Contamination control and preservatives

what does the preservation of pharmaceuticals provide?

-              Provides protection against residual contamination, not excluded by GMP

-              Also provides protection against contamination introduced during use

what types of products require preservation?

o   Not ‘self’ preserved (dry formulations and low pH formulations are self-preserves)

o   Preparations in multidose containers

o   Aqueous preparations

o   Non-terminally sterilised products

what considerations should be taken into account when selecting a preservative?

o   Type of formulation

o   Ingredients

o   Physiochemical properties

o   Route of administration

what are antibiotics?

used in humanswha

what are biocides?

kill microbes but dont have selective targets

what are antiseptics?

-              can apply to people (not to be ingested so, may be the same agent as an antibiotic but at a lower concentration)

what are disinfectants?

used on surfaces and environments, not limited by concentration

what are preservatives?

non-selective and are defined by their action

which preservatives are only affected by a pH above 9?

§  Phenol – 9.98

§  Cresol – 10.08

§  Chlorocresol – 10.08

§  Methylparabens – 8.5

at what pH are catonic preservatives active?

when above pH 4-5

§  Eg chlorhexidine, benzalkonium chloride

§  These interact with the cell membranes as the bacterial cell membrane is negatively charged

§  This means that cationic preservatives need to be in their charged form in order to interact with the negative bacterial membrane

how do micellar systems work?

§  the preservative is solubilised above the critical micelle concentration (CMC), leading to a reduction in preservative in the aqueous phase

·      If you increase the concentration of the surfactant, you go above the CMC and the aqueous phase has a low concentration of the preservatives

·      To counter this, you would have to increase the concentration of the parabens (weakly lipophilic preservatives) to achieve the same concentration of API in the aqueous phase  

what is the CMC?

·      The CMC is the concentration where the preservative is still effective

Above this concentration

what is the concentration exponent?

-              dilution of a preservative does not usually lead to a linear effect

o   If there is a concentration of 6, and there is a 4 fold dilution do 4⁶ = 4096 activity

what is partitioning behaviour?

tells you how effective a preservative and surfactant would be in a multi-phase system

how does solubility affect preservative activity?

-              preservatives need to be soluble in the aqueous phase for antimicrobial activity but lipophilic enough to enable partitioning through microorganisms

o   Cosolvents can enhance solubility and therefore activity

o   Ethanol>propylene glycol>glycerol

o   However, ensure to avoid the marked decrease in activity associated with a lack of availability eg parabens and cyclodextrins

how does temperature affect preservative activity?

-              can affect microbial growth and preservative activity

o   The coefficient for the change of activity per 10°C change in temperature is Q10

o   Varies between compounds but important when extrapolating activity from room temperature (lab) to storage temperature (Eg fridge)

wha must the stability be like for a preservative

-              product shelf life is 2-3 years

o   Not all preservatives are suitable

o   Chloroform and chlorobutol are volatile

o   Bronopol is unstable at an alkaline pH

§  50% is decomposed in 2 months at pH 8

§  Stable for 5 years at pH 4

o   Thiomersal is photolabile

how can the container affect preservative activity?

-              Interaction with containers – aqueous phase concentration can be reduced by adsopriton to the container

o   Glass containers – fairly inert

o   Rubber closures – lipid soluble preservatives are adsorbed eg 60% loss of chlorocresol

o   Plastic containers – significant loss of thiomersal and chlorbutol from contact lens solutions packed in plastic

what considerations must be made for a preservative?

o   Non-irritant

o   Non-sensitising eg parabens have some activity of sensitising patients with dermatitis

o   Non-toxic

o   Colourless

o   Odourless

o   No taste

o   Inexpensive

what is microbial quality assurance?

-              An essential part of documenting the safety and quality of pharmaceutical products

how is microbial quality assurance conudcted>?

-              Inoculate a sample with Staph aureus, Ps aeruginosa, Asperillus niger, candida albicans in its final container

o   Count the microbes to test the effectiveness of the preservative

what is a preservative efficacy test? (PET)

o   For certain products, additional preservatives should be used

§  Eg E.coli for oral mixtures

§  Saccharomyces rouxii for high sugar products

o   PET is not for routine control purposes, but as a part of formulation development

o   Criteria are provided for expected efficacy of preservative in a particular product type

o   Criteria for parenterals or ophthalmic preparations – rapid bactericidal activity

what are the drawbacks for PET?

§  4 organisms are unlikely to truly represent all possible contaminants

§  Only a single challenge which is unlikely for multidose containers

§  Lab strains have different patterns of resistance

§  Inoculum size is unrealistically high

§  Sample of 1ml will be unable to detect <1 organism/ml but just one organism can replicate and cause spoilage

§  28 days cannot be extrapolated to an expected shelf life of 2-3 years