Ritonavir: an extraordinary example of conformational polymorphism.

PURPOSE: In the summer of 1998, Norvir semi-solid capsules supplies were threatened as a result of a new much less soluble crystal form of ritonavir. This report provides characterization of the two polymorphs and the structures and hydrogen bonding network for each form.
METHODS: Ritonavir polymorphism was investigated using solid state spectroscopy and microscopy techniques including solid state NMR, Near Infrared Spectroscopy, powder X-ray Diffraction and Single crystal X-ray. A sensitive seed detection test was developed.
RESULTS: Ritonavir polymorphs were thoroughly characterized and the structures determined. An unusual conformation was found for form II that results in a strong hydrogen bonding network A possible mechanism for heterogeneous nucleation of form II was investigated.
CONCLUSIONS: Ritonavir was found to exhibit conformational polymorphism with two unique crystal lattices having significantly different solubility properties. Although the polymorph (form II) corresponding to the "cis" conformation is a more stable packing arrangement, nucleation, even in the presence of form II seeds, is energetically unfavored except in highly supersaturated solutions. The coincidence of a highly supersaturated solution and a probable heterogeneous nucleation by a degradation product resulted in the sudden appearance of the more stable form II polymorph.