Physicochemical characterization of neuroleptics. Relative stability of 7- and 9-hydroxyrisperidones and their protonated forms in gas phase and in solution.

Conventional ab initio and DFT-B3LYP calculations have been used to investigate on molecular conformation, dipole moments, intramolecular hydrogen bond and relative energies of 9-hydroxy and 7-hydroxyrisperidone metabolites of risperidone, in their neutral and mono-protonated forms in the gas phase and in solution. Three minimum energy conformations characterize the potential energy surface of 7-hydroxyrisperidone, while 9-hydroxyrisperidone is dominated by a strong intramolecular OH...N hydrogen bond of ca. 8 kcal/mol, which drastically reduces in water solution. In the gas phase, 9-hydroxyrisperidone is the most stable isomer both in the neutral and in the protonated forms. Solvent effects favour 7-hydroxyrisperidone rotamers owing to their higher dipole moment values. Under the physiological pH of 7.4, the protonated forms of both isomers in water coexist in almost equivalent amount, in qualitative agreement with the experiment. It is suggested that to stabilize the pharmacologically active 9-hydroxyrisperidone over the 7-OH isomer one has to increase its molecular dipole moment and the intramolecular OH...N hydrogen bond energy.