(T1330-09-48) Controllable Microfluidic Synthesis of Drug-Loaded PLGA/PEG Nanoparticles Using DoE Approaches with Versatile Flow Streams

Purpose: Traditional bulk methods for the production of nano drug delivery systems (NDDSs), including high-energy homogenization techniques developed in our laboratory, often fall short in terms of controllability and uniformity. These methods, particularly when applied to the encapsulation of hydrophilic drugs, frequently result in low encapsulation efficiencies (EE%). In contrast, microfluidic technology offers significant improvements by providing enhanced control over the physicochemical properties of NDDSs, which are critical for their biological efficacy. The effectiveness of these delivery systems is intricately linked to factors such as the type and amount of materials used in their synthesis and the specific methods employed in their production. Quality-oriented manufacturing of nanoparticles is therefore essential to optimize these factors and achieve high-performance NDDSs. In this context, our laboratory has applied Design of Experiment (DoE) methodologies to systematically investigate and optimize the parameters involved in the microfluidic production of drug-loaded nanoparticles. This approach enables a thorough understanding of the process, facilitating the production of high-quality nanoparticles with improved EE%. The present study aims to establish a robust framework for the implementation of DoE as a strategy to enhance the manufacturing process of NDDSs composed of PLGA, PEG2000, and Doxifluridine, a model hydrophilic drug, utilizing the nanoprecipitation method. By leveraging DoE tools, we seek to gain comprehensive insights into the process parameters and their interactions, ultimately leading to the production of NDDSs with superior characteristics and therapeutic potential.

Methods: We employed the Sunshine microfluidic platform from Unchained Labs to synthesize NDDSs using three different micro flow streams via distinct chips for performance comparison. Design-Expert Version 12 software was utilized for the Design of Experiment (DoE) setup. Two factors, total flow rate (TFR) and the ratio of water phase to organic solvent flow rate (FRR), were investigated. The size and polydispersity index (PDI) of the NDDSs were analyzed as responses using Response Surface Methodology (RSM) to optimize the production process and ensure high-quality nanoparticle synthesis.

Results: The Sunny 150 chip with a 5-input configuration yielded a more stable suspension, smaller particle size, and narrower polydispersity index (PDI) compared to the Sunny 490 Trident T and 100XT micromixer configurations. The data on size and PDI allowed for the generation of validated 3D two-factor interaction (2FI) surface models. These models enabled precise optimization of the polymeric NDDSs, controlling size and PDI within a total flow rate (TFR) range of 1000 to 5000 µL/min and a flow rate ratio (FRR) range of 10:1.

Conclusion: We successfully transitioned PLGA/PEG NDDS synthesis from traditional bulk nanoprecipitation methods to a microfluidic platform, demonstrating superior control and optimization. Utilizing DoE modeling, we enabled future controllable microfluidic production of drug-loaded PLGA/PEG nanoparticles, ensuring consistent quality and performance.

References: Yuan Chen, Jing Ma, Huan Xie. Practical Preparation of Reproducible PLGA Nanoparticle for Intravenous Drug Administration. Poster presented at: AAPS 2022, Boston MA.

Acknowledgements: Cancer Prevention & Research Institute of Texas Core Facilities Support Awards (RP180748) and NIH’s Research Centers in Minority Institutes Program (RCMI, U54MD007605).

Microfluidic Synthesis of PLGA/PEG Nanoparticles under DoE optimization

Response surface curve showing the influence of FRR and TFR on the value of particle size

DoE model fit statistics for product characteristics