Page 328 - Chiral Separation Techniques

13.1 Introduction 321

rials for subsequent derivatization (achiral or otherwise) or by using well-character-
ized enantioselective microbial reactions at strategic points in a chemical synthesis
to introduce the desired chiral center. Where the option of synthesizing the required
stereoisomer is not feasible, the enantiomers of the drug must be separated. The tra-
ditional method is fractional crystallization using a chiral counter-ion to produce
diastereoisomeric salts. This technique is still commonly used, but finding a suitable
counter-ion is mainly based on trial and error. Chiral high-performance liquid chro-
matography (HPLC) may provide a suitable preparative method for small amounts
of enantiomers, but is less likely to be commercially viable. New developments such
as simulated moving bed (SMB) chromatography provide exciting possibilities for
the future production of large-scale quantities of pure enantiomers.
Alongside the improvement in procedures for obtaining enantiomerically pure
compounds have come new methods of analysis which are necessary to demonstrate
the effectiveness of manufacturing procedures and to control the quality of the active
ingredient and corresponding medicinal product. The greatest area of evolution has
been in chiral chromatography, particularly HPLC, but methods based on nuclear
magnetic resonance (NMR) spectroscopy are also used and latterly capillary elec-
trophoresis (CE) techniques have become available. Bioanalytical methods are also
required for monitoring the fate of individual isomers after administration [9].
As the new synthetic, preparative and analytical methods arrived, they allowed
growth of the body of evidence demonstrating the pharmacological, pharmacoki-
netic and clinical significance of drug chirality until the stage was reached where the
issue needed to be addressed by both the pharmaceutical industry and the regulatory
authorities responsible for licensing medicinal products. A consultative approach
was adopted by the regulators. In 1992, a Drug Information Association (DIA) work-
shop on chirality was held with a concurrent independent discussion on regulatory
requirements for chiral drugs [10]. Regulators and representatives from the pharma-
ceutical industry in the European Union (EU), Japan and the US debated chiral
issues relating to quality, safety, and efficacy – the three principles which form the
basis for approval of a medicinal product. The workshop recommended a pragmatic
approach to the regulation of chiral drugs whereby the choice of the stereochemical
form should be based on scientific data relating to quality, safety, efficacy and
risk–benefit. The decision as to whether a racemate or enantiomer ought to be devel-
oped should reside with the applicant for the marketing authorization or sponsor of
the product. The workshop recommended that the regulation of chiral drugs should
be consistent with these principles.
Regulatory guidance on the development of chiral drugs was published subse-
quently, first in the US in 1992 and then shortly afterwards by the EU, and indeed
has adopted the pragmatic approach advocated by the DIA workshop. A similar atti-
tude prevails in Japan, although formal guidance has not been produced. The Cana-
dian guidance is also based on the same principles [11]. There is a wider interna-
tional effect of these and other regulatory policies through exchange schemes with
other countries. The same dossier of information may be accepted to register a
medicinal product elsewhere and in some cases an authorization is granted on the
basis of the original assessment report. An example of the latter is the Pharmaceuti-