(189l) Continuous Synthesis of Drug-Loaded PLGA Nanoparticles: The Overlooked Impact of Solvent Evaporation Temperature on Drug Loading and Release

Achieving continuous synthesis of drug-loaded Poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles remains a major bottleneck in the clinical translation of PLGA-based nanomedicines. A key challenge is controlling particle sizes below 100 nm while ensuring sufficient drug loading to reach therapeutic levels [1,2]. In this study, we will present a continuous synthesis platform for Cyclosporin A-loaded PLGA nanoparticles using an ultrasonic microreactor coupled with a continuous stirred-tank reactor (CSTR) cascade. This system allows for the efficient and scalable production of sub-100 nm nanoparticles with high drug loading, optimized for controlled drug release applications.

PLGA nanoparticles were prepared using the oil-in-water (O/W) emulsification–solvent evaporation method, with Cyclosporin A selected as the model drug due to its poor water solubility (Biopharmaceutical Classification System, BCS Class II). The ultrasonic microreactor [3] consists of a borosilicate glass microreactor (microchannel cross-section 1.2 ×1.2 mm², length 700 mm, reactor volume 1 ml), a piezoelectric plate transducer glued to its bottom, and a Peltier cooling element. The aqueous phase (Milli-Q water + Poloxamer 407) and the organic phase (PLGA + Cyclosporin A + ethyl acetate) are supplied to the reactor at controlled flow rates. Operating at 550 kHz, the ultrasonic microreactor produced monodisperse nanoemulsion droplets. The outlet of the microreactor was connected to a 3D-printed continuous stirred-tank reactor (CSTR) cascade comprising five wells (∼1.6 mL each, total volume ∼8 mL) for continuous solvent evaporation. The CSTR wells were linked by a square channel (5 × 2 × 2 mm³), allowing continuous flow between them. Temperature control for the CSTR cascade was achieved by placing it on a glass jacket connected to a circulating water bath. At the bottom, a magnetic stirring plate was set at 250 rpm ensuring uniform mixing via magnetic stirring bars placed in each CSTR well. Nanoports (IDEX) were fixed to the inlet and outlet of the CSTR cascade, with the outlet connected to a syringe pump withdrawing at a flow rate of 200 µL/min for sample collection. The residence time in the CSTR cascade was approximately 40 min.

This system produced monodispersed nanoparticles (70 - 80 nm, PDI < 0.2) and achieved unprecedentedly high drug loading efficiency (double the previous benchmark) by optimizing the CSTR temperature to 35°C. Continuous solvent evaporation reduced processing time from hours to 40 min while meeting regulatory limits for residual solvents. In vitro drug release studies revealed that the optimized evaporation conditions extended the release duration from 9 to 48 hours, promoting a sustained and controlled release profile. This approach effectively mitigated burst release and associated toxicity risks of drug-loaded nanoparticles. Overall, this scalable and robust platform presents a compelling solution for advancing PLGA-based drug delivery systems toward clinical translation.

References:

[1] M.C. Operti, A. Bernhardt, S. Grimm, A. Engel, C.G. Figdor, O. Tagit, PLGA-based nanomedicines manufacturing: Technologies overview and challenges in industrial scale-up, Int J Pharm 605 (2021). https://doi.org/10.1016/j.ijpharm.2021.120807.

[2] N. Desai, Challenges in development of nanoparticle-based therapeutics, AAPS Journal 14 (2012) 282–295. https://doi.org/10.1208/s12248-012-9339-4.

[3] A.P. Udepurkar, L. Mampaey, C. Clasen, V. Sebastián Cabeza, S. Kuhn, Microfluidic synthesis of PLGA nanoparticles enabled by an ultrasonic microreactor, React Chem Eng (2024) 2208-2217. https://doi.org/10.1039/d4re00107a.