(173c) Characterization of a Modular Microfluidic Section for Seeded Nucleation in Multiphase Flow

Microfluidic flow reactors offer several advantages compared to conventional batch reactors, such as improved control, increased performance, and enhanced process safety. The integration of crystallization in these devices has remained difficult, as crystals tend to clog the flow channels ¹. Both active (with an externally applied force, e.g. ultrasound) and passive methods (without external forces, e.g. multiphase flow) have been proposed to tackle this issue ^2,3. Research has shown that the addition of inert microbubbles not only reduces clogging, but can also improve the crystallization of acetaminophen through additional heterogeneous nucleation on the bubbles’ surface ⁴.

Many crystallization processes rely on the addition of seeds to induce secondary nucleation ⁵. Seeding in continuous microfluidic reactors is rarely done, as the seeds are continuously flushed out and the clogging susceptibility increases. A continuously seeded microcrystallizer can however also provide the ideal conditions to study both crystallization, solid transport, and clogging phenomena in parallel. The aim of this project is to first develop a seeded microfluidic nucleation section which can be used for continuous cooling crystallization ⁶. Secondly, the performance of this section is completely characterized for acetaminophen crystallization from water, with and without off-line prepared seeds, and with and without a stream of microbubbles ⁶.

Materials and Methods

The nucleation section consists of a temperature-controlled glass capillary tube (1 mm diameter) and is connected to a seeding module which is used to deliver a suspension of seeds into the nucleation section. Ultrasound is applied to the seeding module to keep the seeds in suspension and to control the temperature. The nucleation section can also be extended with a gas delivery module to inject a stream of N₂-microbubbles.

Results

First, the performance of the off-line continuous seeding platform is established via the seed delivery efficiency, a measure for the seed transport through the seeding module, for constant and oscillatory flows. Second, the yields of seeded and unseeded crystallization are evaluated in the presence and absence of microbubbles. A statistically significant increase in the net yield was obtained when comparing unseeded and seeded crystallization, which can be attributed to the increased nucleation rates because of secondary nucleation. It is shown that also in the presence of seeds, the addition of microbubbles increases the productivity. Third, the clogging behavior of the presented continuous microcrystallizer is discussed for various supersaturations. Finally, also the crystal size distribution is analyzed: the mean crystal size decreases for both single- and two-phase flow when seeds are introduced. The presence of microbubbles resulted in a higher net yield and slightly smaller crystals compared to that of the single-phase flow.

Conclusions

This work provides valuable insights into the design and operation of continuous tubular crystallization processes ⁶. It highlights the importance of a multiparametric characterization approach to determine the operating limits of the setup. The crystallization results can be well interpreted based on the underlying nucleation mechanism (homogeneous, heterogeneous, or secondary nucleation).

References

1 J. Chen, B. Sarma, J. M. B. Evans and A. S. Myerson, Cryst. Growth Des., 2011, 11, 887–895.

2 K. Wu and S. Kuhn, Chim. Oggi/Chemistry Today, 2014, 32, 62–66.

3 R. L. Hartman, Org. Process Res. Dev., 2012, 16, 870–887.

4 N. Fatemi, Z. Dong, T. Van Gerven and S. Kuhn, Langmuir, 2019, 35, 60–69.

5 Y. He, Z. Gao, T. Zhang, J. Sun, Y. Ma, N. Tian and J. Gong, Org. Process Res. Dev., 2020, 24, 1839–1849.

6 C. Devos, E. Brozzi, T. Van Gerven and S. Kuhn, Org. Process Res. Dev., 2023, 27, 311–321.