Racemic drugs enantiomers

In order to illustrate an example of process design for the manufacture of enantiopure drug substances on an industrial SMB system, consider manufacturing 10 ton/ year of an enantiopure drug. The racemic drug by definition is a 50 50 mixture of each enantiomer (products A and B). The goal is to process enantiopure drug substances in order to obtain 99 % purity for both the extract and the raffinate. 

In order to illustrate the critical process parameters of SMB process validation, we will consider the separation of the racemic drug as described in Process design. The study represents the effect of the influence of feed concentration, number of plates and retention factor on the second eluting enantiomer. The simulation of the process for different values of feed concentration is performed and the variations of the extract and raffinate purities are shown in Fig. 10.10. 

The guideline concludes with a note that there is no intention to require further data on established medicinal products which contain a racemic drug unless new evidence emerges concerning the safety or efficacy of one enantiomer. If new claims related to the chiral nature of the active substance are made, then supporting studies on the individual enantiomers will be required. 

The preparation of enantiomerically pure drugs is one factor that makes enantioselective synthesis and the resolution of racemic drugs (separation into pure enantiomers) active areas of research today. 

As human enzymes and cell surface receptors are chiral, the two enantiomers of a racemic drug may be absorbed, activated, or degraded in very different ways, both in vivo and in vitro. The two enantiomers may have unequal degrees... 

Keywords enantioseparation, racemic mixtures, single enantiomer of drug, chromatography, chromatographic resolution. 

Ropivacaine is an amide anaesthetic prepared as the pure S enantiomer of the racemic drug. Adverse cardiac effects appear to be stereo-selective for the R (-) enantiomer and so the intrinsic cardiotoxic potential of the drug may be reduced. Unlike other amide local anaesthetics it has a slight vasoconstricting effect. 

For those drugs that are administered as the racemate, each enantiomer needs lo be monitored separately yet simultaneously, since metabolism, excretion or clearance may be radically different for the two enantiomers. Further complicating drug profiles for chiral drugs is that often the pharmacody namics and pharmacokinetics of the racemic drug is not just the sum of Ihe profiles of the individual enantiomers. 

One further point which should be considered is the importance of dose size. Because of the (R) — (S) conversion, the dosage of the (S) form administered may be as much as two or three times the anticipated dose. One can visualize an elderly 90 lb lady, with decreased renal function, who is administered a racemic drug. She receives the normal dose calculated for a 150 lb person (because of the way the tablets are made up). Because of decreased renal function and increased retention there is time for all the (i ) enantiomer to be converted to the (S) enantiomer. Effectively, she will receive three times the needed dose of the active drug and the area under the dose—time curve will be much greater. It is hardly surprising that adverse side effects sometimes occur.99... 

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