Racemates or enantiomers

The question now arises to decide when and why to use rather racemic mixtures or pure enantiomers. Although it seans good sense to use pure eutomers and to consider the distomer as an unwanted load of xenobiotic (a kind of pollution, or even an impurity) there are however instances whwe it is recommended to use racemates rather then eutomers. 

Thus racemates may be more stable, more active or less toxic or present a favorable combination of the properties of each separate isomer (see below). Finally one can ask if it would not be wise to design effective drugs without centers of asymmetry. 

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These situations are treated as completely new applications which should include an explanation of the decision to develop the enantiomer or racemate. Data on the existing racemate or enantiomer may be included where appropriate with bridging studies as necessary. 

Active Ingredient. An application for a change in an active ingredient such as a different salt, ester, complex, chelate, clathrate, racemate, or enantiomer of an active ingredient in a listed drug containing the same active moiety. 

D. ]. Biikett, "Racemates or enantiomers Regulatory approaches," Clin. Exp. Pharnmcd. Physiol., 16 479-483 (1989). 

VI. RACEMATE OR ENANTIOMER FACTORS TO CONSIDER DURING DRUG DEVELOPMENT... 

Table 4 Racemate or Enantiomer Factors to Consider During Drug Development...

A. Stereoselectivity in biologi- B. Differences in the phar- A. Racemates or enantiomers ... 

Vapor Pressure. Differences in vapor pressure (i.e., in the heat of sublimation [Ai/subiim]) have been observed for enantiomers and racemates. It has been suggested that heterochiral interactions between solid enantiomers (as in a racemic compound) can be either stronger or weaker than the homochiral interactions, i.e., between the crystals of the 1 1 mechanical mixture [32]. These interactions have not been widely investigated in pharmaceutical formulations containing racemates or enantiomers. The difference in A/fsubiim can also be used to separate enantiomers from a mixture, and it is thought to be a better method of separation, at least in some cases, than recrystallization. 

Birkett, D.J. Racemates or enantiomers regulatory approaches. Clin. Exp. Pharmacol. Physiol. 1989,16, 479-483. 

For case I and II, one may consider developing a racemate or enantiomer. However, for case II, if PK is significantly enantioselective, one may consider developing the enantiomer that is more bioavailable, so that a lower dose may be needed. For case III, if safety is not an issue, that is, efficacy is greater in one compared to the other enantiomer, but toxicity is not a problem, one may eonsider developing either a racemate or enantiomer. For case IV, developing the enantiomer with most beneficial PD is more appropriate, especially if safety is the concern. 

This operation is not suitable for molecules whose racemate or enantiomer is not available. If available, the measurement of a pair of enantiomers would assure the reproducibility of observed chiroptical phenomenon if the resultant spectra are in a mirror-image relationship. 

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