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 and variable-temperature powder X-ray diffraction over a temperature range of 173 K to 293 K and differential scanning calorimetry. The results showed that the two forms are isostructural, having the same orthorhombic system with space group P2₁2₁2₁ and different unit cell parameters; especially, the a unit decreased from 9.68 Å to 9.24 Å from 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 that of 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, a potential mechanism behind the polymorph transition is elucidated.