Determination of Retention Behavior and p <i>K</i> _a Values of Some Phenothiazines with Green Chemistry Approach

In this study, environmentally friendly and conventional analytical methods based on green chemistry principles were developed to determine the dissociation constant (p<i>K</i> _a) values of phenothiazine derivatives promethazine, promazine, and trimeprazine by reverse-phase liquid chromatography (RPLC). The retention values of the compounds were determined at a constant flow rate of 1 mL/min using mobile phases containing different concentrations of ethanol (EtOH) and acetonitrile (ACN) in the pH range of 5.5-11.5. The p<i>K</i> _a (_s ^sp<i>K</i> _a) values of the compounds in water-EtOH and water-ACN (50, 55, 60%, v/v) binary mixtures were determined at two different temperatures (25, 37 °C) using a Kinetex EVO C18 Core-Shell column (150 × 4.6 mm ID, 5 μm). Using the _s ^sp<i>K</i> _a values of the compounds in the mobile phase environment and the macroscopic constants (mole fraction, dielectric constant) of the solvent used, the aqueous p<i>K</i> _a (_w ^wp<i>K</i> _a) values of these compounds, which are moderately soluble in water, were calculated. Accordingly, for promethazine, promazine, and trimeprazine, the values were calculated as 9.821, 10.407, and 10.110 at 25 °C and 9.787, 9,836, and 10.027 at 37 °C, respectively. The Green Solvent Selection Tool, the Analytical Greenness Metric Approach, the Green Analytical Procedure Index, and the Blue Applicability Grade Index were applied to assess the environmental impacts of both the green and conventional RPLC methods developed in the study.