QbD‐Based HPLC Method Development for Trace‐Level Detection of Genotoxic 3‐Methylbenzyl Chloride in Meclizine HCl Formulations

A robust and sensitive reversed-phase HPLC method was developed and validated for the quantitative determination of 3-methyl benzyl chloride, a potential genotoxic process impurity, in Meclizine HCl formulations. The separation was achieved on a C18 column using an isocratic mobile phase consisting of a 0.025-M sodium 1-heptanesulfonate buffer (pH 4.0, adjusted with 0.1 N sulfuric acid) and acetonitrile (600:400, v/v). Detection was performed at 210 nm. A quality-by-design approach, specifically a Box-Behnken design, was employed to optimize key chromatographic parameters including flow rate, acetonitrile concentration, and column temperature. The impact of these critical method variables was evaluated on retention time, tailing factor, and theoretical plate count to ensure method robustness and optimal performance. The method was validated per ICH guidelines, assessing specificity, linearity, accuracy, precision, robustness, and limits of detection (LOD) and quantification (LOQ). The LOD and LOQ were determined to be 0.016% and 0.048%, respectively, allowing for trace-level detection of 3-methyl benzyl chloride. The method demonstrated excellent specificity, sensitivity, accuracy (recoveries 95.1%-102.1%), and precision (RSD ≤ 10.0%). This validated and QbD-optimized method is suitable for routine quality control analysis in pharmaceutical manufacturing, ensuring the safety and regulatory compliance of Meclizine HCl formulations.