Quantification of Anions in Pharmaceuticals

Importance of the Topic

Pharmaceutical quality control demands accurate quantification of both active and inactive anionic ingredients to ensure identity, strength, purity and safety. Ionic nonchromophoric species such as halides and organic acids cannot be monitored by UV detection but can be effectively measured via suppressed conductivity ion chromatography.

Objectives and Overview

This study evaluates two anion-exchange columns, AS14 under isocratic conditions and AS11 under a hydroxide gradient, for quantifying common inorganic and organic anions in complex pharmaceutical formulations. Two over-the-counter products, a cough suppressant and a multisymptom cold/flu medication, were selected as representative samples. Performance metrics included selectivity, sensitivity, linearity, precision and recovery.

Methodology and Instrumentation

The separation was performed on a DX-500 system equipped with a GP40 gradient pump, CD20 conductivity detector (or ED40 electrochemical detector), LC ovens or modules, and an autosampler. Key parameters:

• AS14/AG14 columns with 3.5 mM sodium carbonate/0.8 mM sodium bicarbonate isocratic eluent at 1.2 mL/min
• AS11/AG11 columns with a linear sodium hydroxide gradient (0.5 to 38 mM) at 2.0 mL/min
• Suppressed conductivity detection in recycle mode

Sample preparation involved diluting viscous formulations ten-fold or hundred-fold in deionized water, calculating concentrations by density, and filtering against trace anion contamination.

Main Results and Discussion

The AS14 method achieved baseline separation of inorganic anions (fluoride, chloride, nitrite, bromide, nitrate, phosphate, sulfate) within 14 minutes but did not elute larger organic anions. The AS11 gradient method resolved both inorganic and organic anions (acetate, benzoate, citrate, saccharin) in a single run. Detection limits on the AS11 column ranged from 0.3 to 7 ng injected (equivalent to 30 to 700 µg/L) for inorganic and organic species. Linearity exceeded two orders of magnitude with correlation coefficients ≥ 0.995. Precision studies (n = 10–15) yielded area RSD ≤ 0.5% and retention time RSD ≤ 0.2%. Recovery of active counterions bromide and chloride from real samples was between 97 and 109% of label claims. Trace impurities such as sulfate and phosphate were also detected.

Benefits and Practical Applications of the Method

The described approaches provide:

• Orthogonal verification of active-ingredient counterions
• Trace-level detection of anionic impurities
• Rapid throughput under isocratic or gradient conditions
• Broad applicability to diverse pharmaceutical matrices

Future Trends and Opportunities

Future enhancements may include expanded organic solvent usage to minimize peak tailing, external water suppression for lower detection limits, and coupling to mass spectrometry for structural confirmation. Automated sample handling and direct integration with purification workflows could further streamline quality-control processes.

Conclusion

Suppressed-conductivity ion chromatography using the AS11 column offers a robust, sensitive and selective platform for simultaneous determination of inorganic and organic anions in pharmaceutical formulations. The AS14 isocratic method provides rapid profiling of inorganic anions, while the AS11 gradient method extends detection to key organic excipients, supporting regulatory compliance and troubleshooting in pharmaceutical analysis.

Reference

1. FDA 21 CFR Parts 211; 2. Dionex Application Note 106; 3. Rabin et al. J. Chromatogr. 1993; 4. Dionex Application Note 117; 5. Dionex Application Note 115; 6. Dionex Instrumentation Manuals; 7. Standard reagent suppliers