Mechanochemical Synthesis of a Multicomponent Solid Form: The Case of 5-Fluorocytosine Isoniazid Codrug

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 ...