ANALYTICAL QUALITY BY DESIGN FOR THE ANALYSIS OF FORMOTEROL, BUDESONIDE,AND ITS RELATED COMPOUNDS

Significance of the Topic

Implementation of Analytical Quality by Design (AQbD) in liquid chromatography optimizes method robustness and ensures reliable analysis of pharmaceutical compounds. Combining data-driven design principles with high-resolution UPLC-MS addresses critical needs in respiratory drug dosing by enabling precise quantification of Formoterol and Budesonide and their impurities.

Objectives and Study Overview

The study aims to apply AQbD principles to develop a UPLC-MS method for simultaneous determination of Budesonide, Formoterol, and related compounds. Key goals include establishing chromatographic conditions that achieve desired separation, retention, and peak quality within a defined acceptance region.

Methodology and Instrumentation

A test mixture containing all active pharmaceutical ingredients and impurities was prepared at specified concentrations in water/acetonitrile. Initial screening evaluated five stationary phases across pH 2.0 to 4.2. Subsequent high-pH screening explored pH 6.7 to 10.7 using BEH C18 to optimize Formoterol peak shape. Optimization via Design of Experiments supported robust tuning of temperature, flow rate, and gradient time.

• Chromatographic system: ACQUITY UPLC H-Class Plus with Quaternary Solvent Manager, Sample Manager, Column Manager, PDA detector, and QDa mass detector
• Software: Empower 3 CDS and Fusion QbD for data management and method development

Major Results and Discussion

Initial chemistry screening identified BEH C18 as the most suitable stationary phase for broad analyte retention and early elution. High-pH screening markedly improved Formoterol tailing factors, achieving values below 1.3 in two-thirds of runs. Fusion QbD defined a design space where all seven peaks maintain resolution above 2 across temperature (32.2–38.6 °C) and gradient time (13–25 min) variations. The final method at pH 8, 33 °C, flow rate 0.35 mL/min, and a 5–60% acetonitrile gradient over 25 min delivered consistent separation.

Benefits and Practical Applications

Integrating AQbD with UPLC-MS streamlines method development, reduces experimental workload, and enhances robustness. The resulting method supports routine quality control of combination inhaler products, enabling reliable impurity profiling and regulatory compliance.

Future Trends and Opportunities

Advancements may include machine learning for predictive method development, expanded AQbD application to diverse pharmaceutical classes, and high-throughput screening. Real-time adaptive control and automated design-space monitoring will further improve chromatographic efficiency and method transferability.

Conclusion

This study demonstrates the effectiveness of AQbD principles and Fusion QbD software in establishing a robust UPLC-MS method for Formoterol, Budesonide, and related impurities. The approach ensures reliable separation performance across varied conditions and supports efficient quality control workflows.

References

Alkhateeb FL, Rainville P, Haramaki Y. Analytical Quality by Design for the Analysis of Formoterol, Budesonide, and Its Related Compounds. Waters Corporation; 2019.