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5-Fluorocytosine/5-Fluorouracil Drug-Drug Cocrystal: a New Development Route Based on Mechanochemical Synthesis

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Abstract

Purpose

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.

Method

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.

Results

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.

Conclusions

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.

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Funding

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).

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Authors and Affiliations

  1. Instituto de Física de São Carlos, Universidade de São Paulo, 369, São Carlos, Sao Paulo, 13560-970, Brazil

    Cecilia C. P. da Silva, Cristiane C. de Melo, Matheus S. Souza, Luan F. Diniz & Javier Ellena

  2. Departamento de Química, Universidade Federal de São Carlos, São Carlos, Sao Paulo, 13083-887, Brazil

    Cecilia C. P. da Silva & Renato L. Carneiro

  3. Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, Alfenas, Minas Gerias, 37130-000, Brazil

    Cristiane C. de Melo

Authors
  1. Cecilia C. P. da Silva
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  2. Cristiane C. de Melo
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  3. Matheus S. Souza
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  4. Luan F. Diniz
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  5. Renato L. Carneiro
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  6. Javier Ellena
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Corresponding author

Correspondence to Javier Ellena.

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da Silva, C.C.P., de Melo, C.C., Souza, M.S. et al. 5-Fluorocytosine/5-Fluorouracil Drug-Drug Cocrystal: a New Development Route Based on Mechanochemical Synthesis. J Pharm Innov 14, 50–56 (2019). https://doi.org/10.1007/s12247-018-9333-1

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  • DOI: https://doi.org/10.1007/s12247-018-9333-1

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