Ritonavir: an extraordinary example of conformational polymorphism

Pharm Res. 2001 Jun;18(6):859-66. doi: 10.1023/a:1011052932607.


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.

MeSH terms

  • Calorimetry, Differential Scanning
  • Crystallization
  • Crystallography, X-Ray
  • HIV Protease Inhibitors / chemistry*
  • HIV Protease Inhibitors / isolation & purification
  • Hydrogen Bonding
  • Molecular Conformation
  • Nuclear Magnetic Resonance, Biomolecular
  • Ritonavir / chemistry*
  • Ritonavir / isolation & purification
  • Solubility
  • Spectroscopy, Near-Infrared


  • HIV Protease Inhibitors
  • Ritonavir