Crystal forms of torasemide: New insights

Crystallization from various organic solvents results in three crystal forms of torasemide: monotropically related mod. I (melting point, 158-161°C) and mod. II (melting point, 155-158°C), as well as a pseudopolymorphic crystal form (form A, channel inclusion compound with 1.9-4.2% water and alcohol). Physicochemical properties were determined by thermoanalysis (hot-stage microscopy, differential scanning calorimetry, thermogravimetry), Fourier transform infra-red and Raman spectroscopy, and X-ray powder diffractometry. The hygroscopicity, relative stability, true density, and heat of solutions were determined, respectively. The dissolution behaviour of mod. I and II was investigated as a function of pH, temperature, and in addition to surfactants. Mod. II is nearly three times more soluble than mod. I (mod. I, 0.34 mmol l^-1; mod. II, 0.93 mmol l^-1 at 20°C, pH 4.90) and proved to be highly kinetically stable. By crystallization from 1-butanol, a new compound was synthesized, which was identified as [[4-[(3-Methylphenyl)amino]-3-pyridinyl]sulfonyl]-carbamic acid, butyl ester (TOBC). The most important properties of this torasemide derivative are given. The present results give a thorough physicochemical characterization of the crystal forms of torasemide. They clearly indicate a mistaken identity of mod. II with crystal form A in formerly published articles.