Determination of ammonia impurity in potassium bitartrate using ion chromatography

Importance of the topic

Ammonia impurity in pharmaceutical-grade potassium bitartrate must be tightly controlled for drug safety and quality. The United States Pharmacopeia’s current colorimetric assay is nonspecific, uses hazardous reagents, and is time consuming. Modern ion chromatography (IC) provides greater selectivity, sensitivity, and simplicity, aligning with global compendial modernization efforts.

Objectives and study overview

This application note presents the development and validation of a rapid IC method to quantify ammonia impurity in potassium bitartrate following USP <1225> guidelines. The goal was to replace the existing colorimetric monograph test with a robust, five-minute chromatographic procedure.

Instrumentation used

• Thermo Scientific Dionex ICS-6000 RFIC system with pump, eluent generator, high-pressure degasser, conductivity detector, and autosampler modules
• Dionex IonPac CG16 guard column (3 × 50 mm) and CS16 analytical column (3 × 250 mm)
• Dionex EGC 500 methanesulfonic acid (MSA) eluent generator cartridge and CR-CTC 600 trap column
• CDRS 600 dynamically regenerated suppressor (4 mm, recycle mode)
• Chromeleon CDS software version 7.2 for method control and reporting

Methodology

Sample and standard preparation, all in HDPE containers, included:

• Ammonia primary dilution solution (1.0 mg/L) from a 1000 mg/L standard
• Calibration range of 0.01–1 mg/L ammonia in DI water
• Potassium bitartrate test solutions at 1 mg/mL for system suitability and 2.5 mg/mL for recovery assays
• Recovery spikes at 0.02, 0.1, and 0.5 mg/L ammonia

The IC conditions were: 55 mM MSA eluent at 0.7 mL/min, 40 °C column temperature, 25 µL injection, and suppressed conductivity detection at 113 mA.

Main results and discussion

– Separation of ammonium from sodium and potassium was achieved in under five minutes with baseline resolution.
– Precision: retention time RSD <0.07%, peak area RSD 0.09–0.46% (n=3 spikes).
– Accuracy: recoveries of 96–100% across spike levels representing 0.002–0.05% ammonia.
– Linearity: quadratic calibration (r2=1.0) over 0.01–1 mg/L; linear response can be achieved by narrowing range or using a high-capacity salt converter suppressor.
– Sensitivity: LOD 0.003 mg/L and LOQ 0.01 mg/L based on S/N criteria.
– Robustness: method performance remained within acceptance limits (<±11% RT shift, ≤5.4% resolution change) under ±10% variations in flow rate, eluent concentration, and temperature on two column lots.
– Sample analysis showed ammonia levels of 0.001–0.002%, well below the USP limit of 0.01%.

Benefits and practical applications

• Five-minute runtime dramatically increases throughput compared with colorimetric assays.
• Eliminates hazardous reagents by using reagent-free IC with DI water carrier.
• High-capacity CS16 column tolerates high sample load without loss of performance.
• Simplified operations and reproducible results support routine QC and pharmacopeial compliance.

Future trends and potential applications

As compendia continue modernizing impurity tests, IC with RFIC technology is likely to expand to other monographs for basic impurities. Ongoing advances in suppressor design, higher-capacity columns, and automated data processing will further streamline workflows. Integration with hyphenated detectors or mass spectrometry could extend the method to additional volatile or ionic contaminants.

Conclusion

The described IC method provides a rapid, selective, and validated approach for measuring ammonia impurity in potassium bitartrate. It meets USP criteria for precision, accuracy, sensitivity, and robustness, representing an ideal replacement for the legacy colorimetric monograph assay.

Reference

• U.S. Pharmacopeial Convention. Monograph Modernization Proposals. USP online.
• United States Pharmacopeia. Potassium Bitartrate Monograph. USP42–NF37.
• United States Pharmacopeia. Sodium Bicarbonate Monograph. USP42–NF37.
• Thermo Scientific Application Note 1073: Ammonia in Sodium Bicarbonate.
• USP <1225> Validation of Compendial Methods, USP42–NF37.
• USP <621> Chromatography, USP42–NF37.
• ICH Q2A Validation of Analytical Procedures: Definition and Terminology.
• ICH Q2B Validation of Analytical Procedures: Methodology.
• Thermo Fisher Scientific Product Manual: SC-CERS 500 Suppressor.