Influence of encapsulation variables on formation of leuprolide-loaded PLGA microspheres

Emulsion-based solvent evaporation microencapsulation methods for producing PLGA microspheres are complex often leading to empirical optimization. This study aimed to develop a more detailed understanding of the effects of process variables on the complex emulsification processes during encapsulation of leuprolide in PLGA microspheres using a high-shear rotor-stator mixer. Following extensive analysis of previously developed formulation conditions that yield microspheres of equivalent composition to the commercial 1-month Lupron Depot, multiple variables during the formation of primary and secondary emulsion were investigated with the aid of dimensional analysis, including: rotor speed (ω) and time (t), dispersed phase fraction (Φ) and continuous phase viscosity (µ_c). The dimensionless Sauter mean diameter (d_3,2) of primary emulsion was observed to be proportional to the product of several key dimensionless groups (Φ₁,We,Re,ω₁t₁) raised to the appropriate power indices. A new dimensionless group (Θ ) (surface energy/energy input) was used to rationalize insertion of a proportionate time dependence in the scaling of the d_3,2. The dimensionless d_3,2 of secondary emulsion was found proportional to the product of three dimensionless groups ( [Formula: see text] ) raised to the appropriate power indices. The increased viscosity of the primary emulsion, decreased secondary water phase volume and reduced second homogenization time each elevated encapsulation efficiency of peptide by reducing drug leakage to the outer water phase. These results could be useful for dimensional analysis and improving manufacturing of PLGA microspheres by the solvent evaporation method.