Reversible single-crystal-to-single-crystal phase transition of Nirmatrelvir

Abstract

Reversible single-crystal-to-single-crystal (SCSC) transformation induced by temperature was found for Nirmatrelvir, resulting in two polymorphs of Nirmatrelvir (Form 1 and Form 4). Their structures were characterized using variable-temperature single-crystal X-ray diffraction, variable-temperature powder X-ray diffraction over the temperature range of 173 K to 293 K, and differential scanning calorimetry. The results showed that the two forms belonged to iso-structural, which have the same orthorhombic system with space group P212121 and different unit cell parameters, especially the a unit decreasing from 9.68 Å to 9.24 Å when compared Form 1 to Form 4. Form 1 remains stable at temperatures exceeding 273 K, whereas Form 4 is stable at temperatures below 268 K. The structure of Form 4 is distinguished from Form 1 solely by the molecular conformation, with the molecular arrangements remaining essentially unchanged, indicative of an isostructural conformational transformation. The transition from Form 1 to Form 4 at 268 K exemplifies a first-order solid-state phase transition, marked by a significant enthalpy difference between the polymorphs, suggesting a relatively low kinetic barrier for this transition. By combining Hirshfeld surface analysis and energy networks have elucidated the potential mechanism behind the polymorph transition.