Investigating key factors in the phase separation step of microspheres fabrication via coacervation

Coacervation, a common method for microspheres preparation, has not been given sufficient attention and study. This study aims to clarify the key factors in the phase separation step. Firstly, based on the thermodynamics of polymer solutions, the phase equilibrium time, binodal line, and the relationship between the concentration of lactic-glycolic acid copolymer (PLGA) in the coacervate phase (C_PLGA) and the concentration of polydimethylsiloxane (PDMS) in the PLGA-lean phase (C_PDMS) were determined. It was found that the lactic:glycolic ratio (L:G) significantly influences phase separation, and we introduced a method to calculate the compositions and masses of both the coacervate and PLGA-lean phases after phase separation of a system composed of PLGA, PDMS, and dichloromethane (DCM). Furthermore, some impellers aimed at producing narrow size distribution microspheres were designed, and the stirring states were analyzed visually using Computational Fluid Dynamics (CFD), explaining the impact of impeller types and clearance between impeller and vessel on particle size distribution. Measurements of the viscosities of the coacervate and continuous phases, coupled with emulsion theories, clarified the behavior of emulsion during the phase separation step, while also highlighting that the key to preparing narrow size distribution microspheres lies in weakening the coalescence of coacervate droplets. Finally, in vitro release demonstrated that C_PLGA and the particle size distribution of coacervate droplets are key factors in the phase separation step.