Antimicrobial Preservatives W9 Flashcards
Antimicrobial agents
Chemical agents used to destroy, inactivate or inhibit growth of microorganisms
Preservatives
can be incorporated into formulations to prevent spoilage and to kill or inhibit low levels of
contamination introduced during storage or use.
Why do we use AMPS
Prevent microbial growth
Ensure product safety
Increase shelflife and stability
Protect against spoilage and degradation
Regulatory compliance with FDA and EMA
Maintain aesthetic properties
The outcome of using contaminated pharmaceutical products
Generalised bacteraemic shock and death
Broken skin become necked
Spread of infection over several months
Observable signs of microbial contamination
Smell and taste
Discolouration
Loss of viscosity
Change of pH
Gaseous metabolites
Emulsions cracking
Phase seperation
AMP is used with .
✓The majority of oral liquid preparations.
✓Creams and lotions (not ointments).
✓Most multidose eye drops and eye irrigations.
✓Injectables that are allowed to be multi-dose.
✓Nose and ear drops.
No need for AMP with….
✓ Dry powders, tablets and capsules.
✓ Single use sterile products (eye drops or injections
like, intrathecal and IV infusions).
✓ Ointments.
✓ Formulations that have intrinsic preservative activity
(some anti-cancer drugs)
Ideal preservative
Broad spec of activity
Rapid killing rate
Anon-irritant/toxic
Highly selective towards contaminants
Effective at low conc
Stable through life of pharm product
NO SUCH AGENT EXISTS
Commonly used AMP
Acids and esters
Alcohols
Chloroform
Phenolics
Parahydoxybenzoates as Antimicrobials
o Alkyl esters of p-hydroxybenzoic acid.
o Good preservative activity up to ~ pH 8.
o Most effective against fungi.
o Poor activity against Pseudomonas
o Often used in combination
o Inactivated by non-ionic surfactants.
o Can be used e.g., in creams, oral liquids, eye drops and injectables.
Benzoic/Sorbic Acid as Antimicrobials
o Used widely
o only useful up to pH 4.5
o used in oral liquids; also safe to use in parenterals.
o Both have antibacterial and antifungal activity
o used in food industry
o Some organisms can develop resistance to them
Phenolics as Antimicrobials
Effective against bacteria, virus, fungi, spores
Can be toxic
Can be corrosive to metal
Resistance can be developed
An example is phenyl which isn’t used anymore that was common in the 19th century
Alcohols as Antimicrobials
Ethanol can be used but need a higher concentration
Benzyl alcohol has a wide spec of Antimicrobial activity and can be used in injectables and topicals - Not for neonatal injections
Chlorobutanol can b used as njections ans eye drops
Quaternary ammonium compounds as Antimicrobials
Benzalkonium is widely used as AMP in eye drops and injectables
Biguanides as Antimicrobials
Chlorohexadine
- Partially useful in eye preparations
- generally used as acetate or hydrochloride salts
- limited anti fungal activity
- used as antiseptic for mouthwash
Chloroform as Antimicrobials
Useful preservative properties such as activity over a wide pH range and broad spec Antimicrobial activity
It is nephrotoxic and a carcinogen and is volatile
Factors affecting AMP efficiency
- Effect of preservative concentration
- Changes in product temperature
- Size of product
- Preservative capacity
- Factors that affect preservative availability/activity
- Effect of preservative concentration
Changes in the efficacy of preservatives vary with changes in concentration.
The extent of variation depends upon the type of agent. For example, halving the concentration of phenol gives a 64-fold reduction in activity, whilst a similar dilution for chlorhexidine gives a 4-fold reduction in activity
- Changes in product temperature
will alter efficacy in proportions related to different types of preservative and certain groups of microorganisms.
a drop in temperature from 30° to 20°C could result in fivefold and 45-fold losses of killing power towards E.coli by phenol
- Size of product
Preservative molecules are used up as they inactivate microorganisms
they interact non-specifically with the significant quantities of contaminant ‘dirt‘
This will result in a progressive and exponential decline in the efficiency of the remaining preservative.
- Preservative capacity
Describes the cumulative level of contamination that a preserved formulation can cope with before becoming ineffective.
varies with preservative type and complexity of the formulation.
- Factors that affect preservative availability/activity
▪ Product pH
▪ Multiphase systems (Emulsions)
▪ Container or packaging
Effect of product pH on AMP activity : organic acids
Antimicrobial activity is significantly influenced by the protonation state of the acid
Uncharged forms are more effective in their unassociated form which is more likely to penetrate the membrane and disrupt cellular processes
At higher pH, the organic acids dissociate into their ionised form which is less able to cross the cell membrane
At low pH (4 to 5) benzoic acid exists in an unassociated form which is able to pass through microbial membranes but at a higher pH (7+) the benzoate iron dominates which is less effective and penetrating membranes and inhibiting micro growth
Efficiency in multiphase systems
Ie oil in water emulsion
Preservative molecules distribute themselves in an unstable equilibrium between the bulk aqueous phase and:
- the oil phase by partition
- any microorganisms present
- surfactant micelles by solubilisation
Effect of container or packaging
Preservative availability may be reduced by interaction with packaging materials.
Ie - The permeation of phenolic preservatives into the rubber closure of multi-dose injection or eye-drop containers and their interaction with flexible nylon tubes for creams.
Practical considerations when choosing an appropriate AMP
- Microbial challenge
- type and level o expected contamination - Compatibility with formulation ingredients (inert)
- Compatibility with packaging material
- AMP activity and formulation pH
- Route of admin and agent toxicity
- Multiphase produts
Q1. One of these is used as an AMP
a. Formaldehyde
b. Ethylene oxide
c. Benzoic acid
d. Chloroxylenol.
D
Q2. One of these formulations doesn’t
require preservatives addition
a. Oral liquid preparations
b. Creams and lotions
c. Ointments.
d. Nasal drops.
C
Q3. Which of these factors affect the AMP efficacy?
a. Preservative concentration
b. Product temperature
c. Product pH
d. Packaging material
e. All of the above
E
Q4. True or false?
A.Preservatives can be added to mask poorly controlled manufacturing processes
B. Preservatives aren’t added in all the pharmaceutical formulations because it’s costly
C. Preservatives are only used to prevent the growth of m.o but not to kill them
F
T
T
Effect of product pH on AMP activity : coronary ammonium compounds
At slightly neutral to acidic pH (5 to 7)they are in their most active form and can interact efficiently with cell membranes to cause disruption and kill microorganisms
Alkaline pH (7+) they precipitate or become less soluble reducing their ability to interact with microbes and diminishing their antimicrobial effectiveness
Effect of product pH on AMP activity : alcohols
Acidic pH, it may slightly enhance solubility efficacy of alcohols
Alkaline pH doesn’t significantly reduce alcohol activity my older stability of the alcohol and increase evaporation potentially reducing the duration of action
