Transfer of Two USP Compendial Methods for Impurities of Ziprasidone HCL to a Single UPLC Method

Importance of the topic

Ziprasidone HCl impurity analysis is critical for ensuring safety and efficacy in bipolar disorder treatment. Modernizing legacy USP HPLC methods by consolidating them into a single UPLC procedure addresses demands for faster, greener and more robust pharmaceutical testing.

Objectives and Study Overview

This study aimed to merge two USP compendial HPLC methods for early- and late-eluting ziprasidone impurities into one UPLC method. The goal was to reduce run time, solvent use and operational cost while meeting all USP system suitability requirements.

Methodology

A gradient UPLC method was developed using a neutral pH phosphate buffer (pH 6.0) and methanol on a BEH C8 sub-2 µm column. Elution profiles were optimized through scouting gradients and flow rate adjustments. System suitability was evaluated by five replicate injections according to USP criteria for resolution and repeatability.

Used Instrumentation

• Alliance 2695 HPLC with 2489 UV/Visible Detector
• ACQUITY UPLC H-Class with TUV Detector
• XBridge C8 4.6×150 mm, 5 µm column
• ACQUITY UPLC BEH C8 2.1×50 mm, 1.7 µm column
• Empower 3 software

Main Results and Discussion

The optimized UPLC method achieved baseline separation of ziprasidone and four related compounds in 4 minutes, compared to 16+ minutes for combined HPLC methods. Resolution and %RSD values exceeded USP thresholds (resolution ≥1.5 for early and ≥6.0 for late impurities; %RSD ≤10%). Peak width was reduced by 32% and run time by 75%.

Benefits and Practical Applications

• 75% shorter analysis time increases throughput
• 89% reduction in mobile phase consumption lowers costs and waste
• Enhanced resolution and robustness support QC release testing
• Streamlined lab workflows improve operational efficiency

Future Trends and Applications

Adoption of UPLC for compendial methods aligns with regulatory modernization efforts. Further integration with automated sample preparation and real-time data analytics will enhance process analytical technology (PAT) frameworks. Emerging sub-2 µm stationary phases and novel detectors may drive additional gains in speed and sensitivity.

Conclusion

This work demonstrates successful transfer of two USP HPLC methods into a single UPLC procedure, delivering faster, greener and high-performance impurity testing for ziprasidone HCl. The approach can be extended to other small molecule pharmaceuticals to advance routine QC in line with current regulatory expectations.

References

• USP Monograph, Ziprasidone HCl, USP35-NF29, United States Pharmacopeia, May 1, 2012.
• Jones MD, Alden P, Fountain KJ, Aubin A. Implementation of Methods Translation between Liquid Chromatography Instrumentation. Waters Application Note 720003721en, Sept 2010.