Objective To establish a solid-phase extraction coupled with ion chromatography-suppressed conductivity detection (SPE-IC-CD) method for the determination of nitrite and nitrate ions in propranolol hydrochloride tablets and their excipients, and to explore their correlation with the formation of the genotoxic impurityN-nitrosopropranolol (NPPN) as well as their sources. nitrosopropranolol (NPPN) as well as their sources.

Methods The separation was performed on a Dionex IonPac™ AS11-HC RFIC™ anion analytical column (250 mm × 4.0 mm， 9 μm) with a matching AG11-HC RFIC™ guard column (50 mm × 4.0 mm). The column temperature was maintained at 35 ℃, and the conductivity detector cell temperature was set at 40 ℃. The flow rate was 0.8 mL/min, and the injection volume was 100 μL. Gradient elution was carried out using potassium hydroxide solution as the mobile phase, which was generated online by an eluent generator.

Results The calibration curves for nitrite and nitrate showed good linearity in the range of 10.00-500.00 ng/mL, with correlation coefficients greater than 0.999 6. The average recoveries were 97.8% and 98.0% for nitrite and nitrate, respectively, with correspondingRSDvalues of 1.3% and 0.8% (n=9). The limits of detection and limits of quantification were 3.00 ng/mL and 10.00 ng/mL for both analytes, respectively. The target ions were detected in both tablet and excipient samples with different NPPN contents. Correlation analysis revealed a significant positive correlation between NPPN content and the levels of nitrite and nitrate ions (P < 0.05), and the ionic residues were all traced back to the excipients used in the formulation.

Conclusion The developed method exhibits high sensitivity and strong specificity, and is suitable for the determination of nitrite and nitrate in tablets and excipients. The formation of NPPN is directly associated with residual nitrite and nitrate in the excipients. These findings provide important experimental evidence and theoretical reference for establishing quality control strategies for NPPN impurity in the formulation.

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