New Insights\non the Burst Release Kinetics of Spray-Dried\nPLGA Microspheres

Spray drying is one of the leading manufacturing methods\nfor active\npharmaceutical ingredients (APIs) owing to its rapid, single-step,\nand cost-effective nature. It also has the capacity to generate microspheres\ncapable of controlled release of APIs including biomolecules and vaccines.\nHowever, one of the key challenges of spray-dried formulations especially\nwith poly­(lactic-<i>co</i>-glycolic acid) (PLGA)-based controlled-release\ninjectables is burst release, where a significant fraction of the\nAPI is released prematurely within a short period of time following\nadministration, leading to detrimental impact on the performance and\nquality of end products. This study uses a model API, bovine serum\nalbumin (BSA) protein, to identify the sources of burst release that\nmay affect the kinetics and performance of long-acting injectable\nmicrosphere formulations. Spray-dried microspheres with various formulations\n(i.e., variable BSA/PLGA ratios) were characterized in terms of their\nmorphology, particle size, surface area, thermal properties, moisture\ncontent, as well as chemical compositions and their distributions\nto investigate the impact of spray drying on the burst release phenomenon.\nThe results suggest that a relatively high initial release (85%) observed\nis mainly attributed to the protein distribution close to the particle\nsurface. Morphology analysis provided evidence that the microspheres\nretained their spherical structure during the burst release phase.\nX-ray photoelectron spectroscopy, hard X-ray photoelectron spectroscopy,\nand argon cluster sputtering-assisted time-of-flight secondary ion\nmass spectrometry analysis suggest an enrichment of PLGA on particle\nsurfaces with buried BSA protein. The statistically significant difference\nin particle size and surface area between three different formulations\nmay be responsible for an initial variation in release but did not\nseem to alter the overall burst release profile. Considering the suggested\nsource of burst release, the two-fluid spray-drying method, characterized\nby a single liquid feed delivering a preprepared emulsion, generated\nmatrix-type microspheres with a surface layer of PLGA, as evidenced\nby surface analysis. The PLGA surface layer proved to be prone to\ndegradation and pore formation, allowing for faster diffusion of BSA\nout of the microspheres, resulting in a burst release. Increasing\nthe polymer concentration did not seem to halt this process.