A Quality by Design Approach to Development and Validation of a Laser-based Analytical Method for Particle Size Distribution of Dapagliflozin Propanediol

Abstract

Particle size, shape and distribution of an active pharmaceutical ingredient (API) can significantly influence the physicochemical and biopharmaceutical performance of dosage forms. However, development of particle size analytical methods for APIs/formulation with diverse particle characteristics remains challenging. Only a limited number of studies have reported a Quality by Design (QbD) based framework for developing laser diffraction particle size methods beyond conventional trial-and-error approaches. This study aimed to establish a structured, science-driven and risk-based QbD approach for the development and validation of a laser diffraction analytical method for determining the particle size distribution (PSD) of Dapagliflozin Propanediol. The work highlights the application of Analytical Quality by Design (AQbD) principles including predefined objectives, systematic process understanding and effective control of analytical variability to ensure method robustness, reliability and regulatory compliance. Prior knowledge of the API and drug product was used to construct an Ishikawa (cause-and-effect) diagram and to support Failure  Mode and Effects Analysis (FMEA) for analytical risk assessment. An Analytical Target Profile (ATP) was defined to ensure accurate and precise determination of Dv10, Dv50, and Dv90 values within predefined acceptance criteria (Dv10 ≤ 15%, Dv50 ≤ 10%, and Dv90 ≤ 15%). Dispersant type, sonication time, stirrer speed and percentage obscuration were identified as critical method parameters. A Design of Experiments (DoE) strategy was employed to optimize these parameters within defined operational ranges using Fusion QbD software (version 9.9.2  SR3) and a face-centered central composite design (FCCCD). Method development followed ICH Q8–Q10 and ICH Q14 guidelines, while validation was conducted in accordance with ICH Q2 and EP 2.9.31/USP <429>. The optimized method demonstrated excellent precision and reproducibility with repeatability values of 9.96% (Dv10), 5.01% (Dv50), and 11.56% (Dv90). Overall, the QbD-based approach provided enhanced method understanding and control, resulting in a robust and reliable analytical procedure for particle size characterization of Dapagliflozin Propanediol.