Drugs stereochemical purity

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]. 

For the preparation of enantiomeric drugs with a high chemical and stereochemical purity (> 99%), often required nowadays for drugs and for pharmacological investiga-... 

One of the most successful drugs of recent years is captopril [l-(3-mercapto-2-(S)-methyl-l-oxopropyl)-(S)-proIine] [6]. It is an inhibitor of the angiotensin-converting enzyme and is widely used for the treatment of hypertension and congestive heart failure. The stereochemical purity of captopril was investigated after esterification and acylation by enantio-selective gas chromatography using a XE-60-L-val-(S)-a-phenylethyI-amide column (43). 

Optical rotation has the dual advantages of historical use and widespread recognition in the compendia. For an enantiopure material, it defines its configuration when used in conjunction with other valid chemical tests. However, optical rotation has been used ineffectively when the primary analytical goal is the determination of stereochemical purity. The limits selected for the specification seem to be unrelated to the purity required by other methods. For example, the compendial monograph for naproxen requires that the drug substance meet a specification of "between -f-63.0 and -1-68.5"" in a chloroform solution. Based on the published specific rotation, this corresponds to a stereochemical purity of 95.5 to 103.7%, compared to the assay limits of 98.5 to 100,5%, determined by titration with sodium hydroxide (5). 

One of the cardinal features of a receptor-mediated effect is stereoselectivity. It was therefore significant that cannabinoids were shown to be stereoselective as inhibitors of LTP. HU-210 and HU-211 were the first to be tested, since their stereochemical purity is particularly high, and only HU-210 is psychoactive. The experiments by Collins et al. (1994) showed that pre-incubation of adult rat hippocampal slices with 100 nM HU-210, but not HU-211, blocked LTP of the CAI field excitatory postsynaptic potential (fEPSP) induced by high-frequency stimulation (100 Hz for 500 ms). Slices were pre-incubated with the drugs so there was... 

As numerous optical isomers have been shown to reveal major differences in pharmacological activity, metabolic fate, and excretion, the problem of stereochemical purity control seems to be widely appreciated and remains a topical issue, all the more so that it encompasses the problem of drug quality and aims at ensuring maximal safety and therapeutic efficacy. This issue has been investigated in more detail by the authors of other studies [15-17], who reviewed various possible modes of action of enantiomers present in drug products containing racemates. 

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. 

In considering the potency ratios quoted above, it should be remembered that it is difficult to obtain the optical isomers of these alkaloids in a state of high purity, that their solutions racemize with great ease, and that the pharmacological measurements are not very accurate. Nevertheless, the stereochemical specificity of hyoscyamine and scopolamine is of great interest. The usual explanation of such specificity is that the drug forms a three-point attachment to some asymmetrical structure in the living cell on which it acts and consequently that only one of the optical isomers has... 

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