Isostructural Ethanol and Isopropanol Solvates of Nirmatrelvir: Crystal Structures and Physicochemical Characterization

This study reports the successful preparation and detailed characterization of the isostructural ethanol (N-EA) and isopropanol (N-IPA) solvates of nirmatrelvir. Single-crystal X-ray diffraction reveals that both crystallize in the monoclinic P 2₁ space group, exhibiting nearly identical molecular conformations, packing modes, and hydrogen-bond networks. PXRD, TGA/DSC, and hot-stage microscopy confirmed stepwise solvent release, while dynamic vapor sorption demonstrated that the desolvation–resolvation cycle is rapid and strongly affects crystallite integrity. Compared with the solvent-free form N-I, incorporation of ethanol or isopropanol reduces crystal stability, resulting in marked increases in equilibrium solubility (2.6 - 2.9 mg·mL⁻¹ at pH 1.2 and 6.8) and intrinsic dissolution rate (up to 33-fold). These findings demonstrate that isostructural ethanol and isopropanol solvates enable precise modulation of nirmatrelvir’s physicochemical properties and offer a practical strategy for crystal-form engineering.