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Solid‐State Form Screen of Cardiosulfa and Its Analogues
Author(s) -
Kumar S. Sudalai,
Rana Soumendra,
Nangia Ashwini
Publication year - 2013
Publication title -
chemistry – an asian journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 106
eISSN - 1861-471X
pISSN - 1861-4728
DOI - 10.1002/asia.201201162
Subject(s) - molecule , hydrogen bond , crystallography , powder diffraction , chemistry , differential scanning calorimetry , stereochemistry , intermolecular force , infrared spectroscopy , organic chemistry , physics , thermodynamics
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‐9 H ‐carbazol‐3‐yl)benzene sulfonamide skeleton. Cardiosulfa (molecule 1 ; R 1 =NO 2 , R 2 =H, R 3 =CF 3 ), molecule 2 (H, H, CF 3 ), molecule 3 (CF 3 , H, H), molecule 4 (NO 2 , H, H), molecule 5 (H, CF 3 , 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 NH⋅⋅⋅π and CH⋅⋅⋅O interactions but devoid of strong intermolecular NH⋅⋅⋅O hydrogen bonds. Molecule 2 displayed a NH⋅⋅⋅O catemer C (4) chain in form I, whereas a second polymorph was characterized by PXRD. The dimorphs of molecule 3 contain NH⋅⋅⋅π and CH⋅⋅⋅O interactions but no NH⋅⋅⋅O bonds. Molecule 4 is trimorphic with NH⋅⋅⋅O catemer in form I, and NH⋅⋅⋅π and CH⋅⋅⋅O interactions in form II, and a third polymorph was characterized by PXRD. Both polymorphs of molecule 5 contain the NH⋅⋅⋅O catemer C (4) chain, whereas the sulfonamide NH⋅⋅⋅O dimer synthon R 2 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 , 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.