Preservatives

Preservatives

Contents

• Preservation – definition, ideal properties of preservatives

• Factors affecting preservative efficacy

• Quality assurance (QA) and the control of microbial risk in medicines

• Preservative efficacy test

Intended Learning objectives

At the end of this lecture the student will be able to

• Discuss the significance of preservation process

• Explain factors affecting preservatives efficacy

• List methods for detecting microbial presence in formulations

• Describe the challenge test for evaluation of preservatives

• Summarise on quality assurance and the control of microbial risk in medicines

Preservation

• Preservation is the process wherein the microbial growth is minimized or prevented

• Preservation is the process of inhibiting or minimizing the risk of microbial contamination of pharmaceutical products during the storage and multi-dose application

• Example of preservatives include: Citric acid, Benzalkonium Chloride, Benzoic acid, salicylic acid, Phenolic compounds etc

• An antimicrobial ‘preservative’ may be included in a formulation to minimize the risk of spoilage to kill low levels of contaminants introduced during storage or repeated use of a multi-dose container

• Preservatives should never be added to mask poor manufacturing processes

The properties of an ideal preservative are:

– A broad spectrum of activity and a rapid rate of killing microorganisms

– Selectivity in reacting with the contaminants and not the formulation ingredients

– Non-irritant and non-toxic to the patient

– Stable and effective throughout the life of the product

Effect of preservative concentration:

– Reduction in preservative concentration reduces its activity

Temperature:

– Reduction in temperature reduces preservative activity

– Increase in temperature moderately increases its activity

– Very high temperature inactivates preservatives

Size of inoculum:

– Size of inoculum, presence of organic matters and dirt will have significant influence in the preservative activity

– Larger size of inoculum, presence of organic matters and dirt reduces the preservative activity

Preservative ‘capacity’

• It is a term used to describe the cumulative level of contamination that a preserved formulation can tolerate before becoming ineffective

• This will vary with preservative type and complexity of formulation

Factors affecting the ‘availability’ of preservatives

• Effect of the product pH

• Efficiency in multiphase systems

• Effect of container or packaging

 Most preservatives   may   interact   in   solution   form   with formulation ingredients

Effect of the product pH

• Formulation pH can directly influence the sensitivity of microorganisms to preservatives

• Based on formulation pH, suitable preservatives should be selected

– Weakly acidic preservatives - neutral pH to basic pH

– Quaternary ammonium preservatives - at neutral pH

Efficiency in multiphase systems

• Partition coefficients, surfactant and polymer binding constants and oil: water ratios should be performed to carry out residual preservative levels in aqueous phases

Effect of container or packaging

• Certain preservatives show interaction with packaging materials

• For example,

– Phenolics will permeate the rubber wads

– Quaternary ammonium preservative - adsorption onto the surfaces of plastic and glass containers

– Volatile preservatives - routine opening and closing of containers

Preservative efficacy test

• Preservative efficacy tests could be single challenge test where large inoculum of each microorganism is introduced into the product & rate of inactivation is determined at different time intervals

• Multiple challenge test, where the product is exposed to repeated inoculation at set intervals & the efficiency of inactivation is monitored until the system fails (i.e gives better idea of ‘preservative capacity’ but time consuming & more expensive)

• BP, USP & EP describe single challenge test

Problems with these tests:

– Does   the   performance   of   these   tests   gives   reliable prediction of real in-use efficiency?

– Repeated cultivation on microbiological media results in reduced aggressiveness of strains

Summary

• Preservation is the process of inhibiting or minimizing the risk of microbial contamination of pharmaceutical products during the storage and multi-dose application

• Preservative   ‘capacity’ describes the cumulative level of contamination that a preserved formulation can tolerate before becoming ineffective

• Preservative efficacy tests could be single challenge test or multiple challenge test

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