Chirality/Chiral drugs

A much more serious drawback to using chiral drugs as racemic mixtures is illustrated by thalidomide briefly employed as a sedative and antinausea drug in Europe during the period 1959-1962 The desired properties are those of (/ ) thalidomide (S) Thalido mide however has a very different spectrum of bio logical activity and was shown to be responsible for over 2000 cases of serious birth defects in children born to women who took it while pregnant... 

High yields of the enantiomerically pure alcohol and enantiomerically pure ester are reg ularly achieved The growing interest m chiral drugs (see the boxed essay on this topic p 296) has stimulated the development of large scale enzymatic resolution as a com mercial process... 

Organic chemists often use enantiomencally homogeneous starting materials for the synthe SIS of complex molecules (see Chiral Drugs p 296) A novel preparation of the S enantiomer of compound B has been descnbed using a bacterial cyclohexanone monooxygenase enzyme system... 

Asymmetric synthesis is a stimulating academic challenge, but since it has become clear that most chiral drugs can be administered safely only in the enantiomerically pure form, the industrial need for asymmetric methods has made research in asymmetric synthesis absolutely necessary [5]. This has driven a renaissance in the discipline of organic chemistry, because all of the old-established reactions need to be reinvestigated for their application in asymmetric synthesis [6]. This has also applied... 

E. R. Francotte and R Richeit, Applications of simulated moving-bed cliromatography to the separation of the enantiomers of chiral drugs , ]. Chromatogr. 769 101-107 (1997). 

When chiral, drugs and other molecules obtained from natural sources or by semisynthesis usually contain one of the possible enantiomeric forms. However, those obtained by total synthesis often consist of mixtures of both enantiomers. In order to develop commercially the isolated enantiomers, two alternative approaches can be considered (i) enantioselective synthesis of the desired enantiomer or (ii) separation of both isomers from a racemic mixture. The separation can be performed on the target molecule or on one of its chemical precursors obtained from conventional synthetic procedures. Both strategies have their advantages and drawbacks. 

The availability of a new class of efficient separations technology for chiral drugs can have an impact on other business issues now at the forefront of the pharmaceutical industry. For example, the strategy of better drug life cycle management can be... 

Cavoy E., Deltent M. E, Lehoucq S., Miggiano D. (1997) Laboratory-Developed Simulated Moving Bed for Chiral Drug Separations. Design of the System and Separation of Tramadol Enantiomers, J. Chrotnatogr. A 769 49-57. 

Erancotte E., Richert P. (1997) Applications of Simulated Moving-Bed Chromatography to the Separation of the Enantiomers of Chiral Drugs, J. Chrotnatogr. A 769 101-107. 

In November 1997, the Department of Health and Human Services along with the International Conference on Harmonisation (ICH) released a draft guidance for the selection of test procedures, which included chiral drugs. For the development of an enantiopure drug substance, acceptable criteria shall include, if possible, an enan-tioselective assay. This assay should be part of the specification for the identification of an enantiopure drug substance and related enantioenriched impurities [16]. 

The Japanese regulatory authority is the Ministry of Health and Welfare (MHW) and the Pharmaceutical and Medical Safety Bureau (PSMB) is responsible for the promulgation of national and international guidelines in the form of Notifications. Guidelines are available on the Internet web-site of the National Institute of Health and Science (http //www.nihs.go.jp). The MHW has not issued specific guidance on the development of chiral drugs, but has nonetheless responded to the enantiomer-versus-racemate scientific debate. The attitude of the MHW and its advisory body, the Central Pharmaceutical Affairs Council (CPAC) is discussed in two articles by Shindo and Caldwell published in 1991 and 1995 [17, 18]. The latter paper analyzes the results of a survey of the Japanese pharmaceutical industry which sought responses on chirality issues. 

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