5-Fluorocytosine/5-Fluorouracil Drug-Drug Cocrystal: a New Development Route Based on Mechanochemical Synthesis
- 289 Downloads
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).
- 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.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.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.
- 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.Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ. Pharmaceutical cocrystals. J Pharm Sci. 2006;95(3):499–516.Google Scholar
- 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.Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des. 2009;9(6):2950–67.Google Scholar
- 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.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.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.Sekhon BS. Drug-drug co-crystals. Daru. 2012;20(1):45.Google Scholar
- 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.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.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.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.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.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.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.
- 21.Trask AV. An overview of pharmaceutical cocrystals as intellectual property. Mol Pharm. 2007;4(3):301–9.Google Scholar
- 22.Tucker JL. Green chemistry, a pharmaceutical perspective. Org Process Res Dev. 2006;10(2):315–9.Google Scholar
- 23.Clark JH. Green chemistry: challenges and opportunities. Green Chem. 1999;1:1–8.Google Scholar
- 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.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.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.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.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.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.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.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.Jones W, Eddeleston MD. Introductory lecture: mechanochemistry, a versatile synthesis strategy for new materials. Faraday Discuss. 2014;170:9–34.Google Scholar
- 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.Bowmaker GA. Solvent-assisted mechanochemistry. Chem Commun. 2013;49:334–48.Google Scholar
- 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.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.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.Zhang J, Kale V, Chen M. Gene-directed enzyme prodrug therapy. AAPS J. 2015;17(1):102–10.Google Scholar
- 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.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.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.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.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