Solid-state form screen of cardiosulfa and its analogues

Area of Science:

• Medicinal Chemistry
• Solid-State Chemistry
• Pharmacology

Background:

• Cardiosulfa, a sulfonamide, induces abnormal heart development in zebrafish embryos via aryl hydrocarbon receptor (AhR) activation.
• The N-(9-ethyl-9H-carbazol-3-yl)benzene sulfonamide skeleton forms the basis of cardiosulfa and its analogues.
• Solid-state properties significantly impact drug solubility and bioavailability.

Purpose of the Study:

• To systematically investigate the solid-state forms (polymorphs) of cardiosulfa and six related analogues.
• To characterize the crystal structures and intermolecular interactions of these compounds.
• To correlate solid-state properties with solubility and dissolution rates for drug optimization.

Main Methods:

• Synthesis of six N-(9-ethyl-9H-carbazol-3-yl)benzene sulfonamide analogues.
• Polymorph screening and solid-state characterization using X-ray diffraction (XRD), differential scanning calorimetry (DSC), and spectroscopy (FTIR, ssNMR).
• Variable-temperature powder X-ray diffraction (VT-PXRD) was employed for thermal stability studies.

Main Results:

• Multiple polymorphs were identified for molecules 2, 3, 4, 5, and 6, with varying hydrogen bonding motifs (N-H⋅⋅⋅π, C-H⋅⋅⋅O, N-H⋅⋅⋅O).
• Molecule 1 exhibited a single crystalline form stabilized by N-H⋅⋅⋅π and C-H⋅⋅⋅O interactions.
• Higher solubility was observed for compounds with twisted crystal conformations (e.g., molecules 2 and 5), while planar conformations (e.g., molecule 1) showed lower solubility.

Conclusions:

• Substituent groups significantly influence the strong and weak hydrogen-bond motifs in the crystal structures.
• Crystal conformation is directly correlated with solubility and dissolution rates.
• This research provides a framework for modifying drug lead compounds to enhance solubility.