Particle size by design: Standardizing measurements for complex topical drug product assessment

The physicochemical and biopharmaceutical properties of drug substances and dosage forms can be significantly influenced by particle size. However, the diversity of equivalent particle diameters generated by different methods poses a fundamental challenge in particle size analysis. This study aimed to develop an Analytical Quality by Design (AQbD) approach to accurately assess the particle size of a complex formulation – clobetasol propionate (CP) 0.5 mg/g cream – through automated microscopy (AM) and laser light diffraction (LD). Additionally, Raman spectroscopy was utilized to determine the chemical composition of the formulation particles. In the AQbD approach, prior knowledge was considered for the construction of the Ishikawa diagram and estimate failure mode and effects analysis (FMEA). The methods were developed following the ICH Q8-Q10, and ICH Q14 guidelines, and validated according to ICH Q2, ISO 13320:2020, and EP2.9.31./USP<429>. Results indicate that a trade-off between the techniques must be established for a particle size by design: while LD offers higher throughput and more precise values at the expense of peak resolution and broadening, AM has higher variability but more reliable information in terms of size and shape analysis. The validated methods successfully demonstrated the implementation of an AQbD method in the definition of particle size methods. • First time AQbD approach applied to analyze particle size via automated microscopy and laser light diffraction. • Optimization of laser light diffraction method using face-centered central composite design (FcCCD). • Precise particle size measurements were obtained from both automated microscopy and laser light diffraction techniques. • Image analysis produces morphology data that pure laser diffraction may not. • A combined laser diffraction-image analysis method is ideal for analyzing complex semisolid formulation.