Jan exam Flashcards
pass January exam
Classifications of common preservatives and characteristics
Acids and esters - active against bacteria and fungi
Alcohols - broad spectrum; poor penetration of organic matter, volatile
Biguanides - active against Gram + bacteria; inactivated by organic matter; limited antifungal activity
Heavy metals (mercury)- Broad spectrum of antibacterial activity; low capacity to organic matter; toxicity issues
Phenol - cheap; activity against fungi and Gram + bacteria; low water solubility; adsorbed by rubber; volatile; irritant; pH dependent
Quaternary ammonium compounds (QACs) - Actviity agianst Gram + bacteria; organic matter affects activity; pH dependent; non toxic
Common preservatives in oral products
alkyl - Parabens
Acids
QAC
Common preservatives in parenteral products
Alcohols Parabens Phenol Heavy metal Biguanides
Common preservatives in topical products
QACs paraben Alcohols Acids Phenols
Common preservatives in Ophthalmic
QACs Heavy metals Acids Biguanides diazolidinyl urea (imidurea)
The use of which preservatives is discouraged and why
Phenols and organo mercurial use in topical and oral products has been discouraged but they are still used to preserve parenteral
Use of older preservatives been largely discontinued largely due to safety issues
MOA for preservative that target cell wall
Lysis due to enzyme inhibition (e.g. phenol and organo mercurial)
Irreversible cross-linking at the cell wall (e.g. glutaraldehye)
MOA of preservatives that target cell membrane
changes to membrane potential, enzymatic function and permeability
Cetrimide, chlorhexidrine, 2-phenoxyethanol, parabens and phenols affect membrane permeability (leading to leaking of cell constituents and cell death)
Sorbic acid inhibits transport mechanisms across the membrane
Chlorhexidrine inhibits membrane ATPase (at higher concentrations causes precipitation of cytoplasmic nucleic acid ad related proteins)
Chelators com-promise membrane integrity by chelating Ca2+ and Mg2+ (this potentiates other anti-microbial agents)
QACs bind strongly to the cytoplasmic membrane (particularly phospholipid bilayer) and cause damage and leaking
MOA of preservatives cytoplasm
Uncoupling of oxidative and phosphorylation processes or interference with active transport mechanisms
Other preservatives inhibit electron transport chains
Benzoic acid and parabens inhibit folic acid synthesis
Bronopol and organomercurials target thiol enzymes
Imidurea act on he carboxylic acid amino enzymes
Phenols and alcohols cause protein denaturation
Preservatives must …?
Exert a wide spectrum of antimicrobial activity at low concentration
remain essentially in aqueous phase multiphase products
Maintain activity throughout product manufacture, shelf life and usage
Not compromise the quality or performance of the product, pack or deliver system
not adversely affect patient safety or tolerance of the product
How does concentration affect preservative efficacy
The higher the concentration of the biocide the greater the rate of killing
What is the concentration exponent (or dilution coefficient)
Is a measure of changes in the preservative concentration on cell death rate
Calculated by comparing the time taken to achieve a similar rate level of killing and different concentrations of biocide
given by the formula
(C1/C2)^n = T2/T1
n = concentration exponent
Preventatives combination
Benzalkomin chloride is inefefctvie agianst some strains of psudomonas aeruginosa (combinations with EDTA, alcohols can enhance anti-Pseudomonas activity)
Parabens activity increase with increase of alkyl chain (but solubility decrease) as a result parabens are usually used in combination (short chain plus and long chain e.g. methyl and propyl-paraben)
Parabens show some synergy with EDTA, 2-phenylethanol and imidurea
Safety and side effects of preservatives
Alcohols are generally considered to be safe (benzyl alcohol can cause fatal toxic syndrome in low weight neonates)
Carboxylic acids can be gastric irritants and, mildly irritant to skin, eye and mucous membranes
Parabens are considered unsuitinble for parenteral and opthalmic use due to irritancy
Use of organo mercurial preservatives is restricted to due to concerns of toxicity. (still widely used in topical and parenteral formulations)
What does a high or low concentration exponent tell you about a preservatives killing time
The killing time of preservatives with low concentration exponents are less affected by changes in concentration
The killing time of preservatives with high concentration exponents values are greatly effected by changes in concentration
Effect of temperature in preservatives
Killing effect is greater at higher temperature
Effect of temperature may be expressed by means of a temperature coefficient
(Time to kill at T1)/(Time to kill at T2)
Q10 of 5 means that a increases in 10 degrees celcius causes a 5 fold increase in killing time
Factors affect preservative degradation
Exposure to high temperatures
Inappropriate pH
Exposure to light
Interaction with other ingredients
Problems of preservative degradation
Lowering of preservative concentration (increased risk of spoilage)
Preservative degradation can also lead to toxicity
Factors affecting efficacy of preservatives
Preservative concentration
Temperature
Degradation of preservative
Factors affecting availability of preservative
How does pH influence preservative activity
Can cause changes preservative molecule
- ionization of acidic preservatives at high pH
Can cause changes to bacterial cell surface
- increased negative charge on cell surface dues to increased pH can increase binding of positive molecules such as QACs
Effect of organic load on preservatives
Organic matter contaminants can affect preservative availability
Interference of organic matter may reduce preservative concentration
Organic matter may protect microbes from lethal effects of preservatives
How do multiphase systems effect preservative availability
preservative partitions between the multiple phase present within a system
generally preservative availability is related to the small proportion left in the aqueous phase
Preservative adsorb to container walls and evaporate out of the solution
Whats does a preservative efficacy test (PET) involve
Challenging the a product with a defined number of CFU of a variety of organisms
enumeration at time zero and then monitoring kill/survival rate at defined time intervals up to 28 days
what are the 7 BP identified sources of variability in PET
1) Choice of test organism and strain to use
2) inclusion of supplementary strains not listed in the pharmacopoeia
3) Culture maintenance and storage
4) preparation of inoculum
5) Methods employed for microorganism enumeration
6) Assay time and incubation temperature
7) Incorporation of organic load into the test
Which test organisms are recommended by pharmacopoeias
Staph aureus Pseudomonas aeruginosa Aspergillus niger Candida albicans E. coli
Factros effecting PET results
Inoculum levels (large levels results in reduced activity of antimicrobial
The manner in which the inoculum has been grown and prepared (using actively growing cells or old non-dividing cells may influence the experimental results)
Composition of media
- May contain substance that antagonize the action of the test compound
- Organic matter in media may protect organisms from preservative)
pH
- microbial growth rate us influenced by pH
- Preservatives are weakly acidic or basic and are more lippophilic in unionized form
Temperature, duration and redox conditions of incubation and preservative exposure.
Organism developing resistance to preservative
