Solid-state form screen of cardiosulfa and its analogues.

Cardiosulfa is a biologically active sulfonamide molecule that was recently shown to induce abnormal heart development in zebrafish embryos through activation of the aryl hydrocarbon receptor (AhR). The present report is a systematic study of solid-state forms of cardiosulfa and its biologically active analogues that belong to the N-(9-ethyl-9H-carbazol-3-yl)benzene sulfonamide skeleton. Cardiosulfa (molecule 1; R(1) = NO2, R(2) = H, R(3) = CF3), molecule 2 (H, H, CF3), molecule 3 (CF3, H, H), molecule 4 (NO2, H, H), molecule 5 (H, CF3, H), and molecule 6 (H, H, H) were synthesized and subjected to a polymorph search and solid-state form characterization by X-ray diffraction, differential scanning calorimetry (DSC), variable-temperature powder X-ray diffraction (VT-PXRD), FTIR, and solid-state (ss) NMR spectroscopy. Molecule 1 was obtained in a single-crystalline modification that is sustained by N-H⋅⋅⋅π and C-H⋅⋅⋅O interactions but devoid of strong intermolecular N-H⋅⋅⋅O hydrogen bonds. Molecule 2 displayed a N-H⋅⋅⋅O catemer C(4) chain in form I, whereas a second polymorph was characterized by PXRD. The dimorphs of molecule 3 contain N-H⋅⋅⋅π and C-H⋅⋅⋅O interactions but no N-H⋅⋅⋅O bonds. Molecule 4 is trimorphic with N-H⋅⋅⋅O catemer in form I, and N-H⋅⋅⋅π and C-H⋅⋅⋅O interactions in form II, and a third polymorph was characterized by PXRD. Both polymorphs of molecule 5 contain the N-H⋅⋅⋅O catemer C(4) chain, whereas the sulfonamide N-H⋅⋅⋅O dimer synthon R2(2)(8) was observed in polymorphs of 6. Differences in the strong and weak hydrogen-bond motifs were correlated with the substituent groups, and the solubility and dissolution rates were correlated with the conformation in the crystal structure of 1-6. Higher solubility compounds, such as 2 (10.5 mg mL(-1)) and 5 (4.4 mg mL(-1)), adopt a twisted confirmation, whereas less-soluble 1 (0.9 mg mL(-1)) is nearly planar. This study provides practical guides for functional-group modification of drug lead compounds for solubility optimization.