Pantoprazole sodium is a benzimidazole-class proton-pump inhibitor used widely in the management of gastro-oesophageal reflux disease, peptic ulcers, and Zollinger–Ellison syndrome. Because the molecule is acid-labile and oxidation-sensitive, it is formulated as an enteric-coated, gastro-resistant tablet, and its impurity profile must be tightly controlled to meet ICH Q3B(R2) thresholds. This review critically appraises the peer-reviewed literature on reversed-phase high-performance liquid chromatography (RP-HPLC) methods for the quantification of related substances in pantoprazole gastro-resistant tablets and converges on best-practice conditions for new method developers. A structured literature search of PubMed, Scopus, Web of Science, and ScienceDirect (January 2005–December 2025) was conducted following PRISMA 2020 guidance. Thirteen primary analytical studies and twelve regulatory or methodological documents (ICH guidelines, USP and Ph. Eur. monographs, PRISMA 2020, AGREE, GAPI and BAGI tool descriptors, plus PubChem records) were included after screening 84 records. The dominant RP-HPLC configuration uses a C18 stationary phase (250 × 4.6 mm, 5 µm) with a phosphate-buffered (pH 7.0–7.4) mobile phase, acetonitrile as the organic modifier, 1.0 mL min −1 flow, 290 nm UV detection, and a 35°C column temperature. Methods coupling pantoprazole with a partner analyte shift to 239 nm for shared sensitivity. LC–MS/MS is required for genotoxic-impurity profiling below 1 ppm. Green-analytical metrics (AGREE, GAPI, BAGI) and Analytical Quality by Design (AQbD) workflows are emerging but unevenly reported. RP-HPLC remains the workhorse technique for pantoprazole impurity profiling, but the literature is heterogeneous in column temperature, mobile-phase pH, and validation reporting. Standardised reporting of mass balance, AQbD design space, and greenness scores will materially advance the field.
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