Solid-state form screen of cardiosulfa and its analogues

Abstract

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; R1=NO2, R 2=H, R3=CF3), molecule 2 (H, H, CF 3), 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 R22(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, 2, 3, 4, 5, 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. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.