Skip to main content

Advertisement

SpringerLink
Log in

Determination of pKa Values for Some Tyrosine Kinase Inhibitors Using the Reversed-Phase Liquid Chromatography

  • Published:
Journal of Solution Chemistry Aims and scope Submit manuscript

Abstract

The drug dissociation constant (pKa) describes the ionization/protonation states. This physicochemical feature has a direct effect on the ADME properties of the active pharmacological compounds. In this study, using the LC method, the dependence of retention of tyrosine kinase inhibitors, erlotinib, canertinib, and bosutinib which are used in targeted therapy for several types of cancer, on the mobile phase pH was investigated at three different acetonitrile–water buffer compositions, and experimental data were utilized to calculate pKa values and capacity factors. Afterward, Yasuda–Shedlovsky extrapolation and mole fraction of acetonitrile plot used in order to acquire the pKa in aqueous medium. The observed results have been carefully compared to those reported in the literature that were obtained by different approaches. The conclusion is that these findings emphasize the potential of the physicochemical features of medications to aid in the comprehension of several biological systems, including human oral absorption, cell permeability, and protein binding in plasma. In addition, the pKa values of these ionizable molecules in various water–organic binary solutions are useful for the development of separation techniques focused on reversed-phase liquid chromatography and capillary electrophoresis.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

References

  1. Tsimberidou, A.M.: Targeted therapy in cancer. Cancer Chemother. Pharmacol. 76, 1113–1132 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yeuan Ting, L., Yi Jer, T., Chern, E.O.: Molecular targeted therapy: treating cancer with specificity. Eur. J. Pharmacol. 834, 188–196 (2018)

    Article  Google Scholar 

  3. Grunwald, V., Hidalgo., M.: The epidermal growth factor receptor: a new target for anticancer therapy. Curr. Probl. Cancer 26, 109–164 (2002)

    Article  PubMed  Google Scholar 

  4. Rodríguez, J., Castañeda, G., Muñoz, L., et al.: Simultaneous determination of erlotinib and its metabolites in human urine and serum samples by high-performance liquid chromatography. Chromatographia 80, 409–415 (2017)

    Article  Google Scholar 

  5. Pollack, V.A., et al.: Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J. Pharmacol. Exp. Ther. 291, 739–748 (1999)

    CAS  PubMed  Google Scholar 

  6. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021743s025lbl.pdf (accessed 30 September 2022)

  7. Shepherd, F.A., Rodrigues Pereira, J., et al.: Erlotinib in previously treated non–small-cell lung cancer. N Engl J Med. 353(2), 123–132 (2005)

    Article  CAS  PubMed  Google Scholar 

  8. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails (accessed 05 August 2022).

  9. National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium. Available at: https://www.nccn.org/compendia-templates/nccn-templates-main/browse-by-cancer-type (accessed 15 September 2022).

  10. Slichenmyer, W.J., Elliott, W.L., Fry, D.W.: CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin. Oncol. 28, 80–85 (2001)

    Article  CAS  PubMed  Google Scholar 

  11. McIntyre, J.A., Castaner, J., Leeson, P.A.: Canertinib dihydrochloride. Drugs of the Future 30(8), 771–779 (2005)

    Article  CAS  Google Scholar 

  12. Gunhild, K., Schafhausen, P., Brummendorf, T.: Bosutinib: a dual SRC/ABL kinase inhibitor for the treatment of chronic myeloid leukemia. Expert Rev. Hematol. 2(5), 489–497 (2009)

    Article  Google Scholar 

  13. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf (accessed 10 October 2022).

  14. Vallianatou, T., Giaginis, C., Tsantili-Kakoulidou, A.: The Impact of Physicochemical and Molecular Properties in Drug Design: Navigation in the “Drug-Like” Chemical Space. In: GeNeDis 2014, pp. 187–194. Springer, Cham (2015)

    Chapter  Google Scholar 

  15. Avdeef, A.: Physicochemical profiling (solubility, permeability and charge State). Curr. Top. Med. Chem 1, 277–351 (2001)

    Article  CAS  PubMed  Google Scholar 

  16. Manallack, D.T.: The pKa distribution of drugs: application to drug discovery. Perspect. Med. Chem. 1, 25–38 (2007)

    Google Scholar 

  17. Sanli, S., Sanli, N., Alsancak, G.: Determination of protonation constants of some tetracycline antibiotics by potentiometry and LC methods in water and acetonitrile- water binary mixtures. J. Braz. Chem. Soc. 20, 939–946 (2009)

    CAS  Google Scholar 

  18. Gumustas, M., Sanlı, S., Sanlı, N., Ozkan, S.A.: Determination of pKa values of some antihypertensive drugs by liquid Chromatography and simultaneous assay of lercanidipine and enalapril in their binary mixtures. Talanta 82, 1528–1537 (2010)

    Article  CAS  PubMed  Google Scholar 

  19. Erdemgil, F.Z., Sanlı, S., Sanlı, N., Ozkan, G., Barbosa, J., Guiteras, J., Beltran, J.L.: Determination of pKa values of some hydroxylated benzoic acids in methanol–water binary mixtures by LC methodology and potentiometry. Talanta 72, 489–496 (2007)

    Article  CAS  PubMed  Google Scholar 

  20. Demiralay, E.C., Cubuk, B., Alsancak, G., Ozkan, S.A.: Combined effect of polarity and pH on the chromatographic behaviour of some Angiotensin II receptor antagonists and optimization of their determination in pharmaceutical dosage forms. J. Pharm. Biomed. Anal. 53, 475–482 (2010)

    Article  CAS  PubMed  Google Scholar 

  21. Box, K.J., Donkor, R.E., Jupp, P.A., Leader, I.P., Trew, D.F., Turner, C.H.: The chemistry of multi-protic drugs Part 1: a potentiometric, multi-wavelength UV and NMR pH titrimetric study of the micro-speciation of SKI-606. J. Pharm. Biomed. Anal. 47, 303–311 (2008)

    Article  CAS  PubMed  Google Scholar 

  22. http://www.chemicalize.org. (Accessed 20 July 2022).

  23. Pan, X., Wang, H., Li, C., Zhang, J.Z.H., Ji, C.: MolGpka: a web server for small molecule pKa prediction using a graph-convolutional neural network. J. Chem. Inform. Model. 61, 3159 (2021)

    Article  CAS  Google Scholar 

  24. Yasuda, M.: Dissociation constants of some carboxylic acids in mixed aqueous solvents. Bull. Chem. Soc. Jpn. 32, 429–432 (1959)

    Article  CAS  Google Scholar 

  25. Shedlovsky, T.: In: Peasce, B. (ed.) Electrolytes. Pergamon Press. New York (1962)

  26. Rondinini, S., Mussini, P.R., Mussini, T.: Reference value standard and primary standard for pH measurements in organic solvents and water–organic solvent mixtures of moderate to high permittivities. Pure Appl. Chem. 59, 1549–1560 (1987)

    Article  CAS  Google Scholar 

  27. Barbosa, J., Marques, I., Barron, D., Sanz-Nebot, V.: The application of factor analysis to solvatochromic parameters and pHs values for the standardization of potentiometric sensors in mobile phases used in liquid chromatography. Trends Anal. Chem. 18, 543–549 (1999)

    Article  CAS  Google Scholar 

  28. Sherrod, Phillip H. "Nonlinear regression analysis program." Nashville, TN, USA (2005). http:/www.nlreg.com

  29. Barbosa, J., Fonrodona, G., Marqués, I., Sanz-Nebot, V., Toro, I.: Solvent effects on protonation equilibria of peptides and quinolones by factor analysis applied to the correlation between dissociation constants and solvatochromic parameters in acetonitrile–water mixtures. Anal. Chim. Acta. 351, 397–405 (1997)

    Article  CAS  Google Scholar 

  30. Mussini, T., Covington, A.K., Longhi, P., Rondinini, S.: Criteria for standardization of pH measurements in organic solvents and water–organic solvent mixtures of moderate to high permittivities. Pure Appl. Chem. 57, 865–876 (1985)

    Article  Google Scholar 

  31. Barbosa, J., Sanz-Nebot, V.: Autoprotolysis constants and standardization of the glass electrode in acetonitrile-water mixtures effect of solvent composition. Anal. Chim. Acta. 244, 183–190 (1991)

    Article  CAS  Google Scholar 

  32. Barbosa, J., Toro, I., Sanz-Nebot, V.: Acid-base behaviour of tripeptides in solvents used in liquid chromatography. Correlation between pKa values and solvatochromic parameters of acetonitrile–water mixtures. Anal. Chim. Acta. 347, 295–304 (1997)

    Article  CAS  Google Scholar 

  33. Avdeef, A., Box, K.J., Comer, J.E., Gilges, M., Hadley, M., Hibbert, C., Patterson, W., Tam, K.Y.: PH-metric log P 11. pKa determination of water-insoluble drugs in organic solvent–water mixtures. J. Pharm. Biomed. Anal. 20, 631–641 (1999)

    Article  CAS  PubMed  Google Scholar 

  34. Şanli, N., Şanli, S., Özkan, G., Denizli, A.: Determination of pKa values of some sulfonamides by LC and LC-PDA methods in acetonitrile-water binary mixtures. J. Braz. Chem. Soc. 21, 1953–1960 (2010)

    Google Scholar 

  35. Williams, H.D., Ford, L., Han, S., Tangso, K.J., Lim, S., Shackleford, D.M., Vodak, D.T., Benameur, H., Pouton, C.W., Scammells, P.J., Porter, C.J.H.: Enhancing the oral absorption of kinase inhibitors using lipophilic salts and lipid-based formulations. Mole. Pharm. 15(12), 5678–5696 (2018)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The NLREG 4.0 program was graciously provided by Dr. Jose Luis Beltran of the University of Barcelona, and we would like to thank him for that.

Author information

Authors and Affiliations

  1. Department of Chemistry, Faculty of Science and Arts, Uşak University, Uşak, Turkey

    Senem Sanli

  2. Department of Chemistry and Physics, Roger Williams University, One Old Ferry Road, Bristol, RI, 02809, USA

    Nurullah Sanli

Authors
  1. Senem Sanli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nurullah Sanli
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SSanli and NSanli conceived, planned and carried out the experiments. NSanli took the lead in writing the manuscript. Both SSanli and NSanli authors contributed to the final version of the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript.

Corresponding author

Correspondence to Nurullah Sanli.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest to this work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sanli, S., Sanli, N. Determination of pKa Values for Some Tyrosine Kinase Inhibitors Using the Reversed-Phase Liquid Chromatography. J Solution Chem 52, 658–670 (2023). https://doi.org/10.1007/s10953-023-01264-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10953-023-01264-5

Keywords

Search

Navigation