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The thermodynamic dissociation constants of methotrexate by the nonlinear regression and factor analysis of multiwavelength spectrophotometric pH-titration data

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Central European Journal of Chemistry

Abstract

The mixed dissociation constants of methotrexate — chemically (2S)-2-[(4-{[(2,4-diamino-7,8-dihydropteridin-6-yl)methyl] (methyl)amino}phenyl)formamido]pentanedioic acid (the cas number 59-05-2) at various ionic strengths I of range 0.01–0.4, and at temperatures of 25°C and 37°C, were determined with the use of two different multiwavelength and multivariate treatments of spectral data, SPECFIT32 and SQUAD(84) nonlinear regression analyses and INDICES factor analysis according to a general rule of first, determining the number of components, and then calculating the spectral responses and concentrations of the components. Concurrently, the experimental determination of the thermodynamic dissociation constants was in agreement with its computational prediction of the PALLAS programme based on knowledge of the chemical structures of the drug. The factor analysis in the INDICES programme predicts the correct number of light-absorbing components when the data quality is high and the instrumental error is known. Three thermodynamic dissociation constants were estimated by nonlinear regression of {pK a , I} data: for methotrexate pK Ta1 = 2.895(13), pK Ta2 = 4.410(14), pK Ta3 = 5.726(15) at 25°C and pK Ta1 = 3.089(15), pK Ta2 = 4.392(12), pK Ta3 = 5.585(11) at 37°C, where the figure in brackets is the standard deviation in last significant digits. The reliability of the dissociation constants of the drug were proven by conducting goodness-of-fit tests of the multiwavelength spectrophotometric pH-titration data.

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Authors and Affiliations

  1. Department of Analytical Chemistry, University of Pardubice, CZ 532 10, Pardubice, Czech Republic

    Milan Meloun & Zuzana Ferenčíková

  2. IVAX Pharmaceuticals, s.r.o., CZ 747 70, Opava, Czech Republic

    Aleš Vrána

Authors
  1. Milan Meloun
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  2. Zuzana Ferenčíková
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  3. Aleš Vrána
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Correspondence to Milan Meloun.

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Meloun, M., Ferenčíková, Z. & Vrána, A. The thermodynamic dissociation constants of methotrexate by the nonlinear regression and factor analysis of multiwavelength spectrophotometric pH-titration data. cent.eur.j.chem. 8, 494–507 (2010). https://doi.org/10.2478/s11532-010-0023-1

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  • DOI: https://doi.org/10.2478/s11532-010-0023-1

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