Preparation of Amorphous and Polymorph Piretanide and Their Physicochemical Properties and Solubilities

Abstract

We prepared piretanide polymorphs by a new recrystallization procedure maximizing the solubility difference based on the pH difference of the solution. A new polymorph, form C, was formed at an acid-base molar ratio of ≥1 : 1, and amorphous form at <0.975 : 1. At the molar ratio of HCl being 0.975-1, a mixture of form C and the amorphous form was generated. By X-ray powder diffractometry, the amorphous form showed no diffraction peak, and form C was significantly different from forms A (bulk material, BM) and B (polymorph). FT-IR spectra of form C and the amorphous form were significantly different from those of forms A and B at around 1700 and 3200-3400 cm^-1. The DSC curve of the amorphous form showed exothermic peaks at 136 and 209°C and endothermic peaks at 207 and 225°C (corresponding to the melting point of BM), whereas that of form C showed an exothermic peak at 143°C and endothermic peaks at 132 and 224°C (corresponding to the melting point of BM). By the dispersed amount method, the solubilities of the amorphous form and form C were almost the same as that of form B and 2.0- and 1.4-fold higher than that of form A (8.3mg/100ml) in JPXII first fluid (pH 1.2) and were about 4.5-fold higher than those of forms A and B (about 200mg/100ml) in JPXII second fluid (pH 6.8) at 37°C.