Pharmaceutical Development of Suspension Dosage Form

Abstract

This chapter begins with a definition of the Target Product Profile which defines the goal for the drug product and guides formulation research and development activities. Formulation research begins with the generation of the preformulation information (physicochemical properties) and leads to the selection of a prototype suspension formulation. This chapter also outlines the formulation optimization and development activities required to iteractively refine the formulation composition and process as the project proceeds to the point of filing an NDA.

Appendix I: Commonly Used Antimicrobial Preservatives

A brief description of the most commonly used preservatives and their method of use is described here. A detailed information on the most commonly used preservatives can be found in various texts (Martindale 1982). These commonly used preservatives are for pharmaceutical use. One should keep in mind that therapeutic antibiotics are rarely employed as preservative agents in pharmaceutical dosage forms because of concerns about the development of microbial resistance to antibiotics and adverse reactions to specific classes of antibiotics. The exception to this rule is in the preservation of some vaccines where the use of neomycin or streptomycin has been approved.

4.1.1 Quaternary Amines

4.1.1.1 Benzalkonium Chloride

Benzalkonium Chloride (BAK or BAC) is most widely used in ophthalmic, otic, and nasal products. It is generally used in the concentrations of 0.004–0.02%. Benzalkonium Chloride contains a mixture of alkyl chain lengths (mostly C₁₂, C_14, and C₁₆) of dimethyl benzylammonium chloride. The antimicrobial activity of BAK is significantly dependent upon the alkyl composition of the homolog mixture. Pure homologs of BAK, particularly the C₁₂ chain length, have also been used in some ophthalmic preparations.

BAK is active from pH 4–10, very stable at room temperature and readily soluble in water at typical use concentrations, and may be sterilized by autoclaving with loss of efficacy. BAK is active against a wide range of bacteria, yeasts, and fungi, but it is ineffective against some Pseudomonas aeruginosa strains. However, combined with disodium edetate (0.01–0.1% w/v), benzyl alcohol, phenylethanol, or phenylpropanol, the activity against Pseudomonas aeruginosa is increased. Benzalkonium chloride is relatively inactive against spores and molds, but is active against some viruses, including HIV.

Because it is a cationic surfactant, BAK may lose part of its activity in the presence of citrates or phosphates or other anionic species, above its critical micelle concentration, in the presence of high concentrations of other surfactants, and in the presence of suspended solids (to which it may adsorb, reducing the solution concentration). BAK has been shown to be adsorbed to various filtering membranes, especially those that are hydrophobic or anionic, and it may partition into polyvinyl chloride or polyurethane containers.

BAK is usually nonirritating, nonsensitizing, and well tolerated at the concentrations normally employed on the skin and mucous membranes, but it has been associated with adverse effects when used in some pharmaceutical formulations. Ototoxicity can occur when BAK is applied to the ear and prolonged contact with the skin can occasionally cause irritation and hypersensitivity.

4.1.1.2 Cetrimonium Bromide

Cetrimonium Bromide, a.k.a. Cetrimide, is a water-soluble (up to 10%) preservative used in the concentration range of 0.005–0.01%. Cetrimide contains a mixture of alkyl chain lengths (C₁₂, C₁₄ and C₁₆) of trimethylammonium bromide. Cetrimide has characteristics similar to those of BAK; however, it has been found to support the growth of resistant strains of P. aeruginosa. It is most effective at neutral or slightly alkaline pH values, and its activity is enhanced in the presence of alcohols. Cetrimide has variable antifungal activity, is effective against some viruses, and is inactive against bacterial spores.

4.1.1.3 Cetylpyridinium Chloride

Cetylpyridinium Chloride (CPC) is a water-soluble quaternary ammonium preservative used in the concentration range of 0.001–0.05%. It is used in mouthwashes, nasal sprays, and formulations for inhalation, oral, and transdermal drug delivery. As an active ingredient of antiseptic oral mouthwashes, it has a broad antimicrobial spectrum with a rapid bactericidal effect on gram-positive pathogens and a fungicidal effect on yeasts, but there are gaps in its effectiveness against gram-negative pathogens and mycobacteria. CPC, like BAK and Cetrimide, is both cationic and surface active and may strongly adsorb to surfaces, interact with other surfactants, or bind with anionic species resulting in a lower effective concentration in solution.

4.1.2 Organic Acids

4.1.2.1 Benzoic Acid/Potassium Benzoate/Sodium Benzoate

Benzoic acid is used as a preservative at concentration range of 0.1–0.5%. It demonstrates antimicrobial activity only in unionized form. Furthermore, it is only effective in acidic formulation with optimal activity at or below pH 4.5. It has moderate activity against gram-positive bacteria, molds, and yeasts, but is less effective against gram-negative bacteria. Benzoic acid is incompatible with quaternary compounds and nonionic surfactants.

4.1.2.2 Sorbic Acid/Potassium Sorbate

Sorbic acid is used as a preservative in the concentration range of 0.05–0.2%. It has been used extensively in the food industry especially as an antifungal agent. Sorbic acid is one of the least toxic preservatives, as it is readily metabolized by mammalian cells via beta and omega oxidation (Deuel et al. 1954). The undissociated sorbic acid exhibits a greater preservative activity than the dissociated molecule (Bandelin 1958; Wickliffe and Entrekin 1964; Ecklund 1983; Bell et al. 1959). Sorbic acid is effective at acidic pH, preferably in the range of 5.5–6.5. However, sorbic acid is unstable at this pH. Therefore, formulators should be careful when employing sorbic acid as a preservative. It is sensitive to oxidation, resulting in discoloration (McCarthy and Eagles 1976). It is also unstable at temperatures above 38°C. The compatibility of sorbic acid with polyvinyl and polypropylene containers should be carefully investigated.

4.1.2.3 Sodium Dehydroacetate

Sodium Dehydroacetate is used as a preservative typically in the concentration range of 0.02–0.2%. It is similar to sorbic acid and benzoic acid; however it is a better antimicrobial at higher pH because of having a pKa of about 5.3. It is effective in acidic formulations. However, it is incompatible with nonionic surfactants, and cationic excipients and may be adversely affected by the metals present in brown glass.

4.1.2.4 Parabens

Parabens are esters of p-hydoxy benzoic acid. They have been used in pharmaceutical and cosmetic products over the last 50 years. Most commonly used parabens are methyl- and propylparaben. The concentration range for parabens preservatives mostly depends on their water solubility but is typically in the range of 0.005% (for butyl) to 0.20% (for methyl). Parabens are safe and effective against molds, yeasts and gram-positive bacteria. The usefulness of parabens is limited by their water solubility. They can also be lost due to absorption to packaging components such as rubber stoppers. Parabens are incompatible with nonionic surfactants. They are effective in the pH range of 4–8 (Gucklhorn 1969).

4.1.3 Alcohols

4.1.3.1 Benzyl Alcohol

Benzyl alcohol has moderate antimicrobial activity at neutral- to -acidic pH. It has also been used as a cosolvent. Its use in ophthalmic formulations is limited, as it causes ocular discomfort and it has rather slow antimicrobial efficacy. Benzyl alcohol is discontinued in pediatric parenterals because of safety concerns.

4.1.3.2 Chlorobutanol

Chlorobutanol is mostly used in ophthalmic ointments as it has good solubility in petrolatum. Chlorobutanol is quite unstable at pH greater than 6 and thus is less desirable to be used in ophthalmic solutions and suspensions. Furthermore, it is volatile and can be lost through the headspace of plastic containers.

4.1.3.3 Phenylethyl Alcohol

Phenylethyl alcohol is rather a mild preservative. Its activity against fungi and certain Pseudomonas species is almost bacteriostatic. It is commonly used in the concentration range of 0.25–0.5%. Additionally, it is used in combination with other preservatives such as benzalkonium chloride.

4.1.4 Phenols

4.1.4.1 Chlorocresol

Chlorocresol is used as a preservative at a concentration range of 0.1–0.2%. It has good antimicrobial efficacy against both gram-positive and gram-negative bacteria as well as molds and yeasts. The antimicrobial activity of chlorocresol decreases with increasing pH and it has no activity above pH 9. Chrlorocresol is generally used in injectables. Chlorocresol is absorbed in rubber closures and is incompatible with polyethylene and polypropylene containers. Chrlorocresol solutions turn yellow with exposure to light.

4.1.4.2 Cresol

Cresol consists of a mixture of cresol isomers, predominantly m-cresol and other phenols obtained from coal tar or petroleum. It is a colorless, yellowish to pale brownish-yellow, or pink-liquid, with a characteristic odor similar to that of phenol, but more tarlike. An aqueous solution has a pungent taste. Cresol is used at 0.15–0.3% concentration as an antimicrobial preservative for intramuscular, intradermal, and subcutaneous injectable pharmaceutical formulations. It is also used as a preservative in some topical formulations and as a disinfectant. Cresol is not suitable as a preservative for preparations that are to be freeze-dried.

4.1.4.3 Phenol

Phenol is one of the oldest preservative. However, it is now mostly used as a disinfectant. Phenol is toxic, and irritating and has unpleasant smell. It is also incompatible with nonionic surfactants.

phenol exhibits antimicrobial activity against a wide range of microorganisms such as Gram-negative and Gram-positive bacteria, mycobacteria and some fungi, and viruses; it is only very slowly effective against spores. Aqueous solutions of 1% w/v concentration are bacteriostatic, while stronger solutions are bactericidal. Phenol shows most activity in acidic solutions; increasing temperature also increases the antimicrobial activity. Phenol is inactivated by the presence of organic matter.

Phenol is a reducing agent and is capable of reacting with ferric salts in neutral- to- acidic solutions to form a greenish complex. Phenol decolorizes dilute iodine solutions, forming hydrogen iodide and iodophenol; stronger solutions of iodine react with phenol to form the insoluble 2,4,6-triiodophenol.

Phenol is incompatible with albumin and gelatin, as they are precipitated. It forms a liquid or soft mass when triturated with compounds such as camphor, menthol, thymol, acetaminophen, phenacetin, chloral hydrate, phenazone, ethyl aminobenzoate, methenamine, phenyl salicylate, resorcinol, terpin hydrate, sodium phosphate, or other eutectic formers. Phenol also softens cocoa butter in suppository mixtures.

4.1.4.4 Thymol

Thymol is also known as isopropyl-m-cresol and is similar to m-cresol in its properties and use. Thymol is found in oil of thyme and, like the plant, has a very strong aroma. It is widely used in mouthwashes and has also been used as a preservative in the inhalation anesthetic Halothane at 0.01%. In its safety assessment of thymol and other cresols, the Cosmetic Ingredient Review Expert Panel concluded that thymol and other cresols should be used at 0.5% or less (Alan 2006). Thymol, as well as others cresols, may increase the penetartion of other ingredients (Alan 2006).

4.1.5 Mercurial Compounds

4.1.5.1 Phenylmercuric Acetate

Phenylmercuric acetate occurs as a white- to- creamy white, odorless or almost odorless, crystalline powder, or as small white prisms or leaflets. Phenylmercuric acetate is used as an alternative antimicrobial preservative to phenylmercuric borate or phenylmercuric nitrate in cosmetics (in concentrations not exceeeding 0.0065% of mercury calculated as the metal) and pharmaceuticals. It may be used in preference to phenylmercuric nitrate owing to its greater solubility.

Phenylmercuric acetate is also used as a spermicide.

phenylmercuric acetate is a broad-spectrum antimicrobial preservative with slow bactericidal and fungicidal activity similar to that of phenylmercuric nitrate

Incompatible with: halides; anionic emulsifying agents and suspending agents; tragacanth; starch; talc; sodium metabisulfite; sodium thiosulfate; disodium edetate; silicates; aluminum and other metals; amino acids; ammonia and ammonium salts; sulfur compounds; rubber; and some plastics.

Phenylmercuric acetate is reported to be incompatible with cefuroxime and ceftazidime.

4.1.5.2 Phenylmercuric Nitrate

Phenylmercuric salts are used as antimicrobial preservatives mainly in ophthalmic preparations, but are also used in cosmetics, parenteral, and topical pharmaceutical formulations.

Phenylmercuric salts are active over a wide pH range against bacteria and fungi and are usually used in neutral- to -alkaline solutions, although they have also been used effectively at a slightly acid pH. In acidic formulations, phenylmercuric nitrate may be preferred to phenylmercuric acetate or phenylmercuric borate, as it does not precipitate.

Phenylmercuric nitrate is also an effective spermicide, although its use in vaginal contraceptives is no longer recommended.

A number of adverse reactions to phenylmercuric salts have been reported and concerns over the toxicity of mercury compounds may preclude the use of phenylmercuric salts under certain circumstances.

phenylmercuric salts are broad-spectrum, growth-inhibiting agents at the concentrations normally used for the preservation of pharmaceuticals. They possess slow bactericidal and fungicidal activity. Antimicrobial activity tends to increase with increasing pH, although in solutions of pH 6 and below, activity against Pseudomonas aeruginosa has been demonstrated. Phenylmercuric salts are included in several compendial eye drop formulations of acid pH.

Activity is also increased in the presence of phenylethyl alcohol, and in the presence of sodium metabisulfite at acid pH. Activity is decreased in the presence of sodium metabisulfite at alkaline pH (1–3). When used as preservatives in topical creams, phenylmercuric salts are active at pH 5–8 (4).

Bacteria (Gram-positive): good inhibition, more moderate cidal activity. Minimum inhibitory concentration (MIC) against Staphylococcus aureus is 0.5 μg/mL.

Bacteria (Gram-negative): inhibitory activity for most Gram-negative bacteria is similar to that for Gram-positive bacteria (MIC is approximately 0.3–0.5 μg/mL). Phenylmercuric salts are less active against some Pseudomonas species, and particularly Pseudomonas aeruginosa (MIC is approximately 12 μg/mL).

Fungi: most fungi are inhibited by 0.3–1 μg/mL; phenylmercuric salts exhibit both inhibitory and fungicidal activity; for example, for phenylmercuric acetate against Candida albicans, MIC is 0.8 μg/mL; for phenylmercuric acetate against Aspergillus niger, MIC is approximately 10 μg/mL.

Spores: phenylmercuric salts may be active in conjunction with heat. The BP 1980 included heating at 100°C for 30 min in the presence of 0.002% w/v phenylmercuric acetate or phenylmercuric nitrate as a sterilization method. However, in practice this may not be sufficient to kill spores and heating with a bactericide no longer appears as a sterilization method in the BP 2001.

4.1.5.3 Thimerosal

Thimerosal is a mercurial preservative. It is used in the concentration range of 0.002–0.02%. Several years ago, it was extensively used in ophthalmic products because of its rapid broad-spectrum antimicrobial activity, particularly against P. aeruginosa, a virulent pathogen of the eye. Thimerosal is quite stable in the pH range of 6–8. It is incompatible with other mercurial preservatives, nonionic surfactants, and rubber closure.