Factors Affecting The ‘Availability’ of Preservatives

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Chapter: Pharmaceutical Microbiology : Microbial Spoilage, Infection Risk And Contamination Control

Most preservatives interact in solution to some extent with many of the commonly used formulation ingredients via a number of weak bonding attractions as well as with any contaminants present.


FACTORS AFFECTING THE ‘AVAILABILITY’ OF PRESERVATIVES

 

Most preservatives interact in solution to some extent with many of the commonly used formulation ingredients via a number of weak bonding attractions as well as with any contaminants present. Unstable equilibria may form in which only a small proportion of total preservative present is ‘available’ to inactivate the relatively small microbial mass; the resulting rate of kill may be far lower than might be anticipated from the performance of simple aqueous solutions. However, ‘unavailable’ preservative may still contribute to the general irritancy of the product. It is commonly believed that where the solute concentrations are very high, and Aw is appreciably reduced, the efficiency of preservatives is often significantly reduced and they may be virtually inactive at very low Aw. The practice of including preservatives in very low Aw products such as tablets and capsules is ill advised, as it only offers minimal protection for the dry tablets; should they become damp, they would be spoiled for other, non-microbial, reasons.

 

a) Effect Of Product pH

 

In the weakly acidic preservatives, activity resides primarily in the unionized molecules and they only have significant efficacy at pH values where ionization is low. Thus, benzoic and sorbic acids (pKa = 4.2 and 4.75, respectively) have limited preservative usefulness above pH 5, while the 4(p)-hydroxybenzoate (parabens) esters

with their non-ionizable ester group and poorly ionizable hydroxyl substituent (pKa c.8.5) have a moderate protective effect even at neutral pH levels. The activity of quaternary ammonium preservatives and chlorhexidine probably resides with their cations; they are effective in products of neutral pH. Formulation pH can also directly influence the sensitivity of microorganisms to preservatives.

 

b)  Efficiency In Multiphase Systems

 

In a multiphase formulation, such as an oil-in-water emulsion, preservative molecules will distribute themselves in an unstable equilibrium between the bulk aqueous phase and (1) the oil phase by partition, (2) the surfactant micelles by solubilization, (3) polymeric suspending agents and other solutes by competitive displacement of water of solvation, (4) particulate and container surfaces by adsorption and (5) any microorganisms present. Generally, the overall preservative efficiency can be related to the small proportion of preservative molecules remaining unbound in the bulk aqueous phase, although as this becomes depleted some slow re-equilibration between the components can be anticipated. The loss of neutral molecules into oil and micellar phases may be favoured over ionized species, although considerable variation in distribution is found between different systems.

 

In view of these major potential reductions in preservative efficacy, considerable effort has been directed to devise equations in which one might substitute variously derived system parameters (such as partition coefficients, surfactant and polymer binding constants and oil:water ratios) to obtain estimates of residual preservative levels in aqueous phases. Although some modestly successful predictions have been obtained for very simple laboratory systems, they have proved of limited practical value, as data for many of the required parameters are unavailable for technical grade ingredients or for the more complex commercial systems.

 

c)    Effect Of Container Or Packaging

 

Preservative availability may be appreciably reduced by interaction with packaging materials. Phenolics, for example, will permeate the rubber wads and teats of multidose injection or eye drop containers and also interact with flexible nylon tubes for creams. Quaternary ammonium preservative levels in formulations have been significantly reduced by adsorption on to the surfaces of plastic and glass containers. Volatile preservatives such as chloroform are so readily lost by the routine opening and closing of containers that their usefulness is somewhat restricted to preservation of medicines in sealed, impervious containers during storage, with short in-use lives once opened.

 

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