Impact of the Formulation Pathway on the Colloidal State and Crystallinity of Poly-ε-caprolactone Particles Prepared by Solvent Displacement

The formulation pathway and/or the mixing method are known to be relevant in many out-of-equilibrium processes. In this work, we studied the effect of the mixing conditions on the physicochemical properties of poly-e-caprolactone (PCL) particles prepared by solvent displacement. More specifically, water was added in one shot (fast addition) or drop by drop to PCL solution in tetrahydrofuran (THF) to study the impact of the mixing process on particle properties including size, stability, and crystallinity. Two distinct composition maps representing the Ouzo domain characteristic of the presence of metastable nanoparticles have been established for each mixing method. Polymer nanoparticles are formed in the Ouzo domain according to a nucleation and growth (or aggregation) mechanism. The fast addition promotes a larger nucleation rate, thus favoring the formation of small and uniform particles. For the drop-by-drop addition, for which the polymer solubility gradually decreases, the composition trajectories s...