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 p K 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 p K 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 p K a constants in the gas phase are were found to be in close agreement with experimental data. In addition, the errors in the p K 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 H 2 O and H 3 O + suppress the total stable H 3 O + count to some extent.