The dissociation constants of the cytostatic bosutinib by nonlinear least-squares regression of multiwavelength spectrophotometric and potentiometric pH-titration data

Meloun, Milan; Nečasová, Veronika; Javůrek, Milan; Pekárek, Tomáš

doi:10.1016/j.jpba.2015.12.012

Cited by 15 publications

(9 citation statements)

References 18 publications

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“…However, in such a case, a compound must contain a UV-active chromophore close enough to the site of the acid-base function in the molecule. The authors [46][47][48][49] have shown that spectrophotometric titration in combination with suitable chemometric tools can be used to determine dissociation constants pK a even for sparingly soluble drugs [47] [50]. The most relevant algorithms are SQUAD84 [44] and REACTLAB [51].…”

Section: Figmentioning

confidence: 99%

“…Spectrophotometric pH-titration data were treated using the program SQUAD84 [44] and REACTLAB [51] with dissociation constants and molar absorptivity spectral profiles and a distribution diagram of the relative concentrations of the pure species by the nonlinear regression of pH-spectra. A detailed tutorial of the UV-metric titration [42], and alternative pH-metric titration has been previously described [47,50].…”

Section: Computational Detailsmentioning

confidence: 99%

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Multiwavelength UV-metric and pH-metric determination of the dissociation constants of the hypoxia-inducible factor prolyl hydroxylase inhibitor Roxadustat

Meloun

Pilařová

Javůrek

et al. 2018

Journal of Molecular Liquids

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UV-VIS spectra, molar absorption coefficients and protonation equilibriaRoxadustat is an orally bioavailable, hypoxia-inducible factor prolyl hydroxylase inhibitor with potential anti-anemic activity. It is one of the Active Pharmacenutical Ingredients possessing acidic/basic functionalities their ionization state is controlled by solution pH and acid dissociation constants. Nonlinear regression of the pH-spectra with programs REACTLAB and SQUAD84 and of the pH-titration curve with ESAB determined four multiple consecutive dissociation constants with the protonation scheme. A sparingly soluble neutral molecule LH 3 of Roxadustat was dissociated to the soluble anions LH 2-, LH 2-and L 3-or protonated to the cation LH 4 + in an aqueous medium. The graph of molar absorption coefficients of variously protonated species according to wavelength shows that the spectra of two anions LH 2-and LH 2-are nearly the same in colour. The Roxadustat spectrum exhibited five sharp isosbestic points related to the LH 2-/L 3-equilibrium. Four consecutive thermodynamic dissociation constants were estimated using UV-metric data pK T a1 = 3.60(04), pK T a2 = 5.62(14), pK T a3 = 7.66(16), pK T a4 = 9.08(02) at 25°C and pK T a1 = 3.60(04), pK T a2 = 5.73(10), pK T a3 = 7.52(10), pK T a4 = 8.99(02) at 37°C and using pH-metric data pK T a1 = 4.33(09), pK T a2 = 6.57(11), pK T a3 = 8.88(05), pK T a4 = 9.03(04) at 25°C and pK T a1 = 4.25(09), pK T a2 = 6.49(10), pK T a3 = 8.80(06), pK T a4 = 9.00(05) at 37°C The positive values of the enthalpy ΔH 0 showed that the dissociation process is endothermic and the positive values of the Gibbs free energy ΔG 0 at 25°C indicated that the dissociation process was not spontaneous, which also was confirmed by a negative value of the entropy ΔS 0. Four macrodissociation constants of Roxadustat and six protonation locations were predicted by MARVIN.

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Section: Figmentioning

confidence: 99%

Section: Computational Detailsmentioning

confidence: 99%

Multiwavelength UV-metric and pH-metric determination of the dissociation constants of the hypoxia-inducible factor prolyl hydroxylase inhibitor Roxadustat

Meloun

Pilařová

Javůrek

et al. 2018

Journal of Molecular Liquids

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“…Spectrophotometry is a convenient method to determine pK a in very diluted aqueous solutions (about 10 -5 to 10 -6 M), provided that the compound possesses pH-dependent light absorption due to the presence of a chromophore in proximity to the ionization centre [10][11][12]. In previous works [13][14][15][16][17] the authors have shown that the spectrophotometric method in combination with suitable chemometric tools can be used to determine dissociation constants pK a even for sparingly soluble drugs. The most relevant algorithms are SQUAD84 [11,18,19] and REACTLAB [20] or its previous version SPECFIT [21].…”

Section: Introductionmentioning

confidence: 99%

The Thermodynamic Overlapping pKa of the Antitumor Drug Ibrutinib Using Multiwavelength UV/VIS-Spectroscopy and Potentiometry

Meloun¹,

Mikešová²,

Pekárek³

et al. 2017

JAPLR

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Potentiometric and spectrophotometric pH-titrations of the antitumor drug Ibrutinib for dissociation constants determination were compared. Ibrutinib is targeting B-cell malignancies, for treatment of chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Chemometrics approach to the nonlinear regression of the pH-spectra (REACTLAB, SQUAD84) and pH-titration (ESAB) determines four dissociation constants. Ibrutinib exhibits four protonatable centers in a pH range of 2 to 10, where only two pK are well separated (ΔpK > 3), while the others are near dissociation constants of overlapping equilibria. The molecule LH 2 can protonate to sparingly soluble cations LH3+ and LH42+ and dissociate to anions LH -and L 2-. The set of spectra for pH from 2 to 11 in 220 to 300nm exhibits chromophore sensitivity to a pH change. Since pH above 10 and pH below 5 occurs in a titrated solution of a very fine precipitate of Ibrutinib, this part of the potentiometric titration curve pH over 10 and pH below 5 did not undergo regression analysis to estimate pK a´s . Depending on ionic strength the thermodynamic dissociation constants were estimated at 25°C and 37°C: pK a1 T = 3.22 and 3.22, pK a2 T = 4.17 and 5.21, pK a3 T = 6.77 and 6.77, pK a4 T = 9.82 and 9.81. Keywords:

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“…Moreover, the coordination of the Ln 3+ does not significantly influence the singlet-state energy of the ligand. The change of pH does not cause any significant shift in the spectra of the studied systems because some chromophores were only slightly affected by a pH change [52].…”

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confidence: 96%

Potentiometric determination of novel complexes of selected lanthanide ions with N,N’-bis(5-methylsalicylidene)-4-methyl-1,3-phenylenediamine

2017

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The stability constants of the complexes formed in the N,N '-bis(5-methylsalicylidene)-4-methyl-1,3-phenylenediamine (H 2 L) and La(III), Eu(III), Gd(III), Ho(III), and Lu(III) ion systems were determined in solution with the potentiometric method. The pH-metric titrations were performed in dimethyl sulfoxide/water (v:v, 30:70) mixture at 25.0 °C in 0.1 M LiNO 3 ionic strength. The tests were performed for systems with Ln(III) to H 2 L 1:2 and 1:3 molar ratio but only data of the systems with the metal/ligand ratio 1:2 were taken into calculation. The molar ratio 1:1 was not studied because of the high coordination numbers of the lanthanide ions, and inadequate donor atoms of the ligand. Computer analysis (HYPERQUAD software) of potentiometric data indicated that in solution the lanthanide (Ln) complexes exist as LnL 2 , Ln(HL) 2 , and Ln(H 2 L) 2 forms, depending on pH unlike to the solid state where only one form of Ln(H 2 L) 2 occurs. Formation constants increase with decreasing size of the Ln(III) ions. Moreover, complex formation in the Ln 3+ /H 2 L systems in solution was performed using UV-Vis spectrophotometric titration.

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The dissociation constants of the cytostatic bosutinib by nonlinear least-squares regression of multiwavelength spectrophotometric and potentiometric pH-titration data

Cited by 15 publications

References 18 publications

Multiwavelength UV-metric and pH-metric determination of the dissociation constants of the hypoxia-inducible factor prolyl hydroxylase inhibitor Roxadustat

Multiwavelength UV-metric and pH-metric determination of the dissociation constants of the hypoxia-inducible factor prolyl hydroxylase inhibitor Roxadustat

The Thermodynamic Overlapping pKa of the Antitumor Drug Ibrutinib Using Multiwavelength UV/VIS-Spectroscopy and Potentiometry

Potentiometric determination of novel complexes of selected lanthanide ions with N,N’-bis(5-methylsalicylidene)-4-methyl-1,3-phenylenediamine

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