Cocrystallization\nEnables Ensitrelvir to Overcome\nAnomalous Low Solubility Caused by Strong Intermolecular Interactions\nbetween Triazine–Triazole Groups in Stable Crystal Form

Ensitrelvir is a nonpeptide 3CL protease inhibitor used\nfor coronavirus\ndisease 2019 treatment. Four crystalline forms of ensitrelvir, metastable\n(Form I), acetonate (Form II), stable (Form III), and hydrate (Form\nIV), have been analyzed as pharmaceutical crystals. Their rank order\nof solubility is Form I > IV > III. Form III is the stable crystal\nwith a significantly lower solubility than that predicted from its\nlog <i>P</i> value of 2.7. Here, single-crystal structural\nanalysis revealed strong intermolecular interactions between the triazine\n(acidic) and triazole (basic) groups of Form III not Forms I and IV.\nMulticomponent crystals were also designed to improve the solubility\nby altering the intermolecular interactions in Form III. Slurry conversion\nwith equal molar ratios of ensitrelvir and fumaric acid successfully\ninduced the formation of a novel cocrystal (Form V). Fumaric acid\ninhibited the triazine–triazole interactions, and dissolution\nof Form V was approximately 8- and 13-fold higher than that of Form\nIII in pH 1.2 and 6.8 media, respectively. Furthermore, Form V exhibited\nan approximately 16-fold higher flux value than that of Form III.\nTherefore, alterations in intermolecular interactions via cocrystallization\nsignificantly enhance the dissolution and permeation of ensitrelvir.