Analytical And Bioanalytical Methods for The Determination of Naratriptan: A Critical Review with Regulatory Perspectives

Naratriptan, a selective serotonin receptor agonist, is widely used for the treatment of acute migraine attacks. Accurate determination of naratriptan in pharmaceutical formulations and biological samples is crucial for quality control, pharmacokinetic evaluation, and bioequivalence assessment. Over the years, several analytical approaches have been developed for its quantification, including spectrophotometry, high-performance liquid chromatography (HPLC), ultra-performance liquid chromatography (UPLC), and liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). Among these techniques, LC–MS/MS has demonstrated markedly superior sensitivity, with reported lower limits of quantification ranging from 0.05 to 0.2 ng/mL, significantly outperforming conventional HPLC and spectrophotometric methods. Although spectrophotometric and HPLC procedures remain useful for routine pharmaceutical quality control, LC–MS/MS methods offer enhanced selectivity, minimal matrix interference, and greater suitability for pharmacokinetic and bioequivalence investigations. This review provides a comprehensive and critical summary of the analytical and bioanalytical methods reported for the estimation of naratriptan. It integrates analytical performance with current regulatory expectations outlined by USFDA and ICH M10 guidelines and identifies existing methodological gaps in published assays. Particular attention is given to essential bioanalytical validation parameters such as selectivity, accuracy, precision recovery, matrix effects, stability, and calibration linearity in line with regulatory recommendations. Furthermore, the review emphasizes the growing importance of LC–MS/MS in pharmacokinetic and bioequivalence studies and underscores the need for robust, well-validated analytical methodologies for reliable naratriptan determination