Configurational stability of 9-hydroxyrisperidone. Kinetics and mechanism of racemization

The Configurational stability of 9-hydroxyrisperidone, an atypical antipsychotic, was studied under acidic, basic and physiological conditions. The analysis of 9-hydroxyrisperidone was performed using a recently validated chiral capillary electrophoretic method developed using a dual cyclodextrin mode (hydroxypropylated-beta-CD and sulfated-alpha-CD). The kinetic parameters (rate constants, half-lives, and apparent free energy barriers) of the racemization were calculated through a mathematical model of the first-order reaction. The influences of the pH, the temperature, the nature and the concentration of the buffer, and the presence of an organic co-solvent were investigated. The fastest racemizations were observed under acidic conditions with high phosphate buffer concentrations and high temperatures. Under these conditions, the cycloclextrins (beta-CD, methyl-beta-CD, or hydreoxypropulated-beta-CD) added to both enantiomers in various molar ratios were not able to retard the racemization. Finally, the mechanism of racemization was investigated using nuclear magnetic resonance (NMR) and the proton-deuterium exchange of the proton H-9 borne by the chiral carbon has proven the presence of an imine-enamine tautomerism. (C) 2009 Elsevier Ltd. All rights reserved.