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

## TL;DR

This study explores how trimethoprim forms molecular ionic cocrystals and identifies challenges in their rational design.

## Contribution

The work experimentally and computationally investigates synthon preferences in trimethoprim-based molecular ionic cocrystals.

## Key findings

- Trimethoprim forms molecular ionic cocrystals with carboxylic acid coformers via specific hydrogen bonding sites.
- Proton transfer reduces the hydrogen bond acceptor strength at the N3 site of protonated trimethoprim.
- Hirshfeld surface and electrostatic potential analyses reveal insights into hydrogen bonding propensities.

## Abstract

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.