A 5-fluorouracil-kaempferol drug-drug cocrystal: a ternary phase diagram, characterization and property evaluation

• Published in: CrystEngComm Vol. 22; no. 46; pp. 8127 - 8135
• Main Authors: Lv, Wen-Ting, Liu, Xiao-Xu, Dai, Xia-Lin, Long, Xiang-Tian, Chen, Jia-Mei
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 14.12.2020
• Subjects: Anticancer properties; Bioavailability; Crystallization; Crystallography; Differential scanning calorimetry; Fourier transforms; Infrared analysis; NMR spectroscopy; Phase diagrams; Single crystals; Ternary systems; Thermogravimetric analysis; X ray powder diffraction
• ISSN: 1466-8033; 1466-8033
• DOI: 10.1039/d0ce01289k

The synergistic anti-tumor effect of a typical chemotherapy drug, 5-fluorouracil, and a natural flavonoid compound, kaempferol, has been reported recently. However, the oral absorption of 5-fluorouracil is incomplete and nonuniform for different individuals due to fast metabolism and an obvious peak-valley phenomenon, while kaempferol has very poor solubility and this consequently leads to low oral bioavailability. The weakness of each drug greatly restricts the potential of anti-tumor drug combination in the clinical application. In this work, a new 1 : 1 drug-drug cocrystal of 5-fluorouracil and kaempferol was successfully prepared by liquid assisted grinding, slurry conversion crystallization and evaporation crystallization. A ternary phase diagram was constructed to gain some insights into the thermodynamics of the cocrystal system. The obtained cocrystal was comprehensively characterized by single crystal and powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis, as well as Fourier transform infrared and nuclear magnetic resonance spectroscopy. The drug-drug cocrystal enhances the stability of kaempferol and optimizes the dissolution behavior of each single component as compared to pristine drugs. Therefore, the 5-fluorouracil-kaempferol cocrystal has the potential to be developed as efficient oral formulations for drug combination which will overcome the weaknesses of each parent drug. A drug-drug cocrystal of 5-fluorouracil and kaempferol was comprehensively investigated and exhibits optimized solubility behavior in comparison with individual APIs.