Modernization of a HILIC USP Impurity Method for Cetirizine Hydrochloride Tablets

Importance of the Topic

Effective impurity profiling of pharmaceutical products ensures safety and compliance with regulatory standards. Ultraperformance liquid chromatography methods in accordance with USP monographs often rely on legacy column technologies that increase analysis time and reduce throughput. Modernizing these methods can enhance efficiency while preserving analytical quality requirements.

Objectives and Overview of the Study

• Modernize the USP impurity method for cetirizine hydrochloride tablets by implementing columns with smaller particle size.
• Compare performance of a conventional 5 micrometer HILIC column (4.6 x 250 mm) with a 2.5 micrometer column (4.6 x 100 mm).
• Evaluate compatibility with USP system suitability criteria including peak tailing and repeatability.

Methodology

The study followed USP monograph guidelines for impurity analysis of cetirizine HCl tablets using hydrophilic interaction liquid chromatography. The original method employed a 5 micrometer porous silica HILIC column measuring 4.6 x 250 mm operating isocratically with 93% acetonitrile and 7% aqueous tetrabutylammonium hydrogen sulfate solution. Injection volume and flow rate were scaled geometrically to 26.5 microliters and 1.058 milliliters per minute, respectively. Distortion in the cetirizine peak revealed diluent mismatch issues due to higher water content and pH differences. The method was then reconfigured with a shorter 2.5 micrometer column (4.6 x 100 mm), reducing injection volume to 10.6 microliters and increasing flow to 2.116 milliliters per minute while retaining the same mobile phase composition.

Used Instrumentation

• XBridge BEH HILIC Column 5 micrometer, 4.6 x 250 mm
• XBridge BEH HILIC XP Column 2.5 micrometer, 4.6 x 100 mm
• Waters Column Calculator for geometric scaling of injection volume and flow rate
• Standard HPLC system compliant with USP procedures

Key Results and Discussion

Switching to the 2.5 micrometer column reduced run time from 15 minutes to 3 minutes while maintaining Gaussian peak shape and system suitability. The optimized conditions yielded a tailing factor of 1.3 and relative standard deviation of 0.8% for the cetirizine peak, meeting USP criteria of tailing NMT 2.0 and RSD NMT 10%. Narrower peaks preserved detection sensitivity for low-level impurities despite smaller injection volumes.

Benefits and Practical Applications

• Fivefold reduction in analysis time increases laboratory throughput.
• Improved peak shape and method robustness by addressing diluent mismatch.
• Facile adoption on existing HPLC instrumentation without major hardware changes.

Future Trends and Applications

Continued miniaturization and adoption of sub-3 micrometer and core-shell column technologies will accelerate routine impurity analyses. Integration with automated sample preparation and online dilution strategies may further enhance method consistency. Development of USP monograph updates to incorporate modern column formats can promote wider industry uptake.

Conclusion

Modernizing USP impurity methods with smaller particle HILIC columns offers substantial efficiency gains and reliable analytical performance. This approach preserves compliance with pharmacopeial requirements while dramatically reducing run times and improving peak quality, demonstrating a clear pathway for routine laboratory modernization.