Ritonavir: An extraordinary example of conformational polymorphism

Purpose. In the summer of 1998, Norvir semi-solid capsules supplies were th reatened as a result of a new much less soluble crystal form of ritonavir. This report provides characterization of the two polymorphs and the structu res and hydrogen bonding network for each form. Methods. Ritonavir polymorphism was investigated using solid state spectros copy and microscopy techniques including solid state NMR, Near Infrared Spe ctroscopy, powder X-ray Diffraction and Single crystal X-ray. A sensitive s eed detection test was developed. Results. Ritonavir polymorphs were thoroughly characterized and the structu res 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 wit h two unique crystal lattices having significantly different solubility pro perties. Although the polymorph (form II) corresponding to the "cis" confor mation is a more stable packing arrangement, nucleation, even in the presen ce of form II seeds, is energetically unfavored except in highly supersatur ated solutions. The coincidence of a highly supersaturated solution and a p robable heterogeneous nucleation by a degradation product resulted in the s udden appearance of the more stable form II polymorph.