Three-fluid spray-drying vs. spray-freeze-drying of crosslinked alginate microspheres: Elucidating multiscale...

Crosslinked alginate microspheres (CLAMs) are promising drug carriers, but conventional two-fluid atomization is limited by premix clogging and formulation complexity. To address these limitations, this study employed a three-fluid atomization strategy to fabricate CLAMs via spray-drying and spray-freeze-drying, enabling elucidation of multiscale structure-property relationships. With a three-fluid nozzle, sodium alginate and CaCl₂·2H₂O solutions were fed separately, enabling in situ crosslinking upon atomization. A series of CLAMs loaded with diclofenac sodium (DS) were fabricated via subsequent hot-air drying (SD-DS@CLAMs) or freezing followed by vacuum freeze drying (SFD-DS@CLAMs). SD-DS@CLAMs appeared as dense particles with a wrinkled surface, whereas SFD-DS@CLAMs possessed a porous, spherical morphology. In both systems, DS was incorporated in an amorphous state via physical entrapment. Moisture sorption was governed by crosslinking degree, drug hydrophobicity, and drying-dependent microstructure, with porous SFD particles enhancing capacity and reducing hysteresis. Notably, the crosslinking degree of the microspheres exhibited a non-monotonic trend driven by the competition between component segregation and reaction window. Crucially, rapid gel network formation upon hydration decoupled release kinetics from particle morphology, resulting in consistent Fickian diffusion profiles. While spray-drying offers high efficiency, spray-freeze-drying shows great potential for protecting heat-sensitive components and creating porous structures. Based on the current formulation design, these two methods provide complementary fabrication strategies that can be flexibly selected based on specific needs without altering release behavior, thereby expanding the design and application of CLAMs delivery systems.