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

Author(s)

Souza, Matheus S. ^[1] ; Diniz, Luan F. ^[1] ; Vogt, Lautaro ^[1] ; Carvalho Jr, Paulo S. ; D'vries, Richard F. ^{[2, 3]} ; Ellena, Javier ^[2]

Affiliation

^[1] Univ Sao Paulo, Inst Fis Sao Carlos, BR-13560970 Sao Carlos, SP - Brazil

^[2] Carvalho Jr, Jr., Paulo S., Univ Sao Paulo, Inst Fis Sao Carlos, BR-13560970 Sao Carlos, SP - Brazil

^[3] Univ Santiago Cali, Fac Ciencias Basicas, Calle 5 62-00, Cali, Valle Del Cauca - Colombia

• Document type: Journal article
• Source: Crystal Growth & Design; v. 18, n. 9, p. 5202-5209, SEP 2018.
• Web of Science Citations: 3

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 center dot center dot center dot 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. (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