Overlapping p K a of the Multiprotic Hemostyptic Eltrombopag using UV–Vis Multiwavelength Spectroscopy and Potentiometry

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 pK are well separated (ΔpK > 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 LH3 that can be protonated to the soluble species $$ {\text{LH}}_{4}^{ + } $$ and $$ {\text{LH}}_{5}^{2 + } $$ The molecule LH3 can be dissociated to still difficultly soluble species $$ {\text{LH}}_{2}^{ - } $$ , $$ {\text{LH}}^{2 - } $$ and $$ {\text{L}}^{3 - } $$ . 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: $$ {\text{p}}K_{{{\text{a}}1}}^{\text{T}} $$  = 2.69, $$ {\text{p}}K_{{{\text{a}}2}}^{\text{T}} $$  = 6.97, $$ {\text{p}}K_{{{\text{a}}3}}^{\text{T}} $$  = 7.13, $$ {\text{p}}K_{{{\text{a}}4}}^{\text{T}} $$  = 7.65, $$ {\text{p}}K_{{{\text{a}}5}}^{\text{T}} $$  = 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 pK a2 = 6.59(01), pK a3 = 7.56(04), pK a4 = 8.48(59) and pK a5 = 9.29(34) at 25 °C with ESAB.