High solubility crystalline pharmaceutical forms of blonanserin

Abstract

Blonanserin (BLN) is an antipsychotic drug having poor aqueous solubility. In continuation of our preliminary work (CrystEngComm 2012, 14, 2367-2372), the aim of this study was to improve physicochemical properties of the drug, such as solubility, dissolution rate, and stability. Novel crystalline forms of BLN were obtained by liquid-assisted grinding with pharmaceutically acceptable coformers such as succinic acid (SUC), suberic acid (SBA), nicotinic acid (NIA), methanesulfonic acid (MSA), and toluenesulfonic acid (TsOH). Four salts of blonanerin [BLNH+-SUC- (1:1), BLNH+-NIA - (1:1), BLNH+-TsO- (1:1), and BLNH +-MSA- (1:1)], a salt hydrate BLNH+-MSA --H2O (1:1:1), and a cocrystal BLN-SBA (1:0.5) are reported in this paper. All multicomponent phases were characterized by IR, Raman, and 13C ss-NMR spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD), and their structures were confirmed by single crystal X-ray diffraction. The crystal structures are sustained by ionic N+-H⋯O- H-bonds except in the BLN-SBA cocrystal, which has a neutral COOH⋯N(tertiary amine) H-bond. These novel salts exhibited a faster intrinsic dissolution rate (IDR) compared to the parent drug BLN, and they exhibited good stability (2 months) under accelerated ICH conditions of 75% RH at 40°C, except BLN+-MSA- anhydrate. The BLNH+-MSA--H2O salt hydrate exhibited the highest solubility (464 times) and dissolution rate (126 times) in 60% EtOH-water medium together with good stability. © 2014 American Chemical Society.