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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