Cocrystallization of 5-fluorouracil and L-phenylalanine: The first zwitterionic cocrystal of 5-fluorouracil with amino acid exhibiting the perfected in vitro/vivo pharmaceutical properties
In order to highlight the advantages of L-phenylalanine (Phe) in optimizing the in vitro/vivo properties of anticancer drug 5-fluorouracil (Fu) along with enhancing its antitumor activities, the first zwitterionic cocrystal of Fu with amino acid, abbreviated as Fu-Phe, is successfully synthesized via pharmaceutical cocrystallization technique, and its exact structure determined by single-crystal X-ray diffraction analysis confirms that the cocrystal lattice consists of Fu and Phe molecules in equal ratio, and a variety of hydrogen bonds, especially the charge-assisted hydrogen bonds introduced by zwitterionic Phe support the three-dimensional supramolecular network. The in vitro and in vivo properties of the newly synthesized cocrystal are systematically subjected to evaluation. It can be concluded that both the permeability and dissoluvability of Fu from t cocrystal are enhanced with respect to free Fu, and comparatively, the increased degree of the former is more obvious than that of the latter. It's worth mentioning that the ameliorated in vitro biopharmaceutical property of Fu together with the potential carrier role of Phe not only can significantly enhance the antitumor activity of Fu, displaying better and time-dependent cytotoxicity against the tested tumor cell lines, but also can effectively turn into the in vivo pharmacokinetic preponderances, showing the accelerated peak plasma concentration and prolonged half-life as well as increased bio-availability in contrast to pure Fu. The present contribution provides a new solid crystalline form of Fu with broad application prospect and potential commercial value, thus leading to the research and development of zwitterionic amino acid antitumor cocrystal drugs based on cocrystallization strategy.