Physical Characterization of Anhydrous and Hydrous Forms of the Hydrochloride Salt of BVT.5182 A Novel 5-HT6 Receptor Antagonist

ABSTRACT

The physicochemical properties of 1-benzenesulfonyl-4-(piperazin-1-yl)-indole hydrochloride, a novel 5-HT₆ receptor antagonist for the treatment of obesity were characterized. Two solid state forms were identified at ambient conditions (23°C): an anhydrate form (1) and a hydrate form (2), with 1.5 moles of H₂O. The latter easily dehydrates and rehydrates without affecting the crystal morphology. Investigations of the propensity for interconversion between the two forms reveal that a) conversion of 2→1 takes place above 145°C and that b) conversion of 1→2 only occurs after crystallization from supersaturated aqueous solutions at a water activity ≥0.94 or in the presence of comparable amounts of crystals of 2 in water at ambient conditions. However, in an equimolar suspension of 1 and 2 at 37°C no phase transformation was observed. Thus, the difference in chemical potential between the two forms is small. Form 1 was shown to have overall favorable solid state properties and, hence, considered the preferred form for continued pharmaceutical development. The characterization was performed by means of light microscopy, scanning electron microscopy, powder X-ray diffraction, FTIR/NIR-spectroscopy, differential scanning calorimetry, hot stage microscopy, thermogravimetry, dynamic vapor sorption, Karl Fischer water content determination, phase stability studies of suspensions, solubility, and intrinsic dissolution rate measurements.