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

• Published in: CrystEngComm Vol. 21; no. 34; pp. 595 - 515
• Main Authors: Dai, Xia-Lin, Voronin, Alexander P, Gao, Wei, Perlovich, German L, Lu, Tong-Bu, Chen, Jia-Mei
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 2019
• Subjects: Cocrystallization; Crystal structure; Crystallography; Lipids; Penetration; Permeability; Salicylic acid; Single crystals; Solubility
• ISSN: 1466-8033; 1466-8033
• DOI: 10.1039/c9ce00661c

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. This work combined theoretical and experimental methods to explore intermolecular interactions and permeability of 5-fluorouracil cocrystals with isomeric hydroxybenzoic acids.