Skip to main content
SpringerLink
Log in

Host–guest complexation of omeprazole, pantoprazole and rabeprazole sodium salts with cyclodextrins: an NMR study on solution structures and enantiodiscrimination power

  • Original Article
  • Published:
Journal of Inclusion Phenomena and Macrocyclic Chemistry Aims and scope Submit manuscript

Abstract

The application of different cyclodextrins (CDs) as NMR chiral solvating agents (CSAs) for the sodium salts of the proton-pump inhibitors omeprazole, pantoprazole (sesquihydrate) and rabeprazole was investigated. It was proved that the formation of diastereomeric host–guest complexes in D2O solution between the CDs and those substrates permitted the direct 1H NMR discrimination of the enantiomers of the sodium salts of these compounds without the need of previous working-up. Rotating frame nuclear overhauser effect spectroscopy (ROESY) was used to ascertain the solution geometries of the host–guest complexes. The results suggested a preferential binding of the benzimidazole moiety of the guest molecules within the macrocyclic cavity of α-CD, whereas the higher dimensions of β- and γ-CD also permitted the inclusion of the highly substituted pyridine moieties. Moreover, the solution stoichiometries and the binding constants of the complexes formed with pantoprazole at room temperature were determined by 1H and 19F NMR titration. Diffusion-filtered Spectroscopy was applied to obtain clean spectra without the interference of the HOD signal.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

Similar content being viewed by others

Notes

  1. Omeprazole and its analogues present tautomerism in the benzimidazole group [1]. Therefore, both tautomers must be considered in compounds 1 and 2 when using the systematic nomenclature. For simplicity, only the 5-substituted tautomers are represented in Fig. 1.

  2. The measured pDs of freshly prepared solutions were in all cases around 10.

  3. H-16 signal (for the α- and β-CD complexes) and H-4 signal (for the γ-CD complex) were found to give the best linear fits (the squares of correlation coefficients, R2, were equal to 0.9988, 0.9892 and 0.9980 respectively).

References

  1. Claramunt, R.M., López, C., Alkorta, I., Elguero, J., Yang, R., Schulman, S.: The tautomerism of Omeprazole in solution: a 1H and 13C NMR study. Magn. Reson. Chem. 42, 712–714 (2004)

    Article  CAS  Google Scholar 

  2. Lindberg, P., Brändström, A., Wallmark, B., Mattsson, H., Rikner, L., Hoffman, K.J.: Omeprazole: the first proton pump inhibitor. Med. Res. Rev. 10, 1–54 (1990)

    Article  CAS  Google Scholar 

  3. Shi, S., Klotz, U.: Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur. J. Clin. Pharmacol. 64, 935–951 (2008)

    Article  CAS  Google Scholar 

  4. Olbe, L., Carlsson, E., Lindberg, P.: A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nat. Rev. Drug Discov. 2, 132–139 (2003)

    Article  CAS  Google Scholar 

  5. Andersson, T., Weidolf, L.: Stereoselective disposition of proton pump inhibitors. Clin. Drug Investig. 28, 263–279 (2008)

    Article  CAS  Google Scholar 

  6. Anon.: Development of new stereoisomeric drugs. Food and Drug Administration. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122883.htm. Accessed 5 September 2011

  7. Branch, S.: International regulation of chiral drugs. In: Subramanian, G. (ed.) Chiral Separation Techniques. A Practical Approach, pp. 319–342. Wiley-VCH, Weinheim (2001)

    Google Scholar 

  8. Weisman, G.R.: Nuclear magnetic resonance analysis using chiral solvating agents. Asymm. Synth. 1, 153–171 (1983)

    CAS  Google Scholar 

  9. Wenzel, T.J.: Lanthanide chiral solvating agent couples as chiral NMR shift reagents. Trends Org. Chem. 8, 51–64 (2000)

    CAS  Google Scholar 

  10. Yamaguchi, S.: Nuclear magnetic resonance analysis using chiral derivatives. Asymm. Synth. 1, 125–152 (1983)

    CAS  Google Scholar 

  11. Wenzel, T.J., Wilcox, J.D.: Chiral reagents for the determination of enantiomeric excess and absolute configuration using NMR spectroscopy. Chirality 15, 256–270 (2003)

    Article  CAS  Google Scholar 

  12. Courtieu, J., Lesot, P., Meddour, A., Merlet, D., Aroulanda, C.: Chiral liquid crystal NMR: a tool for enantiomeric analysis. In: Grant, D.M., Harris, R. (eds.) Encyclopedia of Nuclear Magnetic Resonance, pp. 497–505. Wiley, New York (2002)

    Google Scholar 

  13. Sugiura, M., Kimura, A., Fujiwara, H.: Discrimination of enantiomers by means of NMR spectroscopy using chiral liquid crystalline solution: application to triazole fungicides, uniconazole and diniconazole. Magn. Reson. Chem. 44, 121–126 (2006)

    Article  CAS  Google Scholar 

  14. Greatbanks, D., Pickford, R.: Cyclodextrins as chiral complexing agents in water, and their application to optical purity measurements. Magn. Reson. Chem. 25, 208–215 (1987)

    Article  CAS  Google Scholar 

  15. Redondo, J., Blázquez, M.A., Torrens, A.: Chiral discrimination of the analgesic cizolirtine by using cyclodextrins: a 1H NMR study on the solution structures of their host-guest complexes. Chirality 11, 694–700 (1999)

    Article  CAS  Google Scholar 

  16. Szejtli, J.: Introduction and general overview of cyclodextrin chemistry. Chem. Rev. 98, 1743–1753 (1998)

    Article  CAS  Google Scholar 

  17. Cserhati, T.: Cyclodextrins in HPLC. Encyclopedia of Chromatography, vol. 1, 3rd edn., pp. 546–556 (2010)

  18. Cserhati, T.: Cyclodextrins in GC. Encyclopedia of Chromatography, vol. 1, 3rd edn., pp. 536–545 (2010)

  19. Chankvetadze, B.: Chiral compounds: separation by CE and MEKC with cyclodextrins. Encyclopedia of Chromatography, vol. 1, 3rd edn, pp. 419–424 (2010)

  20. Thunhorst, M., Holzgrabe, U.: Utilizing NMR spectroscopy for assessing drug enantiomeric composition. Magn. Reson. Chem. 36, 211–216 (1998)

    Article  CAS  Google Scholar 

  21. Cirilli, R., Ferretti, R., Gallinella, B., De Santis, E., Zanitti, L., La Torre, F.: High-performance liquid chromatography enantioseparation of proton pump inhibitors using the immobilized amylose-based Chiralpak IA chiral stationary phase in normal-phase, polar organic and reversed-phase conditions. J. Chromatogr. A 1177, 105–113 (2008)

    Article  CAS  Google Scholar 

  22. Berzas-Nevado, J.J., Castaneda-Penalvo, G., Rodríguez-Dorado, R.M.: Method development and validation for the separation and determination of omeprazole enantiomers in pharmaceutical preparations by capillary electrophoresis. Anal. Chim. Acta 533, 127–133 (2005)

    Article  Google Scholar 

  23. Toribio, L., Alonso, C., del Nozal, M.J., Bernal, J.L., Jiménez, J.J.: Enantiomeric separation of chiral sulfoxides by supercritical fluid chromatography. J. Sep. Sci. 29, 1363–1372 (2006)

    Article  CAS  Google Scholar 

  24. Figueiras, A., Sarraguça, J.M.G., Carvalho, R.A., Pais, A.A.C.C., Veiga, F.J.B.: Interaction of omeprazole with a methylated derivative of β-cyclodextrin: phase solubility, NMR spectroscopy and molecular simulation. Pharm. Res. 24, 377–389 (2007)

    Article  CAS  Google Scholar 

  25. Redondo, J., Capdevila, A., Latorre, I.: Use of (S)-BINOL as NMR chiral solvating agent for the enantiodiscrimination of omeprazole and its analogs. Chirality 22, 472 (2010)

    CAS  Google Scholar 

  26. Coppi, L., Berenguer, R.: Method for obtaining derivatives of [[substituted-pyridyl)methyl]thio]benzimidazole, useful as intermediates for omeprazole and related antiulcer agents. PCT Int. Appl. WO 2001079194 A1

  27. Berenguer, R., Campón, J., Coppi, L.: Method for oxidizing a thioether group into a sulfoxide group in benzimidazole derivatives. PCT Int. Appl. WO 2001068594 A1

  28. Coppi, L., Berenguer, R., Gasanz, Y., Medrano, J.: Process for the preparation of optically active derivatives of 2-(2-pyridylmethylsulfinyl)-benzimidazole via inclusion complex with 1,1′-binaphthalene-2,2′-diol. PCT Int. Appl. WO 2006094904 A1

  29. Anon.: Esomeprazole magnesium trihydrate monograph. European Pharmacopoeia 6th edition 2009 (http://online.pheur.org/entry.htm)

  30. Esturau, N., Espinosa, J.F.: Optimization of diffusion-filtered NMR experiments for selective suppression of residual nondeuterated solvent and water signals from 1H NMR spectra of organic compounds. J. Org. Chem. 71, 4103–4110 (2006)

    Article  CAS  Google Scholar 

  31. Figueiras, A., Sarraguça, J.M.G., Pais, A.A.C.C., Veiga, F.J.B., Carvalho, R.A.: New insight into the discrimination between omeprazole enantiomers by cyclodextrins in aqueous solution. J. Incl. Phenom. Macrocycl. Chem. 62, 345–351 (2008)

    Article  CAS  Google Scholar 

  32. Braga, S.S., Ribeiro-Claro, P., Pillinger, M., Gonçalves, I.S., Fernandes, A.C., Pereira, F., Romao, C.C., Correa, P.B., Teixeira-Dias, J.J.C.: Interactions of omeprazole and precursors with β-cyclodextrin host molecules. J. Incl. Phenom. Macrocycl. Chem. 47, 47–52 (2003)

    Article  CAS  Google Scholar 

  33. Scott, R.L.: Some comments on the Benesi Hildebrand equation. Rec. Trav. Chim. 75, 787 (1956)

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Research and Development, Esteve Química S.A., Caracas Street 17-19, 08030, Barcelona, Spain

    Jordi Redondo, Anna Capdevila, Isabel Latorre & Jordi Bertrán

Authors
  1. Jordi Redondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Capdevila
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabel Latorre
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jordi Bertrán
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jordi Redondo.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 379 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Redondo, J., Capdevila, A., Latorre, I. et al. Host–guest complexation of omeprazole, pantoprazole and rabeprazole sodium salts with cyclodextrins: an NMR study on solution structures and enantiodiscrimination power. J Incl Phenom Macrocycl Chem 73, 225–236 (2012). https://doi.org/10.1007/s10847-011-0046-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10847-011-0046-z

Keywords

Search

Navigation