Polymorphs and Cocrystals of Nalidixic Acid - Crystal Growth & Design

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Article pubs.acs.org/crystal

Polymorphs and Cocrystals of Nalidixic Acid Swarupa Gangavaram,† S. Raghavender,† Palash Sanphui,‡ Sharmistha Pal,*,§ Sulur G. Manjunatha,§ Sudhir Nambiar,§ and Ashwini Nangia*,†,‡ †

Technology Business Incubator, and ‡School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Central University PO, Gachibowli, Hyderabad 500 046, India § Pharmaceutical Development, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560 024, India S Supporting Information *

ABSTRACT: 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···O hydrogen bonded in a six-member ring, and its molecular dimers are assembled via C−H···O synthon. The OH donors on phenolic coformers H bond with the α-keto acid moiety of the drug as connectors and spacers. Intermolecular drug−drug C−H···O interactions in polymorphs are replaced by strong drug−coformer O−H···O hydrogen bonds in cocrystals.

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INTRODUCTION Nalidixic acid is one of the earliest quinolone antibiotics used in the treatment of urinary tract infections.1a The drug is effective against both Gram-positive and Gram-negative bacteria. It is the only FDA approved quinolone drug for pediatric formulation. The drug is insoluble in water at