Racemization,enantiomerization, diastereomerization,and epimerization: Their meaning and pharmacological significance

The configurational lability of enantiomers can be characterized by different terms, each defining a specific process. Racemization relates to the macroscopic and statistical process of the irreversible transformation of one of the enantiomers into the racemic mixture. Enantiomerization refers to the microscopic and molecule process of the reversible conversion of one enantiomer into the other. Methods allowing the experimental determination of rate constants of racemization (k_rac) and enantiomerization (k_enant) are discussed, and it is shown that k_enant = 1/2 k_rac. Neglect of this fact is a source of some confusion in the literature. When two or more elements of chirality are present in a molecule and one of them is configurationally labile, epimerization occurs, a particular case of diastereomerization. These processes of interconversion between diastereomers are kinetically more complicated than racemization and enantiomerization since the rate constants of the forward and reverse reactions are always different (k_diast/A-to-B ≠ k_diast/B-to-A), however small the difference. An important aspect of the configurational lability of stereoisomeric drugs is the time scale of the phenomenon. When interconversion occurs to a significant extent during the residence time of a drug in the body, a pharmacological time scale is implied. In contrast, the pharmaceutical time scale refers to slower rates of interconversion that affect the configurational purity of a drug during its shelf-life. © 1995 Wiley-Liss, Inc.