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The public and the pharmaceutical industry are placing greater attention on impurities in drug as evidenced by the attention
given to pharmaceutical impurities in books, journal articles, and national and international guidelines (1–10). The health
implications of impurities can be significant because of their potential teratogenic, mutagenic, or carcinogenic effects.
Controlling and monitoring impurities in APIs and finished drug products, therefore, is a crucial issue in drug development
and manufacturing.
Part I of this article, which appeared in the February 2012 issue of Pharmaeceutical Technology, discussed the various types and sources of impurities with specific case studies (11). This article, Part II, discusses
chiral, polymorphic, and genotoxic impurities (12, 13). Part III, to be published in the April 2012 issue of Pharmaceutical Technology, will examine various degradation routes of APIs, impurities arising from API–excipient interaction during formulation, metabolite
impurities, various analytical methodologies to measure impurity levels, and measures to control impurities.
Chiral impurities
Impurities can be present in the enantiomers of chiral compounds. Differences in pharmacological and toxicological profiles
have been observed with chiral impurities in vivo (14, 15). The significance of stereochemical purity may be illustrated by formoterol, a selective β2-adrenoceptor agonist
(16). This compound contains two chiral centers. Initial investigations indicated that the β2-agonist activity resided in
the stereoisomer with the (R, R) absolute configuration with a rank order of potency (R, R) > (R, S) > (S, S) > (S, R). Subsequent investigation reported much greater difference with the eudismic ratio R, R/S, S increasing from 50 to 850 when the impurity of the eutomer in the diastereomer decreased from approximately 1.5 % to < 0.1%
(17). Similar examples of stereochemical isomers can be found in the stereospecific drugs of the (S)-enantiomer of a-methyldopa, picenadol, (R)-sopromidine, (+)-(S)-apomorphine, and sertraline (18–24).
Another example is asenapine maleate, an antipsychotic belonging to the dibenzo-oxepino pyrroles class. Based on its receptor
pharmacology, the efficacy is thought to be mediated by its antagonist activity on dopamine (D)-2 and serotonin (5-HT)–2A
receptors (25). Asenapine shows geometric isomerism and is a racemate of (+) and (-) enantiomers. It shows comparable binding
affinities, meaning trans-asenapine showed higher affinity at D4 receptors than (+)/cis-asenapine (26).
Differences in pharmacological and toxicological profiles have been observed with chiral impurities in vivo, suggesting that chiral impurities should be monitored carefully. Although development of chiral drugs as single stereoisomers
is a preferred approach, consideration must be given to unwanted stereoisomers, which may be present as impurities or degradants
in the drug substance or drug product or generated through metabolism in biological systems. Chiral impurities in pharmaceutical
samples may occur as side-products of the synthetic process as a result of an inversion of chiral centers due to chemical
degradation of the drug substance or both. Similarly, inversion of the chiral center may occur in vivo as a result of metabolism, chemical degradation, or both.
Guidelines on the development of chiral compounds are published by regulatory authorities around the world, but they can be
general and leave room for interpretation. The issues involved in chiral drug development are complex, and a coordinated approach
among the many R&D groups is necessary. A multidisciplinary approach serves as a guide to the development of chiral compounds
by coordinating research efforts in the various phases of development (22–36).
