Overlapping pKa of the Multiprotic Hemostyptic Eltrombopag using UV–Vis Multiwavelength Spectroscopy and Potentiometry

• Published in: Journal of solution chemistry 2017, Vol.46 (11), p.2014-2037
• Main Authors: Meloun, Milan, Pilařová, Lucie, Pekárek, Tomáš, Javůrek, Milan
• Format: Article
• Language: English
• Subjects: Chemistry; Chemistry and Materials Science; Condensed Matter Physics; Geochemistry; Industrial Chemistry/Chemical Engineering; Inorganic Chemistry; Oceanography; Physical Chemistry
• ISSN: 0095-9782; 1572-8927
• DOI: 10.1007/s10953-017-0682-z

Dissociation constants of the multiprotic hemostyptic Eltrombopag determined by pH-potentiometric and WApH-spectrophotometric titrations are compared. Hemostyptic and hemostatic Eltrombopag treats low blood platelet counts in adults with chronic immune idiopathic thrombocytopenia ITP. Eltrombopag has five protonatable sites in a pH range of 2–10, where only two p K are well separated (Δp K  > 3), while the other three are near dissociation constants of overlapping equilibria. According to the MARVIN prediction, in neutral medium Eltrombopag occurs in the slightly water soluble form LH 3 that can be protonated to the soluble species LH 4 + and LH 5 2 + The molecule LH 3 can be dissociated to still difficultly soluble species LH 2 - , LH 2 - and L 3 - . Due to the limited solubility of Eltrombopag above pH = 9.5 the protonation was studied up to pH = 10. Five dissociation constants can be reliably determined with REACTLAB and SQUAD84 leading to the same values. From a dependence on ionic strength, the thermodynamic dissociation constants were estimated at 25 °C: p K a 1 T  = 2.69, p K a 2 T  = 6.97, p K a 3 T  = 7.13, p K a 4 T  = 7.65, p K a 5 T  = 8.30. At pH values above 10 and pH below 5 a very fine precipitate of Eltrombopag, forming a slight opalescence, was observed; thus measurements of the potentiometric titration curve above pH = 9 and pH below 5 were excluded from the regression analysis to estimate p K a2  = 6.59(01), p K a3  = 7.56(04), p K a4  = 8.48(59) and p K a5  = 9.29(34) at 25 °C with ESAB. Graphical Abstract