Polymorphs and a Hydrate of Furosemide–Nicotinamide 1:1 Cocrystal

Abstract

Five anhydrous polymorphs (forms I–V) and one hydrate of furosemide–nicotinamide 1:1 cocrystal were discovered, and their solid-state properties were characterized using X-ray powder diffraction and differential scanning calorimetry. The crystal structures of forms I–IV were determined from the X-ray powder diffraction data and showed the structural differences between forms, which are mainly attributable to molecular conformations and supramolecular synthons. The slurry conversion experiments revealed that the order of thermodynamic stability of the polymorphs at 25 °C is I > III > II > V > IV. Dynamic vapor sorption analysis and X-ray single-crystal structure determination of the hydrate were conducted to study the dehydration mechanism. We observed structural similarities between the hydrate and its dehydrate, form IV, such as lattice parameters (except the a-axis length), synthons between furosemide and nicotinamide molecules, and the molecular conformation of furosemide; after dehydration, however, the a-axis contracted and nicotinamide molecules were displaced, along with the pyridine ring twisting.