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.