High solubility crystalline hydrates of Na and K furosemide salts

Abstract

Novel sodium and potassium salts of the poorly soluble loop diuretic drug furosemide were prepared with the intent of improving drug solubility and bioavailability. Furo-Na salt was obtained as a trihydrate upon crystallization from aqueous NaOH solution, and furo-K salt crystallized as a monohydrate from KOH solution. Both salt hydrates were characterized by X-ray diffraction, DSC, TGA, and IR spectroscopy. An exothermic phase transition at 165 °C in the DSC heating curve of the furo-Na salt indicates the likelihood of polymorphism in its anhydrate phase. Based on solubility studies, furo-Na-trihydrate and furo-K-monohydrate in pH 7 phosphate buffer medium exhibited significantly higher aqueous solubilities of 41 mg mL-1 and 106 mg mL-1 compared to the free drug (0.01 mg mL-1). The physical stability of these fast dissolving salts under accelerated ICH conditions of 40 °C and 75% RH was modest, with furo-Na salt being stable for 2 weeks and furo-K salt for 1 week. © 2014 the Partner Organisations 2014.