Polymorphs and Cocrystals of Nalidixic Acid

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.

Mechanochemical Assembly of Nalidixic Acid Bioinspired Metal–Organic Compounds and Complexes toward Improved Solubility

“…This quinolone antibiotic is used to treat urinary tract infections caused by some bacteria, and it is effective primarily against Gram-negative bacteria, with minor anti-Gram-positive activity. Nalidixic acid is known two exist in two polymorphic forms, − and also a few cocrystals with different parabens were reported. , …”

“…Nalidixic acid is known two exist in two polymorphic forms, 6−8 and also a few cocrystals with different parabens were reported. 6,9 Regarding metal complexes, some work has already been disclosed involving the coordination of nalidixic acid to Cu, Ru, Cd, Zn, and Pt. 10−17 None of these coordination compounds form frameworks, and, with exception of a Zn complex, they all involve a second organic ligand (Table 1).…”

Drug–Drug Multicomponent Crystals as an Effective Technique to Overcome Weaknesses in Parent Drugs

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 The preparation of multicomponent crystals, i.e., cocrystals, salts, solvates, and hydrates is a well-established technique for forming new phase(s) and altering the physicochemical properties of drug materials. [1][2][3][4][5][6][7][8][9] Interestingly, recent studies have investigated the potential of multicomponent crystals containing combinations of drugs. [10][11][12][13][14][15] This family of crystals, in addition to providing technological advantages, also offers improved pharmacological benefits and patient compliance.…”

New forms of old drugs: improving without changing

“…A new polymorphic form of adefovir dipivoxil association, used in the treatment of hepatitis C and herpes simplex virus infection, was recently disclosed [108]. Nalidixic acid is one of the earliest fluoroquinolone antibiotics used in the treatment of urinary tract infections, but only in 2012, a systematic search for new solid‐state forms was conducted to expose two new polymorphs (Forms II and III) [109]. A recent study reported the appearance and characterization of three new polymorphic forms of indomethacin, in addition to the four previously reported [110]…”