Understanding the Synthon Preferences in Molecular Ionic Cocrystals of Trimethoprim─An Experimental and Computational Study

Molecular ionic cocrystals (ICCs) are cocrystals of composition A^-BH⁺HA or A^-BH⁺C with charge-assisted hydrogen bonding between A^- and BH⁺ and with HA, B, and C being organic solids at ambient temperature. In contrast to the numerous works on the rational design of ternary A·B·C cocrystals, the application of synthon preferences and hierarchies in the synthesis of molecular ICCs is not widely reported. The antibiotic trimethoprim (tmp) readily forms molecular salts with carboxylic acid coformers including nonsteroidal anti-inflammatory drugs. The carboxylate anion interacts with the protonated N1H⁺/C2-NH₂ site of Htmp⁺ leaving the N3/C4-NH₂ site as a second binding site for potential ICC formation. In this work, we investigated the synthesis of ternary molecular ICCs of tmp. Solution crystallization experiments led to the single crystal structure of Htmp⁺dif^-·H₂fum (dif^- = diflunisal anion; H₂fum = fumaric acid). Hirshfeld surface analysis, molecular electrostatic potential, and site interaction energy calculations were conducted to understand the hydrogen bonding propensity of the N3/C2-NH₂ site in Htmp⁺X^-. Proton transfer from HX to the N1 nitrogen of tmp leads to a decrease in the electrostatic potential of N3 and thus to a reduced hydrogen bond acceptor strength. The data obtained in this study highlight the challenges of developing strategies for the rational synthesis of molecular ICCs of complex molecules.