(394b) Indirect Ultrasonication in Continuous Slug-Flow Crystallization

In the pharmaceutical industry, the continuous generation of crystals of target size distribution has the potential to simplify and/or reduce post-crystallization operations [1]. The joining of two streams in dual impinging jet, coaxial, or radial micromixers has been demonstrated to produce seed crystals of uniform crystal size distribution (CSD) [2][3], but with a nucleation rate that depends on the liquid flow rate [2][3][4]. Ultrasonication is a technology for facilitating primary nucleation that has been useful in various industrial and academic studies [5]. The nucleation rate is a function of ultrasonication parameters rather than just liquid flow rate, which provides extra degrees of freedom for controlling the CSD. Ultrasonication-assisted crystallization seldom has clogging problems, and actually has the opposite effect and is commonly used to remove particles from containers for cleaning purposes [5]. Ultrasonication facilitates primary nucleation by inducing acoustic cavitation in the liquid solution using high-frequency mechanical vibrations from converters (connected sonication generator) [5].

In most studies of sonocrystallization, an ultrasonication probe (or horn) is in direct contact with the liquid solution, which may induce secondary nucleation from metal contact or contaminate the solution with metal after a long time of use [5]. This talk uses an ultrasonication horn and so has spatial localization of ultrasonication energy, but does not directly contact the horn with the liquid solution. This talk also describes the implementation of this indirect ultrasonication-assisted primary nucleation into a slug-flow cooling crystallizer to demonstrate rapid generation of a large amount of crystals of larger size than the nuclei. The main differences compared to high-quality past studies (e.g., [6]) is that this talk (i) uses an ultrasonic probe focused on a small spatial location instead of placing a long tube in a sonication bath, (ii) has order of magnitude lower time in which the solution is in contact with ultrasonication, and (iii) uses a simpler experimental system [7].

References

[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]      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.

[3]      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.

[4]     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.

[5]      J. R. G. Sander, B. W. Zeiger, and K. S. Suslick, “Sonocrystallization and sonofragmentation,” Ultrason. Sonochem., vol. 21, no. 6, pp. 1908–1915, 2014.

[6]      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.

[7]      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.