Impurity Profiling of Paracetamol and Orphenadrine Citrate Fixed-Dose Tablets by a Stability-Indicating HPLC Method

A novel, sensitive, and stability-indicating reverse-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the simultaneous determination of impurities and degradation products in a fixed-dose combination tablet containing paracetamol (500 mg) and orphenadrine citrate (30 mg). The method enabled effective separation and quantification of eight specified impurities, including p-aminophenol, p-nitrophenol, p-chloroacetanilide, diphenhydramine hydrochloride, orphenadrine related compounds B and C, 2-methylbenzhydrol, and 2-methylbenzophenone. Chromatographic separation was achieved using a Waters SunFire C18 column (250 × 4.6 mm, 5 μm) with gradient elution comprising phosphate buffer (pH 3.0) and acetonitrile–water (90:10, v/v) at a flow rate of 1.0 mL/min. Detection was carried out at 220 nm. The method was validated in accordance with ICH Q2(R1) guidelines, demonstrating acceptable specificity, linearity, accuracy, precision, and robustness. Forced degradation studies under hydrolytic, oxidative, photolytic, and thermal conditions confirmed the stability-indicating capability of the method, with all degradation products well resolved from the active pharmaceutical ingredients and their known impurities. The limits of quantitation for all impurities ranged from 0.01% to 0.10% relative to their respective active concentrations. Minor intentional variations in chromatographic conditions did not significantly affect method performance, confirming robustness. The validated method is suitable for routine quality control analysis and stability studies of paracetamol and orphenadrine citrate fixed-dose combination tablets.