Abstract
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.
Highlights
Recent years have witnessed an enormous interest in pharmaceutical cocrystal formation,[1−6] including introducing several drugs into the market in their cocrystal forms
Virtual cocrystal screening tools have attracted a lot of scientific attention with potential for rationalizing the choice of the most appropriate coformers for a given molecule of interest
Our work shows that they may be useful to indicate the most viable coformers worth to be tested experimentally but can help to understand the factors governing the formation of cocrystals in the case of a particular active pharmaceutical ingredient (API)
Summary
Recent years have witnessed an enormous interest in pharmaceutical cocrystal formation,[1−6] including introducing several drugs into the market in their cocrystal forms (among them a cocrystal of ertugliflozin and L-pyroglutamic acid sold under the brand name of Steglatro,[7] a drug−drug cocrystal containing valproic acid and sodium valproate marketed as Depakote,[8] and a cocrystal of celecoxib and tramadol awaiting Food and Drug Administration evaluation[9]). Since it is known that compounds bound together in one crystal lattice have similar 1H relaxation times, the differences observed here further confirm that a cocrystal between LIN and VA was not formed In such a manner, based primarily on the analysis of the 13C CPMAS NMR spectra recorded for all pure components and reaction mixtures obtained after mechanochemical grinding with LIN under different conditions, the formation of LIN cocrystals was evaluated, and if confirmed by the NMR results, corroborated with PXRD, DSC, and TGA measurements. All these experimental data are provided in the Supporting Information. A more diverse selection of coformers could have yielded different results, indicating that MC and HBP approaches may be more beneficial at the early stages of potential coformer selection, while energy-based criteria (MEP maps and intermolecular energy differences) can be more decisive for similar compounds
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