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5‑Fluorouracil Cocrystals with Lipophilic Hydroxy-2-Naphthoic Acids: Crystal Structures, Theoretical Computations, and Permeation Studies

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journal contribution
posted on 09.01.2020, 21:47 by Xia-Lin Dai, Alexander P. Voronin, Yong-Liang Huang, German L. Perlovich, Xing-Hua Zhao, Tong-Bu Lu, Jia-Mei Chen
Topical 5-fluorouracil (5FU) is clinically used for skin cancer. However, the skin penetration of 5FU is low and marginal due to its poor permeability, leading to its limited efficacy for cancer treatment. Cocrystal formation offers an opportunity to improve the permeability of a drug without changing its molecular structure. Herein, two cocrystals of 5FU with lipophilic 6-hydroxy-2-naphthoic acid (5FU–6HNA, 1:1) and 3-hydroxy-2-naphthoic acid (5FU–3HNA, 2:1) were obtained and characterized. The solid-state density functional theory computations followed by Bader analysis based on single crystal structures were carried out in both cases to investigate the molecular packing, intermolecular interactions, and corresponding energies. The permeability study through a silicone membrane shows that 5FU–6HNA and 5FU–3HNA exhibit different but improved membrane permeability when compared with pure 5FU due to their different lipid solubilities and phase stabilities. This study has important implications for the use of the cocrystallization technique to modulate transdermal drugs’ permeability.