Exploration of N3H site in nirmatrelvir: Design, synthesis, evaluation, and DFT studies of solvates and cocrystals

This study successfully obtained three new crystal forms of nirmatrelvir targeting its N3H site: the nirmatrelvir isobutyl acetate solvate (Solvate II), cocrystals with triethylene diamine (Cocrystal I) and 4-dimethylaminopyridine (Cocrystal II), along with the previously reported nirmatrelvir methyl tert-butyl ether solvate (Solvate I), and polymorph Form I. Thermal analysis, single-crystal X-ray diffraction, and Fourier-transform infrared spectroscopy characterization were performed on these solvates and cocrystals to confirm their structural correctness. Concurrently, density functional theory calculations were conducted to determine the unit cell parameters of these five crystal forms, with the predicted spectral absorption peaks aligning well with the experimental data. Molecular electrostatic potential and frontier molecular orbital analyses were also carried out to elucidate the structural features of nirmatrelvir and identify its potential binding sites. To comprehensively understand the N3H site, the interaction region indicator functions and energy decomposition analysis, based on force field methods, were used for qualitative and quantitative analysis of intermolecular interactions. The analysis revealed that weak interactions in solvates and cocrystals are primarily dominated by van der Waals forces, while subtle differences in intermolecular weak hydrogen bonds are mainly attributed to dispersion forces. The solubility of these five crystal forms was investigated, and it was found that the enhancement of solubility is closely related to the type of hydrogen bonds and the hydrophilicity of the coformers. These findings offer new insights into the design of nirmatrelvir crystal forms and the study of their properties.