Microdroplet cryo-crystallization for producing budesonide microparticles with optimized physicochemical properties--颗粒学报PARTICUOLOGY

Guo, S., Liu, Z., Zhang, Y., Wang, J., Gao, Z., & Gong, J. (2025). Microdroplet cryo-crystallization for producing budesonide microparticles with optimized physicochemical properties. Particuology, 103, 128-140. https://doi.org/10.1016/j.partic.2025.05.014

Microdroplet cryo-crystallization for producing budesonide microparticles with optimized physicochemical properties

Shengzheng Guo, Ziyi Liu, Yuxin Zhang, Jingkang Wang, Zhenguo Gao^*, Junbo Gong

School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin, 300072, China

10.1016/j.partic.2025.05.014

Volume 103, August 2025, Pages 128-140

Received 16 March 2025, Revised 4 May 2025, Accepted 20 May 2025, Available online 27 May 2025, Version of Record 5 June 2025.

E-mail: zhenguogao@tju.edu.cn

Highlights

• Microdroplet cryo-crystallization was proposed to prepare ultrafine crystals.

• Engineering budesonide ultrafine crystals with superior size, shape, and crystallinity.

• Revealing the phase transformation mechanism of nanoprecursors during suspension process.

• MCC-BUD microcrystals exhibit superior dissolution performance compared to those produced by conventional methods.

Abstract

Inhalation therapies are pivotal for treating pulmonary diseases, yet their efficacy critically depends on the physicochemical properties of drug particles. This study introduces a novel microdroplet cryo-crystallization (MCC) technique to fabricate inhalable budesonide (BUD) particles. The MCC process combines rapid cryogenic freezing of drug-loaded microdroplets in liquid nitrogen, followed by additive-guided suspension crystallization in an anti-solvent environment. Cryogenic freezing suppresses molecular mobility and prevents aggregation, preserving uniform solute distribution. Subsequent controlled crystallization in the anti-solvent system enables precise tailoring of nanoparticle morphologies while avoiding supersaturation-driven amorphization. Systematic optimization identified MCC conditions yielding BUD ultrafine crystals with a volume median diameter of 3.0 μm, >94 % sphericity, >98 % crystallinity, and minimal hygroscopicity (<0.5 %). Compared to conventional air-jet milled BUD (∼90 % crystallinity and ∼3 % hygroscopicity), the MCC-engineered particles exhibit significantly improved physicochemical stability and dissolution performance (94 % in 180 min). The MCC strategy decouples cryogenic freezing and phase transformation, avoiding top-down limitations (e.g., milling-induced amorphization) and bottom-up issues (uncontrolled nucleation/aggregation) to achieve scalable and highly precise production of inhalable drug particles.

Graphical abstract

Keywords

Cryo-crystallization; Budesonide; Microparticle; Particle engineering; Particle size distribution; Crystallinity

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