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

Abstract

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 LH2 can protonate to sparingly soluble cations LH3+ and LH42+ and dissociate to anions LH- and L2-. 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 pKa´s. Depending on ionic strength the thermodynamic dissociation constants were estimated at 25°C and 37°C: pKa1T = 3.22 and 3.22, pKa2T = 4.17 and 5.21, pKa3T = 6.77 and 6.77, pKa4T = 9.82 and 9.81.