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.

本论文报道了4种呋塞米（furosemide，化学名：4-氯-2-[(2-呋喃甲基)氨基]-5-氨磺酰基苯甲酸）共晶体的晶体生长过程；呋塞米是一种用于治疗高血压与水肿的袢利尿剂类药物，本研究以对氨基苯甲酸、烟酰胺以及异烟酰胺作为共晶形成剂制备得到上述共晶体。本研究报道了4种全新的晶体结构，并阐明了各共晶体中的分子间相互作用。这些晶体结构展现出颇具研究价值的超分子化学特性：包含多种不同的超分子合成子，同时存在带有部分质子转移的短强氢键，以及质子无序的相关迹象。本研究借助粉末X射线衍射、固态核磁共振以及热分析技术，为两种配比的体相样品制备提供了佐证：分别为呋塞米与对氨基苯甲酸的1:1共晶体，以及呋塞米与异烟酰胺的2:1共晶体；该结果凸显了采用多技术联用手段表征研磨法制备的有机固体（包括共晶体与溶剂化物）的普遍必要性。最后，本研究将本工作首次报道的结构特征，与此前已发表的呋塞米共晶体的药理学相关性质（溶解度与固有溶出速率）进行了关联。