Ionization Efficiency and Protonation Mechanisms of Tenoxicam and Piroxicam Drug Active Compounds in Water and Water-Acetonitrile Mixtures

Abstract

Herein, the ionization efficiency of different acetonitrile-water media for tenoxicam and piroxicam molecules was investigated using the high-performance liquid chromatography (HPLC) method, and their aqueous pK a values were calculated using the mole fraction and Yasuda-Shedlovsky equations. Additionally, the increase in solubility upon the addition of acetonitrile to the medium was simulated using the quantum mechanical model DFTB3 (Third-order density functional tight binding). The pK a constants of tenoxicam and piroxicam compounds were also calculated using the semi-empirical PM6-D3H4X model implemented in MOPAC (molecular orbital package). It is observed that the pK a constants in the gas phase are were found to be in close agreement with experimental data. In addition, the errors in the pK a constants obtained in solution are discussed and the most suitable proton transfer mechanism is determined. Concurrently, the intermediates formed during proton transfer were determined using the Mann-Kendall value, while their formation rates were calculated using the classical ReaxFF model. Microscopic reactive factors affecting the formation and dissociation mechanisms of the highest-population intermediate, hydronium, were determined by following the movement traces of atoms at the femtosecond level. Furthermore, the faster elastic collisions between H2O and H3O+ suppress the total stable H3O+ count to some extent.