Journal of Pharmaceutical Innovation

, Volume 14, Issue 1, pp 50–56 | Cite as

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

  • Cecilia C. P. da Silva
  • Cristiane C. de Melo
  • Matheus S. Souza
  • Luan F. Diniz
  • Renato L. Carneiro
  • Javier EllenaEmail author
Original Article



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.


Mechanochemistry 5-Fluorocytosine 5-Fluorouracil Cocrystal Physical stability Solid-state characterization 


Funding information

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).


  1. 1.
    Aitipumala S, et al. Polymorphs, salts, and cocrystals: what’s in a name? Cryst Growth Des. 2012;12(5):2147–52.Google Scholar
  2. 2.
    Surov AO, Voronin P, Manin AN, Manin NG, Kuzmina LG, Churakov AV, et al. Pharmaceutical cocrystals of diflusinal and diclofenac with theophylline. Mol Pharm. 2014;11(10):3707–15.Google Scholar
  3. 3.
  4. 4.
    See Regulatory Classification of Pharmaceutical Co-crystals Guidance for Industry.
  5. 5.
    Trask AV, Motherwell WDS, Jones W. Pharmaceutical cocrystallization: engineering a remedy for caffeine hydration. Cryst Growth Des. 2005;5(3):1013–21.Google Scholar
  6. 6.
    Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ. Pharmaceutical cocrystals. J Pharm Sci. 2006;95(3):499–516.Google Scholar
  7. 7.
    Berry DJ, Seaton CC, Clegg W, Harrington RW, Coles SJ, Horton PN, et al. Applying hot-stage microscopy to co-crystal screening: a study of nicotinamide with seven active pharmaceutical ingredients. Cryst Growth Des. 2008;8(5):1697–−1712.Google Scholar
  8. 8.
    Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des. 2009;9(6):2950–67.Google Scholar
  9. 9.
    Cheney ML, Shan N, Healey ER, Hanna M, Wojtas L, Zaworotko M, et al. Effects of crystal form on solubility and pharmacokinetics: a crystal engineering case study of lamotrigine. Cryst Growth Des. 2010;10(1):394–405.Google Scholar
  10. 10.
    Cheney ML, Weyna DR, Shan N, Hanna M, Wojtas L, Zaworotko MJ. Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics. J Pharm Sci. 2011;100(6):2172–81.Google Scholar
  11. 11.
    Báthori NB, Lemmerer A, Venter GA, Bourne AS, Caira MR. Pharmaceutical co-crystals with isonicotinamide–vitamin B3, clofibric acid, and diclofenac–and two isonicotinamide hydrates. Cryst Growth Des. 2011;11(1):75–87.Google Scholar
  12. 12.
    Sekhon BS. Drug-drug co-crystals. Daru. 2012;20(1):45.Google Scholar
  13. 13.
    Aitipumala S, Chow PS, Tan RBH. Trimorphs of a pharmaceutical cocrystal involving two active pharmaceutical ingredients: potential relevance to combination drugs. Cryst Eng Comm. 2009;11:1823–7.Google Scholar
  14. 14.
    Évora AOL, Castro ERA, Maria TMR, Rosado MTS, Silva MR, Beja AM, et al. Pyrazinamide–diflunisal: a new dual-drug co-crystal. Cryst Growth Des. 2011;11(11):4780–8.Google Scholar
  15. 15.
    Aitipumala S, Wong ABH, Chow PS, Tan RBH. Pharmaceutical cocrystals of ethenzamide: structural, solubility and dissolution studies. Cryst Eng Comm. 2012;14:8515–24.Google Scholar
  16. 16.
    Jiang l HY, Zhang Q, He H, Xu Y, Mei X. Preparation and solid-state characterization of dapsone drug-drug co-crystals. Cryst Growth Des. 2014;14(9):4562–73.Google Scholar
  17. 17.
    Sowa M, Slepokura K, Matczak-jon E. A 1:1 pharmaceutical cocrystal of myricetin in combination with uncommon piracetam conformer: X-ray single crystal analysis and mechanochemical synthesis. J Mol Struct. 2014;1058:114–21.Google Scholar
  18. 18.
    Daurio D, Medina C, Saw R, Nagapudi K, Alvarez-Núnez F. Application of twin screw extrusion in the manufacture of cocrystals, part I: four case studies. Pharmaceutics. 2011;3(3):582–600.Google Scholar
  19. 19.
    Fonseca JC, Clavijo JCT, Alvarez N, Ellena J. Novel solid solution of the antiretriviral drugs lamivudine and emtricitabine. Cryst Growth Des. 2018; ASAP
  20. 20.
    Lusi M. Engineering crystal properties through solid solutions. Cryst Growth Des. 2018; ASAP.
  21. 21.
    Trask AV. An overview of pharmaceutical cocrystals as intellectual property. Mol Pharm. 2007;4(3):301–9.Google Scholar
  22. 22.
    Tucker JL. Green chemistry, a pharmaceutical perspective. Org Process Res Dev. 2006;10(2):315–9.Google Scholar
  23. 23.
    Clark JH. Green chemistry: challenges and opportunities. Green Chem. 1999;1:1–8.Google Scholar
  24. 24.
    Constable DJC, Dunn PJ, Hayler JD, Humphrey GR, Leazer JL Jr, Linderman RJ, et al. Key green chemistry research areas—a perspective from pharmaceutical manufacturers. Green Chem. 2007;9:411–20.Google Scholar
  25. 25.
    Shan N, Jones WA. Green chemistry approach to the synthesis of a crystalline organic inclusion compound. Green Chem. 2003;5:728–30.Google Scholar
  26. 26.
    Weyna DR, Shattock T, Vishweshwar P, Zaworotko MJ. Synthesis and structural characterization of cocrystals and pharmaceutical cocrystals: mechanochemistry vs evaporation from solution. Cryst Growth Des. 2009;9(2):1106–23.Google Scholar
  27. 27.
    Friscic T, Jones W. Recent advances in understanding the mechanism of cocrystal formation via grinding. Cryst Growth Des. 2009;9(3):1621–37.Google Scholar
  28. 28.
    Hu Y, Gniado K, Erxleben A, McArdle P. Mechanochemical reaction of sulfathiazole with carboxylic acids: formation of a cocrystal, a salt, and coamorphous solids. Cryst Growth Des. 2014;14(2):803–13.Google Scholar
  29. 29.
    Bruni G, Maietta M, Berbenni V, Mustarelli P, Ferrara C, Freccero M, et al. Mechanochemical synthesis of bumetanide–4-aminobenzioc acid molecular cocrystals: a facile and green approach to drug optimization. J Phys Chem B. 2014;118(31):9180–90.Google Scholar
  30. 30.
    Karki S, Friscic T, Jones W, Motherwell WDS. Screening for pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding. Mol Pharm. 2007;4(3):347–54.Google Scholar
  31. 31.
    Song J-X, Yan Y, Yao J, Chen J-M, Lu T-B. Improving solubility of lenalidomide via cocrystals. Cryst Growth Des. 2014;14(6):3069–77.Google Scholar
  32. 32.
    Jones W, Eddeleston MD. Introductory lecture: mechanochemistry, a versatile synthesis strategy for new materials. Faraday Discuss. 2014;170:9–34.Google Scholar
  33. 33.
    Haneef J, Chadha R. Drug-drug multicomponent solid forms: cocrystal, coamorphous and eutectic of three poorly soluble antihypertensive drugs using mechanochemical approach. AAPS PharmSciTech. 2017;18(6):2279–90.Google Scholar
  34. 34.
    Bowmaker GA. Solvent-assisted mechanochemistry. Chem Commun. 2013;49:334–48.Google Scholar
  35. 35.
    Malet-Martino M, Martino R. Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S–1): a review. Oncologist. 2002;7(4):288–323.Google Scholar
  36. 36.
    Vermes A, Guchelaar H-J, Dankert J. Flucytosine: a review of its pharmacology, clinical interactions, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother. 2000;46(2):171–9.Google Scholar
  37. 37.
    Nishiyama T, Kawamura Y, Kawamoto K, Matsumura H, Yamamoto N, Ito T, et al. Antineoplastic effects in rets of 5-fluorocytosine in combination with cytosine deaminase capsules. Cancer Res. 1985;45(4):1753–61.Google Scholar
  38. 38.
    Zhang J, Kale V, Chen M. Gene-directed enzyme prodrug therapy. AAPS J. 2015;17(1):102–10.Google Scholar
  39. 39.
    Maleksha OM, Chen X, Nomani A, Sarkar S, Hatefi A. Enzyme/prodrug systems for cancer gene therapy. Curr Pharmacol Rep. 2016;2(6):299–308.Google Scholar
  40. 40.
    Christie C, Pomeroy A, Nair R, Berg K, Hirschberg H. Photodynamic therapy enhances the efficacy of gene-directed enzyme prodrug therapy. Photodiagn Photodyn Ther. 2017;18:140–8.Google Scholar
  41. 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.Google Scholar
  42. 42.
    da Silva CCP, Pepino RO, de Melo CC, Tenorio JC, Ellena J. Controlled synthesis of new 5-fluorocytosine cocrystals based on the pKa rule. Cryst Growth Des. 2014;14(9):4383–93.Google Scholar
  43. 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

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Instituto de Física de São CarlosUniversidade de São PauloSão CarlosBrazil
  2. 2.Departamento de QuímicaUniversidade Federal de São CarlosSão CarlosBrazil
  3. 3.Faculdade de Ciências FarmacêuticasUniversidade Federal de AlfenasAlfenasBrazil

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