Ion-pair RP-HPLC strategy for resolving polarity-mismatched APIs in sustained-release capsules: an AQbD-driven mechanistic and statistical optimization

A robust ion-pair reversed-phase HPLC (RP-HPLC) method was developed for the simultaneous separation of pseudoephedrine sulfate (PSE) and loratadine (LOR) in sustained-release capsules. Due to the pronounced polarity mismatch between PSE (hydrophilic, log P 0.9) and LOR (lipophilic, log P 5.20), sodium 1-octanesulfonate was employed as an ion-pairing reagent to modulate retention and enhance selectivity. Method development was guided by an Analytical Quality by Design (AQbD) framework using central composite design (CCD) to evaluate the influence of column temperature, pH, organic solvent ratio, and ion-pair concentration. Optimal separation was achieved at pH 2.6, with PSE and LOR exhibiting kʹ values of 2.42 and 5.8, and resolution exceeding 2.0. The method was validated per ICH Q2(R2), showing excellent specificity, linearity (r² > 0.999), accuracy (98–102%), precision (RSD < 2%), and robustness. Mechanistic interpretation revealed electrostatic–hydrophobic dual retention control, providing insight into polarity-bridging strategies in RP-HPLC. This method advances separation science for challenging analyte combinations in complex pharmaceutical matrices.