Solid‐State Form Screen of Cardiosulfa and Its Analogues |
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Authors: | S Sudalai Kumar Dr Soumendra Rana Prof?Dr Ashwini Nangia |
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Institution: | School of Chemistry, University of Hyderabad, Central University PO, Prof. C. R. Rao Road, Gachibowli, Hyderabad 500 046 (India) |
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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, R2=H, R3=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 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. |
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Keywords: | cardiosulfa drug delivery molecular conformation polymorphism X‐ray diffraction |
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