Mechanochemical synthesis and characterization of a novel AAs-Flucytosine drug-drug cocrystal: A versatile model system for green approaches

Author(s)

Carneiro, Renato L. ^[1] ; de Melo, Cristiane C. ^{[2, 3]} ; de Alvarenga Jr, Benedito R. ; Owoyemi, Bolaji C. Dayo ^[4] ; Ellena, Javier ^[5] ; da Silva, Cecilia C. P. ^{[5, 4]}

Affiliation

^[1] Fed Univ Sao Carlos UFSCar, Dept Chem, Rod Washington Luis Km 235, BR-13560905 Sao Carlos, SP - Brazil

^[2] Univ Fed Alfenas, Inst Chem, Rua Gabriel Monteiro da Silva 701, BR-37130001 Alfenas, MG - Brazil

^[3] Univ Fed Alfenas, Pharmaceut Sci Fac, Rua Gabriel Monteiro da Silva 701, BR-37130001 Alfenas, MG - Brazil

^[4] de Alvarenga Jr, Jr., Benedito R., Fed Univ Sao Carlos UFSCar, Dept Chem, Rod Washington Luis Km 235, BR-13560905 Sao Carlos, SP - Brazil

^[5] Univ Sao Paulo, Sao Carlos Inst Phys, CP 369, BR-13560970 Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: Journal of Molecular Structure; v. 1251, MAR 5 2022.
• Web of Science Citations: 0

Abstract

Mechanochemistry approach is addressed herein for the green formation of a novel 1:1 drug-drug cocrystal (DDC) involving the antifungal prodrug Flucytosine (5FC) and the non-steroidal anti-inflammatory acetylsalicylic acid (AAS). This DDC was designed considering the huge market demand for new antifungal agents and the antifungal activity reported for some non-steroidal anti-inflammatory drugs, including AAS. The structure-properties characterization of the 5FC-AAS cocrystal was determined by X-ray diffraction (single crystal and powder), differential scanning calorimetry, thermogravimetric analysis, spectroscopic techniques (Raman and Fourier transform infrared), and hot-stage microscopy. The strong O-H center dot center dot center dot O and N-H center dot center dot center dot O hydrogen bonds formed between the hydroxyl group of AAS and the carbonyl and amine groups of two symmetry-related 5FC molecules maintain the crystalline packing, together with the same classical R-2(2) (8) homodimers observed in other 5FC cocrystals. The direct exposure under accelerated conditions (75% relative humidity/40 degrees C for 7 days) and at 12-months at room condition were also evaluated. Although the hygroscopicity addressed to 5FC was observed in the cocrystal during the stability studies, nevertheless this property discrepancy can easily be handled with the use of appropriate excipients and packing. DDC production was interestingly achieved by solvent evaporation, neat, and solvent-drop grinding (manually and in a ball-milling), resulting in a very fast production with suitable yield. In this sense, it is believed that this new model DDC will serve as a potential binary base cocrystal system for further developments of related higher dimensional cocrystals in this field, alongside other important drug molecules or in relation to the feasibility of using it therapeutically. (C) 2021 Elsevier B.V. All rights reserved. (AU)

• FAPESP's process: 10/16520-5 - Application of calibration chemometrics methods and multivariate curve resolution in Raman spectroscopy for qualitative, quantitative and polymorphism analyses in medicines
• Grantee: Renato Lajarim Carneiro
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/13095-0 - Experimental design applied to forced degradation of Nitazoxanide and Sofosbuvir pharmaceutical drugs
• Grantee: Benedito Roberto de Alvarenga Junior
• Support Opportunities: Scholarships in Brazil - Doctorate