Predicting the ritonavir crisis by revisiting the polymorph landscape with crystal structure prediction and form 4 structure solution

The transformation of ritonavir form 1 into a less soluble form 2 is the most notorious example of the risks associated with crystal polymorphism in pharmaceuticals. Since then, significant advancements have occurred in the field of theoretical crystal structure prediction, which forecasts the potential polymorphs of a molecule and their stability ranking. However, a question remains whether in silico modeling would have predicted the ritonavir disaster and informed appropriate action. Furthermore, the experimental landscape of ritonavir remains incomplete as no solution of form 4 has been deposited. Here, we show that CSP would have foreseen the existence of more stable then-unfound form 2 of ritonavir at room temperature. From a risk standpoint, the threat posed by this polymorph would have been considered severe due to its unique conformational and structural characteristics, combined with the formulation's low tolerance for solubility reduction. This would have prompted additional work that could have averted the crisis. Furthermore, we determined the crystal structure of form 4 of ritonavir by three-dimensional electron diffraction, combined with in silico modeling and experimental powder X-ray diffraction, revealing a disordered motif and proving it is thermodynamically unstable.