Verification method for the required sample size in determining particle morphology of pharmaceutical particles via image analysis using relative standard deviation as a model-free approach--颗粒学报PARTICUOLOGY

Verification method for the required sample size in determining particle morphology of pharmaceutical particles via image analysis using relative standard deviation as a model-free approach

Daisuke Sasakura^a *, Sho Kimura^b

a Malvern Panalytical, a Division of Spectris Co., Ltd, Daiichi Building 7-3, Hamamatuchou 1-Chome, Minato-ku, Tokyo, 105-0013, Japan
b Department of Regional Agricultural Engineering, Faculty of Agriculture, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa, 903-0213, Japan

10.1016/j.partic.2026.04.002

Volume 114, July 2026, Pages 62-73

Received 3 February 2026, Revised 20 March 2026, Accepted 2 April 2026, Available online 12 April 2026, Version of Record 18 April 2026.

E-mail: daisuke.sasakura@malvernpanalytical.com

Highlights

• A novel model-free framework verifies particle count for irregular morphologies.

• Non-parametric strategy eliminates reliance on predefined geometric assumptions.

• Protocol ensures high transparency and ICH/USP regulatory compliance for APIs.

• Method is versatile and independent of SIA or DIA analytical techniques.

• Framework is empirically validated using large-scale, realistic API datasets.

Abstract

In pharmaceutical formulation development, accurate understanding of particle size and shape is critical for product quality, manufacturability, and regulatory compliance. Automated particle image analysis (APIA) enables high-throughput morphological characterization; however, determining the required particle number for reliable analysis remains challenging. Conventional parametric or simulation-based approaches often rely on restrictive assumptions regarding particle geometry or size distribution, limiting applicability to multimodal or irregular particles frequently encountered in practice. This study presents a strategically designed, model-free validation framework that leverages large-scale experimental APIA datasets to determine particle count requirements without assumptions regarding shape, size distribution, or analytical method. The framework is flexible, versatile, and applicable across diverse particle morphologies, and is largely independent of specific APIA system configurations if numerical morphological data are available. To meet pharmaceutical regulatory expectations, it integrates key elements from multiple certified standards, providing a compliance-ready solution. Sample size adequacy is evaluated through trend analysis of percentage relative standard deviation (%RSD), offering intuitive visualization for both quantitative and qualitative assessment. With modest computational requirements and a reproducible workflow, this framework supports robust characterization while facilitating effective communication among scientists and external stakeholders.

Graphical abstract

Keywords

Particle size; Particle shape; Particle image analysis; Non-spherical shaped particle; Active pharmaceutical ingredient; Method validation

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