Modernization and Troubleshooting of the USP Organic Impurity Method for Cetirizine Hydrochloride Tablets: Demonstration of XBridge HILIC Robustness Capabilities Across HPLC and UHPLC Instruments

Significance of the Topic

Modernization of compendial impurity assays is essential for reducing analysis time and improving compatibility with modern HPLC, UHPLC, and LC–MS platforms. Addressing peak distortion due to sample solvent effects enhances method robustness and ensures reliable quality control of cetirizine hydrochloride tablets.

Objectives and Overview

This work demonstrates:

• Scaling the USP organic impurity method from a 4.6 × 250 mm column to a 4.6 × 100 mm XBridge HILIC XP column
• Evaluation of performance on four LC platforms (Waters Alliance, Agilent 1100, 1260, and 1290)
• Troubleshooting distorted peak shapes by investigating sample diluent composition and injection volume
• Adapting the method for mass detection using an MS-compatible buffer

Methodology and Instrumentation

Sample Preparations:

• Crushed 10 mg cetirizine HCl tablets extracted to 0.5 mg/mL using various diluents
• Tested original USP diluent, matched organic/aqueous diluent, and buffer‐containing diluent
• MS‐compatible preparation with 93:7 acetonitrile:200 mM ammonium formate (pH 2.9)

Used Instrumentation:

• Chromatography: Waters Alliance e2695 HPLC, Agilent 1100 Binary HPLC, Agilent 1260/1290 Quaternary UHPLC with UV/DAD detectors
• Column: Waters XBridge HILIC XP 2.5 µm, 4.6 × 100 mm
• Detection: UV at 220 nm and ACQUITY QDa single-quadrupole mass detector
• Software: Empower 3 CDS

Main Results and Discussion

• The scaled HILIC method met USP system suitability criteria (tailing ≤ 2.0, RSD ≤ 0.8 %) on all four systems
• UHPLC systems showed peak fronting at 10.6 µL injections; reducing to 4 µL restored Gaussian peak shapes
• Peak distortion was primarily due to mismatched sample diluent strength; matching acetonitrile/water ratio (93:7) to mobile phase eliminated distortion up to 30 µL
• Absence of buffer in the diluent had only a minor effect on peak symmetry
• Transition to MS-compatible buffer provided mass confirmation of cetirizine and enabled detection of known and two unknown impurities

Benefits and Practical Applications

• Reduced analysis time from 15 min to 3 min without full method revalidation
• Demonstrated cross-platform robustness for seamless method transfer between LC and UHPLC systems
• Troubleshooting guidance for resolving strong solvent effects via diluent adjustment and injection volume optimization
• Integration of mass detection adds specificity and impurity identification capability

Future Trends and Potential Applications

• Applying modernization strategies to other pharmacopeial impurity assays
• Leveraging advanced column chemistries and AI-driven method development
• Expanding LC–MS workflows for comprehensive impurity profiling
• Extending solvent effect insights to supercritical fluid chromatography and novel separation techniques

Conclusion

Modernizing the USP cetirizine HCl impurity assay with XBridge HILIC XP columns and optimized sample solvents yielded fast, robust separations across four LC platforms. Matching diluent composition to the mobile phase is critical to avoid peak distortion. Adapting the method to MS detection further enhances impurity identification without extensive revalidation.

References

1. United States Pharmacopeia. Cetirizine Hydrochloride Tablets Monograph. USP 39-NF 34, 2016.
2. United States Pharmacopeia. Chapter <621> Chromatography. USP38-NF33 S1, 2015.
3. Sehajpal J, Fairchild JN. Modernization of a HILIC USP Impurity Method for Cetirizine Hydrochloride Tablets. Waters Technology Brief 720005825en, 2016.
4. Summers M, Carlson G. Future-proof Solutions for Regulated Laboratories in the Face of Changing USP <621> Guidelines. Waters White Paper 720005153en.
5. Fairchild JN, Hill JF, Iraneta PC. Influence of Sample Solvent Composition for SFC Separations. LC GC North America 31(4):326–333 (2013).
6. Jaber AMY, Al Sherife HA, Al Omari MM, Badwan AA. Determination of Cetirizine Dihydrochloride and Related Impurities in Oral Dosage Forms. J Pharm Biomed Anal 36:341–350 (2004).
7. Yu H, Cornett C, Larsen J, Hansen SH. Formation of Esters between Cetirizine and Polyols. J Pharm Biomed Anal 53:745–750 (2010).