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.

中文翻译：

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5-氟尿嘧啶共晶体与亲脂性羟基-2-萘甲酸：晶体结构，理论计算和渗透研究

外用5-氟尿嘧啶（5FU）在临床上用于皮肤癌。然而，由于5FU的渗透性差，其皮肤渗透率低且微不足道，导致其在癌症治疗中的功效有限。共晶形成提供了在不改变其分子结构的情况下提高药物渗透性的机会。在此，5FU与亲脂性6-羟基-2-萘甲酸（5FU–6HNA，1：1）和3-羟基-2-萘甲酸（5FU–3HNA）的两个共晶体，2：1）并进行了表征。在两种情况下均进行了固态密度泛函理论计算，然后进行了基于单晶结构的Bader分析，以研究分子堆积，分子间相互作用和相应的能量。通过硅胶膜的渗透性研究表明，与纯5FU相比，5FU–6HNA和5FU–3HNA表现出不同但改善的膜渗透性，这是因为它们的脂质溶解度和相稳定性不同。这项研究对于使用共结晶技术调节透皮药物的渗透性具有重要意义。