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Pharm Res. 2001 Jun;18(6):859-66.

Ritonavir: an extraordinary example of conformational polymorphism.

Author information

1
Pharmaceutical Products Division, Abbott Laboratories, North Chicago, Illinois 60045, USA. john.f.bauer@abbott.com

Abstract

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.

PMID:
11474792
DOI:
10.1023/a:1011052932607
[Indexed for MEDLINE]

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