Ion chromatography determination of nitrate and nitrite in ranitidine drug substance and drug products

Significance of the topic

The presence of nitrate and nitrite impurities in pharmaceutical products poses a risk due to their potential conversion into carcinogenic N-nitrosamines such as NDMA. Following the 2019 ranitidine recall, stringent control of these anions in drug substances and finished products is essential to meet regulatory safety limits and protect public health.

Objectives and Study Overview

The primary goal was to develop and validate a robust ion chromatography method for the simultaneous measurement of nitrate and nitrite in ranitidine active pharmaceutical ingredient (API) and tablet formulations. The study provides a comprehensive workflow covering instrument configuration, reagent preparation, eluent composition, sample treatment, chromatographic settings and validation results.

Methodology

The analysis employed suppressed conductivity detection with a sodium hydroxide gradient to enhance anion separation. Key procedural steps include:

• Eluent preparation: Ports with 100 mM NaOH and DI water, gradient from 5 % to 50 % NaOH over 30 min.
• Standard solutions: 1000 mg/L stock for nitrate and nitrite; calibration range 0.9–100 mg/L; LOD at 0.3 mg/L; LOQ at 0.9 mg/L.
• API sample: 0.3 g dissolved in 2 mL DI water, vortex, 0.2 µm filtration and OnGuard II RP cleanup.
• Tablet sample: Average weight of 15 tablets (~0.3838 g), extraction with 2 mL DI water, vortex, centrifugation, 0.2 µm filtration.
• Chromatography: 40 min run, flow rate 1.0 mL/min, injection 10 µL, column oven 40 °C, autosampler at 10 °C.

Instrumentation Used

The following Thermo Scientific equipment was employed:

• Dionex ICS-6000 HPIC system with gradient pump and thermostatted autosampler.
• Dionex IonPac AS19 analytical column (4×250 mm, 4 µm) with AG19 guard column.
• ADRS600 suppressor (4 mm, recycled mode).
• Conductivity detector.

Key Results and Discussion

The method demonstrated excellent linearity for both analytes (R² = 0.999). Precision studies at 45 mg/L yielded RSD values of 0.63 % for nitrite and 0.60 % for nitrate. Recovery experiments across LOQ, 50 %, 100 % and 150 % levels ranged between 90 % and 115 %. In real samples, ranitidine API contained 45.9–49.9 mg/kg nitrite and 3.5–4.0 mg/kg nitrate. Tablet formulations showed 7.3–7.6 mg/kg nitrite and 3.8–3.9 mg/kg nitrate.

Advantages and Practical Applications

This ion chromatography approach enables simultaneous quantification of nitrite, nitrate and other common anions (fluoride, bromide, phosphate, sulfate) in a single run. Its high sensitivity and throughput make it suitable for routine quality control, stability testing and regulatory compliance in pharmaceutical laboratories.

Future Trends and Prospects

Emerging developments include the integration of RFIC technology with automated NaOH/KOH cartridge systems to streamline gradient delivery. The method can be extended to other drug molecules at risk of nitrosamine formation. Coupling with mass spectrometric detection may further enhance specificity, while method miniaturization and faster gradients could reduce analysis time and solvent consumption.

Conclusion

The validated ion chromatography method provides a reliable, precise and sensitive solution for monitoring nitrate and nitrite in ranitidine API and tablets, supporting industry efforts to control nitrosamine impurities and comply with regulatory guidelines.

References

• FDA Updates and Press Announcements on NDMA in Zantac (ranitidine), accessed July 7, 2021.
• AN73987: Determination of Nitrite in Pharmaceuticals, accessed March 23, 2021.
• TN74093: Designing Ion Chromatography Methods for Determining Amines in Pharmaceuticals.