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Although considered pharmacologically inert, excipients can initiate, propagate
or participate in chemical or physical interactions with drug compounds, which
may compromise the effectiveness of a medication. Excipients may also contain
impurities or form degradation products that in turn cause decomposition of
drug substances. This article explores some of these interactions and reactions,
and calls for a better understanding of excipient properties.
is a Vice President in
Excipients are included in dosage forms to aid
irritation of the skin or mucosal surfaces, sensitization
manufacture, administration or absorption.
reactions or adversely affect appearance or
Other reasons for inclusion concern product differ-
organoleptic properties. However, such effects are
entiation, appearance enhancement or retention of
not usually a consequence of drug–excipient interac-
quality.1 They rarely, if ever, possess pharmacological
tion per se, so are not considered in this review.
activity and are accordingly loosely categorized as‘inert.’ However, excipients can initiate, propagate or
Modes of drug decomposition
Dr Luigi G Martini
participate in chemical or physical interactions with
Medicinal agents invariably have structural features
an active, possibly leading to compromised quality or
that interact with receptors or facilitate metabolic
performance of the medication. Chemical interaction
handling. These inevitably confer some degree of
can lead to degradation of the active ingredient,
lability, making them vulnerable to degradation (and
thereby reducing the amount available for thera-
interaction with other materials). Common modes of
peutic effect; reaction products may compromise
safety or tolerance. Physical interactions can affect
Drugs with functional groups such as
rate of dissolution, uniformity of dose or ease of
esters, amides, lactones or lactams may be suscep-
administration. Understanding the chemical and
tible to hydrolytic degradation. It is probably the
physical nature of excipients, the impurities or
most commonly encountered mode of drug and
residues associated with them and how they may
product degradation because of the prevalence of
interact with other materials, or with each other,
such groups in medicinal agents and the ubiquitous
forewarns the pharmaceutical technologist of possi-
nature of water. Water can also act as a vehicle for
bilities for undesirable developments.
interactions or can facilitate microbial growth.Oxidation.
Oxidative degradation is probably second
only to hydrolysis as a mode of decomposition. In
Excipients may have functional groups that interact
contrast to hydrolysis, oxidative mechanisms are
directly with active pharmaceutical ingredients.
complex, involving removal of an electropositive
Alternatively, they may contain impurities or
atom, radical or electron or, conversely, addition of
residues, or form degradation products that in turn
an electronegative moiety. Oxidation reactions can
cause decomposition of the drug substance.
be catalysed by oxygen, heavy metal ions and light,
Excipients can be a source of microbial contami-
leading to free radical formation (induction). Free
nation. They can also cause unwanted effects such as
radicals react with oxygen to form peroxy radicals,
Direct interactions between
actives and excipients
into its optical or geometric isomer.
interactions lead to loss of quality.
Soluble and ion-
of interactions in solid state systems.
Reactions such as oxida-
Reactions with lactose.
coloured entities. This ‘Maillard reac-
Reactions with silicon dioxide.
catalysed oxidation of diethylstilbestrol
to the peroxide and conjugatedquinone degradation products.
Table I Modes of degradation of medicinal agents.
linoleate to peroxides with subse-quent decomposition to aldehydes
the presence of colloidal silicondioxide.11 Interaction between
‘qualified’ by toxicology studies.
Lactose is one of the most
removal during isolation and drying.
found in spray-dried lactose,16 as hasthe hexose degradation product,5-hydroxymethylfurfural, probably
Table II Impurities found in common excipients.
generated by heat encounteredduring spray-drying.17 As an alde-
participate in addition reactions withprimary amino groups, resulting in
Figure 1 Degradation pathways of diethylstilbestrol.
Figure 2 Glucose and galactose, and the hexose degradation product
5-hydroxymethylfurfural, are found in spray-dried lactose.
Effect of pH.
The presence of
Figure 3 Moisture sorption profile of microcrystalline
cellulose at 25 °C.
(Reprinted with permission from reference 22.)
Reactions with residues or
Effect of processing.
A number of
Peroxide residues in
Figure 4 Relationship between nitrazepam decomposition
rate constant and nitrogen adsorption energies of various
(Reprinted with permission from reference 12.)
a ‘bound’ state, but will rapidly equi-
tion if the drug is moisture sensitive.
Figure 5 Organic impurities in microcrystalline cellulose
ϭ methyl group).
or does so to any significant extent.
lizing the active ingredient as well.
stabilizers in biotechnology products.
Conclusions and perspectives
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