Assay for Citrate and Phosphate in Pharmaceutical Formulations Using Ion Chromatography

Significance of the Topic

Citric acid plays a critical role in pharmaceutical formulations as an effervescent agent, buffering component, flavor masker, stabilizer, and anticoagulant. Accurate measurement of citric acid and associated anions such as phosphate is essential for quality control, product stability, and regulatory compliance.

Objectives and Study Overview

This work describes the development and validation of a single ion chromatography (IC) method for simultaneous quantification of citrate and phosphate in various pharmaceutical dosage forms. The aim is to consolidate up to eighteen USP monographs into one efficient assay, reducing analysis time and complexity.

Methodology and Instrumentation

The method employs suppressed conductivity detection following isocratic elution with 20 mM potassium hydroxide generated electrolytically. Key procedural elements include:

• Low-capacity, hydroxide-selective anion-exchange column for rapid elution of polyvalent anions
• Electrolytic eluent generation to minimize carbonate contamination and ensure reproducibility
• Suppressed conductivity detection in recycle mode for enhanced sensitivity
• Standard and sample preparation in dilute NaOH to maintain analyte stability

Instrumentation

• Thermo Scientific Dionex ICS-2000 RFIC system with EGC II KOH cartridge and CR-ATC module
• Dionex IonPac AG11 guard column (4 × 50 mm) and AS11 analytical column (4 × 250 mm)
• Dionex ASRS ULTRA II suppressor, 4 mm, operated in recycle mode
• Dionex AS50 autosampler and Chromeleon 6.5 chromatography workstation

Main Results and Discussion

The validated method exhibited excellent linearity over 2–100 mg/L for citrate and 1.2–60 mg/L for phosphate with r2 ≥ 0.9990. The limit of quantitation was approximately 0.2 mg/L (S/N=10). Intraday precision RSDs were <1% for citrate and <0.5% for phosphate; interday RSDs were <2% and <1%, respectively. Recoveries ranged from 94.8% to 105.1% across diverse formulations, and ruggedness testing under varied analysts, instruments, column lots, and eluent preparations yielded total RSDs below 2.4%. Analysis of nine commercial products demonstrated close agreement with label claims, meeting USP specifications.

Benefits and Practical Applications

• Single IC method replaces multiple USP assays for citrate and phosphate, streamlining laboratory workflows
• Fast analysis time (<10 min) and simplified sample preparation without colorimetric reagents
• Automated, reagent-free eluent generation enhances consistency and reduces operational costs
• Applicable to a wide range of pharmaceutical matrices including effervescents, injections, and tablets

Future Trends and Applications

Advances may include coupling IC with mass spectrometry or UV detection for improved specificity, further automation of sample handling, development of greener eluents, and extension of the method to additional anions in complex pharmaceutical matrices.

Conclusion

The described IC method combining a hydroxide-selective column with suppressed conductivity detection offers a rapid, accurate, and reproducible approach for simultaneous determination of citrate and phosphate. It fulfills USP requirements and enables consolidation of multiple monographs into a single, automated assay.

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