Implementation of QbD Approach in Analytical Method Development of Acebrophylline and Erdosteine by HPLC

Abstract

The present study focuses on the development and validation of a robust, reliable, and regulatory-compliant analytical method for the simultaneous estimation of Acebrophylline and Erdosteine using High-Performance Liquid Chromatography (HPLC) under a Quality by Design (QbD) framework. The QbD approach ensures systematic understanding of method variables, enhanced robustness, and regulatory flexibility. Design of Experiments (DoE) was applied to evaluate critical analytical parameters (CAPs) such as mobile phase ratio, flow rate, and pH, which influence critical analytical attributes (CAAs) including retention time, tailing factor, and theoretical plates. The optimized method was validated according to ICH Q2(R2) guidelines for parameters such as accuracy, precision, linearity, robustness, and specificity. The results demonstrated that the developed RP-HPLC method is accurate, precise, and suitable for routine analysis of the combination.

Introduction

Analytical method development is essential in pharmaceutical quality assurance to ensure a drug’s identity, strength, quality, and purity. Traditional OFAT approaches are limited because they do not consider interactions between variables, whereas the Quality by Design (QbD) framework provides a systematic, science-based method focused on predefined objectives, risk assessment, and process understanding.

This study applies a QbD approach to develop a robust RP-HPLC method for the simultaneous estimation of Acebrophylline and Erdosteine, two mucolytic and bronchodilator agents commonly combined for treating COPD and bronchitis. No validated analytical method previously existed for this drug combination.

The QbD framework involves defining the Analytical Target Profile (ATP), identifying Critical Method Parameters and Analytical Attributes, using Design of Experiments (DoE) to study parameter interactions, and establishing a Method Operable Design Region (MODR) to ensure robustness. This approach improves reproducibility and minimizes method variability.

RP-HPLC was selected as the analytical technique due to its precision and versatility, using a C18 column, controlled flow rate, and UV/PDA detection. The optimized mobile phase of methanol and buffer provided effective separation of both drugs.

Drug profiles highlight their mechanisms, solubility characteristics, and therapeutic uses. Literature review shows multiple analytical methods for each drug individually, but no simultaneous RP-HPLC method for the combination—creating a gap that this work addresses.

Regulatory frameworks, including ICH Q8, Q9, Q10, and Q2(R2), guide method development and validation. The combination product received CDSCO approval for Phase III trials in 2023, adding regulatory relevance.

Future scope includes routine quality control applications, stability and degradation studies, bioanalytical method development for pharmacokinetics, and further optimization using Green Analytical Chemistry principles.

Conclusion

The implementation of the Quality by Design (QbD) approach in RP-HPLC method development provides a structured, scientific, and risk-managed pathway for analytical research. The developed method for simultaneous estimation of Acebrophylline and Erdosteine demonstrates robustness, precision, and regulatory compliance. This approach not only ensures consistent analytical performance but also aligns with modern quality paradigms in pharmaceutical development.

References

[1] Das V, Bhairav B, Saudagar RB. Quality by design approaches to analytical method development. Res J Pharm Technol. 2017;10(9):3188–94. [2] Nadpara NP, Thumar RV, Kalola VN, Patel PB. Quality by Design (QbD): A complete review. Int J Pharm Sci Rev Res. 2012;17(2):20–8. [3] Singh B et al. QbD: A systematic approach for analytical method development. J Drug Deliv Ther. 2019;9(3):1006–12. [4] Patel H, Parmar S, Patel B. Review on QbD in pharmaceuticals. Int J Pharm Sci Rev Res. 2013;21(1):223–36. [5] Raman NVVSS et al. Analytical QbD approach in method validation. J Chem. 2015;2015:1–8. [6] DrugBank & PubChem: Acebrophylline (DB13141), Erdosteine (DB05057). [7] CDSCO approval: Acebrophylline 100 mg + Erdosteine 300 mg combination. (2023).

Copyright

Copyright © 2025 Sahil Prajapati , Dr. Deepa Patel. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.