Determination of oxalate in cromolyn sodium

Significance of the Topic

Oxalate is a potential impurity in cromolyn sodium drug substance with regulatory limits set by pharmacopeia. Rapid and reliable measurement of oxalate is essential for quality control in pharmaceutical production and ensures patient safety and compliance with standards.

Study Objectives and Overview

The goal of this study was to develop and validate an automated ion chromatography method using a Reagent Free IC system with suppressed conductivity detection for quantifying oxalate in cromolyn sodium. The method aims to replace the existing USP spectrophotometric assay that relies on a chemical reaction and hazardous reagents with a faster and more reproducible approach.

Methodology

An isocratic separation was performed on a high capacity Dionex IonPac AS20 anion exchange column using 30 mmol per liter potassium hydroxide eluent generated electrolytically. Key chromatographic conditions included a flow rate of 0.3 milliliter per minute, column temperature of 30 Celsius, injection volume of 2.5 microliters and suppressed conductivity detection under constant current operation.

Instrumentation

• Dionex Integrion HPIC system with EGC 500 KOH eluent generator and CR ATC trap column
• Dionex IonPac AG20 guard 2 × 50 mm and AS20 analytical 2 × 250 mm columns
• Dionex ADRS 600 suppressor in recycle mode for conductivity detection
• Autosampler with 250 microliter injection loop and degasser

Main Results and Discussion

The method achieved baseline separation of oxalate from sulfate and phosphate in under six minutes. Calibration was linear over a 0.03 to 10 mg per liter range with an r2 of 0.999. Limits of detection and quantification were 4 and 10 micrograms per liter, respectively. Recovery tests in a 50 mg per liter cromolyn sodium matrix yielded recoveries between 97.7 and 105 percent. Precision studies showed retention time RSD below 0.05 percent and peak area RSD below 2.9 percent across multiple days. Robustness evaluation under ±10 percent variations in flow rate, eluent concentration, and temperature confirmed method resilience.

Benefits and Practical Applications

This IC assay offers a rapid, automated, and reproducible alternative to the traditional wet chemical method. Using only deionized water and online generated eluent reduces handling of reagents, improves safety, and enhances sustainability. The approach is suitable for routine quality control of cromolyn sodium and can be extended to other pharmaceutical substances.

Future Trends and Applications

Advances in reagent free IC systems and high throughput autosamplers will further streamline impurity profiling in pharmaceuticals. Integration with mass spectrometry and adoption of greener eluents could expand applications to trace analysis of multiple organic acids. The trend toward monograph modernization will likely favor such automated IC methods in pharmacopeial standards.

Conclusion

A validated ion chromatography method using a reagent free IC system was developed for oxalate quantification in cromolyn sodium. It meets USP guidelines for linearity, sensitivity, accuracy, precision, and robustness, offering clear advantages over conventional assays. Adoption of this method can modernize pharmacopeial monographs and enhance analytical efficiency.

References

1. National Center for Biotechnology Information PubChem Database Cromolyn sodium CID 27503 Accessed Feb 3 2020
2. Murphy S Kelly HW Cromolyn sodium a review of mechanisms and clinical use in asthma Drug Intelligence & Clinical Pharmacy 1987 1(1) 22–35
3. U S Pharmacopeial Convention Cromolyn Sodium USP42–NF37 Rockville MD 2019
4. U S Pharmacopeial Convention USP seeks submissions for Monograph Modernization Accessed Sep 26 2019
5. U S Pharmacopeia Validation of Compendial Methods General Chapter <1225> USP42–NF37 2019
6. U S Pharmacopeia Physical Tests <621> Chromatography USP42–NF37 2019