Process and Formulation Parameters Governing Polymeric Microparticle Formation via Sequential NanoPrecipitation (SNaP)

Abstract

Polymeric microparticles (MPs) are valuable drug delivery vehicles for extended-release applications, but current manufacturing techniques present significant challenges in balancing size control with scalability. Industrial synthesis processes provide high throughput but limited precision, while laboratory-scale technologies offer precise control but poor scalability. This study explores Sequential NanoPrecipitation (SNaP), a two-step controlled precipitation process for polymeric microparticle production, to bridge the gap between laboratory precision and industrial scalability. We systematically investigated critical process parameters governing MP formation, focusing on poly(lactic acid) (PLA) MPs stabilized with poly(vinyl alcohol) (PVA). By comparing vortex and impinging jet mixing geometries, we demonstrated that vortex mixing provides superior performance for core assembly, particularly at higher polymer concentrations. We established the influence of delay time (T_d) and core stream concentration (C_core) on particle size, confirming that microparticle assembly follows Smoluchowski diffusion-limited growth kinetics within defined operational boundaries. Through this approach, we achieved precise control over microparticle size (1.6–3.0 μm) with narrow polydispersity. The versatility of SNaP was further demonstrated by the successful formation of MPs with different stabilizers while maintaining consistent size control. Finally, we validated the pharmaceutical relevance of SNaP by encapsulating itraconazole with high efficiency (83–85%) and characterizing its sustained release profile. These findings establish SNaP as a robust, scalable platform for high-quality pharmaceutical microparticle production with superior control over critical quality attributes.

Introduction

Polymeric microparticles (MPs) have emerged as important drug delivery vehicles, particularly for extended-release parenteral formulations, inhalable formulations and vaccines. (1−5) Their biocompatibility, favorable tissue retention, and controllable release kinetics make them well-suited for depot applications. (3,4,6,7) Commercial successes include extended-release parenteral formulations such as naltrexone (Vivitrol) for opioid addiction, risperidone (Risperdal Consta) for schizophrenia, and metoprolol succinate (Betaloc ZOK) for angina. (8−10) Despite these achievements, pharmaceutical MP production faces significant challenges across scales. Industrial processes like spray drying and emulsification suffer from limited control over particle size and uniformity. (4,11) Moreover, scaling down spray drying to small batch sizes for formulation development proves technically difficult. (12) Conversely, newer laboratory technologies such as microfluidics and membrane emulsification excel at precise size control and small-scale operation but face severe scale-up limitations due to their inherently low throughput capacities (<10 mL/min). (12−17) This dichotomy creates a critical gap between laboratory-scale precision and industrial-scale production capacity.
The nascent Sequential NanoPrecipitation (SNaP) process has the potential to bridge this gap. SNaP is a two-step controlled precipitation process that enables the production of polymeric particles ranging from nanometers to microns in size with narrow polydispersities. (18,19) SNaP leverages the same rapid micromixing and hydrophobic-driven particle self-assembly principles as the scalable Flash NanoPrecipitation (FNP) process. (20,21) However, unlike FNP which assembles nanoparticles in one step, (21) in SNaP, the particle core formation and stabilization are decoupled, enabling enhanced control over particle assembly and unlocking the previously unattainable micron particle size scale. (18)

This is achieved by performing micromixing in series under continuous flow (Figure 1). In the first mixing step, dissolved core materials are rapidly mixed with antisolvent under turbulent conditions (Re > 2000) to achieve micromixing, followed by the induction of nucleation and core growth. In the second micromixing step, stabilizer is introduced to arrest particle growth. By tuning the delay time (Td) between the first and second mixing steps, we can control the core growth time and hence particle size. Moreover, SNaP can controllably generate composite inorganic–organic nanoparticles and nanoparticles with extremely high drug loadings (>70 wt % drug). (19,22) A key advantage of SNaP is its flexibility in scale: it can be run with small micromixers and low minimum stream volumes required to simulate continuous flow (<3 mL per stream required when using a 60 mL/min stream flow rate) for formulation development with minimal material requirements as we will show herein, and also has the potential to be scaled-up with larger micromixers for continuous flow production at industrial rates (>5 L/min total output rate). (23,24)

Figure 1. Schematic of the SNaP process. An organic stream containing the microparticle core components is rapidly mixed against an antisolvent in the first micromixing step to initiate the core formation. The outlet is connected to a second micromixer, which introduces the stabilizer and arrests the microparticle growth. The delay time between the first and second mixing steps controls the time of the core growth.

In this study, we systematically investigated SNaP process parameters and formulation variables to elucidate the governing principles of MP property control. We employed SNaP to synthesize spherical polymeric MPs comprising industry-standard components: hydrophobic polylactic acid (PLA) cores stabilized via hydrophilic poly(vinyl alcohol) (PVA). We first investigated the core assembly mixing step by evaluating the importance of mixing geometry for uniform particle assembly. We subsequently explore the process parameters of Td and core stream solids concentration (Ccore), establishing the variable parameter space, identifying regions of tunable particle assembly, and determining the boundaries of process stability. Through this systematic approach, we demonstrate precise and reproducible size control of monodisperse particles within the 1.6–3.0 μm diameter range, ideal for inhalation delivery applications. We go on to show consistency in PLA MP size across different stabilizing polymers. Finally, we validate the drug loading capability of the system through reproducible, high-efficiency encapsulation of itraconazole and characterize the MP drug release rate. With these findings, we present the SNaP process as a promising new standard for high quality production of polymeric MPs.

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Materials

Tetrahydrofuran (THF, HPLC grade), acetonitrile (ACN, HPLC grade) were purchased from Fisher Scientific (USA). Rubrene (98%), poly(vinyl alcohol) (PVA, 13–23 kDa), polyvinylpyrrolidone (PVP, 40 kDa) and Tween-80 (ultrapure) were purchased from Sigma-Aldrich (USA). Polyethylene glycol polylactic acid block copolymer (PEG–PLA, 5kD-5kD) was purchased from Evonik Inc. (Germany). Itraconazole (98%) was purchased from TCI America. Ultrapure water (18.2 MΩ·cm) was generated by a MilliporeSigma Milli-Q Water Purification System (USA). Polylactic acid homopolymer (PLA, 10–18 kDa) was synthesized in-house according to the protocol described in Section 2.2.1. For mixer assembly, Tefzel tubing (0.040” & 0.060” ID), female LuerTight syringe fitting systems (1/16” OD), VacuTight Fittings (1/4–28 – 1/8), and flangeless male nut fittings (1/4–28, 1/16”) were purchased from Idex Health and Science (USA). O-rings (75 Viton, 1.5 × 35 mm) and heated inserts for 3D printed mixer inlets were purchased from McMaster Carr (USA).

Parker K. Lewis, Nouha El Amri, Erica E. Burnham, Natalia Arruz, and Nathalie M. Pinkerton, Process and Formulation Parameters Governing Polymeric Microparticle Formation via Sequential NanoPrecipitation (SNaP), ACS Engineering Au 0, 0, pp, DOI: 10.1021/acsengineeringau.5c00035