Comparison of the crystal structures and thermochemistry of a novel soluble guanylate cyclase stimulator riociguat and its solvates.

Riociguat (Rio) is the first oral soluble guanylate cyclase stimulator to be approved for pulmonary arterial hypertension. In this study, form (II) of riociguat and three solvates with acetonitrile [form (III)], N,N-dimethylformamide [form (IV)] and ethyl acetate [form (V)] were crystallized. They were identified and characterized by differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction, and their crystal structures were determined by single-crystal X-ray diffraction. No crystal structure has previously been reported for the known form (II) of riociguat. Crystal structure determination of Rio and its new solvates revealed that the dimeric R2 2 (14) motif is common in both structures. The crystal packing of solvates adopts channel-like patterns, whereas form (II) of riociguat adopts sheet-like patterns. Strong π-π interactions exist in the above four forms. The conformation of the riociguat in one molecule of 0.5-DMF solvate was found to be significantly different from the conformations found in the other solvates. Desolvation of the three solvates was studied by thermogravimetric analysis and X-ray diffraction, and was shown to transform them into form (I) of riociguat.