Strong Hydrogen Bond Leads to a Fifth Crystalline Form and Polymorphism of Clonixin

Over 30 years since the discovery of four crystal forms (I, II, III and IV) of Clonixin [2-(3-chloro-2-methyl-phenylamino)-nicotinic acid], a fifth form, a dimethylformamide (DMF) solvate, has been obtained by crystal growth in DMF. The new form was characterized by single-crystal X-ray diffraction, FT-IR, and Raman spectroscopy. The crystal structure is stabilized by the strong hydrogen bond between the carboxylic acid OH and the DMF carbonyl whose strength is on par with those of the four solvent-free forms, which are based on either the acid-acid homosynthon or the acid-pyridine heterosynthon, depending on the dihedral angle between the two aromatic rings. This solvate loses DMF to convert into form I, as confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Other aspects of this polymorphic/solvatomorphic system were investigated both experimentally and theoretically. Theoretical studies such as lattice energy calculation, hydrogen-bond strength estimation and Hirshfeld analysis were performed, providing further insight into the polymorphism/solvatomorphism of this system. Based on the analysis of the new form and the whole system, more solvates/cocrystals could be designed and unveiled in due time.