Quality-by-design evaluation of Pickering emulsion-assisted spherical crystallization: A case study on ibuprofen.

Spherical crystallization is a widely used particle design technique in pharmaceuticals, integrating crystallization, milling, and granulation into a single step to reduce production costs and improve quality control. Pickering emulsions, stabilized by colloidal particles, provide a promising alternative to surfactant-stabilized emulsions for spherical crystallization, with feasibility recently demonstrated by the authors (Wang et al., 2022, J. Pharm. Sci. 111(6): 1625-1632). The present work extends beyond that proof-of-concept, evaluating the potential of Pickering emulsions within a QbD framework. To efficiently identify the design space with fewer experimental trials, an innovative approach combining Definitive Screening Design and Bayesian Optimization is proposed. The flowability of products derived from both Pickering- and surfactant-based emulsions is benchmarked using evaporative crystallization of ibuprofen. The results show that Pickering emulsions offer a larger design space, producing products with superior sphericity and smoother surfaces. These differences are attributed to distinct agglomerate formation mechanisms: in Pickering emulsions, agglomerates form from large individual droplets, while in surfactant-stabilized emulsions, they arise from irregularly shaped, widely distributed droplet clusters.