Ultrasound-enhanced slug-flow continuous crystallization of ibuprofen investigated by multiphysics CFD-PBE modeling and experiments--颗粒学报PARTICUOLOGY

a National Engineering Research Center for Industrial Crystallization Technology, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China
b Engineering Research Center of Green Refining Process, Ministry of Education, Tianjin University, Tianjin, 300072, China

10.1016/j.partic.2026.04.024

Volume 114, July 2026, Pages 431-445

Received 3 February 2026, Revised 20 April 2026, Accepted 27 April 2026, Available online 8 May 2026, Version of Record 19 May 2026.

E-mail: x_huang@tju.edu.cn; hongxunhao@tju.edu.cn

Highlights

• Unified CFD-PBE model elucidates ultrasound slug-flow crystallization.

• Acoustic streaming and slug vortices create pseudo-perfect mixing.

• Ultrasonic frequency refines pressure field, and amplitude boosts cavitation.

• Optimized cooling flow effectively mitigates ultrasonic heat accumulation.

• Synergistic intensification yields narrow PSD and prevents channel fouling.

Abstract

The production of active pharmaceutical ingredients (APIs) crystals with narrow and controllable size distributions presents significant challenges. In this study, an ultrasound-enhanced slug-flow tubular crystallizer was developed and was systematically investigated by experiments and a unified simulation framework which integrates nonlinear acoustic modeling with multiphase CFD, thermal analysis and high-resolution population balance equations (PBE). Acoustic fields were computed using nonlinear Helmholtz equation and coupled to Volume of Fluid (VOF) solver to resolve slug-flow hydrodynamics, while PBE simulations were adopted to capture nucleation and crystal growth under spatially varying supersaturation. Parametric studies demonstrate that ultrasonic frequency can refine pressure-field patterns without altering total energy dissipation, while higher pressure amplitudes can expand high-pressure zones and enhance cavitation-driven microstreaming. Furthermore, simulation results reveal that ultrasound-induced acoustic streaming generates toroidal vortices within liquid slugs, which could enhance micromixing and prevent particle clogging. The calculated results from coupled thermal model which was validated against experimental temperature profiles indicate that localized thermal accumulation can be effectively suppressed by optimizing the cooling medium flow rate. Finally, residence time analyses elucidate that the synergistic effect of segmented flow and acoustic mixing jointly contributed to a narrow particle size distribution (PSD) span even under extended operation. Overall, the intensified tubular crystallizer and the modeling strategy presented in this work could provide practical platform for preparing pharmaceutical crystals with tailored and uniform PSD.

Graphical abstract

Keywords

CFD-PBE modeling; Gas-liquid flow; Ultrasound; Continuous flow tubular crystallization; Ibuprofen

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