Stereochemically specific identity test

For drug substances and drug products, applications for enantiomers and racemates should include a stereochemically specific identity test and/or a stereochemically selective assay. The choice of control tests should be based on the method of manufacture and stability characteristics and, in the case of the finished product, its composition. 

Many chiral compounds are known by the chemist to be racemic because of the lack of stereoselective influences on the synthesis or to be enantiopure because of natural origin. Such knowledge, while based on a sound technical foundation, may not be suitable for regulatory purposes. For example, the commercial availability of a racemate or the "opposite" enantiomer may make its substitution for the approved component conceivable. Therefore, it may be necessary to bring other factors (e.g synthetic feasibility or commercial sources) into consideration to establish whether a stereochemically specific identity test is necessary. 

Few drugs make use of X-ray powder diffraction as a regulatory test. However, this method has a unique advantage as a stereochemically specific identity test for chiral drugs. The crystal structure, and therefore the powder diffraction pattern, are necessarily different between the racemate and the enantiomer, except in the case of a racemic conglomerate. Furthermore, published reference data are readily available. In combination with the invariance of the d-spadng measurements, this msy make X-ray diffraction more attractive to the regulatory scientist. 

The specifications for both enantiopure and racemic chiral drug substances should be sufficient to establish both chemical and stereochemical aspects of identity, strength, quality and purity. This implies both that the identity test use a stereochemically specific method and that the assay method be stereochemically selective. 

Certain identity tests intended to establish the stereochemical identity of a drug are known. Their applicability to a specific drug substance may vary depending upon the magnitude of differences between the values to be determined. These are discussed below in the following order (which does not suggest the suitability of the technique for regulatory purposes) ... 

A relatively common use of optical rotation is as an identity test for a racemate with specification limits that are symmetrical around zero. Such a specification has Little if any regulatory significance. Its validation necessarily depends upon knowledge of the specific rotation and thus requires the resolution of the racemate on a laboratory scale. Furthermore, even with such supporting data, the method is dependent upon the accuracy of the sample preparation, since a solvent blank would also show a rotation of zero. Other analytical methods are far more appropriate for the stereochemically specific identification of racemates. 

The guideline on chiral active substances states that particular attention should be paid to identity and stereochemical purity. It states that specifications for a racemate should include a test to show that the substance is indeed a racemate and this is a position supported by the requirements of the European Pharmacopoeia for drug substance monographs [16]. 

Some chiral drug substances either occur naturally or are synthetic derivatives of natural products. In these cases, the controls on the raw materials are often assumed to guarantee the stereochemical identity of the finished bulk drug substance product without the use of a specific stereochemically sensitive test. Such an assertion is of little significance for regulatory purposes. First, determination of the source species for an... 

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