Exploring the cocrystallization potential of urea and benzamide

TL;DR

This study combines experimental synthesis and theoretical analysis to explore the cocrystallization potential of urea and benzamide with carboxylic acids, revealing differences in predictability and intermolecular interactions.

Contribution

It provides new synthesized benzamide cocrystals and compares their cocrystallization behavior with urea using thermodynamic and virtual screening methods.

Findings

More potential benzamide pairs are attractive than urea.

Prediction of urea cocrystals is more straightforward than benzamide.

Known urea cocrystals fall within specific thermodynamic quartiles.

Abstract

The cocrystallization landscape of benzamide and urea interacting with aliphatic and aromatic carboxylic acids was studied both experimentally and theoretically. Ten new cocrystals of benzamide were synthesized using an oriented samples approach via a fast dropped evaporation technique. Information about types of known bi-component cocrystals augmented with knowledge of simple binary eutectic mixtures was used for the analysis of virtual screening efficiency among 514 potential pairs involving aromatic carboxylic acids interacting with urea or benzamide. Quantification of intermolecular interaction was achieved by estimating the excess thermodynamic functions of binary liquid mixtures under supercooled conditions within a COSMO-RS framework. The smoothed histograms suggest that slightly more potential pairs of benzamide are characterized in the attractive region compared to urea. Finally, it is emphasized that prediction of cocrystals of urea is fairly direct, while it remains ambiguous for benzamide paired with carboxylic acids. The two known simple eutectics of urea are found within the first two quartiles defined by excess thermodynamic functions, and all known cocrystals are outside of this range belonging to the third or fourth quartile. On the contrary, such a simple separation of positive and negative cases of benzamide miscibility in the solid state is not observed. The difference in properties between urea and benzamide R2,2(8) heterosynthons is also documented by alterations of substituent effects...