Thursday, April 15, 2021

Preservatives Used In Pharmaceutical Suspensions: Typical Use Levels and Comments

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.

1. Alcohol

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.

a. Benzyl alcohol

Benzyl alcohol is a clear, colorless, oily liquid with a faint aromatic odor and a sharp, burning taste.

Typical use levels of benzyl alcohol in pharmaceutical suspensions

  • Up to 5.0% (oral)
  • Up to 3.0% (topical; 50% as gel)

Comments

  • Moderately effective.
  • Most effective at pH<5.
  • Antimicrobial activity may be compromised in the presence of non-ionic surfactants. May be absorbed by polyethylene containers

b. Chlorobutanol

Chlorobutanol is a volatile, colorless or white crystals with a musty, camphoraceous odor.

Typical use levels of chlorobutanol in pharmaceutical suspensions

  • 3% (topical)
  • 6% (ophthalmic)

Comments

  • Ineffective above pH 5.5.
  • Synergies with other antimicrobial preservatives.
  • May be adsorbed onto suspended solids, e.g. magnesium trisilicate and bentonite.
  • Not used for oral products in the US

c. Ethanol

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.

Typical use levels of ethanol in pharmaceutical suspensions

  • Up to 90% (oral and topical)

Comments

  • Below 50% v/v may be bacteriostatic; 50–90% bactericidal.
  • May potentiate other microbial preservatives.
  • Ineffective against bacterial spores

d. Phenylethyl alcohol

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.

Typical use level of phenylethyl alcohol in pharmaceutical suspensions

  • 5–1% (topical)

Comments

  • Also used as a preservative in vaccines.
  • Effective over a wide pH range.
  • Commonly used in combination with other antimicrobial preservatives, e.g. parabens.
  • Not used for oral products in the US

e. Phenoxyethanol

Phenoxyethanol is a colorless, slightly viscous liquid with a faint pleasant odor and burning taste.

Typical use levels of phenoxyethanol in pharmaceutical suspensions

  • 25–0.5% (nasal, otic and ophthalmic)
  • Up to 1% (topical)

Comments

  • Optimum activity <pH 5; inactive >pH 8.
  • Synergies reported with glycols, chlorhexidine, and phenylmercuric acetate.
  • Less susceptible to non-ionic surfactants than, e.g. paraben preservatives.
  • Not listed under this name in the FDA’s Inactive Ingredients Database

2. Benzoates

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.

a. Benzoic acid

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.

Typical use levels of benzoic acid in pharmaceutical suspensions

  • 01–0.75% (oral solution)
  • 1% (oral suspension)
  • Up to 0.25% (topical)

Comments

  • Also used in rectal and vaginal preparations.
  • Optimum antimicrobial activity in range pH 2.5 – 4.5

b. Potassium benzoate

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.

Typical Use Levels of Potassium benzoate

  • ≤ 0.1% (food)
  • 03–0.08% (carbonated beverages)

Comments

  • Most effective at < pH 4.5.
  • At low pH benzoic acid formation may give rise to a slight taste in food.
  • May be used as an alternative to sodium benzoate in low sodium preparations.
  • Not currently listed in the FDA’s Inactive Ingredient Database

c. Sodium benzoate

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.

Typical use levels of sodium benzoate in pharmaceutical suspensions

  • 2–3.75% (oral)
  • Up to 10% (i.m./ i.v. injection, more typically around 0.1%)
  • 1–0.5% (cosmetics)

Comments

  • Effective range pH 2–5.
  • See also benzoic acid and potassium benzoate

3. Parabens

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.

a. Butylparaben

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.

Typical use levels of butylparaben in pharmaceutical suspensions

  • Up to 0.8% (oral – typically lower)
  • 02–0.4% (topical)

Comments

  • Most active and least soluble of the commonly used paraben esters.
  • Commonly used in combination with methyl- and propylparaben

b. Ethylparaben

Ethylparaben (BP: Ethyl Hydroxybenzoate, JP: Ethyl Parahydroxybenzoate, PhEur: Ethyl Parahydroxybenzoate, USP-NF: Ethylparaben) occurs as a white, odorless or almost odorless, crystalline powder.

Comments

  • Commonly used in combination with methyl- and propylparaben.
  • Used in both oral and topical formulations, but no concentrations listed in the Inactive Ingredient Database.
  • Widely used in cosmetics

c. Methylparaben

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.

Typical use levels of methylparaben in pharmaceutical suspensions

  • 065–0.75% (i.m./i.v. injection)
  • 015–13% (oral)
  • 02–18% (topical)

Comments

  • Often used in combination with methylparanem.
  • Also used in inhalation, nasal, ophthalmic, rectal, and vaginal preparations

d. Propylparaben

Propylparaben (BP: Propyl Hydroxybenzoate, JP: Propyl Parahydroxybenzoate, PhEur: Propyl Parahydroxybenzoate, USP-NF: Propylparaben) occurs as a white, crystalline, odorless, and tasteless powder.

Typical use levels of propylparaben in pharmaceutical suspensions

  • 005–20% (i.m., i.v., s.c. injection)
  • 01–20% (oral)
  • 01–10% (topical lotion)
  • 30% (topical gel)

Comments

  • Often used in combination with methylparaben.
  • Also used in inhalation, nasal, ophthalmic, rectal and vaginal preparations

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