USP Method Modernization for Lidocaine Formulations Using XBridge Columns and Different LC Systems

Importance of the Topic

The analysis of lidocaine in semisolid and solution pharmaceutical forms presents unique challenges due to complex excipient matrices and the need for rapid, high-throughput testing in quality control environments. Modernizing United States Pharmacopeia (USP) liquid chromatography methods by employing advanced stationary phases and optimized column geometries can deliver faster run times, improved resolution, and robust performance across different instrument platforms, thereby enhancing laboratory productivity and compliance with compendial standards.

Goals and Overview of the Study

This study aimed to update USP assay methods for lidocaine hydrochloride jelly, ointment, and oral topical solution by transferring from legacy C18 columns to Waters XBridge BEH columns. The objectives included:

• Reducing analysis time without sacrificing resolution or system suitability.
• Demonstrating method equivalence across HPLC and UHPLC systems from Waters, Agilent, and Shimadzu.
• Adhering to USP General Chapter <621> guidelines for method modernization.

Methodology and Instrumentation

Sample Preparation:

• Semisolid forms (jelly 2% w/v, ointment 5% w/w) were diluted in 0.1% aqueous phosphoric acid/acetonitrile (50:50 v/v), sonicated, and brought to target lidocaine concentrations per USP monographs.
• Oral topical solution (2% w/v) was buffered to pH 8 and diluted in buffer/acetonitrile (70:30 v/v) to achieve 1 mg/mL lidocaine.

Column Modernization Steps:

• Switched from Atlantis dC18 (5 µm, 4.6×150 mm) or XTerra RP18 (3.5 µm, 4.6×150 mm) to XBridge BEH C18 phases (5 µm, then 3.5 µm, and finally 2.5 µm XP formats) following USP allowed changes for particle size and L/dp equivalency.
• Adjusted flow rates according to USP equation for isocratic speed scaling, achieving up to 73% time reduction in semisolid methods and 50% in solution assays.

Instrumentation:

• Waters Alliance e2695 and 2489 UV/Visible detector with Empower 3 CDS Software
• Shimadzu Nexera-i LC 2040C 3D UHPLC
• Agilent 1100 Binary LC with DAD detector
• Agilent 1260 Infinity Quaternary LC with DAD detector

Main Results and Discussion

Semisolid Formulations:

• Transition to XBridge BEH C18 (5 µm) improved selectivity and reduced analysis time by ~11% versus Atlantis dC18.
• Downscaling to BEH C18 (3.5 µm) and BEH C18 XP (2.5 µm, 4.6×75 mm) columns accelerated runs by 38% and 73%, respectively, while maintaining baseline resolution of lidocaine and related impurities.
• Comparable chromatograms were observed on all tested HPLC and UHPLC systems, with minor retention time shifts reflecting system void volumes.

Solution Formulation:

• Replacing XTerra RP18 with XBridge BEH Shield RP18 (3.5 µm) yielded enhanced separation of related compound H and ropivacaine A.
• Modernizing to the XP format (2.5 µm, 4.6×100 mm) cut run time by 50% without compromising peak quality.
• Method performance was consistent across Waters, Agilent, and Shimadzu platforms, with expected pressure increases on UHPLC instruments.

Benefits and Practical Applications of the Method

• Substantial reduction in analysis time increases sample throughput in QC labs.
• Enhanced resolution ensures reliable quantitation of impurities and active ingredient.
• Robust BEH hybrid particles offer long column lifetime and consistent performance.
• Cross-vendor applicability allows seamless integration into diverse laboratory setups.

Future Trends and Potential Applications

Further advancements may include integration of sub-2 µm and core-shell particles for even faster separations, adoption of green solvent systems to reduce environmental impact, and application of automated method development tools coupled with artificial intelligence for rapid chromatographic optimization. Moreover, inline process analytical technologies (PAT) could leverage these modernized methods for real-time monitoring in manufacturing environments.

Conclusion

The modernization of USP LC methods for lidocaine formulations using XBridge BEH columns achieved significant decreases in run times and improved resolution while maintaining compliance with compendial requirements. Demonstrated across multiple instrument platforms, these modernized assays deliver reliable, high-throughput performance suitable for pharmaceutical quality control.

References

1. USP40–NF35 S1 Monograph: Lidocaine Hydrochloride Oral Topical Solution.
2. USP40–NF35 S1 Monograph: Lidocaine Hydrochloride Jelly.
3. USP40–NF35 S1 Monograph: Lidocaine Ointment.
4. Waters Column Calculator v2.0 for chromatographic scaling.
5. USP General Chapter <621> Chromatography.
6. Swann T.; Nguyen J. M. USP Method Modernization Using “Equivalent L/dp” with CORTECS Columns, Waters Application Note (2016).
7. USP General Notices Section 6.30 on alternative and harmonized procedures.
8. USP General Chapter <1225> Validation of Compendial Procedures.
9. USP General Notices: Testing Practices and Procedures.