(9) Preservation of pharmaceutical 1 + 2 Flashcards
(17 cards)
European Medicines Agency states that choice
of preservative is supported by the following:
– Why the preservative is included
– Proof of its effectiveness
– Methods and standards for its control in the product
– Labelling details on the product
– Relevant safety information
for preservatives to be effective, what properties must they have?
- preservation must be available in the aqueous phase
- they need to be unionised (if they are ionised them they will cross the membrane of microorganism and therefore undergoing a dilution event = overall available amount of preservative available decreased.
outlibe phenols as preservatives
Widely used as disinfectants and preservatives
• 0.5% solution of phenol will kill most vegetative bacteria
• Activity markedly diminished by dilution and presence of organic matter
• Numerous incompatibilities
• Odour, toxicity and volatility issues
outline circumstances which preservative efficacy and avilability may be altered.
- Partitioning into oil/aqueous or biophase
- Ionic status & pH
- Adsorption & Permeation to container & Closure
- Temperature & Surfactant
- Status in tablets, suspensions, gels, creams, nasal and eye drops
- Physical or Chemical interaction with other formulation components
- Microbial Challenge (dilution of the preservative as microorganisms take it in the overall concentration available reduces)
outline cresol as preservative
• Mixture of o-, m- and p-methylphenol
• Poor solubility
• 0.3 – 0.5% effective concentration ranges in suitable formulations
• Similar activity range to phenol but less caustic
and less poisonous
• Activity not reduced in presence of organic
matter
outline parabens as preservative.
- Series of alkyl esters of p-hydroxybenzoicacid
• Less readily ionised than parent acid
• pKa values around 8.0 -8.5
• Exhibit good preservative activity even at pH 7-8
• Mixtures of esters to protect the various phases in a multiphase formulation
outline preservative efficacy testing
- The test may be conducted in either five original market containers or in five sterile, capped bacteriological containers into which a sufficient volume of the formulation has been transferred
- Each container is inoculated with one of the prepared
and standardised inoculum to give a final concentration
of microorganisms in the test formulations of 10^5 – 10^6
cfu per mL or per g of the product, - mixed thoroughly to ensure homogeneous distribution
of microorganims throughout the formulation - Incubate the inoculated containers at 22.5 +/-2.5C (USP)/20-25C protected from light (BP) and sample each container at appropriate intervals, over a maximum of 28 days, according
to the type of product. - BP suggests 1 mL or 1 g sample sizes taken at the appropriate intervals, starting from zero hour
- The number of viable organisms in each sample is determined by plate count (USP) or by plate count or membrane filtration (BP)
- Any changes to the appearance of the product should also be recorded
- its important to quench the reacrtion at the time points so that we dont get a better result than we actually did
outline the mechanism of action of weak acid preservatives.
• Lipophilic Unionised species diffuses across membrane
• Encounter cytoplasmic pH near neutrality
• Forced to Dissociate to charged ions
• Charged ions cannot return across membrane – Anions concentrate in cytoplasm
• Dissociation of acid derives proton
• Cytoplasm acidification
• Growth is Inhibited
what 4 ways does the acidification of cytoplasm inhibit growth
• Inhibition of glycolysis
• Inhibition of folic acid synthesis
• Prevents Active Transport
• Interference/ Inhibition of signal transduction
what characteristics must every pharmaceutical product have?
• Elegant (must look like how its meant to)
• Efficacious
• Stable
• Safe
All throughout their intended life
what does Aw stand for?
What is the use in this?
product water activity
- In complex formulations, microorganisms must compete for water against other components of the formulation which
interact with water - Certain products may be protected by manipulation of Aw (ready availability of water to contaminants), to values below
those required for growth
it can be lowered to give preservation effects by addition of water binding low molecular weight solutes
what effects does suspended solids have in a solution?
they completely wipe out any preservative
what is an objectional organism
An objectionable organism is a microorganism that, if present in a product or manufacturing environment, poses a risk to product quality, safety, or compliance with regulatory standards.
what is the definition of a preservative?
Substances added to pharmaceutical formulations/medicines to
prevent microbial spoilage, retard deterioration, and restrain organismic growth to low levels
what is the validation process of preservation efficacy testing?
it must demonstrate:
– Adequate mixing of the inoculum with the product
– Effectiveness of the inactivator or method used to neutralize preservative activity within the sample
– Lack of microbiological toxicity of the inactivator which would interfere with the test data and;
– Ability of the procedure to bring about the necessary reductions in viable count of the starting inoculum within the formulation/product.
when must preservatives be added to formulation?
by law they need to be added to any formulation which is to be used more than once from the same container
why is pH control ineffective as a preservation technique?
pH dictates the type of spoilage that occurs
Eg
• Low pH fruit juice-flavoured medicines inhibit bacterial growth but favour fungal growth
• Higher pH anatacids etc. favour growth of pseudomonads
