Furosemide Cocrystals:
Structures, Hydrogen Bonding,
and Implications for Properties
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Abstract
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 <i>p</i>-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 <i>p</i>-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