Efficient Production of Inhalable Micro-Nanoparticles: Mechanism, Process Optimization, and Modular Continuous Micro-Crystallizer Design

Abstract

Batch production of micro-nanoparticles suffers from high energy consumption and low efficiency, and continuous crystallization is considered a promising solution. This study reported the design of a modular continuous coaxial mixing crystallizer (CCMC) system for the production of micro-nanoparticles of the pharmaceutical compound fluticasone propionate (FP), and the performance of the system was evaluated. Guided by experimentally determined thermodynamic and kinetic data of FP crystallization, computational fluid dynamics simulations were employed to optimize the crystallizer design, resulting in enhanced mixing efficiency occurring within 40 ms. Through a three-stage experimental protocol, the continuous crystallization process was optimized: (1) key process parameters were screened using factorial design; (2) the operational design space was mapped via response surface methodology; and (3) particle size control mechanisms were elucidated through analysis of mixing processes. Quantitative analysis identified the antisolvent-to-solution ratio as the dominant factor governing particle size distribution, attributed to its critical role in nucleation kinetics. The CCMC platform demonstrated robust and efficient operation for 25 min, delivering a single-run output equivalent to 990 doses of commercial formulation. Comparative studies revealed advantages over batch processing, including comparable powder crystallinity, improved crystal morphology, and narrower size distributions within a micro-nanometer range. The coaxial mixing crystallizer system exhibits excellence in flexibility, productivity, and material recovery.