Products and materials vulnerable to spoilage

Spoilage, in the sense of detectable physical or chemical change within a pharmaceutical product, nearly always follows growth and reproduction of the contaminating organisms. The pharmacopoeial and regulatory limits for the maximum permissible numbers of microorganisms in manufactured products or raw materials are typically not more than 100–1000 colony-forming units per millilitre or gram depending
on the dosage form in question.

Whilst these concentrations may allow some pathogens to initiate infections, they are not normally sufficient to cause
detectable changes in chemical composition, physical appearance or stability.

Bacteria and fungi are just
the same as all other living organisms in requiring water for growth (although not necessarily for mere survival). This means that only products containing
sufficient water to permit such growth are vulnerable to spoilage. Consequently, spoilage is not normally a problem in anhydrous products such as ointments
and dry tablets or capsules, although hygroscopic materials such as gelatin and glycerol may absorb enough water from the atmosphere to enable moulds
(but not normally bacteria) to grow. Similarly, cellulosic materials, particularly paper and other packaging, may show mould growth if stored in humid atmospheres (e.g. in tropical climates).

The fact that a product contains water and is obviously a liquid does not necessarily mean that the water is available to participate in chemical reactions and enable microorganisms to grow. Some of the water present in a solution is bound to the solute because of hydrogen bonding or other mechanisms.

Thus, a parameter that indicates the proportion of ‘free’ or available water is a useful guide for the ease with which microorganisms might grow in the product.

Such a parameter is water activity (Aw), which is the ratio of the water vapour pressure of a solution to the water vapour pressure of pure water at the same temperature. Aw is expressed on a scale from 0 to 1 with a value of 1 representing pure water.

As the concentration of solute in a solution is increased, Aw falls proportionately, and the range of organisms able to grow in the solution progressively diminishes.

Thus it is possible to construct a table indicating the minimum Aw values that permit the growth of different types of microorganism (Table 48.1).

To a certain extent, the values of Aw in Table 48.1 are reflective of the natural habitats of the organisms concerned; pseudomonads (species within the genus
Pseudomonas) and other waterborne organisms therefore tend to require high Aw values for optimum growth, whilst skin organisms such as staphylococci
and micrococci that exist in relatively high salt concentrations (from sweat glands) will tolerate significantly lower values.

Pharmaceutical materials that have high solute concentrations (e.g. syrups) may to a large extent be self-preserving, just like salted foods. Syrup BP, for example, is 67% by weight sucrose, has an Aw value of 0.86 and so is not susceptible to bacterial growth, but may contain chemical preservatives to protect it from mould spoilage.

Variations in water activity may arise within a single container of a manufactured medicine by, for example,
water evaporating from the bulk liquid during storage at high temperatures and that water vapour condensing on cool glass around the neck of a bottle as the storage temperature drops, then running back to dilute the surface layer of the product. It is for this reason that
syrups should not be stored in conditions where the temperature fluctuates.

The possibility also exists for contaminants to grow and generate water from respiration and so produce
localized increases in Aw which allow other less osmotolerant organisms to grow subsequently.

Reducing the water activity of a product as a means of diminishing its susceptibility to spoilage is a formulation strategy that should not be overlooked.

However, sugars and glycerol are the only common and acceptable ingredients that may be used in this way in oral
products; alcohols and glycols may also be used in topical products.

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