Fluconazole: Synthesis and Structural Characterization of Four New Pharmaceutical Cocrystal Forms

Abstract

Pharmaceutical cocrystals have emerged over the past several decades as an alternative path for synthesizing stable and/or improved crystalline forms of active pharmaceutical ingredients. In this contribution, we developed a reproducible cocrystallization path for the supramolecular synthesis of four new pharmaceutical cocrystal forms of fluconazole (FLZ), an antifungal multifunctional drug: fluconazole–fumaric acid monohydrate (1:1:1), fluconazole–malic acid (1:1), fluconazole–dipicolinic acid (1:1), and fluconazole–adipic acid (1:1). All the new cocrystals were characterized by powder/single-crystal X-ray diffraction, Raman, Fourier transform infrared spectroscopy, differential scanning calorimetry/thermogravimetric analysis, and hot-stage polarized optical microscopy, and their water solubility was determined. Structurally, although the coformers were different, the same strong O–H···N hydrogen bond between the FLZ molecule and the coformers was observed. The aqueous solubility studies revealed that all the cocrystals were found to exhibit improved aqueous solubility when compared to the commercialized FLZ polymorph.

Intermolecular interaction energies and molecular conformations in N-substituted 4-aryl-2-methylimidazoles with promising in vitro antifungal activity

“…Notably, this imidazolic alcohol (5f) contains two 2,4-dichloro-substituted benzene rings (2,4-Cl 2 Ph) similar to MCZ (Mangas-Sá nchez et al, 2011;Becher & Wirsel, 2012), which is also its constitutional isomer (Scheme 1). In addition, the presence of halogen atoms such as F or Cl seems to be key to the antifungal activity of the Nsubstituted 4-aryl-2-methylimidazoles studied (most azoles in clinical use possess halo-substituted benzene rings) (Borgers, 1980;Fromtling, 1988;Di Santo et al, 2005;Espinel-Ingroff, 2009;Strushkevich et al, 2010;Emami et al, 2017;White et al, 1998;Kathiravan et al, 2012;Shrestha et al, 2017;Kastelic et al, 2010;Tsutsumi et al, 2011;Dayo-Owoyemi et al, 2019;Pershing et al, 2002;Elewski & Vlahovic, 2014;Mangas-Sá nchez et al, 2011;Becher & Wirsel, 2012), since the polyhalogenated compounds [(4b), (4d) (Elejalde et al, 2018) and (5f)] presented the lowest IC 50 values.…”

“…These results showed that the hydroxyl group of (5) also favors intermolecular hydrogen bonds for directing the imidazolic and 2-arylethyl moieties in a parallel conformation, such as occurs in some azole drugs [Fig. 2(b)] (Kastelic et al, 2010;Tsutsumi et al, 2011;Dayo-Owoyemi et al, 2019). In our most recent work (Macías, Elejalde et al, 2018), a complete study by X-ray diffraction of the electronic effects of the 4-aryl substituent of NH-imidazoles (3a)-(3c) and their in vitro antifungal evaluation was reported.…”

“…Similar systems such as miconazole (MCZ), ketoconazole (KTZ), econazole (ECZ) and tioconazole (TCZ) are antifungal imidazoles that have not only the imidazole ring, but also the 2-haloaryl-2-alcoxyethyl group at position 1 (Borgers, 1980;Fromtling, 1988;Di Santo et al, 2005;Espinel-Ingroff, 2009;Strushkevich et al, 2010;Emami et al, 2017). This moiety is also part of the antifungal triazoles itraconazole (ITZ), voriconazole (VCZ) and fluconazole (FLZ), but these have a hydroxyl instead of an alcoxyl group (White et al, 1998;ISSN 2052-5206 # 2019 International Union of Crystallography Kathiravan et al, 2012;Shrestha et al, 2017;Kastelic et al, 2010;Tsutsumi et al, 2011;Dayo-Owoyemi et al, 2019). Interestingly, the hydroxyl group of these antifungals favors hydrogen-bond interactions that contribute to directing the heterocyclic and haloaryl moieties to form a parallel conformation in the solid state (Kastelic et al, 2010;Tsutsumi et al, 2011;Dayo-Owoyemi et al, 2019), which was also observed in our previous work [see the 2-aryl-2-hydroxyethyl fragment joined to the imidazole ring, in bold, in Figs.…”

“…This moiety is also part of the antifungal triazoles itraconazole (ITZ), voriconazole (VCZ) and fluconazole (FLZ), but these have a hydroxyl instead of an alcoxyl group (White et al, 1998;ISSN 2052-5206 # 2019 International Union of Crystallography Kathiravan et al, 2012;Shrestha et al, 2017;Kastelic et al, 2010;Tsutsumi et al, 2011;Dayo-Owoyemi et al, 2019). Interestingly, the hydroxyl group of these antifungals favors hydrogen-bond interactions that contribute to directing the heterocyclic and haloaryl moieties to form a parallel conformation in the solid state (Kastelic et al, 2010;Tsutsumi et al, 2011;Dayo-Owoyemi et al, 2019), which was also observed in our previous work [see the 2-aryl-2-hydroxyethyl fragment joined to the imidazole ring, in bold, in Figs. 1 and 2(b)] (Elejalde et al, 2018).…”

Investigations on the Solubility of Vortioxetine Based on X-ray Structural Data and Crystal Contacts

“…In recent years, the study of solid-state pharmaceutical chemistry, including cocrystals, salts, polymorphs, and solvates, has been extensively applied in the area of pharmaceutical technology [1][2][3][4][5]. Thus, the design of pharmaceutical solid forms of drugs has become an important step in the pharmaceutical process [6].…”