Ion Chromatography Assay for Lithium in Lithium Hydroxide

Significance of the Topic

Lithium compounds are the mainstay in treatment of bipolar disorder and require precise quantification in raw materials and formulations. The current pharmacopeial assay for lithium hydroxide relies on manual titration with hazardous reagents, which is laborious and prone to variability. An automated ion chromatography (IC) approach can streamline analysis, improve safety, and meet regulatory requirements for cation determinations.

Objectives and Study Overview

This study aims to develop and validate an IC method for determination of lithium in lithium hydroxide using a reagent free RFIC system with suppressed conductivity detection. The method must separate lithium from sodium, calcium, and other common cations, deliver accurate results within USP monograph limits, and demonstrate robustness under small method variations.

Methodology and Instrumentation

Instrumentation

• Thermo Scientific Dionex ICS 5000 plus RFIC system with single or dual pump module and suppressed conductivity detector
• Dionex AS AP autosampler with 10 microliter injection loop
• Dionex IonPac CS16 cation exchange column with CG16 guard
• Dionex EGC III MSA eluent generator cartridge with CR CTC II trap column
• Dionex CERS 500 suppressor in recycle mode
• Chromeleon chromatography data system version 7.2

Method

• Eluent program using electrolytically generated methanesulfonic acid: isocratic 10 mmol per liter MSA for 0 to 11 minutes, step to 65 mmol per liter for 11 to 16 minutes, then reequilibration to 10 mmol per liter for 16 to 22 minutes
• Flow rate 0.45 milliliter per minute and column temperature 40 °C
• Injection volume 10 microliter in push full mode
• Suppressed conductivity detection at 86 mA current
• Sample preparation with stock solutions from lithium carbonate or hydroxide diluted in 10 mmol per liter acetic acid
• Validation following USP general chapters for linearity, accuracy, precision, robustness, and LOD/LOQ determination

Main Results and Discussion

Separation
Efficient resolution of lithium, sodium, ammonium, potassium, magnesium, and calcium was achieved in a 22 minute run. Initial low concentration eluent enabled separation of lithium from sodium followed by rapid elution of remaining cations. Linearity and Sensitivity
Lithium showed linear response over 0.3 to 20 mg/L with coefficient of determination r2 0.9999. Calcium calibration from 0.03 to 2 mg/L also achieved r2 0.9999. Calculated limit of detection for lithium was 2.0 μg/L and limit of quantification 6.1 μg/L. Accuracy, Precision, and Recovery
Sample assays of lithium hydroxide yielded lithium content within 98.0 to 102.0 percent of label claim. Recovery of spiked lithium ranged from 98.6 to 99.6 percent. Calcium spiking at USP limit 0.2 percent produced recoveries between 93.4 and 94.7 percent. Precision was demonstrated by retention time RSD below 0.03 percent and peak area RSD below 4.2 percent. Robustness
The method remained unaffected by ±10 percent variations in flow rate, initial and final eluent concentrations, and column temperature. Peak symmetry, resolution, and retention times met acceptance criteria under all test conditions.

Benefits and Practical Applications

• Fully automated workflow reduces operator intervention and exposure to corrosive reagents
• Simultaneous determination of multiple cations enhances information content
• Reagent free eluent generation simplifies maintenance and improves reproducibility
• Meets regulatory requirements for pharmaceutical quality control

Future Trends and Potential Applications

• Adoption of modern IC assays in pharmacopeial monographs to replace manual titrations
• Extension of the approach to other lithium salts and complex matrices
• Integration with on line sample preparation and mass spectrometric detection for trace analysis
• Development of greener eluent systems and miniaturized IC platforms

Conclusion

The developed IC method provides a fast, accurate, and robust assay for lithium in lithium hydroxide that complies with USP monograph requirements. With automated reagent free eluent generation and suppressed conductivity detection, the method offers a safer and more informative alternative to traditional titration based assays and is an excellent candidate for routine quality control and pharmacopeial modernization.

References

1. Choi SJ, Derman RM, Lee KS Bipolar Affective Disorder Lithium Carbonate and Ca ATPase Journal of Affective Disorders 1981 3 77 79
2. United States Pharmacopeial Convention Lithium Hydroxide USP37 NF32 2014 3575
3. United States Pharmacopeial Convention USP Seeks Submission of Proposals for Monograph Modernization 2014
4. Fritz JS, Gjerde DT, Becker RM Cation Chromatography with a Conductivity Detector Analytical Chemistry 1980 52 1519 1522
5. Thermo Scientific IC Assay for Lithium Sodium and Calcium in Lithium Carbonate Application Note 1090 2016
6. Thermo Scientific Ion Chromatography Assay for Lithium in Lithium Citrate Application Note 1121 2016
7. United States Pharmacopeia Validation of Compendial Methods General Chapter 1225 USP36 NF31 2013 983
8. United States Pharmacopeia Physical Tests Chromatography General Chapter 621 USP36 NF21 2013 268
9. International Conference on Harmonization Validation of Analytical Procedures Q2R1 2005