Ritonavir: An Extraordinary Example of Conformational Polymorphism
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
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.
- J. Haleblian and W. McCrone. Pharmaceutical applications of polymorphism. J. Pharm. Sci. 58:911-929 (1969).
- J. Dunitz, and J. Berstein. Disappearing polymorphs. J. Acc. Chem. Res. 28:193-200 (1995).
- M. Hassan, M. S. Salem, M. S. Sueliman, and N. M. Najib. Characterization of famotidine polymorphs. Int. J. Pharm. 149:227-232 (1997).
- N. V. Phadnis and R. Suryanarayanan. Polymorphism in anhydrous theophylline—Implications on the dissolution rate of theophylline tablets. J. Pharm. Sci. 86:1256-1263 (1997).
- R. Li, P. T. Mayer, J. Trivedi, and J. Fort. Polymorphism and crystallization behavior of Abbott-79175, a second generation 5-lipoxygenase inhibitor. J. Pharm. Sci. 85:773-780 (1996).
- D. Apperley, R. Fletton, R. Harris, R. Lancaster, S. Tavener, and T. Threlfall. Sulfathiazole polymorphism studied by magic-angle spinning NMR. J. Pharm. Sci. 88:1275-1280 (1999).
- M. Kuhnert-Brandstätter. Demonstration of the terms enantiotropy and monotropy in polymorphism research exemplified by flurbiprofen. J. Pharm. Sci. 88:103-108, (1999).
- C. Spancake. Solubility behavior of lamivudine crystal forms in recrystallization solvents. J. Pharm. Sci. 85:193-199 (1996).
- L. Carima. Crystal forms of piroxicam pivalate: Preparation and characterization of two polymorphs. J. Pharm. Sci. 87:333-337 (1998).
- Remington's Pharmaceutical Sciences, Osol, A Mack Publishing Co, 1980 pp. 1358.
- H. L. Sham, C. Zhao, K. D. Stewart, D. Betebenner, S. Chang, H. Park, X. Kong, W. Rosenbrook, Jr., T. Herrin, D. Madigan, S. Vasavanonda, N. Lyons, A. Molla, A. Saldivar, K. C. Marsh, E. McDonald, N. E. Wideburg, J. F. Denissen, T. Robins, D. J. Kempf, J. J. Plattner, and D. W. Norbeck. A novel picomolar inhibitor of HIV type1 protease. J. Med. Chem. 39:392-397 (1996).
- D. Kempf, K. C. Marsh, J. F. Denissen, E. McDonald, S. Vasavanonda, C. A. Flentge, B. E. Green, L. Fino, C. H. Park, X. P. Kong, N. E. Wideburg, A. Saldivar, L. Ruiz, W. M. Kati, H. L. Sham, T. Robins, K. D. Stewart, A. Hsu, J. J. Plattner, J. M. Leonard, and D. W. Norbeck. ABT-538 is a potent inhibitor of Human Immunodeficiency Virus protease and has high oral bioavailability. Proc. Natl. Acad. Sci. 92:2484-2488 (1995).
- H. L. Sham, C. Zhao, K. C. Marsh, D. A. Betebenner, S. Q. Lin, E. Mcdonald, S. Vasavanonda, N. Wideburg, A. Saldivar, T. Robins, D. J. Kempf, J. J. Plattner, D. W. Norbeck. Potent inhibitors of HIV-1 protease with good oral bioavailabilities. Biochem. Biophys. Res. Commun. 211:159-165 (1995).
- W. I. Higuchi, P.K. Lau, T. Higuchi, J. W. Shell. Polymorphism and drug availability. J. Pharm. Sci. 52:150 (1963).
- J. Berridge. Proceedings of the Fourth International Conference on Harmonization, Brussels, P.F. D'Arcy, D. W. G. Harron (eds.), Physico-Chemical Characteristics of Drug Substances, Queen's University of Belfast, 1997 p. 66.
- S. R. Byrn, R. Pfeiffer, and J. Stowell. Solid-State Chemistry of Drugs, second edition, SSCI Inc., 1999 p. 148.
- H. Brittain, S.J. Bogdanowich D. E. Bugay, J. DeVincentis, G. Lewens, and A. Newman. Physical characterization of pharmaceutical solids. Pharm. Res. 8:963-973 (1991).
- W. Ostwald. Uber die vermeintliche Isomeric des roten und gelben Quecksilberoxyds und die Oberflashen spannung fester Korper. Z. Physikal Chem. 34:495-503 (1900).
- A. Burger and R. Ramberger. On the polymorphism of pharmaceuticals and other molecular crystals I. Mikrochim. Acta (Wien) II:259-271 (1979).
- A. Burger and R. Ramberger. On the polymorphism of pharmaceuticals and other molecular crystals II. Mikrochim. Acta (Wien) II:273-316, (1979).
- Ritonavir: An Extraordinary Example of Conformational Polymorphism
Volume 18, Issue 6 , pp 859-866
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers-Plenum Publishers
- Additional Links
- crystal forms
- AIDS drug
- Industry Sectors