Determination of nitrite in pharmaceuticals

Significance of the Topic

NDMA is a potent carcinogen that has been detected in certain drug products, prompting recalls and regulatory scrutiny. Limiting nitrite levels in pharmaceuticals is essential because nitrite can react with secondary or tertiary amines to form nitrosamines.

Objectives and Study Overview

This study aimed to establish and validate an ion chromatography method with UV detection for quantifying nitrite in pharmaceutical substances and finished products, thereby evaluating the potential for nitrosamine formation.

Methodology and Instrumentation Used

An RFIC system (Thermo Scientific Dionex ICS-6000 HPIC) generated KOH eluent electrolytically. Separation was performed on a Dionex IonPac AS19-4µm guard (2×50 mm) and analytical column (2×250 mm) under a gradient from 20 to 60 mM KOH at 0.25 mL/min, 30 °C. Sequential suppressed conductivity detection (Dionex ADRS 600 suppressor in recycle mode) and UV absorbance at 210 nm were used in series. Chromeleon CDS v7.2.10 managed data. Samples (API or product) were dissolved in water at 1 mg/mL, sonicated, centrifuged, diluted, and filtered through a 0.2 µm PES filter.

Key Results and Discussion

The method achieved an LOD of 0.918 µg/g API (S/N=3) and a linear calibration from 5 to 500 µg/L (r2=0.9999). Precision was high (area RSD 0.56%, retention time RSD 0.10%). Spike recoveries ranged from 96.3 to 101%. In seven samples, nitrite was detected in six, ranging from 4.45 to 95.5 ppm; one API was below the LOD. The UV detection eliminated interference from high chloride levels in hydrochloride products.

Benefits and Practical Applications of the Method

This IC-UV method offers sensitive and selective nitrite quantification without derivatization or extensive sample preparation. It is suitable for routine quality control to monitor nitrite and manage nitrosamine risk in pharmaceutical manufacturing.

Future Trends and Opportunities

Advances may include coupling ion chromatography to mass spectrometry for lower detection limits, automated inline process monitoring, high-throughput workflows, microfluidic IC systems, and integrated multi-analyte impurity profiling.

Conclusion

A robust, accurate, and precise IC-UV method for nitrite determination in pharmaceuticals was developed, supporting effective control of nitrosamine precursors in drug substances and products.

References

1. WHO Concise International Chemical Assessment Document 38: N-Nitrosodimethylamine.
2. EPA IRIS Summary for N-Nitrosodimethylamine.
3. FDA recall announcement for valsartan-containing medicines.
4. FDA updates on NDMA in ranitidine.
5. Mylan recall of nizatidine capsules due to NDMA.
6. FDA updates on NDMA in metformin.
7. FDA Guidance: Control of Nitrosamine Impurities in Human Drugs.
8. USP General Chapter <1469> Nitrosamine Impurities Prospectus.
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10. Ashworth I et al. Org Process Res Dev. 2020; DOI:10.1021/acs.oprd.0c00224.
11. Thermo Scientific Technical Note 74093: Amines in Pharmaceuticals by IC.
12. Thermo Scientific Dionex ICS-6000 Operator’s Manual, 2018.
13. ICH Guideline Q2B Validation of Analytical Procedures, 1996.