Polymorphs and Cocrystals of Nalidixic Acid

Only one X-ray crystal structure of the parent quinolone antibiotic nalidixic acid is known in the published and patent literature. A systematic search for new solid-state forms of the drug yielded two polymorphs (forms II and III) and six cocrystals with resorcinol, catechol, hydroquinone, pyrogallol, orcinol, and phloroglucinol. Of these, X-ray crystal structures were determined for polymorph II and cocrystals with resorcinol, catechol, hydroquinone, and pyrogallol, whereas the remaining solid forms were identified by their unique powder X-ray diffraction patterns. Nalidixic acid is intramolecularly O-H center dot center dot center dot O hydrogen bonded in a six-member ring, and its molecular dimers are assembled via C-H center dot center dot center dot O synthon. The OH donors on phenolic coformers H bond with the a-keto acid moiety of the drug as connectors and spacers. Intermolecular drug drug C-H center dot center dot center dot O interactions in polymorphs are replaced by strong drug-coformer O-H center dot center dot center dot O hydrogen bonds in cocrystals.