Crystal Structure of Ritonavir Polymorphs I and II Revisited with the Application of NMR Crystallography

Abstract Ritonavir, a protease inhibitor sold under the brand name Norvir®, is an antiviral medication that effectively targets the human immunodeficiency virus (HIV). Being probably the most important and best‐known example of the crystal polymorphism in the field of pharmaceutics, ritonavir has been extensively studied in the last 30 years, which eventually led to the discovery of its new polymorph, Form III, in 2023. So far, two crystal structures of both Forms I and II of ritonavir were deposited in CCDC database. The aim of this study was to revisit those crystal structures, using NMR crystallography by recording the 13 C CP/MAS NMR spectra and performing GIPAW NMR calculations with CASTEP. The obtained results revealed the major discrepancies between the calculated and experimental NMR chemical shift values. Those differences were explained at the molecular level, as resulting from the differences in the experimentally determined and DFT‐optimized positions of some atoms, mostly those forming phenyl and thiazole rings. This work is an example of how NMR crystallography can be used to verify and improve the already published crystal structures.