Racemic drug

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 selectivity of another cellulose-based CSP, Chiralcel OJ, has also been examined in SFC [60]. Separations of racemic drugs such as benoxaprofen, temazepam, and mephobarbital were obtained. Acetonitrile proved to be a better modifier than methanol for some of the compounds investigated. The four optical isomers of a calcium channel blocker were resolved by Siret et al. on the Chiralcel OJ CSP [30]. In LC, two CSPs were required to perform the same separation. 

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. 

Relatively selective stimulation of Pi-adrenergic receptors can be achieved with dobutamine. This is a racemic drug of which both isomers activate the Pi-receptor, and in addition the (-) isomer activates ( -receptors whereas the (+) isomer activates p2-receptors the simultaneous activation of ai- and p2-receptors results in no major net effect on peripheral resistance, and thus the overall cardiovascular effects are mediated by Pi-stimulation leading to increases in cardiac contractility and output. Dobutamine is used for the short-term treatment of acute cardiac failure and for diagnostic purposes in stress echocardiography. 

Mixing the additive in the eluent used as a mobile phase can also modify the chromatographic system (dynamic modification), but the use of modified adsorbents has led to an improvement of resolution. Example works include that by Armstrong and Zhou [11], who used a macrocyclic antibiotic as the chiral selector for enantiomeric separations of acids, racemic drugs, and dansyl amino acid on biphenyl-bonded silica. 

Which bioequivalence study for racemic drug , Eur. J. Drug Metab. Pharmacokinet., 23, 166 (1998). 

Okamoto et al [85] performed the optical resolution of primaquine and other racemic drugs by high performance liquid chromatography using cellulose and amylose tris-(phenylcarbamate) derivatives as chiral stationary phases. Primaquine and other compounds were effectively resolved by cellulose and/or amylose derivatives having substituents such as methyl, tertiary butyl, or halogen, on the phenyl groups. 

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... 

Finally, it is important to remember that, in case of racemic drugs, it is important to resort to stereoselective methods to detect possible differences in the actions of the test compounds at the desired target and hERG channels. For instance, a recent study detected differences between (R)- and (S)-methadone [115]. 

Aboul-Enein, H.Y and Ali, I., Optimization strategies for HPLC enantioseparation of racemic drugs using polysaccharides and macrocyclic antibiotic chiral stationary phases, II Farmaco, 57, 513, 2002. 

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. 

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