Physical characterization of anhydrous and hydrous forms of the hydrochloride salt of BVT.5182 a novel 5-HT(6) receptor antagonist.
The physicochemical properties of 1-benzenesulfonyl-4-(piperazin-1-yl)-indole hydrochloride, a novel 5-HT(6) receptor antagonist for the treatment of obesity were characterized. Two solid state forms were identified at ambient conditions (23 degrees C): an anhydrate form (1) and a hydrate form (2), with 1.5 moles of H(2)O. 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 degrees C and that b) conversion of 1-->2 only occurs after crystallization from supersaturated aqueous solutions at a water activity >or=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 degrees 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.
Hugerth
Andreas
A
Biovitrum AB, Preclinical R&D, Pharmaceutics, SE-112 76, Stockholm, Sweden. andreas.hugerth@pfizer.com
Brisander
Magnus
M
Wrange
Ulla
U
Kritikos
Mikael
M
Norrlind
Björn
B
Svensson
Marianne
M
Bisrat
Mikael
M
Ostelius
Jan
J
D019440:Anti-Obesity Agents / Q000737:chemistry*; D002623:Chemistry Techniques, Analytical; D004355:Drug Stability; D007211:Indoles / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry*; D058829:Serotonin 5-HT1 Receptor Antagonists; D012995:Solubility; D014867:Water / Q000737:chemistry
D019440:Anti-Obesity Agents; C511767:BVT.5182; D007211:Indoles; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D014867:Water