Protonation of Tyrosine Kinase Inhibitor Lapatinib: A Theoretical and Experimental Study

Abstract

The protonation process of tyrosine kinase inhibitor lapatinib was studied by means of 1HNMR and UV/Vis spectroscopy joint with the theoretical calculations at DFT and semi-empirical levels. DFT/M06-2X geometries were used to describe and compare the different cationic forms of lapatinib, while ZINDO/S-CI method performed on those geometries allowed for the interpretation of experimental UV/Vis spectra of lapatinib at various pH. We found that at low pH two different dicationic forms (N2N1 and N1N3) of lapatinib were present in ethanol and DMSO-d6 solutions. The first protonation, however, occurred on the aliphatic N1 in DMSO-d6, while in ethanol solutions most probably the quinazoline nitrogen atom N2 was also protonated.