Preservatives and antioxidants

PHRM 210

Preservatives and antioxidants

• Commonly used as additives in pharmaceutical products: to extend shelf life

• Antioxidants: Retard the oxidation of active ingredients and excipients

• Preservatives: Inhibit microbial proliferation

Preservatives

• Antimicrobial preservatives are used to prevent or inhibit the growth of microorganisms to avoid the degradation of the medicinal product or risk of infection

• Microorganisms are: molds, yeast and bacteria (Pseudomonas, E. coli, Salmonella and Staphylococcus)

Preservatives: Where to use?

• Chemical antimicrobial agents are added to all multi-dose sterile formulations and to aqueous and aqueous-based non-sterile pharmaceuticals

Reason of contamination

• Contamination during use• Raw materials (natural gum, sucrose solution)

being excellent growth media• Incorrect storage

Preservatives: Where to use?

• Which contain water such as solutions, suspensions and emulsions to be taken orally

• Solution for external use, creams, and • Sterile preparations used repeatedly (e.g.

injectable multidose preparations and eyedrops)

Preservatives: Where to use?

• Certain intravenous preparations, given in large volumes as blood replenishers or as nutrients are not permitted to contain bacteriostatic additives, because the amounts required to preserve such large volumes would constitute a health hazard when administered to the patients

Preservatives: Where to use?

• Consequences to patient’s health need to be evaluated, especially since most liquid pharmaceutical products are administered to pediatric population

Preservatives: Where to use?

• Although it may be most desirable to develop a ‘‘preservative-free’’ formulation to address the increasing concerns about the biological activity of these compounds, most formulations require some kind of preservative to ensure no microbial growth.

Preservatives: Mode of action

The majority of preservatives are bacteriostatic rather than bacteriocidal.

Preservatives interfere with microbial growth, multiplication, and metabolism though one or more of the following mechanisms:

• Modification of cell membrane permeability and leakage of cell constituents(partial lysis)

• Lysis and cytoplasmic leakage

Preservatives: Mode of action

• Irreversible coagulation of cytoplasmic constituents(e.g., protein precipitation)

• Inhibition of cellular metabolisms through interference with enzyme systems or inhibition of cell wall synthesis

• Oxidation of cellular constituents• Hydrolysis

Preservatives: Types

• Can be acidic or neutral• Among the acidic types are phenol,

chlorocresol, O-phenyl phenol, alkyl esters of parahydroxybenzoic acid (parabens), benzoic acid, boric acid, and sorbic acid, and their respective salts.

• Neutral preservatives include chlorobutanol, benzyl alcohol, and beta-phenylethyl alcohol.

Preservatives: Types

• The pH of solution, and the pKa of the preservative need to be carefully evaluated prior to selecting an acidic preservative for a formulation.

• Under alkaline conditions, it is generally regarded that most microbial growth is significantly retarded, which reduces the need for a preservative.

Preservatives: Selection & Problem

• The solubility of many preservatives in a mostly aqueous system may not be high enough for effective antimicrobial activity.

• For example, the parabens often require heating in order to be solubilized.

Preservatives: Selection & Problem

• Preservatives can partition between organic and aqueous phases in such a way that their activity is significantly reduced.

• Methyl paraben micellization by tween 80 is a well-known example of this phenomenon

Micelle

Preservatives: Selection & Problem

• Preservatives often contain reactive functional groups, which are responsible for their antimicrobial activity but lead to unwanted reactions.

Preservatives: Selection & Problem

• In addition to the excipient’s antimicrobial activity, other parameters should be evaluated during the stability studies such as its compatibility with the API, other excipients, and the container system.

Antioxidants

• Antioxidants are used to reduce the oxidation of active substances and excipients in the finished product.

• Oxidative degradation can be accelerated by light and by the presence of mineral impurities: because of the formation of free radicals.

• Drug drug or Drug excipient interactions

Oxidation: Consequences

• The oxidation of a chemical in a pharmaceutical preparation is usually attendant with an alteration in the color of that preparation.

• It may also result in precipitation or a change in the usual odor of preparation.

Antioxidants: Class and M/A• True antioxidants: They probably inhibit

oxidation by reacting with free radicals blocking the chain reaction.

• Antioxidants act by providing electrons or hydrogen atoms that are accepted more readily by the free radicals than the drugs and drugs remain protected.

• Gallic acid, Propyl gallate, L-tocopherol, Butylated hydroxytoluene (BHT), Butylated hydroxyanisole (BHA)

Antioxidants: Class and M/A

• Reducing agents: These substances have lower redox potentials than the drug or adjuvant which they are intended to protect, and are therefore more readily oxidized.

• Ascorbic acid (ASA), Thioglycolic acid (TGA), Ascorbyl palmitate (ASP)

Antioxidants: Class and M/A

• Antioxidant synergists: They usually have little antioxidant effect themselves but probably enhance the action of antioxidants in the first group by reacting with heavy metal ions which catalyze oxidation.

• EDTA, Lecithin

Antioxidant: Selection

• Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT), L-tocopherol and the alkyl galates are particularly popular in pharmaceuticals and cosmetics.

• BHT and BHA have a pronounced odor and should be used at low concentrations.

Antioxidant: Selection

• Alkyl gallates have a bitter taste, where as L-tocopherol is well suited for edible and oral preparations, such as those containing vitamin A.