspending Agents The following materials are those most widely used for the modification of suspension viscosity. o Polysaccharides 1. Acacia 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 electrolyte (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.

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2. Tragacanth 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 used for the extemporaneous preparation of suspensions with a short shelf-life. 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. 3. 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 60C 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 sodium alginate dispersion will produce

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Mixtures

calcium alginate, which has a much higher viscosity. Several different viscosity grades are commercially available. 4. 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 glycolate (Explotab, Primojel), a derivative of potato starch, has also been evaluated for its use in the extemporaneous preparation of suspensions. 5. 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. o Water-soluble celluloses Several cellulose derivatives are available that will disperse in water to produce viscous colloidal solutions suitable for use as suspending agents. 1. Methylcellulose (Celacol, Methocel) This is a semisynthetic polysaccharide of the general formula:

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
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Mixtures

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 50C; on cooling the original form is regained. 2. 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. 3. Carmellose sodium (sodium carboxymethylcellulose) This material can be represented by:

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
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sodium carboxymethylcellulose 50 at a concentration of 2% will have a viscosity of 50 mPa s. 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. 4. 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. o 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.
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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. 1. 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. 2. Magnesium aluminium silicate (Veegum) It is 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 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. Veegum/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.
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3. 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. o Carbomers (carboxypolymethylene) 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. o 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.

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2. SUSPENSIONS
Definition of suspension: Suspensions are preparations that contain fine drug particles distributed uniformly throughout a vehicle in which the drug exhibits minimum solubility. A pharmaceutical suspension is usually a coarse dispersion in which insoluble solid particles are dispersed in a liquid system. The particles usually have diameter greater than 0.1 m.

Physical properties of well formulated suspensions o The product must remain sufficiently homogenous for at least the period between shaking the container and removing the required amount. o The sediment produced on storage, if any, must be easily re-suspended by moderate agitation of the container. o The product may be required to be thickened in order to reduce the rate of settling of the particles. The resulting viscosity must not be so high that removal of the product from the container and transfer to the site of application is difficult. o Any suspended particles should be small and uniformly sized in order to give a smooth, elegant product, free from a gritty texture. Theory of suspension 1. Surface free energy: For the formulation of suspensions work must be done to reduce a large solid material into small particles and disperse them in a continuous medium.

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Particle size reduction may be achieved by; Milling, Micro-pulverization, Fluid energy grinding, jet milling or micronizing, spray drying. This comminution process results in the generation of surface free energy that makes the system thermodynamically unstable as the resultant small particles are highly energetic and tend to regroup in such a way as to decrease the total area and reduce the surface free energy. The particles in a liquid suspension therefore tend to form light, fluffy conglomerates known as floccules that are held together by weak van der Waals forces. Under certain conditions, the particle may adhere by stronger forces to form aggregates known as cakes. The formation of any type of aggregate, either floccules or cakes, is perceived as a measure of the system's tendency to reach a more thermodynamically stable state. An increase in the work, W, or surface free energy, G, brought about by dividing the solid into smaller particles and eventually increasing the total surface area, A, is given by: G = SL A Where SL , is the interfacial tension between the liquid medium and the solid particles. In order to approach a stable state, the system tends to reduce the surface free energy. This may be achieved either by a reduction of interfacial tension or by a reduction of the interfacial area. Interfacial tension can be reduced by the addition of a surfactant. Reduction of interfacial area, on the other hand, is achieved through formation of floccules or cakes.

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2. Electrical properties: 2.1 Electric Double Layer o When dispersed particles are in contact with an aqueous solution of an electrolyte, the particles may selectively adsorb one charge species. If the adsorbed species is an anion, the particles will be overall negatively charged. o The ions that give the particle its charge, anions in this case, are called potential-determining ions or co-ions. o Remaining ionic species in the solution are the rest of the anions and the total number of cations added. This means, there will be excess cations than anions in the dispersion medium. o These cations having a charge opposite to that of the potentialdetermining ions are known as counter-ions. They are attracted to the negatively charged surface by electric forces. o Counter-ions also repel the approach of any further anions to particle surface, once the initial adsorption is complete. o These electric forces and thermal motion keeps an equal distribution of all the ions in solution. It results in an equilibrium condition where some of the excess cations approach the surface and the rest of the cations will be distributed in decreasing the amounts as one moves away from the charged surface. This situation is explained in Fig. 2.1. o The part of the solvent immediately surrounding the particles will almost entirely comprise of the counter-ions. This part of the solvent, along with these counter-ions is tightly bound to the particle surface and is known as the Stern layer. o When particles move through the dispersion medium, the Stern layer moves along with them and thus the shear plane is the one peripheral to the Stern layer.

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o There are fewer counter-ions in the tightly bound layer than co-ions adsorbed onto the surface of the solid. Therefore, the potential at the shear plane is still negative. o Surrounding the Stern layer is the diffuse layer that contains more counter-ions than co-ions. The ions in this layer are relatively mobile and, because of thermal energy, they are in a constant state of motion into and from the main body of the continuous phase. o Electric neutrality occurs where the mobile diffuse layer ends. Beyond the diffuse layer, the concentrations of co- and counter-ions are equal, that is, conditions of electric neutrality prevail throughout the remaining part of the dispersion medium.

o Thus, the electric distribution at the solidliquid interface can be visualized as a double layer of charge. The Stern layer, the first layer is tightly bound to the solid surface and contains mostly the counter-ions. The second layer is more mobile containing more counter-ions than coions. These two layers are commonly known as the electric double layer. o The thickness of the double layer depends upon the type and concentration of ions in solution. It is important to note that the

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suspension, as a whole is electrically neutral despite the presence of unequal distribution of charges in the double layer. o Two other situations may arise. Should the concentration of counter-ions in the tightly bound layer be equal to that of the co-ions on the solid surface, then electric neutrality will occur at the shear plane and there will be only one layer of medium and ions, instead of double layer. o However, if the total charge of the counter-ions in the Stern layer exceeds the charge due to the co-ions, the net charge at the shear plane will be positive rather than negative. It means electric neutrality will be achieved where the electric double layer ends and the diffuse layer, will contain more co-ions than counter-ions. o The charge density at any distance from the surface is determined by taking the difference in concentration between positive and negative ions at that point.

2.2 Nernst and Zeta Potentials o The electric double layer is formed in order to neutralize the charged particles in a suspension. o As discussed before the electrical potential at any point in a suspension system depends on its exact location. o The potential in the diffuse layer gradually changes as one moves away from a solid particle. This is shown in Fig. 2.2. o The difference in electric potential between the actual or true surface of the particle and the electroneutral region is referred to as the surface or electrothermodynamic or Nernst potential (E). o Hence, Nernst potential is controlled by the electrical potential at the surface of the particle due to the potential determining ions. o The potential difference between the shear plane and the electroneutral region is known as the electrokinetic or zeta (z) potential (Fig. 2.3).
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o While Nernst potential has little influence in the formulation of stable suspension, zeta potential has significant effect on it. o Zeta potential governs the degree of repulsion between adjacent, similarly charged solid dispersed particles. If the zeta potential is reduced below a certain value, which depends on the specific system under investigation, the attractive forces between particles due to van der Waals force, overcome the forces of repulsion and the particles come together to form floccules. This phenomenon is known as flocculation. o The magnitude of surface and zeta potentials is related to the surface charge and the thickness of the double layer.

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Rationale for suspensions formulation o The reasons for preparing a suspension are: 1. Certain drugs are chemically unstable in solution phase but stable in suspension. In this case, the suspension can assure the stability while delivering the drugs in liquid dosage form. 2. Many patients prefer the liquid formulation over the solid form of the same drug since it is easier to swallow. 3. The flexibility in administration of a range of doses for a liquid dosage form than a solid dosage form (as tablets) for infants, children, and the elderly. 4. Suspension helps improve the taste of some poor-tasting drugs, because the dispersion medium can be sweetened and flavored. 5. A suspension is often a suitable dosage form to be given orally, in dermatology (Topical or on the skin) and for the parenteral (IM, SC) administration of insoluble drugs. 6. Many antibiotic agents are unstable in solution for a period of time; therefore, packaging as a dry powder to be reconstituted by adding the dispersion medium when filling the prescription is a good approach. o Common pharmaceutical suspensions belong to three groups: (1) Oral suspensions (syrups) which have the most common application of suspension, (2) external suspension (lotions), and (3) parenteral suspensions. o The following are examples of some common oral suspensions: Alumina, magnesia, and simethicone oral suspension. Magnesia and alumina oral suspension. Sulfamethoxazole and trimethoprim oral suspension. Amoxicillin for oral suspension. Ampicillin for oral suspension. Cefixime for oral suspension.
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Chapter 2

Suspensions

o The last three preparations consist of specific amounts of dry powder mixtures or granules, which are intended to be suspended in a specific quantity of water or some other vehicle prior to oral administration to produce a specific concentration. Formulation of Suspension 1. Particle size control o 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. o Large particles, if greater than about 5 m diameter, will also impart a gritty texture to the product, and may cause irritation if injected or instilled into the eyes. o 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 m diameter, particularly if they are acicular in shape rather than isodiametric. o A particular particle size range may also be chosen in order to control the rate of dissolution of the drug and hence its bioavailability. o 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. o If the drug is polydispersed, then the very small crystals of less than 1 m diameter will exhibit a greater solubility than the larger ones. o Over a period of time the small crystals will become even smaller, whereas the diameters of the larger particles will increase.
30

Chapter 2

Suspensions

o 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. o 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.

2. The use of wetting agents o Some insoluble solids may be easily wetted by water and will disperse readily throughout the aqueous phase with only minimal agitation. o 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. o The foam produced on shaking will be slow to subside because of the stabilizing effect of the small particles at the liquid/air interface. o 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. o The particles will then disperse readily throughout the liquid, particularly if an intense shearing action is used during mixing. o 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. o The following is a discussion of the most widely used wetting agents for pharmaceutical products.
31

Chapter 2

Suspensions

a. Surface-active agents Surfactants 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. b. 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.
32

Chapter 2

Suspensions

c. 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. 3. Flocculated and deflocculated systems o 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. o Whether or not a suspension is flocculated or deflocculated depends on the relative magnitudes of the forces of repulsion and attraction between the particles. o 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. o 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. o 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. o This phenomenon is also called caking or claying, and is the most serious of all the physical stability problems encountered in suspension formulation.
33

Chapter 2

Suspensions

o In a flocculated system, the aggregation of particles 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. o 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. o 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. The volume of the final sediment will still be large and will easily be redispersed by moderate agitation. o In a flocculated system the supernatant quickly becomes clear, as the large flocs that settle rapidly are composed of particles of all sizes.

The sedimentation behaviour of flocculated and deflocculated suspensions. Within a few minutes of manufacture (a) there is no apparent change within the deflocculated system compared to its initial appearance. Even after several hours (b) there is still little obvious change, except that the concentration of solids in the lower layers has increased at the expense of the upper layers owing to slow particle sedimentation. There is a small amount of a compact sediment. After prolonged storage (c), depending on the physical stability of the system, the supernatant has cleared, leaving a compact sediment. In the flocculated system at (a) there is some clear supernatant with a distinct boundary between it and the sediment. At (b) there is a larger volume of clear supernatant with a relatively large volume of a porous sediment, which does not change further even after prolonged storage (c).

34

Chapter 2

Suspensions

o 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. a. 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 which the suspension is partially flocculated to enable easy redispersion if necessary, and viscosity is controlled so that the sedimentation rate is at a minimum. So 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

35

Chapter 2

Suspensions

an aqueous solution, and can therefore act both electrostatically and sterically. These materials are also termed polyelectrolytes. b. 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. i. 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,
36

Chapter 2

Suspensions

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. ii. Surfactants Ionic surface-active agents may also cause flocculation by neutralizing the charge on each particle. 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. iii. 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
37

Chapter 2

Suspensions

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.
Table.1. Relative properties of flocculated and deflocculated suspensions Character Particles Rate of sedimentation Deflocculated Exist in suspension as individual entities. Slow Very closely packed and the resulting hard cake is difficult, if not impossible, to redisperse after settling it remains cloudy. Flocculated Form loose aggregates or floccules. high loosely packed and easy to redisperse

The sediment

supernatant

After rapid settling, a clear boundary exists between the sediment and the supernatant.

Preparation of suspension o In the preparation of a suspension, the pharmacist must be familiar with the characteristics of both the dispersed phase and the dispersion medium. o In some cases, the dispersed phase (powder) is readily wetted when added to the medium. However, sometimes the particles clump together and float on top of the vehicle and cause an uneven suspension. In these cases, the powder must be wetted firstly with wetting agent. o Examples of wetting agents used in case of aqueous vehicle as dispersion medium are alcohol, glycerol, propylene glycol or other hygroscopic liquids.
38

Chapter 2

Suspensions

o Once the powder is wetted, the dispersion medium is added and mixed thoroughly before addition of the vehicle. o The final product is then passed through a colloid mill or blender to insure uniformity. A preservative may be added to protect against bacterial contamination. Extemporaneous compounding of suspensions o Unfortunately, not all medicines are available in a convenient, easy-totake liquid dosage form. Therefore, patients who are not able to swallow solid dosage medicines such as infants and elderly may present a special need. o Thus pharmacist may have to use a solid dosage form of the drug and extemporaneously compound a liquid product. o The contents of the capsule are to be putted into a mortar; if it is in tablet form, it will be crushed in a mortar with a pestle. Then the selected vehicle is slowly added to the powder and mixed well to create a paste before being diluted to the desired volume. o The difficulty that confronts the pharmacist is the stability of the drug when it is incorporated into a liquid vehicle. Drugs in liquid form have faster decomposition rates than those in solid form. To overcome this, the pharmacist can contact the pharmaceutical manufacturer to obtain stability information. Settling/Sedimentation in suspensions o Settling of the suspended particles leading to separation of dispersed particles and dispersion medium is the most important factor associated with the physical stability of a suspension. o Many factors involved in the rate of settling of the particles of a suspension are summarized in the equation of Stokes' law:
39

Chapter 2

Suspensions
2 dx d ( p m ) g = dt 18

Where dx/ dt is the sedimentation rate, d is the diameter of the particles, p is the density of particles, m is the density of medium, g is the gravitational constant, and is the viscosity of the medium, o The equation is valid only in an ideal situation in which uniform, perfectly spherical particles settle in a very dilute suspension (i.e., no collision of the particles), without effecting turbulence in the medium and without chemical or physical attraction between the particles and the medium. o While in practical cases, conditions are not in strict accord with the assumptions of Stokes' law, the above equation does give the factors that influence the rate of settling. It is apparent from the equation that rate of sedimentation (dx/dt) will be reduced by A. Decreasing the particle size (d), provided the particles are kept in a deflocculated state. This may be achieved by communition of the particles using appropriate techniques (pestle and mortar, colloid mills, etc.)., B. Minimizing the difference in densities between the particles and the dispersion medium (p- m). In fact control of settling by minimizing the difference in densities between the particles and the dispersion medium is not too practical. C. Increasing the viscosity of the dispersion medium (). Viscosity of the dispersion medium can always be increased by the addition of
40

Chapter 2

Suspensions

viscosity

building

polymers

(methyl

cellulose,

carboxy

methylcellulose, etc.). However, too high a viscosity is undesirable, as it may affect the redispersability and pourability of the suspension.

41