Physicochemical and biopharmaceutical characterization of endo-2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-1H-benz[e]isoindol-1-one (CR3124) a novel potent 5-HT3 receptor antagonist

The physicochemical and biopharmaceutical properties, such as pK a, crystal habit, water solubility, logD, molecular structure and dynamics, and membrane permeability of CR3124 (endo-2-(8-methyl-8-azabicyclo[3. 2.1]oct-3-yl)-2,3-dihydro-1H-benz[e]isoindol-1-one, a novel potent 5-HT 3 receptor antagonist) have been studied in order to obtain preformulation information. The study showed that CR3124 is a very rigid molecule in which conformational freedom due to the presence of a rotatable bond is restricted by the interaction between an activated hydrogen and the amide oxygen and the conformation of the tropane piperidine ring is regulated by the environment in such a manner as to optimize the intermodular interactions with the solvent. This chameleon behavior appears to be capable of explaining the biopharmaceutical properties showed by CR3124, such as low wettability, relatively good solubility, and very high membrane permeability. © 2006 Wiley-Liss, Inc.