456813 Process Intensification for Continuous Slug-Flow Crystallization

Tuesday, November 15, 2016: 9:55 AM
Cyril Magnin III (Parc 55 San Francisco)
Mo Jiang1, Charles D. Papageorgiou2, Josh Waetzig3, Andrew Hardy3, Marianne Langston3 and Richard D. Braatz1, (1)Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, (2)Takeda Pharmaceuticals International Co., Cambridge, MA, (3)Takeda Pharmaceuticals International Co.

In the pharmaceutical and chemical industries, the continuous generation of crystals of target size distribution has the potential to improve efficiency for post-crystallization operations [1]. The control of crystallization processes can be challenging when undesirable phenomena such as particle attrition and breakage occur. Slug-flow crystallization has been demonstrated to allow enhanced control of crystal properties such as size and shape [2][3]. The slurry flow is combined with an air flow and fed to a tube to induce a multiphase hydrodynamic instability that spontaneously generates well-mixed slugs where the crystals continue to grow. These slugs are well-mixed without having the mixing blades as in traditional crystallizer designs that induce undesirable particle attrition.

This presentation will elaborate: (1) the process design and strategies for continuous slug-flow crystallization that controls the crystallization phenomena; (2) nucleation systems based on multiphase hydrodynamics from joining two streams in dual impinging jet, coaxial, or radial micromixers, which has been demonstrated to produce seed crystals of uniform crystal size distribution (CSD) [4][5], with a nucleation rate that depends on the liquid flow rate [4][5][6]; and (3) nucleation facilitated by advanced ultrasonication (e.g., focused and indirect) which provides extra degrees of freedom for controlling the CSD by decoupling the nucleation rate from liquid flow rate [3]. Process intensification strategy to improve the crystal growth control is also discussed which makes the whole process more robust. Experimental validation confirms that the proposed crystallizer designs reduce production time and equipment cost by orders of magnitude while suppressing secondary nucleation, attrition, and aggregation—dominant but undesired phenomena that worsen the ability to control the crystal properties.


[1] Z. Sun, N. Ya, R. C. Adams, and F. S. Fang, “Particle size specifications for solid oral dosage forms: A regulatory perspective,” Am. Pharm. Rev., vol. 13, no. 4, pp. 68–73, 2010.

[2] R. J. P. Eder, S. Schrank, M. O. Besenhard, E. Roblegg, H. Gruber-Woelfler, and J. G. Khinast, “Continuous sonocrystallization of acetylsalicylic acid (ASA): Control of crystal size,” Cryst. Growth Des., vol. 12, no. 10, pp. 4733–4738, 2012.

[3] M. Jiang, C. D. Papageorgiou, J. Waetzig, A. Hardy, M. Langston, and R. D. Braatz, “Indirect ultrasonication in continuous slug-flow crystallization,” Cryst. Growth Des., vol. 15, no. 5, pp. 2486–2492, 2015.

[4] M. Jiang, Z. Zhu, E. Jimenez, C. D. Papageorgiou, J. Waetzig, A. Hardy, M. Langston, and R. D. Braatz, “Continuous-flow tubular crystallization in slugs spontaneously induced by hydrodynamics,” Cryst. Growth Des., vol. 14, no. 2, pp. 851–860, 2014.

[5] M. Jiang, M. H. Wong, Z. Zhu, J. Zhang, L. Zhou, K. Wang, A. N. Ford Versypt, T. Si, L. M. Hasenberg, Y. E. Li, and R. D. Braatz, “Towards achieving a flattop crystal size distribution by continuous seeding and controlled growth,” Chem. Eng. Sci., vol. 77, pp. 2–9, 2012.

[6] A. J. Mahajan and D. J. Kirwan, “Micromixing effects in a two-impinging-jets precipitator,” AIChE J., vol. 42, no. 7, pp. 1801–1814, 1996.

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