A quality by design (QbD)-based high-resolution, stability-indicating high-performance liquid chromatography (HPLC) method was developed for determining impurities in loperamide hydrochloride (LPH) tablet dosage forms. Using this method, eight known impurities were qualified, and three degradants were quantified with excellent peak resolution. Mobile Phase-A consisted of 0.05-M tetrabutylammonium hydrogen phosphate buffer and acetonitrile (80:20, v/v), while Mobile Phase-B contained the same buffer and acetonitrile (20:80, v/v). The gradient program was as follows: 0 min, MP-A 95%, MP-B 5%
15 min, MP-A 30%, MP-B 70%
17 min, MP-A 30%, MP-B 70%
19 min, MP-A 95%, MP-B 5%
and 24 min, MP-A 95%, MP-B 5%. Chromatographic separation was performed using a column zodiac C18 (100 mm × 4.6 mm, 3.0 μm) with a flow rate of 1.5 mL/min, detection at 220 nm, an injection volume of 10 μL, and a column temperature of 35°C. Stress studies revealed LPH's sensitivity to acidic, oxidative, and thermal conditions. Under all forced degradation conditions, the purity angle was found to be less than the purity threshold, demonstrating the robustness of the method. Validation confirmed its suitability for quality analysis and stability studies in routine manufacturing processes.