Improved quality-by-design compliant methodology for method development in reversed-phase liquid chromatography

Area of Science:

• Analytical Chemistry
• Pharmaceutical Analysis
• Chromatography

Background:

• Quality-by-Design (QbD) principles are crucial for developing robust and reliable analytical methods.
• Traditional liquid chromatography (LC) method development can be time-consuming and inefficient.
• Automated strategies are needed to expedite method development and ensure compliance.

Purpose of the Study:

• To evaluate a comprehensive Quality-by-Design (QbD) strategy for compliant method development in liquid chromatography (LC).
• To automate and expedite the QbD method development process using design of experiments (DOE), modeling, and simulations.
• To achieve a robust and baseline separation of 15 antipsychotic drugs within a short analysis time.

Main Methods:

• Utilized a four-step QbD approach: screening, selectivity optimization, column adaptation, and robust resolution optimization.
• Employed design of experiments (DOE), multiple linear regression modeling, and Monte Carlo simulations for error propagation.
• Integrated an automated UHPLC system with short columns (sub-2 μm particles) and automated column/solvent selection.

Main Results:

• Successfully developed a complex chromatographic separation for 15 antipsychotic basic drugs.
• Achieved baseline separation in under 15 minutes using the automated QbD workflow.
• Demonstrated method robustness concurrently with the method development phase.

Conclusions:

• The proposed automated QbD strategy is effective for developing complex LC separations efficiently and compliantly.
• The workflow allows for simultaneous optimization of resolution and demonstration of robustness.
• This approach significantly expedites analytical method development for pharmaceutical applications.