Cocrystallization Enables Ensitrelvir to Overcome Anomalous Low Solubility Caused by Strong Intermolecular Interactions between Triazine–Triazole Groups in Stable Crystal Form

Ensitrelvir is a nonpeptide 3CL protease inhibitor used
for coronavirus
disease 2019 treatment. Four crystalline forms of ensitrelvir, metastable
(Form I), acetonate (Form II), stable (Form III), and hydrate (Form
IV), have been analyzed as pharmaceutical crystals. Their rank order
of solubility is Form I > IV > III. Form III is the stable crystal
with a significantly lower solubility than that predicted from its
log P value of 2.7. Here, single-crystal structural
analysis revealed strong intermolecular interactions between the triazine
(acidic) and triazole (basic) groups of Form III not Forms I and IV.
Multicomponent crystals were also designed to improve the solubility
by altering the intermolecular interactions in Form III. Slurry conversion
with equal molar ratios of ensitrelvir and fumaric acid successfully
induced the formation of a novel cocrystal (Form V). Fumaric acid
inhibited the triazine–triazole interactions, and dissolution
of Form V was approximately 8- and 13-fold higher than that of Form
III in pH 1.2 and 6.8 media, respectively. Furthermore, Form V exhibited
an approximately 16-fold higher flux value than that of Form III.
Therefore, alterations in intermolecular interactions via cocrystallization
significantly enhance the dissolution and permeation of ensitrelvir.