Phase inversion dynamics of PLGA solutions related to drug delivery. Part II. The role of solution thermodynamics and bath-side mass transfer.

The role of solvent properties and bath-side composition on the phase inversion dynamics and in vitro protein release kinetics of polylactic-co-glycolic acid (PLGA) solutions has been examined using dark ground imaging, in vitro release rate, and SEM techniques. Thermodynamic phase diagrams for three model systems (PLGA in 1-methyl-2-pyrrolidinone (NMP), triacetin, and ethyl benzoate) suggest two general classes of precipitation behavior, depending on the relative solvent strength and water miscibility. Drug release from the NMP-based system is primarily governed by the dynamics of phase inversion and exhibits a distinct burst region followed by a much slower release. Alternatively, depots with low solvent/water affinity (PLGA in triacetin or ethyl benzoate) undergo much slower phase inversion, resulting in a less porous, more fluid, two-phase structure that also releases protein more uniformly. Addition of a small chain triglyceride or organic salt to the aqueous receptor bath also evokes a significant increase in the mass transfer rate of protein from the low solvent/non-solvent affinity depots. An interpretation of these results in terms of a qualitative model for the protein release mechanism is also given.