Virtual Cocrystal Screening Methods as Tools to Understand the Formation of Pharmaceutical Cocrystals-A Case Study of Linezolid, a Wide-Range Antibacterial Drug

Experimental mechanochemical screening of cocrystals with linezolid (LIN) resulted in the formation of six new crystal phases, including three neat cocrystals and three cocrystal hydrates, in addition to seven previously described cocrystals. In an attempt to understand the factors governing the formation of these phases, different experimental conditions of the mechanochemical reactions (polymorphic forms of LIN and presence of different solvents to create liquid-assisted grinding conditions) were tested and the results were compared with the predictions from three commonly used virtual cocrystal screening tools: molecular complementarity, hydrogen bond propensity, and molecular electrostatic potential maps. It is shown that these three methods can be used to help understand a molecule's preferences to form cocrystals with particular coformers. The influence of molecular conformation on the outcome of the predictions is also evaluated. A comparison between the prediction methods indicates that while considering a set of similar coformers, the approach based on molecular electrostatic potential maps seems to be more consistent with the experimental results than molecular complementarity and hydrogen bond propensity tools. Instead, these two latter approaches are recommended at the early stages of coformer selection. In addition, intermolecular energy contribution (lattice energy) to the total energy of crystal forms of coformers was found to be indicative of the feasibility of cocrystal formation in the case of coformers capable of forming similar supramolecular synthons.

Automated summary

Experimental mechanochemical screening of cocrystals with linezolid resulted in the formation of multiple new crystal phases. Virtual cocrystal screening tools, particularly molecular electrostatic potential maps, can help understand molecules' preferences for forming cocrystals with specific coformers. Molecular conformation influences prediction outcomes, with the electrostatic potential map method being more consistent with experimental results compared to molecular complementarity and hydrogen bond propensity tools.