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

Jia Zhou; Richard Schutzman; Nian-Qiu Shi; Rose Ackermann; Karl Olsen; Yan Wang; Steven P Schwendeman

doi:10.1016/j.jcis.2022.11.122

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

J Colloid Interface Sci. 2023 Apr 15:636:401-412. doi: 10.1016/j.jcis.2022.11.122. Epub 2022 Nov 30.

Authors

Jia Zhou¹, Richard Schutzman¹, Nian-Qiu Shi², Rose Ackermann¹, Karl Olsen¹, Yan Wang³, Steven P Schwendeman⁴

Affiliations

¹ Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA.
² Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA; School of Pharmacy, Jilin Medical University, Jilin 132013, Jilin Province, China.
³ Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA.
⁴ Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel Blvd., Ann Arbor, MI 48109, USA. Electronic address: schwende@med.umich.edu.

PMID: 36640551
DOI: 10.1016/j.jcis.2022.11.122

Abstract

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.

Keywords: Dimensional analysis; Leuprolide; Lupron Depot®; Microspheres formation; PLGA microspheres; Solvent evaporation.