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Mechanochemistry synthesis was applied to the supramolecular synthesis and green scale-up production of a 1:1 drug–drug cocrystal involving the antimetabolite prodrug 5-Fluorocytosine (5-FC) and the tuberculostatic drug Isoniazid (INH), namely, 5FC-INH. Crystalline material, also obtained by traditional slow evaporation methods, was analyzed by single-crystal X-ray diffraction (XRD). The crystal packing is stabilized by a classical N–H···N hydrogen-bond interaction between the amine moiety of 5-FC and the INH pyridine nitrogen. IR and Raman data provided spectroscopic evidence about the hydrogen atom positions, thereby confirming the neutral nature of the cocrystal. Furthermore, 5FC-INH codrug was also evaluated by a range of analytical techniques such as powder XRD and thermal (thermogravimetric analysis, differential scanning calorimetry, hot stage microscopy) analyses. A physical stability study was performed in high relative humidity conditions to verify possible 5-FC solid-state hydration and/or INH degradation. The equilibrium solubility of this codrug was compared to the anhydrous 5-FC and INH raw materials, in pH 1.2 buffer media, and it was found to be similar to that of 5-FC, a biopharmaceutics classification system class I drug. The results show that the cocrystal has superior phase stability properties against moisture when compared to the starting pharmaceutical ingredients, so it could be considered as a potential candidate for the treatment of concomitant fungal infections, tuberculosis, and cancer.

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.

Ethambutol (ETB) is a chiral dibasic compound formulated and marketed as the (S,S)-ethambutol dihydrochloride, (S,S)-EDH, to treat tuberculosis. It is administered orally in a solid formulation composed of isoniazid, rifampicin, and pyrazinamide as a fixed-dose combination tablet. Because of its high hygroscopicity, (S,S)-EDH is known for catalyzing the degradation of isoniazid by rifampicin to yield isonicotinyl hydrazone. In order to avoid or even minimize these mutual drug–drug interactions, in this work we have focused on the development of less hygroscopic multicomponent solid forms of ETB. Four salts of this drug, namely, oxalate (ETBOXA), maleate, terephthalate, and trichloroacetate, were prepared via supramolecular synthesis by the slow evaporation method and characterized by X-ray diffraction (single crystal X-ray diffraction, powder X-ray diffraction), spectroscopic (Fourier transform-infrared), and thermal (thermogravimetric analysis, differential scanning calorimetry, hot stage microscopy) techniques. The hygroscopic nature of these salts, including (S,S)-EDH, were evaluated, and all of them were found to be hygroscopic, with the exception of ETBOXA.

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Supramolecular reaction of 5-FC with caffeine, p-aminobenzoic and caprylic acid gave rise to solid forms physically stable in humid environments.

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.