Assay of sodium thiosulfate and ionic impurities in sodium thiosulfate using ion chromatography

Significance of the Topic

Sodium thiosulfate is a critical active pharmaceutical ingredient approved for acute cyanide poisoning treatment and under evaluation as a chemoprotectant. Modernizing its compendial assay methods enhances accuracy, robustness, and aligns with global pharmacopeial standards.

Objectives and Study Overview

The main goals were to validate two ion chromatography (IC) methods proposed for the United States Pharmacopeia monographs: one for quantifying sodium thiosulfate assay and another for determining ionic impurities (chloride, sulfite, sulfate) in both the API and its injection form. The study followed USP General Chapter <1225> validation guidelines.

Methodology and Instrumentation

The analyses employed a Thermo Scientific Dionex ICS-5000+ RFIC system with suppressed conductivity detection using a Dionex AERS 500 suppressor and Dionex IonPac AS12A analytical column (4×250 mm) plus AG12A guard column. Key conditions:

• Assay method: isocratic eluent of 13.5 mM Na₂CO₃/1.5 mM NaHCO₃, flow 1.5 mL/min, 30 °C, 25 µL injection, run time 10 min.
• Impurity method: gradient between eluent A (2.7 mM Na₂CO₃/0.3 mM NaHCO₃) and B (13.5 mM Na₂CO₃/1.5 mM NaHCO₃), flow 1.5 mL/min, 30 °C, 25 µL injection, run time 35 min.
• Standards and samples prepared in DI water or 2 g/L D-mannitol diluent to stabilize sulfite.

Results and Discussion

• Assay method linearity was demonstrated from 0.2 to 150 µg/mL (r² = 0.999), with a one-point calibration at 100 µg/mL acceptable for routine analysis. Quadratic fit was required only above 150 µg/mL.
• LOD and LOQ for thiosulfate were 0.05 µg/mL and 0.17 µg/mL, respectively.
• Accuracy (99–108% recovery) and precision (intraday ≤0.6% RSD; interday ≤0.8% RSD) met USP criteria. Robustness tests (±10% flow rate, eluent strength, temperature) showed negligible impact on retention time, asymmetry, and assay results.
• Impurity method exhibited linear calibration for chloride (0.04–2 µg/mL, r² = 1.000), sulfite (0.2–10 µg/mL, r² = 0.9995–0.9998), and sulfate (0.2–10 µg/mL, r² = 1.000).
• LOD/LOQ values for impurities were 0.004/0.01 µg/mL for chloride, 0.09/0.3 µg/mL for sulfite, and 0.02/0.08 µg/mL for sulfate.
• Recovery for spiked sodium thiosulfate samples ranged 95–101% for chloride, 86–100% for sulfite, and 107–109% for sulfate. Precision was ≤3.3% intraday and ≤4.1% interday.
• A test sample exceeded the proposed chloride limit (0.022% vs. 0.02%), illustrating the method’s sensitivity and the need for tight quality control.

Benefits and Practical Applications

The validated IC methods offer rapid, sensitive, and robust alternatives to titration-based assays, enabling precise quantitation of sodium thiosulfate and its key ionic impurities. These methods are directly applicable for quality control in pharmaceutical manufacturing and regulatory compliance.

Future Trends and Opportunities

Advancements may include coupling IC with mass spectrometric detection for enhanced selectivity, automated sample preparation for high throughput, and extending the methodology to related sulfur-containing APIs and formulations. Integration with digital laboratory platforms will further streamline pharmacopeial testing workflows.

Conclusion

Both IC methods fully comply with USP validation requirements for assay and impurity determination of sodium thiosulfate. They demonstrate excellent linearity, sensitivity, accuracy, precision, and robustness, supporting their adoption in updated pharmacopeial monographs.

References

1. FDA Approved Drug Products: Nithiodote.
2. FDA Notice Regarding Sodium Nitrite and Sodium Thiosulfate.
3. Freyer DR et al. Lancet Oncol. 2017;18:63–74.
4. USP General Chapter <1225> Validation of Compendial Methods.
5. USP General Chapter <621> Chromatography.