Through spoilage, active drug constituents may be metabolized to less potent or chemically inactive forms. Under laboratory conditions, it has been shown that a variety of microorganisms can metabolize a wide assortment of drugs, resulting in loss of activity.
PHARMACEUTICAL INGREDIENTS SUSCEPTIBLE TO MICROBIAL ATTACK
• Therapeutic agents. Through spoilage, active drug
constituents may be metabolized to less potent or chemically inactive forms.
Under laboratory conditions, it has been shown that a variety of microorganisms
can metabolize a wide assortment of drugs, resulting in loss of activity.
Materials as diverse as alkaloids (morphine, strychnine, atropine), analgesics
(aspirin, paracetamol), thalidomide (still used in the treatment of some forms
of cancer), barbiturates, steroid esters and mandelic acid can be metabolized
and serve as substrates for growth. Indeed, the use of microorganisms to carry
out subtle transformations on steroid molecules forms the basis of the
commercial production of potent therapeutic steroidal agents. In practice,
reports of drug destruction in medicines are less frequent. There have,
however, been some notable exceptions: the metabolism of atropine in eye drops
by contaminating fungi; inactivation of penicillin injections by β-lactamase producing
bacteria; steroid metabolism in damp tablets and creams by fungi; microbial
hydrolysis of aspirin in suspension by esterase-producing bacteria; and
chloramphenicol acetylase-producing contaminant.
• Surface-active agents. Anionic surfactants, such as the
alkali metal and amine soaps of fatty acids, are generally stable because of
the slightly alkaline pH of the formulations, although readily degraded once
diluted into sewage. Alkyl and alkylbenzene sulphonates and sulphate esters are
metabolized by ω-oxidation of their terminal methyl groups followed by
sequential β-oxidation of the alkyl chains and fission of the aromatic rings.
The presence of chain branching involves additional α-oxidative processes. Generally,
ease of degradation decreases with increasing chain length and complexity of
branching of the alkyl chain.
• Non-ionic surfactants, such as alkyl-polyoxy-ethylene
alcohol emulsifiers, are readily metabolized by a wide variety of
microorganisms. Increasing chain lengths and branching again decrease ease of
attack. Alkylphenol polyoxyethylene alcohols are similarly attacked, but are
significantly more resistant. Lipolytic cleavage of the fatty acids from
sorbitan esters, polysorbates and sucrose esters is often followed by degradation
of the cyclic nuclei, producing numerous small molecules readily utilizable for
microbial growth. Ampholytic surfactants, based on phosphatides, betaines and
alkylamino substituted amino acids, are an increasingly important group of
surfactants and are generally reported to be reasonably biodegradable. The
cationic surfactants used as antiseptics and preservatives in pharmaceutical
applications are usually only slowly degraded at high dilution in sewage.
Pseudomonads have been found growing readily in quaternary ammonium antiseptic
solutions, largely at the expense of other ingredients such as buffering
materials, although some metabolism of the surfactant has also been observed.
• Organic polymers. Many of the thickening and suspending
agents used in pharmaceutical formulations are subject to microbial
depolymerization by specific classes of extracellular enzymes, yielding
nutritive fragments and monomers. Examples of such enzymes, with their
substrates in parentheses, are: amylases (starches), pectinases (pectins),
cellulases (carboxy methyl celluloses, but not alkylcelluloses), uronidases
(polyuronides such as in tragacanth and acacia), dextranases (dextrans) and
proteases (proteins). Agar (a complex polysaccharide) is an example of a
relatively inert polymer and, as such, is used as a support for solidifying
microbiological culture media. The lower molecular weight polyethylene glycols
are readily degraded by sequential oxidation of the hydrocarbon chain, but the
larger congeners are rather more recalcitrant. Synthetic packaging polymers
such as nylon, polystyrene and polyester are extremely resistant to attack,
although cellophane (modified cellulose) is susceptible under some humid
conditions.
• Humectants. Low molecular weight materials such as
glycerol and sorbitol are included in some products to reduce water loss and
may be readily metabolized unless present in high concentrations.
• Fats and oils. These hydrophobic materials are usually
attacked extensively when dispersed in aqueous formulations such as
oil-in-water emulsions, aided by the high solubility of oxygen in many oils.
Fungal attack has been reported in condensed moisture films on the surface of
oils in bulk, or where water droplets have contaminated the bulk oil phase. Lipolytic
rupture of triglycerides liberates glycerol and fatty acids, the latter often
then undergoing β-oxidation of the alkyl chains and the production of odiferous
ketones. Although the microbial metabolism of pharmaceutical hydrocarbon oils
is rarely reported, this is a problem in engineering and fuel technology when
water droplets have accumulated in oil storage tanks and subsequent fungal
colonization has catalysed serious corrosion.
• Sweetening, flavouring and colouring agents. Many of the
sugars and other sweetening agents used in pharmacy are ready substrates for
microbial growth. However, some are used in very high concentrations to reduce water
activity in aqueous products and inhibit microbial attack (see section 2.3.3).
At one time, a variety of colouring agents (such as tartrazine and amaranth)
and flavouring agents (such as peppermint water) were kept as stock solutions
for extemporaneous dispensing purposes, but they frequently supported the
growth of Pseudomonas spp., including Ps. aeruginosa.
Such stock solutions should now be preserved, or freshly made as required by
dilution of alcoholic solutions which are much less susceptible to microbial
attack.
• Preservatives and disinfectants. Many preservatives and
disinfectants can be metabolized by a wide variety of Gram-negative bacteria,
although most commonly at concentrations below their effective ‘use’ levels.
Growth of pseudomonads in stock solutions of quaternary ammonium antiseptics
and chlorhexidine has resulted in infection of patients. Pseudomonas spp.
have metabolized 4-hydroxybenzoate (parabens) ester preservatives contained in
eyedrops and caused serious eye infections, and have also metabolized the
preservatives in oral suspensions and solutions. In selecting suitable
preservatives for formulation, a detailed knowledge of the properties of such
agents, their susceptibility to contamination and limitations clearly provides
invaluable information.
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