SRX Pharmacology

SRX Pharmacology / 2010 / Article

Research Article | Open Access

Volume 2010 |Article ID 481497 | 10 pages | https://doi.org/10.3814/2010/481497

Recent Progress in the pKa Estimation of Druglike Molecules by the Nonlinear Regression of Multiwavelength Spectrophotometric pH-Titration Data

Received19 Oct 2009
Revised03 Dec 2009
Accepted21 Dec 2009
Published02 Mar 2010

Abstract

Recent developments in the computational diagnostic tools for the pKa estimation of druglike molecules carried out by the nonlinear regression of multiwavelength spectrophotometric pH-titration data are demonstrated on the protonation equilibria of silybin. The factor analysis of spectra predict the correct number of components when the signal-to-error ratio SER is higher than 10. The mixed dissociation constants of the drug silybin at ionic strength I = 0.03 and a temperature of 25C were determined using two different programs, SPECFIT32 and SQUAD(84). A proposed experimental and computational strategy for the determination of the dissociation constants is presented. The dissociation constant pKa was estimated by nonlinear regression of the {pKa,I} data at 25C with SQUAD (and SPECFIT); that is, pKa1 = 6.898(0.022) and 6.897(0.002); pKa2 = 8.666(0.021) and 8.667(0.012); pKa3 = 9.611(0.010) and 9.611(0.004); pKa4 = 11.501(0.008) and 11.501(0.007). While great progress has been achieved in terms of the reliability of the protonation model estimation, among the most efficient diagnostics of the nonlinear regression of multiwavelength pH-spectra are the goodness-of-fit test, Cattel's scree plot of the factor analysis, spectra deconvolution, the signal-to-error SER ratio analysis, and other tools of efficient spectra analysis.

References

  1. F. R. Hartley, C. Burgess, and R. M. Alcock, Solution Equilibria, Ellis Horwood, Chichester, UK, 1980.
  2. M. Meloun, J. Havel, and J. Högfeldt, Computation of Solution Equilibria, Ellis Horwood, Chichester, UK, 1988.
  3. M. Meloun and J. Havel, Computation of Solution Equilibria, Part 1. Spectrophotometry, vol. 25, Folia Facultatis Scientarum Naturalium Universitatis Prkynianae Brunensis (Chemia), Brno, Czech Republic, 1984.
  4. M. Meloun and J. Havel, Computation of Solution Equilibria, Part 2. Potentiometry, vol. 26, Folia Facultatis Scientarum Naturalium Universitatis Prkynianae Brunensis (Chemia), Brno, Czech Republic, 1985.
  5. L. G. Sillén and B. Warnqvist, “Equilibrium constants and model testing from spectrophotometric data, using LETAGROP,” Acta Chemica Scandinavica, vol. 22, p. 3032, 1968. View at: Google Scholar
  6. D. J. Leggett, Ed., Computational Methods for the Determination of Formation Constants, Plenum Press, New York, NY, USA, 1985.
  7. J. Havel and M. Meloun, “General computer programs for the determination of formation constants from various types of data,” in Computational Methods for the Determination of Formation Constants, D. J. Leggett, Ed., pp. 221–289, Plenum Press, New York, NY, USA, 1985. View at: Google Scholar
  8. M. Meloun, M. Javůrek, and J. Havel, “Multiparametric curve fitting-X. A structural classification of programs for analysing multicomponent spectra and their use in equilibrium-model determination,” Talanta, vol. 33, no. 6, pp. 513–524, 1986. View at: Google Scholar
  9. D. J. Leggett and W. A. E. McBryde, “General computer program for the computation of stability constants from absorbance data,” Analytical Chemistry, vol. 47, no. 7, pp. 1065–1070, 1975. View at: Google Scholar
  10. D. J. Leggett, “Numerical analysis of multicomponent spectra,” Analytical Chemistry, vol. 49, no. 2, pp. 276–281, 1977. View at: Google Scholar
  11. D. J. Leggett, S. L. Kelly, L. R. Shiue, Y. T. Wu, D. Chang, and K. M. Kadish, “A computational approach to the spectrophotometric determination of stability constants-II. Application to metalloporphyrin-axial ligand interactions in non-aqueous solvents,” Talanta, vol. 30, no. 8, pp. 579–586, 1983. View at: Google Scholar
  12. J. J. Kankare, “Computation of equilibrium constants for multicomponent systems from spectrophotometric data,” Analytical Chemistry, vol. 42, no. 12, pp. 1322–1326, 1970. View at: Google Scholar
  13. P. Gans, A. Sabatini, and A. Vacca, “Investigation of equilibria in solution. Determination of equilibrium constants with the HYPERQUAD suite of programs,” Talanta, vol. 43, no. 10, pp. 1739–1753, 1996. View at: Publisher Site | Google Scholar
  14. H. Gampp, M. Maeder, C. J. Meyer, and A. D. Zuberbühler, “Calculation of equilibrium constants from multiwavelength spectroscopic data—I: mathematical considerations,” Talanta, vol. 32, no. 2, pp. 95–101, 1985. View at: Google Scholar
  15. H. Gampp, M. Maeder, C. J. Meyer, and A. D. Zuberbühler, “Calculation of equilibrium constants from multiwavelength spectroscopic data—II: specfit: two user-friendly programs in basic and standard fortran 77,” Talanta, vol. 32, no. 4, pp. 251–264, 1985. View at: Google Scholar
  16. H. Gampp, M. Maeder, C. J. Meyer, and A. D. Zuberbühler, “Calculation of equilibrium constants from multiwavelength spectroscopic data—III: model-free analysis of spectrophotometric and ESR titrations,” Talanta, vol. 32, no. 12, pp. 1133–1139, 1985. View at: Google Scholar
  17. H. Gampp, M. Maeder, C. J. Meyer, and A. D. Zuberbühler, “Calculation of equilibrium constants from multiwavelength spectroscopic data—IV: model-free least-squares refinement by use of evolving factor analysis,” Talanta, vol. 33, no. 12, pp. 943–951, 1986. View at: Google Scholar
  18. K. Y. Tam and K. Takács-Novák, “Multi-wavelength spectrophotometric determination of acid dissociation constants: a validation study,” Analytica Chimica Acta, vol. 434, no. 1, pp. 157–167, 2001. View at: Publisher Site | Google Scholar
  19. Z.-P. Chen, Y.-Z. Liang, J.-H. Jiang, Y. Li, J.-Y. Qian, and R.-Q. Yu, “Determination of the number of components in mixtures using a new approach incorporating chemical information,” Journal of Chemometrics, vol. 13, no. 1, pp. 15–30, 1999. View at: Google Scholar
  20. Z.-P. Chen, J.-H. Jiang, Y. Li, H.-L. Shen, Y.-Z. Liag, and R.-Q. Yu, “Smoothed window factor analysis,” Analytica Chimica Acta, vol. 381, no. 2-3, pp. 233–246, 1999. View at: Publisher Site | Google Scholar
  21. M. Meloun, J. Čapek, P. Mikšík, and R. G. Brereton, “Critical comparison of methods predicting the number of components in spectroscopic data,” Analytica Chimica Acta, vol. 423, no. 1, pp. 51–68, 2000. View at: Publisher Site | Google Scholar
  22. M. Meloun and M. Pluhařová, “Thermodynamic dissociation constants of codeine, ethylmorphine and homatropine by regression analysis of potentiometric titration data,” Analytica Chimica Acta, vol. 416, no. 1, pp. 55–68, 2000. View at: Publisher Site | Google Scholar
  23. M. Meloun and P. Černohorský, “Thermodynamic dissociation constants of isocaine, physostigmine and pilocarpine by regression analysis of potentiometric data,” Talanta, vol. 52, no. 5, pp. 931–945, 2000. View at: Publisher Site | Google Scholar
  24. M. Meloun, D. Burkoňová, T. Syrový, and A. Vrána, “Thermodynamic dissociation constants of silychristin, silybin, silydianin and mycophenolate by the regression analysis of spectrophotometric data,” Analytica Chimica Acta, vol. 486, no. 1, pp. 125–141, 2003. View at: Publisher Site | Google Scholar
  25. M. Meloun, T. Syrový, and A. Vrána, “Determination of the number of light-absorbing species in the protonation equilibra of selected drugs,” Analytica Chimica Acta, vol. 489, no. 2, pp. 137–151, 2003. View at: Publisher Site | Google Scholar
  26. M. Meloun, T. Syrový, and A. Vrána, “The thermodynamic dissociation constants of ambroxol, antazoline, naphazoline, oxymetazoline and ranitidine by the regression analysis of spectrophotometric data,” Talanta, vol. 62, no. 3, pp. 511–522, 2004. View at: Publisher Site | Google Scholar
  27. M. Meloun, T. Syrový, and A. Vrána, “The thermodynamic dissociation constants of losartan, paracetamol, phenylephrine and quinine by the regression analysis of spectrophotometric data,” Analytica Chimica Acta, vol. 533, no. 1, pp. 97–110, 2005. View at: Publisher Site | Google Scholar
  28. M. Meloun, T. Syrový, and A. Vrána, “The thermodynamic dissociation constants of haemanthamine, lisuride, metergoline and nicergoline by the regression analysis of spectrophotometric data,” Analytica Chimica Acta, vol. 543, no. 1-2, pp. 254–266, 2005. View at: Publisher Site | Google Scholar
  29. M. Meloun, M. Javůrek, and J. Militký, “Computer estimation of dissociation constants. Part V. Regression analysis of extended Debye-Hückel law,” Mikrochimica Acta, vol. 109, no. 5-6, pp. 221–231, 1992. View at: Publisher Site | Google Scholar
  30. INDICES, http://meloun.upce.cz/, and the block Algorithms.
  31. M. Meloun, S. Bordovská, T. Syrový, and A. Vrána, “Tutorial on chemical model building and testing to spectroscopic data with least-squares regression,” Analytica Chimica Acta, vol. 580, no. 1, pp. 107–121, 2006. View at: Google Scholar
  32. M. Meloun, J. Militký, and M. Forina, Chemometrics for Analytical Chemistry, Vol. 1. PC-Aided Statistical Data Analysis, Ellis Horwood, Chichester, UK, 1992.
  33. M. Meloun, J. Militký, and M. Forina, Chemometrics for Analytical Chemistry, Vol. 2. PC-Aided Regression and Related Methods, Ellis Horwood, Chichester, UK, 1994.
  34. G. L. Amidon, H. Lennernas, and V. P. Shah, “A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability,” Pharmaceutical Research, vol. 12, no. 3, pp. 413–420, 1995. View at: Google Scholar
  35. US Department of Health and Human Service, FDA Center for Drug Evaluation and Research (CDER) Draft Guidance: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Dosage Forms Containing Certain Active Moieties/Active Ingredients Based on a Biopharmaceutic Drug Classification System. CDERGUID-2062 DFT.WPD, January 1999.
  36. The Merck Index, An Encyclopedia of Chemicals, Drugs and Biologicals, Merck & Co., Whitehouse Station, NJ, USA, 13th edition, 2001.
  37. H. Wagner, P. Diesel, and M. Seitz, “Chemistry and analysis of silymarin from Silybum marianum Gaertn,” Arzneimittel-Forschung/Drug Research, vol. 24, no. 4, pp. 466–471, 1974. View at: Google Scholar
  38. V. Šimánek, V. Křen, J. Ulrichová, J. Vičar, and L. Cvak, “Silymarin: what is in the name ...? An appeal for a change of editorial policy,” Journal of Hepatology, vol. 32, no. 2, pp. 442–444, 2000. View at: Publisher Site | Google Scholar
  39. SPECFIT/32: Spectrum Software Associates, 2004, 197M Boston Post Road West, Marlborough, Mass, USA, http://www.bio-logic.info/rapid-kinetics/index.html.
  40. S-PLUS, http://www.insightful.com/products/splus/.
  41. ORIGIN: OriginLab Corporation, One Roundhouse Plaza, Suite 303, Northampton, Mass, USA.

Copyright © 2010 Milan Meloun et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

93 Views | 0 Downloads | 0 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19. Sign up here as a reviewer to help fast-track new submissions.