Density Functional Theory-Supported Studies of the Spectrophotometric Determination of Tramadol via Charge-Transfer Complexation with Picric Acid

Charge-transfer (CT) complexation offers a valuable strategy in pharmaceutical analysis for determining active pharmaceutical ingredients in both pure and formulated forms. In this study, tramadol hydrochloride (TM) acted as an electron donor and 2,4,6-trinitrophenol (picric acid, PA) as a π-acceptor, forming a stable 1 : 1 CT complex in acetonitrile. The reaction was optimized for spectrophotometric quantification, showing linearity over 30–180 μg/mL with high correlation coefficient. The method was validated according to the International Council for Harmonization guidelines, demonstrating satisfactory accuracy, precision, selectivity, and sensitivity. Application to commercial tramadol formulations confirmed its suitability for routine quality control. Complementary density functional theory (DFT) and time-dependent-DFT calculations provided molecular-level insight into the CT mechanism. Frontier molecular orbital analysis verified electron transfer from TM (highest occupied molecular orbital) to PA (lowest unoccupied molecular orbital), while molecular electrostatic potential mapping identified favorable donor-acceptor regions stabilizing the complex. Overall, the combined experimental-theoretical approach establishes a simple, rapid, and reliable spectrophotometric method for TM determination.