Preservatives

What is an antiseptic?

Aims to reduce microbial contamination on the skin. Higher concentrations of a drug applied to the skin e.g. clean skin prior to injection

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What is a disinfectant?

Same agent to clean the surface of the bench you are about to make the product on e.g. kill microbes on surfaces, not placed in the body

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What is a preservative?

Used to extend shelf-life, used in lowest amounts, don’t discriminate between microbes and humans, in sufficient concentrations for function, aqueous preparations, make preservation efficacious to achieve microbial quality without harming the patient

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What is a biocide? (1)

In the right concentration, interferes with biological systems, stop microbes growing in product, when product is taken it doesn’t cause harm to human (not chemical adverse effect), preservations not in intra-spinal injections due to BBB

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What is a biocide? (2)

Limited volume, only use unit doses with single use

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What is an antibiotic?

Work against a particular organism, used in people, selective (target in microbes which are not present in humans, safe in people but kills bacteria), issues with AMR, products aims to treat infective diseases

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State features for the preservation of pharmaceuticals (1)

Protection against residual contamination, not excluded by GMP. Contamination introduced during use (not to cover bad manufacturing practice)

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State features for the preservation of pharmaceuticals (2)

Make best quality product, then add preservative (may not need preservative due to formulation properties e.g. low pH)

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What are the types of products?

Not 'self' preserved. Preparations in multi-dose containers. Aqueous preparations. Non-terminally sterilised products

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Which factors are considered when selecting a preservative?

Not straightforward, considerations (type of formulation, ingredients, physico-chemical properties, ROA)

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State features of factors affecting preservative activity

Ideal broad spectrum (Gram +/-, yeast/fungi), limited activity (require use of combinations to get coverage of microbes or preservatives used independently can cause toxicity due to concentration)

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State features of formulation pH (1)

Activity of some antimicrobials pH dependent. Drug compounds change depending on pH conditions/ionisation, some preservatives require to be ionised (for charge interactions), some are undissociated (need to penetrate microbes)

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State features of formulation pH (2)

Phenolics – in alkaline form, need to be undissociated to penetrate microbes.

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State features of formulation pH (3)

Cationic preservatives – need to be in charged form, work with charge interactions (+ charged species, interact with negatively charged cell wall)

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State features of formulation pH (4)

Determine if drug is effective in ionised/unionised form, determine pH level and choice of preservative suitable for the pH of the formulation

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State features of formulation constituents (1)

Incompatibility (-ve charged preservatives – neutralised by cationic surfactants, no longer preserved, due to charge interaction). +ve charged preservatives – neutralised by anionic surfactants (no longer preserved, due to charge interactions))

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State features of formulation constituents (2)

Solubilisation (disperse phase, continuous phase, microbes want to be in area with high water content, microbial growth in water, preservative needs to be in the water to prevent microbial growth

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State features of formulation constituents (3)

If preservative is solubilised, could lead to low amount of preservative in aqueous phase. Preservative is solubilised above CMC, leading to a reduction in preservative in aqueous phase

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State features of formulation constituents (4)

Plot – total concentration of parabens in formulation vs concentration of Tween 80 surfactant in formulation

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State features of formulation constituents (5)

Above micelle concentration, increase amount of Tween 80, increases amount of micelles, parabens partitions into micelles, to keep the same amount of parabens in the aqueous phase (blue line)

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State features of formulation constituents (6)

More parabens required in formulation to get sufficient concentration in the aqueous phase (cannot increase – due to toxicity)

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State features of formulation constituents (7)

More surfactant, more micelles, more preservation in micelle, more preservative needed to get a constant amount in the aqueous (required more preservative in formulation, not realistic due to toxicity issues)

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State features of formulation constituents (8)

Aqueous phase containing preservative – more significant compared to amount of preservative in total formulation

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Describe features of solids (1)

Active drug, thickening agents or suspending agents. Preservatives become adsorbed to particle surface, reduces aqueous concentration e.g. chlorhexidine, kaolin, talc, penicillin, methylparabens, benzalkonium chloride

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Describe features of solids (2)

More solid SA, more adsorption of preservative, less preservative available to act against microbes

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Describe features of concentration exponent (1)

Two concentrations of preservatives, determine time taken to reduce viable population of organisms, compare effect of how the dilution changes the time it takes to reduce microbial population

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Describe features of concentration exponent (2)

Four fold dilution (4 times less effective), not all preservative susceptible to reducing concentration. (Equation)

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Describe features of concentration exponent (3)

Partitioning behaviour – understand where preservative goes in the formulation, need to know free concentration in water (Cw)

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Describe features of concentration exponent (4)

Cw is affected by (factors affecting integrity of the product)– total concentration in the formulation, oil: water ratio, oil: water partition coefficient, ratio of bound: unbound in aqueous phase

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Describe features of concentration exponent (5)

Pharmacopoeia - preservative efficacy test (determine efficacy against type of organism)

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Describe features of solubility (1)

Preservatives need to be soluble in aqueous phase of formulation to ensure antimicrobial activity but also requires lipophilicity to partition through microbes outer walls. Parabens increases activity with longer ester chain but solubility decreases

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Describe features of solubility (2)

Combination of parabens is used at saturation concentration. Co-solvents enhance solubility/activity, ethanol > propylene glycol > glycerol. Avoid marked decrease in activity associated with lack of availability e.g. parabens and cyclodextrins

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Describe features of solubility (3)

Phenyl hydroxyesters, longer ester, more lipophilic, less soluble, less antimicrobial (combinations usually used – methyl/propyl compounds), cosolvents to enhance solubility (in aqueous phase)

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Describe features of solubility (4)

Cyclodextrins (sugar solubility enhancers, hydrophobic pocket, solubilise lipophilic component, if preservative is in cyclodextrin, less preservative is in the aqueous phase)

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Describe features of temperature (1)

A change in temperature can affect preservative activity. Coefficient for change of activity per 10 degrees Celsius change in temperature = Q10. Varies between compounds (important during extrapolation, room temp, storage temp in fridge)

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Describe features of temperature (2)

Preservative works differently at different temperatures, usually increasing temperature – preservatives work better but microbes grow faster, fridges reduce preservative efficacy but discourage microbial growth

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Describe features of stability (1)

Product shelf-life 2-3 years. Not all preservatives are suitable. Chloroform/chlorbutol (volatile), bronopol (unstable at alkaline pH, 50% decomposed in 2 months at pH 8, stable for 5 years at pH 4). Thiomersal (photolabile)

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Describe features of stability (2)

Preservative needs to be able as well as API, some preservatives are volatile (e.g. chloroform, no longer used), bronopol, photolabile (formulation with drug, preservative, packaging, storage conditions)

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Describe features of interactions with containers (1)

Aqueous phase concentration can be reduced by adsorption to container. Glass container (fairly inert). Rubber closures (lipid soluble preservatives adsorbed e.g. 60% loss of chlorocresol)

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Describe features of interactions with containers (2)

Plastic containers (significant loss of thiomersal/chlorobutol from contact lens solutions packed in plastic). Adsorption to container, plasticisers

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What are the other considerations for the ideal preservative? (1)

Non-irritant (e.g. inhalation, topical, sometimes interacts with disease states). Non-sensitising (e.g. parabens - sensitise patients with existing dermatitis, immunological route, sensitive to skin)

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What are the other considerations for the ideal preservative? (2)

Non-toxic (non-mutagenic, chlorform - mutagenic, natural products – not always safe, debate between synthetic medicines between preservatives and natural products without preservatives)

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What are the other considerations for the ideal preservative? (3)

(e.g. parabens in deodorant causing breast cancer – study dismissed but public still scared about issue).

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What are the other considerations for the ideal preservative? (4)

colourless, odourless, no taste, inexpensive (don’t want to increase cost). Safety efficacy, quality

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Preservatives

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