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DRUG–EXCIPIENT INTERACTIONS
Drug–Excipient Interactions
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.
Patrick Crowley
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 Hydrolysis. 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
General considerations
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
Isomerization. Isomerization
into its optical or geometric isomer.
interactions lead to loss of quality.
Charge interactions.Soluble and ion-
of interactions in solid state systems.
Photolysis. Reactions such as oxida-
Reactions with lactose. Lactose can
coloured entities. This ‘Maillard reac- Polymerization. Intermolecular
Reactions with silicon dioxide.
Hydrogen-donating interactions.
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 Hydrolysis
Oxidation
Isomerization
Photolysis
Polymerization
the presence of colloidal silicondioxide.11 Interaction between ‘qualified’ by toxicology studies.
Physical interactions
Lactose. Lactose is one of the most
Excipient residues
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- Excipient
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
impurities. Peroxide residues in
Figure 4 Relationship between nitrazepam decomposition
rate constant and nitrogen adsorption energies of various
Microcrystalline cellulose. This com-
excipients. (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
(Me ϭ methyl group).
or does so to any significant extent.
Water-based reactions. Several
Biopharmaceutical products
lizing the active ingredient as well.
stabilizers in biotechnology products.
Conclusions and perspectives
References
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