Page 324 - Chiral Separation Techniques

Chiral Separation Techniques: A Practical Approach, Second, completely revised and updated edition
Edited by G. Subramanian
Copyright © 2001 Wiley-VCH Verlag GmbH
ISBNs: 3-527-29875-4 (Hardcover); 3-527-60036-1 (Electronic)
13 International Regulation of Chiral Drugs 1

Sarah K. Branch

13.1 Introduction

The regulation of chiral drugs provides a good demonstration of the mutual rela-
tionship between progress in scientific methodology and the development of regula-
tory guidelines. It is also an example of international debate between regulatory
authorities and the pharmaceutical industry leading to a consensus in recognition of
the global nature of pharmaceutical development. The significance of optical iso-
merism in drug action is well-established; for example, it was known in 1926 that
the biological activity of atropine resided in only one stereoisomer [1]. However, the
absence of suitable methods for either the large-scale preparation of pure enan-
tiomers or for stereoselective analysis meant that the majority of stereochemically
pure drugs on the market were of natural origin. That drug metabolism could be
stereoselective was already acknowledged by the 1970s [2], but it was only in the
following decade that the wider implications of chirality in clinical pharmacokinet-
ics and drug safety began to be recognized and then only after some vigorous cam-
paigning, for example, by Ariëns [3, 4]. The “enantiomer-versus-racemate” debate
will not be reiterated here as the published literature is quite extensive and has been
previously reviewed [e.g., 5–8]. A summary, however, is given in Table 13-1 of the
different scenarios, illustrated by single examples, associated with the administration
of a racemate which might need be taken into account during development of new
drug substances.
Historically, synthetic chiral drugs were mainly presented as the racemate due to
the technical difficulties of either synthesizing the pure enantiomers or separating
them to yield the individual isomers. The 1980s saw the introduction of new meth-
ods for the preparation of single enantiomers accompanied by advances in chiral
analytical procedures. The field of asymmetric synthesis in organic chemistry bur-
geoned and a wide range of chiral precursors and reagents are now commercially
available as a result. There has also been exploitation of biosynthetic pathways in
micro-organisms to produce drug substances, either employing chiral starting mate-

1 The views expressed in this chapter are those of the author and do not necessarily represent the views or the opin-
ions of the Medicines Control Agency, other regulatory authorities or any of their advisory committees.