5-Fluorocytosine/5-Fluorouracil Drug-Drug Cocrystal: a New Development Route Based on Mechanochemical Synthesis
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Mechanochemistry is addressed here for the green formation of a 1:1 pharmaceutical cocrystal involving the antifungal prodrug 5-Fluorocytosine (5-FC) and the antineoplastic drug 5-Fluorouracil (5-FU). Crystalline material of this drug-drug cocrystal (DDC) was previously obtained by slow evaporation from solution (SES) and was then structurally analyzed.
In this paper, neat grinding and solvent-drop grinding (SDG) were applied in an attempt to achieve a route for the supramolecular synthesis of this cocrystal, exhibiting suitable yield and amount for solid characterization, which were not achieved via the SES method.
SDG provided the solid drug-drug cocrystal form. The resulting material had its physical stability monitored for 2 years and was then evaluated by a range of analytical technologies: X-ray powder diffraction, differential scanning calorimetry, hot-stage microscopy, thermogravimetric, and spectroscopic analysis.
The new cocrystal proved to be stable for 6 months and in environments with high relative humidity. In this sense, it is believed that the new DDC is a potential model system which could be used as a base for further developments in the field, for other molecules or in relation to the feasibility of using this cocrystal therapeutically.
KeywordsMechanochemistry 5-Fluorocytosine 5-Fluorouracil Cocrystal Physical stability Solid-state characterization
The authors received financial support from CAPES (C.C.P.S. and M.S.S.), CNPq (C.C.M., J.E. grant #305190/2017-2), and FAPESP (L.F.D. grant #15/25694-0).
- 3.See US FDA GRAS List. http://www.fda.gov/food/ingredientspackaginglabeling/gras/default.htm.
- 4.See Regulatory Classification of Pharmaceutical Co-crystals Guidance for Industry. https://www.fda.gov/downloads/Drugs/Guidances/UCM281764.pdf.
- 19.Fonseca JC, Clavijo JCT, Alvarez N, Ellena J. Novel solid solution of the antiretriviral drugs lamivudine and emtricitabine. Cryst Growth Des. 2018; https://doi.org/10.1021/acs.cgd.8b00164. ASAP
- 20.Lusi M. Engineering crystal properties through solid solutions. Cryst Growth Des. 2018; https://doi.org/10.1021/acs.cgd.7b01643. ASAP.
- 41.Funaro MG, Nemani KV, Chen Z, Bhujwalla ZM, Griswold KE, Gimi B. Effect of alginate microencapsulation on the catalytic efficiency and in vitro enzyme-prodrug therapeutic efficacy of cytosine deaminase and of recombinant E. coli expressing cytosine deaminase. J Microencapsul. 2016;33(1):64–70.CrossRefPubMedGoogle Scholar
- 43.Rastogi VK, Palafox MA, Lang K, Singhal SK, Soni RK, Sharma R. Vibrtional spectra and thermodynamics of biomolecule: 5-chlorocytosine. Indian J Pure Appl Phys. 2006;44:653–60.Google Scholar