Furosemide - isonicotinamide cocrystals: An investigation of properties and structural disorder

Abstract from article: Furosemide is a loop diuretic drug marketed in solid form which suffers from low solubility and low permeability. The pharmaceutically relevant properties of a recently described furosemide-isonicotinamide 2:1 cocrystal (2FS-INA) were investigated and compared with those of other known furosemide cocrystals. The intrinsic dissolution rate of 2FS-INA was found to be 1.27 times that of the commercial FS, while the equilibrium solubility of 2FS-INA is 5.6 times higher than that of pure FS. The extensive structural disorder in 2FS-INA observed by diffraction methods was also investigated by variable-temperature solid-state NMR in conjunction with first principles calculations. 15N NMR confirmed the absence of proton disorder in the short OH - - - Nhydrogen bond. The disordered sulphonamide group was found to be dynamic by variable temperature 2H experiments, involving fast exchange of the sulphonamide NH2 protons combined with a rotation of the whole sulphonamide group about the C-S bond with an activation parameter of Ea = 14.9 Å ± 0.6 kJ mol-1. The disorder of the furan rings of both the unique furosemide molecules was also found to be dynamic by 13C experiments, with the same activation barrier of about 23 kJ mol-1 for both rings.