Chiral drugs difference between enantiomers

Polymorphism and pseudopolymorphism are known among chiral drugs. Whereas the enantiomers of chiral drugs may display ordinary polymorphism, the racemic species show a special type of polymorphism, namely conversion between the different types of racemate. For example, racemic sodium ibuprofen exhibits three polymorphs, the stable polymorph at room temperature being the conglomerate while the other two polymorphs, which are racemic compounds, are obtained by rapidly cooling the melt of the conglomerate [21]. 

Ethotoin (3-ethyl-5-phenylhydantoin) is a chiral anticonvulsant drug with utility in generalized tonic-clonic and complex partial seizures. In six healthy volunteers given single 1 g oral doses, the only significant difference between enantiomers was in the AUC, which was 580 and 510 pg x h/mL for the R(—) and S(-l-) enantiomers, respectively [166]. 

It is nowadays a truism (but therefore also true) to say that life is a chiral process. The implication for the subject of this book is that those pharmaceutical compounds that contain one or more chiral centers could weU show differences between enantiomers with respect to their efficacy. Since most pharmaceutical drugs are administered as race-mates, it is sometimes important in drug development to be able to track the enantiomers separately, and this presents a significant challenge to the analyst in addition to the usual demands of validation and GLP etc. Since mass spectrometry can not in general distinguish between enantiomers, the chiral selectivity must be provided by chromatographic separation (Section 4.4.Id). 

If the only difference between enantiomers was in their rotation of plane-polarised light, the whole area of asymmetric synthesis would be relegated to little more than a scientific curiosity. That this is not so is because the world around us is chiral and most of the important building-blocks which make up the biological macromolecules of living systems do so in one enantiomeric form only. When, therefore, a biologically active chiral compound, such as a g, interacts with its receptor site which is chiral, it should come as no surprise that the two enantiomers of the drug interact differently and may lead to different effects. 

In another study, the authors reported a comparative study of the enantiomeric resolution of miconazole and the other two chiral drugs by high performance liquid chromatography on various cellulose chiral columns in the normal phase mode [79], The chiral resolution of the three drugs on the columns containing different cellulose derivatives namely Chiralcel OD, OJ, OB, OK, OC, and OE in normal phase mode was described. The mobile phase used was hexane-isopropanol-diethylamine (425 74 1). The flow rates of the mobile phase used were 0.5, 1, and 1.5 mL/min. The values of the separation factor (a) of the resolved enantiomers of econazole, miconazole, and sulconazole on chiral phases were ranged from 1.07 to 2.5 while the values of resolution factors (Rs) varied from 0.17 to 3.9. The chiral recognition mechanisms between the analytes and the chiral selectors are discussed. 

At the cellular level, the various types of receptor, transporter, enzyme and ion charmel are all chiral in form. Thus although the enantiomers of a drug may have identical physicochemical properties, the way in which they may interact with chiral targets at the level of the cell will give rise to different pharmacod)mamic and pharmacokinetic properties. A few simple examples will illustrate how taste and olfactory receptors can differentiate between enantiomers. Thus R-carvone tastes like spearmint whereas the S-isomer tastes like caraway. Similarly, R-limolene smells like lemon whereas the S-enantiomer tastes of orange. 

Paroxetine and sertraline are chiral drugs as well, but only one enantiomer form of each has been marketed. Fluvoxamine is notably different in that it is achiral (Baumann, 1996). Table 22.2 summarizes active metabolites and elimination half-lives of each SSRI. Much of this information does not distinguish between the different enantiomer forms of each drug. 

The important anticoagulant drug warfarin is chiral and is administered cimically as the racemic mixture. Significant pharmacodynamic and pharmacokinetic differences between the enantiomers have generated considerable interest in the stereochemical aspects of this drug (145),... 

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. 

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