API particle size governs in situ forming implant formation, microstructure evolution and performance

Abstract

In situ forming implants (ISFIs) are long-acting injectable (LAI) drug delivery systems that undergo phase inversion upon contacting an aqueous environment, resulting in the formation of a semisolid–solid implant. To date, six ISFI products are commercially available, four of which are suspension-based formulations. Despite their growing clinical use, no generic ISFI products have reached the market. This underscores the need to better understand their complex behavior and to elucidate the critical quality attributes (CQAs) that govern their performance. While relationships between polymer physicochemical properties (e.g., molecular weight, lactic-to-glycolic acid ratio, end-group chemistry) and release kinetics have been extensively explored, the influence of the active pharmaceutical ingredient (API) remains insufficiently defined. To fill this knowledge gap, the present study investigates a risperidone ISFI that is qualitatively and quantitatively (Q1/Q2) equivalent to the commercial product Perseris®. Previous work has shown that Q1/Q2 equivalence alone does not ensure equivalent performance in vitro and in vivo, prompting the need to investigate additional formulation attributes. The current work focuses on evaluating the impact of API particle size and morphology on implant formation and in vitro release behavior. Thus, formulations containing risperidone with different particle sizes were prepared and evaluated. Subsequently, implant microstructure, water uptake, polymer degradation, and drug release were extensively characterized. A novel aspect of this work is the application of multiple imaging strategies, including laser scanning confocal microscopy (LSCM) for surface imaging and an adhesive thin-film technique for internal imaging, enabling detailed investigation of the evolution of microstructural differences between formulations. The findings highlight the importance of API particle size in governing implant microstructure, water uptake, polymer degradation, and in vitro release behavior, providing insight that will support the development of future generic and innovator ISFI products.