Fluconazolium oxalate: synthesis and structural characterization of a highly soluble crystalline form

Author(s)

Dayo Owoyemi, Bolaji C. ^[1] ; da Silva, Cecilia C. P. ^[1] ; Diniz, Luan F. ^[2] ; Souza, Matheus S. ^[2] ; Ellena, Javier ^[2] ; Carneiro, Renato L. ^[1]

Affiliation

^[1] Fed Univ Sao Carlos UFSCar, Dept Chem, Rod Washington Luis Km 235, BR-13560905 Sao Carlos, SP - Brazil

^[2] Univ Sao Paulo, Inst Fis Sao Carlos, CP 369, BR-13560970 Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: CrystEngComm; v. 21, n. 7, p. 1114-1121, FEB 21 2019.
• Web of Science Citations: 3

Abstract

Fluconazole (FLZ) is one of the most used antifungal drugs worldwide and has been the focus of various investigations with the aim of enhancing its biomedical application. Most of the new solid forms achieved for this drug were determined by powder X-ray diffraction, and a few reports on polymorphs, solvates, cocrystals, and one salt-cocrystal by single-crystal X-ray diffraction (SCXRD) are available. By considering that FLZ is a very weak base (pK(a) = 1.76, when protonated), salt formation with this drug is expected with the use of very strong organic acids, in order to dislocate the proton from the acid to the FLZ. To the best of our knowledge, only one organic salt of FLZ with picric acid (pK(a) = 0.38) and one salt-cocrystal (maleate- maleic, pK(a)1 = 1.92) were reported by SCXRD until now. Having in mind all the advantages that pharmaceutical salts have in drug delivery, in this work we depict the methodology and techniques employed to synthesize a new salt of FLZ using oxalic acid (pK(a) 1 = 1.23). The screening process was initially monitored using Raman spectroscopy, while further characterization by X-ray diffraction (powder and single crystal) and thermal analysis (DSC and TG) was performed to confirm the new salt fluconazolium oxalate (1 : 1). Finally, salt equilibrium solubility studies confirmed an improvement, about 7-fold, when compared to the commercialized active pharmaceutical ingredient (polymorph II). In addition, this is the first reported GRAS (generally regarded as safe) salt of the antifungal drug fluconazole. (AU)

• FAPESP's process: 15/25694-0 - Obtaining, characterization and evaluation of novel crystalline solid forms of drugs used treatment of tuberculosis
• Grantee: Luan Farinelli Diniz
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 10/16520-5 - Application of calibration chemometrics methods and multivariate curve resolution in Raman spectroscopy for qualitative, quantitative and polymorphism analyses in medicines
• Grantee: Renato Lajarim Carneiro
• Support Opportunities: Regular Research Grants