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BACKGROUND Dual therapeutic nature drug mast cell stabilizer and histamine receptor antagonist Olopatadine hydrochloride (OPT) nasal spray does not have the official monograph, and no literature is not available. Eye drops monograph had the official monograph for impurities, but the determination was done in two methods. OBJECTIVE A simple and effective green liquid chromatography method to develop and validate for the related substances of OPT nasal spray formulation. METHOD 25 min gradient method was employed to separate impurities and OPT with a 1.0 mL/min flow rate using Boston green C8 (150 mm × 4.6 mm, 5 µm) HPLC column. The set wavelength and column oven temperatures were 299 nm and 30 °C, respectively. pH 3.5 phosphate buffer: acetonitrile ratio (70:30, v/v) as mobile phase and (50:50, v/v) as mobile phase B. A Quality by Design (QbD) based Design of Experiments (DoEs) was employed to evaluate the robustness characteristics of the analytical method validation. RESULTS The obtained % RSD from the precision and intermediate precision was 0.4% to 4.1%. The % recovery of the impurities from LOQ to 150% of specification level was 87.5% to 110.3%. The linear regression curves for the impurities with a correlation coefficient of > 0.999 indicate that all peak responses are linear with the concentration. The sample and standard solutions were stable till 24 h at benchtop and refrigerator conditions. CONCLUSION All the critical peaks were well separated from the forced degradation studies' diluent, placebo, and generated degradation peaks. The method validation data and QbD based robustness study results indicate that the developed impurities method fits the routine quality control laboratory use. National environmental index (NMEI), Green analytical procedure index (GAPI), Analytical Eco-scale and Analytical greenness (AGREE) tools expressed the method greenness. HIGHLIGHTS The proposed method is QbD utilized and green chemistry assessed impurities determination method for OPT in nasal spray formulation.