Chirality in Drug Design and Development 第1章.pdf

1 Effects of Crystal Structure and Physical Properties on the Release of Chiral Drugs Chong-Hui Gu* and David J. W. Grant University of Minnesota, Minneapolis, Minnesota, U.S.A. 1. INTRODUCTION Chiral drugs are a subgroup of drug substances that contain one or more chiral centers. More than one-half of marketed drugs are chiral [1]. It is well established that the opposite enantiomer of a chiral drug often differs significantly in its pharmacological [2], toxicological [3], pharmacodynamic, and pharmacokinetic [4,5] properties. Therefore from the points of view of safety and efficacy, the pure enantiomer is preferred over the racemate in many marketed dosage forms. However, the chiral drug is often synthesized in the racemic form, and it is frequently costly to resolve the racemic mixture into the pure enantiomers. Currently, then, most chiral drugs, including some ‘‘blockbuster’’ drugs, such as fluoxetine hydrochloride (Prozac) and omeprazole (Losec), are still marketed as racemates. However, the recent trend is toward marketing more single-enantiomer drugs [6]. In addition, a ‘‘racemic switch,’’ which involves the development of a pure enantiomer of a drug that is already marketed as a racemate, is actively pursued by many companies to improve its therapeutic effiacy and to ex