Preservation - Victor

• contains water which supports micro-organism growth

• natural occurring sources of microbes and spores - acacia and tragacanth

• Microbes can stick to the surfaces of fine powders (a process called adsorption). This surface sticking gives them a stable environment, helping them settle, survive, and stay alive longer in liquid mixtures. - kaolin (clay), magnesium trisilicate

• microbes are attached to or surrounded by inactive ingredients (polymers/powders), they get a protective "shield". This makes them harder to kill with heat or drying (desiccation) - starch

need for preservatives in suspensions

• Resistance of microorganisms to preservatives can be increased - by surfactants, suspending agents and proteins.

• can chemically bind or react with the thickeners used to give a medicine its texture.

• tragacanth, alginates - interact with preservative

• pushing away the water holding the ingredients together - adsorption of parabens on to magnesium trisilicate and other natural hydrocolloids,

material that can affect the preservatives

• a preservative doesn't just stick to the surface of a solid (adsorption)—it goes a step further and actually soaks inside the solid material, forming a "solid solution

• when liquid medicines are stored in plastic containers. If the plastic "drinks up" or absorbs the preservative, the preservative is removed from the liquid, meaning there won't be enough left to protect the medicine from germs.

• Phenolics and parabens can soak heavily into nylon and plasticized PVC

adsorption of a preservative leading to absorption of solids

• Different preservative levels may be permitted for different applications.

• final choice of preservative will depend on the product nature and the other components present, and the nature of the micro- organisms likely to be encountered during manufacture and use

• alcohols, benzoates, sorbates, parabens

preservative types

• bactericidal and fungicidal

• denaturation of cell proteins.

• antimicrobial activity of the aliphatic alcohols increases with the chain length up to 10 carbon atoms, above which the water solubility is too low to allow for general use.

• Ethanol concentration greater than 15% is required to be effective as a preservative, but such high concentration may result in incompatibilities in suspension and emulsion systems.

• Propylene glycol 15–30% is used frequently as a preservative in solutions, suspensions and emulsions.

• Chlorobutanol and phenylethyl alcohol used in lower concentrations (approximately 1%) as preservatives.

alcohols

• ionised form is preferred as hydrophilic remains in the aqueous phase

• Benzoic acid has a low water solubility,

• Incompatible with quaternary ammonium surfactants, calcium, ferric and heavy metal salts.

• Optimum activity at pH values below 4.5 - for acidic pH

• Adsorption to kaolin decrease antimicrobial activity

benzoates

• Nonionized form has preservative action; only effective in acid media.

• Optimum antibacterial activity at pH 4.5

• Low water solubility

• subject to oxidation particularly in the presence of light and in aqueous solutions.

• Activity against bacteria can be variable, due to its limited stability.

• used in combination with other antimicrobial preservatives or glycols for synergistic effects

sorbates

• Antimicrobial activity increases with increasing alkyl moiety chain length;

• Water solubility decreases as the molecular weight increases, from 0.25% (methyl ester) to 0.02% (butyl ester).

• the paraben esters are more active against Gram +ve than Gram −ve micro-organisms.

• Paraben esters are more active against yeasts and molds than bacteria.

• antimicrobial activity of paraben esters is optimal at pH range of 4 – 8, but more active in acidic media.

• paraben mixtures are frequently used to provide effective preservation.

• Preservative efficacy is improved by propylene glycol (2–5%) or in combination with other antimicrobial agents.

• in alkaline solutions, ionization reduces activity and hydrolytic decomposition of the ester group leads to a loss of activity.

• binding to nonionic surfactants reduces activity

parabens

• Contaminated Emulgent

• Deionized water (Bacteria grow in resin beds)

• Equipment

• Poorly closed container

• Some ingredients of emulsions promote the growth of micro-organisms by providing nutrients - bacteria feed on non-ionic and ionic surfactants - glycerin, oil, liquid paraffin

conditions when a preservative is needed in an emulsion

• Microbes consume the surfactants that hold the mixture together, which lowers stability - causes the oil droplets to separate and float to the top much faster, a process known as creaming

• Microbes break down the oils (lipolysis) to release fatty acids, which lowers the product's pH - this acid release causes oil globules to merge together (coalescence) and completely destroy the emulsion so that oil and water separate entirely, known as cracking.

• The leftover fatty acids and their breakdown products (ketonic oxidation products) give the product a sour taste and unpleasant smell

• As microbes digest parts of the formula, they release gas, resulting in visible bubbles trapped inside the product

• Microbial activity can cause noticeable discolouration - leads to unwanted changes in thickness and flow, altering the rheological properties of the emulsion

oil-in water emulsion spoilage

• preservatives can move (diffuse and partition) out of the water and get trapped inside the oil phase

• Microorganisms primarily live, grow, and multiply in the aqueous (water) phase of an emulsion

• Water-soluble preservatives work best because they ensure a high concentration of free, unbound preservative remains in the water phase to stop microbial growth.

movement of preservatives in phases

• In complex formulas like an oil-in-water emulsion, preservative molecules spread out and try to find a balance (unstable equilibrium) between the water and all the other ingredients

• preservatives can go into the oil phase (by partitioning/dissolving into the oil droplets), surfactant micelles (trapped inside tiny soap-like clusters), thickeners and polymers (by pushing water molecules away and binding with the thickening agents), solid particles or container surfaces (by sticking to them through adsorption), microorganisms themselves

• changing of volume ratio has no effect on the preservatives

where preservatives go in an emulsion

• If K0 w is high, then it becomes extremely difficult to maintain adequate preservative levels in the aqueous phase without an excessive total preservative concentration

partition co-efficent

• The preservative molecules that are floating freely (unbound) in the water are the ones doing all the active work to kill microorganisms.

• Overall preservative efficiency depends heavily on that small fraction of molecules left free in the water phase.

• As those free molecules get used up, a slow balancing process happens, causing more preservative to shift back out of storage to replace the ones that were consumed.

• Neutral (uncharged) preservative molecules are more likely to be pulled away and lost into oil or micelle (soap-like cluster) phases compared to charged (ionized) molecules.

• However, how these molecules distribute themselves can vary a lot from one formula system to another.

unbound preservative molecules in aqueous phase

• Adding a non-ionic surfactant to the mixture causes the preservative to redistribute itself between the oil and the total aqueous (water) phase.

• The surfactant's role in the formula - non-ionic surfactant acts as a third ingredient in the system and is officially considered part of the aqueous phase

• Interaction of preservatives by non-ionic surfactants may be micellar solubilisation or complex formation between the two molecules.

• R = SC + 1 shows that the amount of preservative trapped by a non-ionic surfactant is directly tied to how much surfactant is in the formula.

non ionic surfactant affect on preservatives

• Surfactant micelles give preservative molecules an extra place to hide, which changes their normal partition coefficient.

• Instead of just dividing between the oil and water, the preservative now partitions between the oil globules and the water-based micelle clusters

• Because calculating these interactions mathematically becomes a very long and complicated process, formulas alone aren't always enough

• get so complex, a direct experimental approach—such as using a dialysis technique—is often the only practical way to accurately measure how much free preservative is left in the water.

Surfactant micelles alter the native partition coefficient of the preservative molecule