SC I K. Stereochemistry

This section describes the way in which the stereochemistry of a substance is indicated in the chemical definitions and graphic formulae of the British Pharmacopoeia and the way it may be identified and/or controlled within the tests in a monograph.

1. Many medicinal substances that contain one or more chiral centres and that are already on the market have been made available for pharmaceutical use as racemic mixtures with little known about the biological activities of the separate isomers. This has been reflected in the monograph in the Pharmacopoeia and a test to show that the substance is the racemic mixture has not usually been included unless it was known that at least one of the separate enantiomers was also available commercially. Nevertheless, with increasing concern by regulatory authorities for substances to be made available as single isomers, tests for enantiomeric composition will become more common (see section on tests below).

Chemical definition

(monographs other than those of the European Pharmacopoeia)

2. In the case of substances containing a single chiral centre, the descriptor ‘(RS)-’ is included at the appropriate position in the chemical definition of the substance to indicate a racemic mixture.

3. For substances containing multiple chiral centres and comprising a mixture of all possible stereoisomers the term ‘all-rac-’ has been used, for example Isoaminile. In those few substances existing as diastereoisomeric mixtures, that is where in one or more centres the stereochemistry is explicit but in other centres it is not, each centre is defined either as the specific (R)- or (S)- configuration, or as racemic (RS)-, respectively.

Graphic formulae

4. When a medicinal substance is a racemate, an indication is given by means of the graphic formula.

5. Because in graphic formulae there is no generally accepted convention for depicting a racemate, each racemic substance with one chiral centre is shown in the (R)- form with the appended text ‘and enantiomer’ for example, Carteolol Hydrochloride. For the all-rac- mixtures, such as Docusate Sodium and Alpha Tocopheryl Acetate, non-stereospecific graphic formulae are drawn and the legend ‘mixture of n stereoisomers’ added beneath (where n is the number of possible stereoisomers); the stereogenic carbon atoms concerned are identified by means of asterisks.

6. In diastereoisomeric mixtures, the unique configuration centres are drawn as such, while each racemic centre (with equal amounts of the (R) and (S) configuration) are indictated by an asterisk and the legend ‘racemic at C*’ appended. For example, Carbenicillin Sodium is drawn in this way; the chiral atoms in the penicillanic acid ring each in their single specific configuration and the phenylmalonyl side-chain chiral atom marked with an asterisk.

Tests

7. In future, when a monograph describes an enantiomer, it will include both a test for specific optical rotation under Identification and a test, using methods such as chiral chromatography, to control enantiomeric purity.

8. When both the racemic mixture and the enantiomer are available, the monograph for the racemic mixture will, where appropriate, specify a test for angle of rotation together with a cross reference under Identification. The test for angle of rotation will normally specify low, symmetrical limits about zero where this has been shown to limit the presence of optically active impurities and demonstrate approximately equal proportions of the enantiomers.

9. When only the racemic mixture is available, the monograph for the racemic mixture may, where appropriate, specify a test for angle of rotation.