Membrane-Assisted Antisolvent Crystallization: Interfacial Mass-Transfer Simulation and Multistage Process Control

Abstract

Antisolvent crystallization is an important purification technology for the pharmaceutical and fine chemical industries. Herein, we investigated the mass-transfer mechanism of membrane-assisted antisolvent crystallization (MAAC) and developed a multistage operation to reinforce the manufacturing features of antisolvent crystallization. Computational fluid dynamics simulation results via a developed mathematics model and the experimental images via in situ detection technology jointly illustrated the advantages of MAAC for accurate masstransfer control. Further, a three-stage MAAC process was investigated to reveal the process control performance. The diverse functional regions of multistage MAAC under different antisolvent addition strategies were then highlighted by manufacturing the crystal products with a narrow size distribution, a uniform aspect ratio, and the desired morphology. Multistage MAAC that intensifies the product capacity under a stable control is a promising direction for new-generation antisolvent crystallization.

Key Parameters Impacting the Crystal Formation in Antisolvent Membrane-Assisted Crystallization

“…The impact of antisolvent composition was investigated by reducing ethanol (the antisolvent) concentration in ethanol-water mixture with 80, 60 and 40 wt.%, using the mixture as the antisolvent solution instead of pure ethanol. All previous studies in the literature used 100% antisolvent solution [ 20 , 21 , 22 , 23 , 28 , 29 ] except Di Profio et al [ 24 ], who used 40% ethanol in their system besides maintaining a temperature difference between the two sides of the membrane, to avoid membrane wetting by the crystallizing solution. The intent of reducing the concentration of the antisolvent is in theory to reduce the activity difference, hence it can further control the transmembrane flux rate; in other words, the antisolvent addition rate.…”

“…Gravity is a factor that was pointed out in the literature in several occasions for a proper adjustment of MAAC operation, in the sense that the membrane module can be put for example in a vertical position to prevent the crystal clogging inside the module or the tubing [ 20 , 21 , 22 , 28 , 29 ]. Li et al put the membrane module at different angles of 33, 50 and 55° which impacted the density of crystals such that the bulk density decreased as the repose angle increased [ 23 ]. This shows that the module position impacts the forces applied by gravity on the antisolvent transmembrane mass transfer, which eventually influences the crystal formation kinetics.…”

“…Previous studies ( Table 1 ) have reported different conditions during MAAC operation. Mostly, the velocity of either the crystallizing or antisolvent velocity, was optimized [ 20 , 21 , 22 , 23 ], other studies preferred varying the antisolvent concentration or the temperature [ 24 ]. Besides, the membrane module position, i.e., whether placed horizontally or at a different angle, could affect the gravity resistance, hence the flowability of the solution and avoid clogging with the formed crystals [ 23 ].…”

“…Mostly, the velocity of either the crystallizing or antisolvent velocity, was optimized [ 20 , 21 , 22 , 23 ], other studies preferred varying the antisolvent concentration or the temperature [ 24 ]. Besides, the membrane module position, i.e., whether placed horizontally or at a different angle, could affect the gravity resistance, hence the flowability of the solution and avoid clogging with the formed crystals [ 23 ]. Nonetheless, a correlation between these parameters and the resulting crystal properties has not yet been established, so this study investigates the impact of these key four parameters, i.e., the solution velocity, the antisolvent composition, the temperature and gravity resistance on the crystal properties (i.e., the crystal shape, crystalline system, and size distribution).…”

Improved Spherical Particle Preparation of Ceftriaxone Sodium via Membrane-Assisted Spherical Crystallization

“…In addition, membrane separation technology coupled with crystallization has been successfully applied to produce coated drug particles with better morphology and narrower crystal size distribution. − In the membrane crystallization process, the spatial and temporal distributions of supersaturation were effectively regulated, and the control accuracy of crystallization was improved to achieve continuous production of high-purity products. , Membrane-assisted antisolvent crystallization via a hollow fiber membrane module was applied to drug preparation with improved crystal size distribution (CSD) by Zarkadas et al Through long-term research and development, hollow fiber membrane-assisted antisolvent crystallization (MAAC) was usually operated by adding an antisolvent in the tube side and crystallizing in the shell side to avoid membrane module clogging for continuous operation . In the authors’ previous work, MAAC was developed to add the antisolvent through the hollow fiber membrane interface, with higher microscopic mixing scale and higher mixing efficiency of the antisolvent and drug solution. − A simple pressure-driven model and the theory of interfacial liquid layer mass transfer in MAAC were proposed and confirmed. However, the construction of homogeneous phase separation droplets through a hollow fiber membrane and the application in the spherical crystallization process still need in-depth investigations.…”