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···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.

已发表文献及专利文献中，仅报道过1种母体喹诺酮类（quinolone）抗生素萘啶酸（nalidixic acid）的X射线晶体结构。本研究通过系统性筛选该药物的新型固态形式，成功获得2种多晶型（Ⅱ型与Ⅲ型），以及与间苯二酚（resorcinol）、邻苯二酚（catechol）、对苯二酚（hydroquinone）、连苯三酚（pyrogallol）、苔黑酚（orcinol）和间苯三酚（phloroglucinol）形成的6种共晶。其中，多晶型Ⅱ以及与间苯二酚、邻苯二酚、对苯二酚、连苯三酚形成的共晶的X射线晶体结构已被解析测定；其余固态形式则通过其特征性粉末X射线衍射（powder X-ray diffraction）图谱完成鉴定。萘啶酸分子内存在六元环结构的O–H···O氢键作用，其分子二聚体通过C–H···O超分子合成子（synthon）组装而成。酚类共晶形成剂（coformer）上的OH供体与该药物的α-酮酸部分形成氢键，充当连接基与间隔基。多晶型中存在的分子间药物-药物C–H···O相互作用，在共晶中被强度更高的药物-共晶形成剂O–H···O氢键所取代。