Solvent hydrolysis rate determines critical quality attributes of PLGA microspheres prepared using non-volatile green solvent.

This study aimed to develop a solvent hydrolysis-based microencapsulation technique that could fabricate PLGA microspheres, while using dimethyl carbonate as a green dispersed solvent. Instead of existing physical solvent removal techniques, a strategy was derived to use a chemical reaction that could transform oil droplets into microspheres. An oil-in-water emulsion was first produced by emulsifying a PLGA/Nile red/progesterone/dimethyl carbonate dispersed phase in an aqueous phase. Adding a NaOH solution into the emulsion led to the decomposition of dimethyl carbonate that partitioned to the water phase. This chemical reaction allowed the continuous diffusion of dimethyl carbonate existing in emulsion droplets into the aqueous phase and its complete removal. The solvent hydrolysis rate was identified as the most important process parameter affecting the major quality attributes of PLGA microspheres. For instance, it was shown through a 3D analysis that Nile red was uniformly dispersed across the microsphere matrix at a fast solvent hydrolysis rate. In comparison, a slow solvent hydrolysis rate allowed the dye to disperse heterogeneously in the microsphere matrix. A drug crystallization phenomenon, being commonly observed in conventional emulsion-templated processes, was inhibited by increasing the hydrolysis rate of dimethyl carbonate. Furthermore, adjusting the solvent hydrolysis rate made it possible to improve drug encapsulation efficiency, to disperse drug homogeneously across microsphere matrix, and to reduce variations in size distribution. The green solvent hydrolysis-based microencapsulation technique could be a promising alternative to conventional microencapsulation methods using toxic halogenated organic solvents.