Furosemide Cocrystals: Structures, Hydrogen Bonding, and Implications for Properties

In this paper, we report the crystal growth of four cocrystals of furosemide (4-chloro-2-[(2-furanylmethyl)amino]-5-sulfamoylbenzoic acid), a loop diuretic drug used for the treatment of hypertension and edemas, prepared with p-aminobenzoic acid, nicotinamide, and isonicotinamide as coformers. We present four new crystal structures and elucidate the intermolecular interactions present in the cocrystals. The structures display interesting supramolecular chemistry: a number of different synthons, as well as short strong hydrogen bonds with partial proton transfer and indications of proton disorder. Using powder X-ray diffraction, solid state NMR, and thermal analysis, we provide evidence for the preparation of bulk samples of two compositions, namely, the 1:1 cocrystal of furosemide and p-aminobenzoic acid and 2:1 cocrystal of furosemide and isonicotinamide, highlighting the general necessity of such multitechnique approaches to characterize organic solids (including cocrystals and solvates) prepared by grinding methods. Finally, we correlate the structural features reported for the first time in this work with the previously published pharmacologically relevant properties (solubility and intrinsic dissolution rate) of the furosemide cocrystals.