Intermolecular interactions and permeability of 5-fluorouracil cocrystals with a series of isomeric hydroxybenzoic acids: a combined theoretical and experimental study

5-Fluorouracil (5FU) is a BCS class III drug with good aqueous solubility and poor permeability, which severely limits its transdermal permeation through the stratum corneum. Herein, four cocrystals of 5FU with a series of isomeric hydroxybenzoic acids, including salicylic acid (2 : 1), 3-hydroxybenzoic acid (1 : 1) and 4-hydroxybenzoic acid (forms I and II, 1 : 1) were prepared and subjected to membrane permeation. They exhibited significantly improved membrane permeability due to the lipid solubility enhancement caused by cocrystallization. Solid-state DFT computations followed by Bader analysis based on single crystal structures were carried out to quantify the pattern of non-covalent interactions in the cocrystals. The lattice energy values were estimated as a sum of energies of non-covalent intermolecular interactions, which show a negative correlation with the lipid solubility of 1 : 1 cocrystals. This study has important implications for the use of the cocrystallization approach to improve the permeability of transdermal drugs.