Polymorphism in the Anti-inflammatory Drug Flunixin and Its Relationship with Clonixin

Crystallization of the nonsteroidal anti-inflammatory drug (NSAID) flunixin in acetone and in acetone–hexane produced two conformational polymorphs, as predicted by hydrogen-bond propensity analyses, which are similar to three of the polymorphs of the related NSAID clonixin. The two polymorphs of flunixin display an intramolecular hydrogen bond between the amine N–H and the carbonyl oxygen of the carboxylic group. However, the intermolecular hydrogen-bond pattern of Form I (crystallized from acetone) is characterized by the acid–pyridine heterosynthon, while Form II (from acetone-hexane) displays the acid–acid homosynthon. Form I of flunixin is similar to form I of clonixin, while form II of flunixin is related to forms III and IV of clonixin. Hirshfeld surface maps were used to show the differences in the interactions present in the two flunixin polymorphs and the similarities with the polymorphs of the related compound clonixin. Energy framework calculations corroborate the similarity between Form I of flunixin and clonixin and indicate that Form II of flunixin is more closely related to Form IV of clonixin than to Form III.