Chiral interconversion monitoring of a drug candidate by supercritical fluid chromatography (SFC)

Stereoisomer interconversion of chiral drug substances is of significant importance if it occurs within pharmacological and pharmaceutical time scales and under physiological and shelf life conditions. Several analytical techniques exist for the determination of first order rate constants and enantiomerization energy barriers by dynamic and stopped flow chromatography, mathematical models and functions, and computer programs. The focus of this work is to utilize a simple supercritical fluid chromatography (SFC) chiral assay to determine the possibility of interconversion of the desired R and less active S isomers of a drug candidate. The rate constants of racemization and enantiomerization, the half life of racemization, and enantiomerization energy barriers were determined for the R -> S (or, forward) and S -> R (or, reverse) conversions. The method was selective and sensitive enough to detect less than 1% interconversion occuring under the conditions studied. The method also demonstrated that R reversible arrow S racemization was possible only under extreme conditions of prolonged heating (80 degrees C) and highly basic pH (9.5). (C) 2009 Elsevier B.V. All rights reserved.