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Title: Mechanochemical Synthesis of a Multicomponent Solid Form: The Case of 5-Fluorocytosine Isoniazid Codrug
Authors: Souza, Matheus S.
Diniz, Luan F.
Vogt, Lautaro
Carvalho Jr., Paulo S.
D’vries, Richard F.
Ellena, Javier
Keywords: Atoms;Crystalline materials;Hydrogen bonds;Single crystals;Stability;X ray diffraction
Issue Date: 12-Jul-2018
Publisher: American Chemical Society
Abstract: 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.
ISSN: 15287483
Appears in Collections:Artículos Científicos

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