Hugo W.B., Russel A.D.(ed). Pharmaceutical Microbiology

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deterioration have quite unpleasant tastes and smell even at low levels, and would

deter most from using such a medicine.

1.2.2 Chemical and physico-chemical deterioration of pharmaceutical products

Microorganisms form a major part of the natural recycling processes for biological

matter in the environment. As such, they possess a wide variety of degradative

capabilities, which they are able to exert under relatively mild physico-chemical

conditions. Mixed natural communities are often far more effective co-operative

biodeteriogens than the individual species alone, and sequences of attack of complex

substrates occur where initial attack by one group of microorganisms renders them

susceptible to further deterioration by secondary, and subsequent, microorganisms.

Under suitable environmental selection pressures even novel degradative pathways

emerge, able to attack newly introduced synthetic chemicals (xenobiotics). However,

the rates of degradation of materials released into the environment can vary

greatly, from half lives of hours (phenol) to months ('hard' detergents) to years

(halogenated pesticides). The overall rate of deterioration of a chemical will depend

upon:

1 its chemical structure;

2 the physico-chemical properties of a particular environment;

3 the type and quantity of microbes present;

4 whether the metabolites produced can serve as sources of usable energy and

precursors for biosynthesis of cellular components, and hence the creation of more

microorganisms.

Pharmaceutical formulations may be considered as specialized micro-environments

and their susceptibility to microbial attack assessed using conventional ecological

criteria. Some naturally-occurring ingredients are particularly sensitive to attack, and

quite a few synthetic components, such as modern surfactants, have been deliberately

constructed to be readily degraded after disposal into the environment. Crude vegetable

and animal drug extracts often contain wide assortments of microbial nutrients besides

the therapeutic agents. This, combined with frequently conducive and unstable physico-

chemical characteristics, leaves many formulations with a high potential for microbial

attack, unless steps are taken to minimize it.

1.2.3 Pharmaceutical ingredients susceptible to microbial attack

Surface-active agents. Anionic surfactants such as the alkali metal and amine soaps of

fatty acids are generally stable due to the slightly alkaline pH of the formulations,

although readily degraded once diluted out into sewage. Alkyl and alkylbenzene

sulphonates and sulphate esters are metabolized by co-oxidation of their terminal methyl

groups followed by sequential /3-oxidation of the alkyl chains and fission of the aromatic

rings. The presence of chain branching involves additional a-oxidative processes.

Generally, ease of degradation decreases with increasing chain length and complexity

of branching of the alkyl chain. Sulphonate and sulphate ester residues are converted

to sulphate, although sulphonate residues are significantly more recalcitrant than the

esters.

Microbial spoilage and preservation of pharmaceutical products 357

Non-ionic surfactants such as alkylpolyoxyethylene alcohol emulsifiers are readily

metabolized by a wide variety of microorganisms. Increasing chain lengths and

branching again decreases 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 pharmacy 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 pharmacy

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

(carboxymethylcelluloses, but not alkylcelluloses), uronidases (polyuronides such as

in tragacanth and acacia), dextranases (dextrans) and proteases (proteins). Agar (complex

polysaccharides) 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 are usually readily metabolized unless present

in high concentrations (see section 1.3.3).

Fats and oils. These hydrophobic materials are usually attacked extensively when

dispersed in aqueous formulations such as oil-in-water emulsions, although fungal attack

is reported in condensed moisture films on the surface of oils in bulk, or where water

droplets have contaminated the bulk oil phase. Oil-in-water emulsion-based medicines

are less commonly encountered than in food formulations where their microbial attack

can also occur, aided by the high solubility of oxygen in many oils. Lipolytic rupture of

triglycerides liberates glycerol and fatty acids, the latter often then undergoing fi-

oxidation of the alkyl chains and the production of odiferous ketones. While 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 some aqueous products

and inhibit microbial attack (see section 1.3.3). 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. It

is now recommended that such stock solutions contain preservatives or are made

freshly as required by dilution of alcoholic solutions which are much less susceptible

to microbial attack.

Therapeutic agents. It is possible to demonstrate that a variety of microorganisms under

laboratory conditions can metabolize a wide assortment of drugs, resulting in loss of

activity. Materials as diverse as alkaloids (morphine, strychnine, atropine), analgesics

(aspirin, paracetamol), thalidomide, 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 (see Chapter 25). Reports

of drug destruction in actual medicines are less frequent. However, examples include

the metabolism of atropine in eye drops by contaminating fungi, inactivation of penicillin

injections by /3-lactamase-producing bacteria (see Chapter 5), steroid metabolism in

damp tablets and creams by fungi, the microbial hydrolysis of aspirin in suspension by

esterase-producing bacteria, and chloramphenicol deactivation in an oral medicine by

a chloramphenicol acetylase-producing contaminant.

Preservatives and disinfectants. Many preservatives and disinfectants can be metab-

olized by a wide variety of Gram-negative bacteria, although more commonly at

concentrations below their effective 'use' levels. However, quaternary ammonium

antimicrobial agents are only slowly attacked. Organomercurial preservatives discharged

into rivers from paper mills have been extensively converted to insidiously toxic

alkylmercury compounds which could reach humans via an ascending food chain.

Degradation of agents at 'use' concentrations in pharmacy and medicine is less

commonly reported, but there are incidents of the growth of pseudomonads in stock

solutions of quaternary ammonium antiseptics and chlorhexidine with resultant infection

of patients. Pseudomonas spp. have metabolized 4-hydroxybenzoate ester preservatives

contained in eye-drops and caused serious eye infections, and metabolized them in oral

suspensions and solutions. It is important to remember this possibility when selecting

preservatives for formulations.

1.2.4 Observable effects of microbial attack on pharmaceutical products

Microbial contaminants will usually need to be able to attack ingredients of a medicine

and create substrates necessary for biosynthesis and energy production before they can

replicate to levels where obvious spoilage becomes apparent since, for example, 10

microbes will have an overall degradative effect around 10

time faster than one cell.

However, growth and attack may well be localized in surface moisture films or very

unevenly distributed within the bulk of viscous formulations such as creams. Early

Microbial spoilage and preservation of pharmaceutical products 359

Fig. 18.1 Section (xl.5)

through an inadequately

preserved olive oil, oil-in-water,

emulsion in an advanced state of

microbial spoilage showing:

A, discoloured, oil-depleted,

aqueous phase; B, oil globule-

rich creamed layer; C, coalesced

oil layer from 'cracked'

emulsion; D, fungal mycelial

growth on surface. Also present

are a foul taste and evil smell!

indications of spoilage are often organoleptic, with the release of very unpleasant

smelling and tasting metabolites such as 'sour' fatty acids, 'fishy' amines, 'bad eggs',

bitter, 'earthy' or sickly tastes and smells. Products frequently become unappealingly

discoloured by microbial pigments of various shades. Thickening and suspending agents

such as tragacanth, acacia or carboxymethylcellulose can be depolymerized, resulting

in loss of viscosity, and sedimentation of suspended ingredients. Alternatively, microbial

polymerization of sugars and surfactant molecules can produce slimy, viscous, masses

in syrups, shampoos and creams, and fungal growth in creams has produced 'gritty'

textures. Changes in product pH can occur depending on whether acidic or basic

metabolites are released, and become so modified as to permit secondary attack by

microbes previously inhibited by the initial product pH. Gaseous metabolites may be

seen as trapped bubbles within viscous formulations.

When a complex formulation such as an oil-in-water emulsion is attacked, a gross

and progressive spoilage sequence may be observed. Metabolism of surfactants will

reduce stability and accelerate 'creaming' of the oil globules. Lipolytic release of fatty

acids from oils will lower pH and encourage coalescence of oil globules and 'cracking'

of the emulsion. Fatty acids and their ketonic oxidation products will provide a sour

taste and unpleasant smell, whilst bubbles of gaseous metabolites may be visible, trapped

in the product, and pigments may discolour the product (see Fig. 18.1).

1.3 Factors affecting microbial spoilage of pharmaceutical products

An understanding of the influence of the chemical and physico-chemical parameters of

an environment on microorganisms might allow for subtle manipulation of a formulation

to create conditions which are as unfavourable as possible for growth and spoilage,

360 Chapter 18

within the limitations of patient acceptability and therapeutic efficacy. Additionally,

the overall characteristics of a particular formulation will indicate its susceptibility to

attack by various classes of microorganisms.

1.3.1 Types, and size, of contaminant inoculum

Whilst there will be some chance that a particularly aggressive microbe may enter and

contaminate a medicine, some element of prediction is possible if one considers the

environment and usage to which the product is likely to be subjected during its life and

the history of similar medicines (see Chapters 17 and 19). A formulator can then build

in as much protection as possible against non-standard encounters, such as additional

preservation for a syrup if osmotolerant yeast contamination is particularly likely.

Should failure subsequently occur, a knowledge of microbial ecology and careful

identification of the contaminant(s) can be most useful in tracking down the defective

steps in the design or production process. Very low levels of contaminants which are

unable to replicate in a product might not cause appreciable spoilage but, should an

unexpected surge in the contaminant bioburden occur, the built-in protection could

become swamped and spoilage ensue. This might arise if:

1 raw materials were unusually contaminated;

2 a lapse of the plant-cleaning protocol occurred;

3 large microbial growths detached themselves from within supplying pipework;

4 a change in production procedures allowed unexpected growth of contaminants

during the modified operation;

5 there was demolition work in the vicinity of the manufacturing site or;

6 there had been gross misuse of the product during administration.

However, inoculum size alone is not always a reliable indicator of likely spoilage

potential. A very low level of, say, aggressive pseudomonads in a weakly preserved

solution may suggest a greater risk than tablets containing fairly high numbers of fungal

and bacterial spores.

When an aggressive contaminant enters a medicine, there may be an appreciable

lag period before significant spoilage begins, the duration of which decreases

disproportionately with increasing contaminant loading. It is possible to provide some

control over extemporaneously dispensed formulations by specifying short shelf-lives

of, say, 2 weeks. However, since there is usually a long delay between manufacture

and administration of factory-made medicines, growth and attack could ensue during

this period unless additional steps are taken to prevent it.

The isolation of a particular microorganism from a markedly spoiled product does

not necessarily mean that it was the initiator of the attack. It could be a secondary

opportunist contaminant which has overgrown the primary spoilage organism once the

physico-chemical properties had been favourably modified by the primary spoiler.

1.3.2 Nutritional factors

The simple nutritional requirements and metabolic adaptability of many common

saprophytic spoilage microorganisms enable them to utilize many of the components

of medicines as substrates for biosynthesis and growth, including not only the intended

Microbial spoilage and preservation of pharmaceutical products 361

ingredients but also the wide array of trace materials contained in them. The use of

crude vegetable or animal products in a formulation provides an additionally nutritious

environment. Even demineralized water prepared by good ion-exchange methods will

normally contain sufficient nutrients to allow significant growth of many water-borne

Gram-negative bacteria such as Pseudomonas spp. When such contaminants fail to

grow in a medicine it is unlikely to be as a result of nutrient limitation but due to other,

non-supportive, physico-chemical or toxic properties.

Most acute pathogens require specific growth factors normally associated with the

tissues they infect but which are often normally absent in pharmaceutical formulations.

They are thus unlikely to multiply in them, although they may remain viable and infective

for an appreciable time in some dry products where the conditions are suitably protective.

1.3.3 Moisture content: water activity (A )

Microorganisms require ready access to water in appreciable quantities for growth.

Although some solute-rich medicines such as syrups may appear to be 'wet', microbial

growth in them may be difficult since the microbes have to compete for water molecules

with the vast numbers of sugar and other molecules of the formulation which also

readily interact with water via hydrogen bonding. An estimate of the proportion of the

uncomplexed water in a formulation available to equilibrate with any microbial

contaminants and facilitate growth can be obtained by measuring its water activity

). (This can be calculated from: A

= vapour pressure of formulation -*- vapour

pressure of water under similar conditions). The greater the solute concentration,

the lower is the water activity. With the exception of halophilic bacteria, most

microorganisms grow best in dilute solutions (high A

) and, as solute concentration

rises (lowering A

), growth rates decline until a minimal, growth-inhibitory A

reached. Limiting A

values are of the order of: Gram-negative rods, 0.95; staphylococci,

micrococci and lactobacilli, 0.9; and most yeasts, 0.88. Syrup-fermenting osmotolerant

yeasts have been found spoiling products with A

levels as low as 0.73, whilst some

filamentous fungi can grow at even lower values, with Aspergillus glaucus as low as

0.61.

The A

of aqueous formulations can be lowered to increase resistance to microbial

attack by the addition of high concentrations of sugars or polyethylene glycols. However,

even Syrup BP (66% sucrose; A

= 0.86) has been reported to fail occasionally to inhibit

osmotolerant yeasts and additional preservation may be necessary. With a trend towards

the elimination of sucrose from medicines continuing, alternative solutes are being

investigated, such as sorbitol and fructose, which are not thought to encourage dental

caries. The use of brine to preserve some meats would be organoleptically unacceptable

for medicines. A

can also be reduced by drying, although the dry, often hygroscopic

medicines (tablets, capsules, powders, vitreous 'glasses') will require suitable packaging

to prevent resorption of water and consequent microbial growth (Fig. 18.2). Tablet

film coatings are now available which greatly reduce water vapour uptake during storage

whilst allowing ready dissolution in bulk water. These might contribute to increased

microbial stability during storage in particularly humid climates, although suitable foil

strip packing may be more effective, if also more expensive.

362 Chapter 18

Fig. 18.2 Fungal growth on a

tablet which has become damp

(raised A

) during storage under

humid conditions. Note the

sparseness of mycelium, and

conidiophores. The contaminant

is thought to be a Penicillium sp

Condensed water films can accumulate on the surface of otherwise 'dry

products

such as tablets or bulk oils following storage in damp atmospheres with fluctuating

temperatures, resulting in sufficiently high localized A

to initiate fungal growth. More

water, produced from respiration, may then raise A

even further, encouraging growth.

Dilute aqueous films similarly formed on the surface of viscous products such as syrups

and creams, or exuded by syneresis from hydrogels, can and do reach sufficiently high

to permit surface yeast and fungal spoilage.

Inhibition of microbial growth by reduction of A

is more complex than by a simple

binding of water molecules alone as some solutes are more effective than others at

inhibiting microbial attack by particular types of microorganisms even when used to

generate similar A

levels. Mechanisms are thought to involve interference with cellular

osmoregulation and energy production.

1.3.4 Redox potential

The ability of microbes to grow in an environment is influenced by its oxidation-

reduction balance (redox potential) since they will require compatible terminal electron

acceptors to permit function of their respiratory pathways. Vacuum packing of foodstuffs,

or the inclusion of oxygen absorbers in the package to minimize oxygen levels, reduces

attack by some of the obligate aerobic spoilage bacteria, but does not eliminate all spoilage.

Oxygen removal to control spoilage in medicines is not a practical proposition although

it is used to control non-biological oxidation. The use of pressurized carbon dioxide for

soft drinks preservation relies more on the specific antimicrobial action of carbonic

acid than to removal of oxygen. Some viscous foodstuffs, particularly those containing

meat, have sufficiently low redox potentials to permit growth of dangerous anaerobic

Clostridia, but this is unlikely in most pharmaceuticals. The redox potential even in

fairly viscous emulsions may be quite high due the appreciable solubility of oxygen in

most fats and oils.

Microbial spoilage and preservation of pharmaceutical products 363

1.3.5 Storage temperature

Spoilage of pharmaceuticals could occur over the range of about -20° to 60°C, although

much less likely at the extremes. The actual storage temperature may selectively

determine spoilage by particular types of microorganisms. Storage in a deep freeze at

-20°C or lower is used for long-term storage of foodstuffs and some pharmaceutical

raw materials, and dispensed total parenteral nutrition (TPN) feeds have been stored in

hospitals for short periods at -20°C to even further minimize the risk of growth of any

contaminants which might have been introduced during their aseptic compounding.

Reconstituted syrups and multi-dose eyedrop packs are sometimes dispensed with the

instruction to 'store in a cool place' such as a domestic fridge (8°-12°C), partly to

reduce the risk of in-use contamination growing before the expiry date. Conversely,

pharmacopoeial Water for Injections is recommended to be held at 80°C or above after

distillation and prior to packing and sterilization to prevent possible regrowth of Gram-

negative bacteria, and the release of endotoxins.

1.3.6 pH

Extremes of pH prevent microbial attack, although feeble mould growth even in

dilute hydrochloric acid necessitates the preservation of analytical acid standards.

Around neutrality bacterial spoilage is more likely, with reports of pseudomonads and

related Gram-negative bacteria growing in antacid mixtures, flavoured mouth washes

and in distilled or demineralized water. Above pH 8, for instance with soap-based

emulsions, spoilage is rare. For products with low pH levels such as the fruit juice-

flavoured syrups (ca. pH 3-4) mould or yeast attack is more likely. Yeasts can metabolize

organic acids and raise the pH to levels where secondary bacterial growth can occur.

Although the use of low pH adjustment to preserve foodstuffs is well established

(pickling, coleslaw, yoghurt etc.) it is not practicable to make deliberate use of this for

medicines.

1.3.7 Packaging design

Packaging can have a major influence on microbial stability of some formulations, to

control the entry of contaminants during both storage and use. Enormous efforts have

gone into the design of containers to prevent the ingress of contaminants into medicines

for parenteral administration because of the high risks of infection by this route. Self-

sealing rubber wads must be used to prevent microbial entry into multi-dose injection

containers (Chapter 21) following withdrawals with a hypodermic needle. Wide-

mouthed cream jars will allow the entry of fingers with their concomitant high bioburden

of contamination, and this can be reduced by replacement with narrow nozzle and

flexible screw capped tubes. Where medicines rely on their low A

to prevent spoilage,

packaging such as strip foils must be of water vapour-proof materials with fully efficient

seals. Cardboard outer packaging and labels themselves can become substrates for

microbial attack under humid conditions, and preservatives are often included to reduce

their risk of damage.

364 Chapter 18

1.3.8 Protection of microorganisms within pharmaceutical products

The survival of microorganisms in particular environments is influenced by the presence

of various relatively inert materials. Thus, microbes can be more resistant to heat or

desiccation in the presence of some polymers such as starch, acacia or gelatin. Adsorption

onto naturally occurring particulate material may aid establishment and survival in

some environments. There is a belief, but limited hard evidence, that the presence of

suspended particles such as kaolin, magnesium trisilicate or aluminium hydroxide gel

may influence contaminant longevity in medicines containing them, and that the presence

of some surfactants, suspending agents and proteins can increase the resistance of

microorganisms to preservatives, over and above their direct inactivating effect on the

agents.

2 Preservation of medicines using antimicrobial agents:

basic principles

2.1 Introduction

An antimicrobial 'preservative' may be included in a formulation to further reduce the

risk of spoilage and, preferably, kill any anticipated low levels of contaminants remaining

in a non-sterile medicine after manufacture or which might enter while stored, or during

the repeated withdrawal of doses from a multi-dose container. If a medicine is unlikely

to encourage growth or survival of contaminants and the infective risk is low, such as

with tablets, capsules and dry powders, then a preservative might be pointless.

Preservatives should not be added to deal with erratic failures in poorly controlled

manufacturing processes, due to the uncertainty of success, and their possible depletion

before fulfilling their intended role (see section 2.2). The bad practice of including

preservatives in medicines sterilized by filtration to guard against undetected failure of

the filter did not tackle the real problem of the need for properly validated filtration

systems.

Ideally, such preservatives should:

1 be able to kill rapidly all microbial contaminants as they enter the medicine;

2 not be irritant or toxic to the patient;

3 be stable and effective throughout the life of the medicine; and,

4 be selective in reacting with the contaminants and not the ingredients of the medicine.

Unfortunately, the most active antimicrobial agents are often generally non-selective

in action, inter-reacting significantly with formulation ingredients and patients as well

as microorganisms. Once the more toxic, irritant and reactive agents are excluded,

those remaining generally have only modest antimicrobial efficacy, and there are now

no preservatives considered sufficiently non-toxic for use in highly sensitive areas,

e.g. for injection into central nervous system tissues or for use within the eye. A number

of microbiologically effective preservatives used in cosmetics are reported to cause

significant incidences of contact dermatitis, and are thus precluded from use in

pharmaceutical creams. Although it may be preferable to rapidly kill all contaminants

as they enter a medicine, this may only be possible for relatively simple aqueous solutions

such as eye-drops or injections. For physico-chemically complex systems such as

Microbial spoilage and preservation of pharmaceutical products 365

emulsions and creams, only inhibition of growth and rather slow, or no, rates of killing

may be realistically achieved.

In order to maximize what preservative efficiency is possible, an appreciation of

those parameters which influence antimicrobial activity within medicines is essential.

2.2 Effect of preservative concentration, temperature and size of inoculum

Changes in the efficacy of preservatives vary exponentially with changes in

concentration (see concentration exponent, 77, Chapter 11), the extent of variation

depending upon the type of agent. For example, halving the concentration of phenol

(rj = 6) gives a 64-fold (2

) reduction in activity, whilst a similar dilution for

chlorhexidine (77 = 2) reduces killing power by only fourfold (2

). Changes in product

temperature will alter efficacy in proportions, related to different types of preservative

and certain groups of microorganisms (see temperature coefficient, Q

, Chapter 11).

Thus, a drop in temperature from 30 to 20°C could result in fivefold and 45-fold

losses of killing power towards Escherichia coli by phenol (Q

= 5) or ethanol

(Q = 45), respectively. If both temperature and concentration vary concurrently, the

situation is more complex, but it has been suggested, for example, that if a 0.1%

chlorocresol (77 = 6, Q

= 5) solution completely killed a suspension of E. coli at

30°C in 10 minutes, it would require around 90 minutes to achieve a similar effect if

the temperature was lowered to 20°C and slight overheating during production had

resulted in a 10% loss by vaporization in the chlorocresol concentration (other

factors remaining constant).

Preservative molecules are used up as they inactivate microorganisms and as they

interact non-specifically with the significant quantities of contaminant 'dirt' also

introduced during use. This will result in a progressive and exponential decline in the

efficiency of the remaining preservative. Preservative 'capacity' is a term used to describe

the cumulative level of contamination that a preserved formulation is likely to cope

with before becoming so depleted as to become ineffective. This will vary with

preservative type and complexity of the formulation.

2.3 Factors affecting the 'availability' of preservatives

Most preservatives interact in solution with many of the commonly used ingredients of

pharmaceutical formulations to varying extents via a number of weak bonding attractions

as well as with any microorganisms present. This can result in unstable equilibria in

which only a small proportion of the total preservative present is 'available' to inactivate

the relatively small microbial mass, and the resultant rate of killing may be far lower

than might be anticipated from the performance of simple aqueous solutions. The

'unavailable' preservative may still, however, contribute to the general irritancy of the

product. It is commonly believed that where the solute concentrations are very high,

and A

is appreciably reduced, the efficiency of preservatives is often appreciably

reduced and may be virtually inactive at very low A

. A practice of including pre-

servatives in very low A

products such as tablets and capsules misses the point.

This would only offer minimal protection for the dry tablets, and if they should be-

come damp they will be spoiled for other, non-microbial, reasons.

366 Chapter 18