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-β-CD and sulfated-α-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 cyclodextrins (β-CD, methyl- β-CD, or hydroxypropylated-β-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 H9 borne by the chiral carbon has proven the presence of an imine–enamine tautomerism.

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