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

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.