Synthesis of 5-Fluorouracil Cocrystals with Novel Organic Acids as Coformers and Anticancer Evaluation against HCT-116 Colorectal Cell Lines

Farhat Jubeen, Aisha Liaqat, Fiza Amjad, Misbah Sultan, Sania Zafar Iqbal, Imran Sajid, Muhammad Bilal Khan Niazi, Farooq Sher

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    5-Fluorouracil (5-FU) being a mainstream anticancer drug is under keen and detailed investigation for prodrugs formulations in order to minimize the associated side effects. Cocrystallization of 5-FU is an innovative technique for the synthesis of 5-FU prodrugs to improve its anticancer effectiveness. The present study is based on the synthesis of 5-FU supramolecular synthons with four coformers: succinic acid, cinnamic acid, malic acid, and benzoic acid utilizing acetone as a solvent. Solid state grinding followed by a slow evaporation solution method was applied. Colorless clear crystals were obtained in all the cases. The cocrystal formation was supported with the help of Fourier transform infrared (FTIR) spectroscopy and powder X-ray diffraction (PXRD). Through FTIR, the main peaks of interest in the spectrum of 5-FU were N–H (3409.02 cm–1) and carbonyl group (1647.80 cm–1), which were prominently shifted in all spectra of the cocrystals demonstrating the replacement as well as the development of already present interactions with the new ones. For 5-FU–cinnamic acid cocrystals, the anticipated peaks were observed at 1673.13 cm–1 (−C═O) and 3566.89 cm–1 (N–H) manifesting a significant change in comparison to 5-FU. Furthermore, with the help of PXRD characterization, the representative peak of 5-FU was recorded at 2θ = 28.80°. The shifting of this specific peak and development of many new ones in the spectra of cocrystals proved the development of new structural entities. Finally, the anticancer activity of all cocrystals was evaluated in comparison to that of API. All cocrystals manifest significantly greater growth inhibition potential than the main active pharmaceutical ingredient. 5-FU–Cinnamic acid (3C) was the one that proved to be the most potent anticancer agent at all four concentrations: 4.82% (12 μg/mL), 34.21% (25 μg/mL), 55.08% (50 μg/mL), and 67.29% (100 μg/mL). In short, this study proved to be a true example to enhance the anticancer potential of 5-FU following fairly easy fabrication requirements of the cocrystallization phenomenon. After the successful synthesis of these supramolecular synthons and subsequent enhancement of growth inhibition potential of 5-FU, these cocrystals can further be evaluated for in vivo trials and membrane crossing potentials in the future.
    Original languageEnglish
    Pages (from-to)2406-2414
    Number of pages9
    JournalCrystal Growth & Design
    Issue number4
    Early online date10 Feb 2020
    Publication statusPublished - 1 Apr 2020

    Bibliographical note

    This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Crystal Growth & Design,, copyright © American Chemical Society after peer review. To access the final edited and published work see

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    ASJC Scopus subject areas

    • Chemistry(all)
    • Materials Science(all)
    • Condensed Matter Physics


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