An antimicrobial agent is a natural or synthetic substance that interferes with the growth and activities of microorganisms that may accidentally contaminate pharmaceutical dosage forms. Pharmaceutical suspensions with water as the continuous phase are susceptible to microbial spoilage. The source of the microbial growth may be raw materials, e.g. materials of natural origin such clays (mined) and alginates (extracted from marine algae), process-related (airborne contamination or from operators), or during use by the patient.
Whilst every effort is made to keep raw material and process-related contamination to an acceptable minimum, it is almost impossible to eliminate micro-organisms entirely. In addition, the risk of microbial contamination and subsequent product spoilage is much increased during use by the patient.
For these reasons, pharmaceutical suspension formulations contain antimicrobial preservatives. The preservative system has to be effective against both bacteria, and yeasts and molds, and typically, combinations of preservatives are used.
This article contains a list of antimicrobial agents suitable for use in oral pharmaceutical suspensions together with their typical use levels. This list includes preservatives used for oral and topical medicines. In some instances, different levels may be permitted for different applications.
There are of course a number of other antimicrobial agents that may be approved for use in other types of product. Information on these other antimicrobial agents is available in The Handbook of Pharmaceutical Excipients. The mercury-based antimicrobial agents have been omitted. They are still permitted for some very specific applications, but there are concerns regarding long term safety of these agents.
The final choice of preservative will depend very much on the nature of the product and the other components present, and the nature of the micro-organisms likely to be encountered during manufacture and use.
The action of alcohol is generally bactericidal and fungicidal but not sporicidal. The mechanism of microbial inactivation seems to be due to denaturation of cell proteins. The antimicrobial activity of the aliphatic alcohols increases with the chain length up to 10 carbon atoms, above which the water solubility is too low to allow for general use.
Benzyl alcohol is a clear, colorless, oily liquid with a faint aromatic odor and a sharp, burning taste.
Chlorobutanol is a volatile, colorless or white crystals with a musty, camphoraceous odor.
The term “ethanol” (BP) is used without other qualification refers to ethanol containing ≥ 99.5% v/v of C2H6O. The term ‘alcohol’, without other qualification, refers to ethanol 95.1–96.9% v/v. Where other strengths are intended, the term ‘alcohol’ or ‘ethanol’ is used, followed by the statement of the strength.
Phenylethyl alcohol is a clear, colorless liquid with an odor of rose oil. It has a burning taste that irritates and then anesthetizes mucous membranes.
Phenoxyethanol is a colorless, slightly viscous liquid with a faint pleasant odor and burning taste.
Benzoates refer to the aromatic compound benzoic acid and its salts, esters, and alcohols. Benzoates are incompatible with quaternary ammonium surfactants, calcium, ferric and heavy metal salts. Benzoates may be adsorbed by kaolin with resulting decrease in antimicrobial activity.
Benzoic acid occurs as feathery, light, white, or colorless crystals or powder. It is essentially tasteless and odorless or with a slight characteristic odor suggestive of benzoin.
Potassium benzoate occurs as a slightly hygroscopic, white, odorless or nearly odorless crystalline powder or granules. Aqueous solutions are slightly alkaline and have a sweetish astringent taste.
Sodium benzoate occurs as a white granular or crystalline, slightly hygroscopic powder. It is odorless, or with faint odor of benzoin and has an unpleasant sweet and saline taste.
Parabens are a class of widely used preservatives in cosmetic, personal hygiene products, food products, and pharmaceutical products. Chemically, they are a series of parahydroxybenzoates or esters of parahydroxybenzoic acid (also known as 4-hydroxybenzoic acid).
In general, the paraben esters are more active against Gram +ve than Gram −ve micro-organisms. Paraben esters are more active against yeasts and molds than bacteria. The antimicrobial activity of paraben esters is optimal at pH range of 4 – 8, but more active in acidic media.
Paraben esters are inactive at higher pH due to the formation of phenolate ion. Antimicrobial activity increases with increase in alkyl chain length, but solubility decreases. Antimicrobial activity is reduced in presence of non-ionic surfactants. Activity is enhanced in the presence of propylene glycol, phenylethyl alcohol and edetic acid. Sodium salts are also available with increased solubility but may need pH buffer. The hydrolysis product, p-hydroxybenzoic acid, is inactive. At high concentrations, paraben esters can modify taste sensation.
Butylparaben (BP: Butyl Hydroxybenzoate, JP: Butyl Parahydroxybenzoate, PhEur: Butyl Parahydroxybenzoate, USP-NF: Butylparaben) occurs as colorless crystals or a white, crystalline, odorless or almost odorless, tasteless powder.
Ethylparaben (BP: Ethyl Hydroxybenzoate, JP: Ethyl Parahydroxybenzoate, PhEur: Ethyl Parahydroxybenzoate, USP-NF: Ethylparaben) occurs as a white, odorless or almost odorless, crystalline powder.
Methylparaben (BP: Methyl Hydroxybenzoate, JP: Methyl Parahydroxybenzoate, PhEur: Methyl Parahydroxybenzoate, USP-NF: Methylparaben) occurs as colorless crystals or a white crystalline powder. It is odorless or almost odorless and has a slight burning taste.
Propylparaben (BP: Propyl Hydroxybenzoate, JP: Propyl Parahydroxybenzoate, PhEur: Propyl Parahydroxybenzoate, USP-NF: Propylparaben) occurs as a white, crystalline, odorless, and tasteless powder.
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