4. Phenolics
Phenolics are compounds containing hydroxylated aromatic rings, the hydroxy group being attached directly to the phenyl, substituted phenyl, or other aryl groups. Phenolics are incompatible with non-ionic surfactants.
a. Chlorocresol
Chlorocresol is a colorless or almost colorless, dimorphous crystals or crystalline powder with a characteristic phenolic odor.
Typical use level of chlorocresol in pharmaceutical suspensions
- Not recommended for oral products or preparations that come into contact with mucosal tissues. More active at acid pH; inactive above pH 9.
- Active against Gram −ve and Gram +ve micro-organisms, spores, yeasts, and molds.
- Synergies reported with other antimicrobial preservatives.
- May be absorbed into rubber closures and some plastics.
- Incompatible with some APIs, e.g. opiates.
- Not used for oral products in the US
b. 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-colored liquid, with a characteristic odor similar to phenol but more tarlike. An aqueous solution has a pungent taste
Typical use level of cresol in pharmaceutical suspensions
- Similar to phenol but more active.
- Active at <pH 9; best in acidic media.
- Synergies reported with other antimicrobial preservatives.
- Three isomer o-, m- and p-.
- m-cresol is the least toxic.
- Not active against bacterial spores.
- Not used in oral medicines in the US
c. Phenol
Phenol occurs as colorless to light pink, caustic, deliquescent needle-shaped crystals or crystalline masses with a characteristic odor. When heated gently phenol melts to form a highly refractive liquid. The USP 32 permits the addition of a suitable stabilizer; the name and amount of substance used for this purpose must be clearly stated on the label.
Typical use level of phenol in pharmaceutical suspensions
- Most active in acidic media.
- <1% – bacteriostatic; higher concentrations bactericidal.
- Inactivated by organic matter
d. Thymol
Thymol occurs as colorless or often large translucent crystals, or as a white crystalline powder with a herbal odor (aromatic and thymelike) and a pungent caustic taste.
Typical Use Level of thymol in pharmaceutical suspensions
- Approved in at least one oral product on US market.
- More active than phenol, but less soluble.
- Irritant to tissues.
- Has antioxidant properties.
- Inactivated by organic matter, e.g. proteinaceous matter, and oxidizing agents.
- Mainly used in topical preparations, mouthwashes and inhalation cold remedies.
5. Quaternary ammonium compounds
Quaternary ammonium compounds (commonly known as quats or QACs) are cationic surfactants that combine bactericidal and virucidal (generally only enveloped viruses) activity with good detergency and, therefore, cleaning ability. QACs are incompatible with anionic surfactants and other organic anions.
a. Benzalkonium chloride
Benzalkonium chloride occurs as a white or yellowish-white amorphous powder, a thick gel, or gelatinous flakes. It is hygroscopic, soapy to the touch, and has a mild aromatic odor and very bitter taste.
Typical use levels of benzalkonium chloride in pharmaceutical suspensions
- 01–0.02% (parenteral)
- Up to 0.2% (topical)
- 20% (inhalation solution)
- Often used in combination with disodium edetate to enhance its activity against Pseudomonas
- Better activity against Gram −ve than Gram +ve bacteria.
- Activity increases with pH; best activity in range pH 4–10.
- Not active against bacterial spores, but active against some viruses.
- Also used in ophthalmic, nasal and otic products
b. Benzethonium chloride
Benzethonium chloride occurs as a white crystalline material with a mild odor and very bitter taste.
Typical use levels of benzethonium chloride in pharmaceutical suspensions
- 01–0.02% (ophthalmic and otic)
- Up to 0.012% (parenteral)
- Active over the range pH 4 – 10.
- Activity is enhanced by ethanol.
- Used mainly in topical products
c. Cetrimonium bromide
Cetrimonium bromide (CTAB: cetyltrimethylammonium bromide) is hexadecyltrimethylammonium bromide is a quaternary ammonium surfactant.
Typical Use Levels
- Used topically up to 1% as an antiseptic for burns and up to 3% in shampoos.
- More active against Gram +ve than Gram −ve micro-organisms.
- Activity reduced in acidic media; optimal activity in neutral to slightly alkaline media.
- Activity enhanced in the presence of ethanol.
- Inactive against bacterial spores.
- May be absorbed by suspended solids, e.g. bentonite.
- Not currently listed in the Inactive Ingredient Database
d. Cetylpyridinium chloride
Cetylypyridinium chloride is a white powder with a characteristic odor. It is slightly soapy to the touch.
Typical use level of cetylpyridinium chloride in pharmaceutical suspensions
- Used mainly as an active principle in sore throat remedies.
- May adsorb onto suspended solids
6. Sorbates
Sorbates are salts and esters of sorbic acid. Sorbates are prone to oxidation but are not inactivated by non-ionic surfactants.
a. Potassium sorbate
Potassium sorbate occurs as a white crystalline powder with a faint, characteristic odor.
Typical use levels of potassium sorbate in pharmaceutical suspensions
- 1–0.65% (oral)
- Up to 0.47% (topical)
- Active < pH 6.
- Synergies reported with other antimicrobial preservatives and glycols.
- More soluble than sorbic acid.
b. Sorbic acid
Sorbic acid is a tasteless, white to yellow-white crystalline powder with a faint characteristic odor.
Typical use levels of sorbic acid in pharmaceutical suspensions
- 05–0.5% (oral)
- Up to 2.7% (topical)
- Optimum activity at about pH 4.5; no activity >pH 6.
References
1. Kulshreshtha A., Singh O. and Wall M. (2010). Pharmaceutical Suspensions: From Formulation Development to Manufacturing. London, New York, Dordrecht Heidelberg: Springer.
2. Rowa R., Sheskey P. and Quinn M. (2009). Handbook of Pharmaceutical Excipients. USA: Pharmaceutical Press and American Pharmacists Association.
