Multiwavelength UV-metric and pH-metric determination of the dissociation constants of the hypoxia-inducible factor prolyl hydroxylase inhibitor Roxadustat
| Autor: | Tomáš Pekárek, Milan Meloun, Lucie Pilařová, Milan Javůrek |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Isosbestic point
Chemistry 010401 analytical chemistry Enthalpy Protonation Condensed Matter Physics 01 natural sciences Endothermic process Atomic and Molecular Physics and Optics Acid dissociation constant 0104 chemical sciences Electronic Optical and Magnetic Materials Gibbs free energy Dissociation constant 010404 medicinal & biomolecular chemistry symbols.namesake Ionization Materials Chemistry symbols Physical chemistry Physical and Theoretical Chemistry Spectroscopy |
| Zdroj: | Journal of Molecular Liquids. 268:386-402 |
| ISSN: | 0167-7322 |
| DOI: | 10.1016/j.molliq.2018.07.076 |
| Popis: | The dissociation constant pKa of the Roxadustat with UV-VIS spectra, molar absorption coefficients and protonation equilibria are the key physicochemical parameters influencing many biopharmaceutical characteristics. Roxadustat is an orally bioavailable, hypoxia-inducible factor prolyl hydroxylase inhibitor with potential anti-anemic activity. It belongs to Active Pharmacenutical Ingredients, which have 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 LH3 of Roxadustat was dissociated to the soluble anions LH2−, LH2− and L3− or protonated to the cation LH4+ in an aqueous medium. The graph of molar absorption coefficients of variously protonated species according to wavelength shows that the spectra of two anions LH2− and LH2− are nearly the same in colour. The Roxadustat spectrum exhibited five sharp isosbestic points, which were related to the LH2−/L3− equilibrium. Four consecutive thermodynamic dissociation constants were estimated using UV-metric data pKTa1 = 3.60(04), pKTa2 = 5.62(14), pKTa3 = 7.66(16), pKTa4 = 9.08(02) at 25 °C and pKTa1 = 3.60(04), pKTa2 = 5.73(10), pKTa3 = 7.52(10), pKTa4 = 8.99(02) at 37 °C and using pH-metric data pKTa1 = 4.33(09), pKTa2 = 6.57(11), pKTa3 = 8.88(05), pKTa4 = 9.03(04) at 25 °C and pKTa1 = 4.25(09), pKTa2 = 6.49(10), pKTa3 = 8.80(06), pKTa4 = 9.00(05) at 37 °C The positive values of the enthalpy ΔH0 showed that the dissociation process is endothermic and the positive values of the Gibbs free energy ΔG0 at 25 °C indicated that the dissociation process was not spontaneous, which also was confirmed by a negative value of the entropy ΔS0. Four macro-dissociation constants of Roxadustat and six protonation locations were predicted by MARVIN. |
| Databáze: | OpenAIRE |
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