(409c) Decoupling Nucleation and Growth for Continuous Crystallization in Microfluidics

1. Introduction

Microfluidics provide several advantages such as high efficiency, easy control and safety over conventional, and mostly batch reaction systems[1]. Therefore it can be seen as a replacement for batch crystallization as one of the most important separation and purification process especially in pharmaceutical industries[2,3].

The aim of this project is the design of a modular and decoupled microfluidic system consisting of separate nucleation and growth sections. The strategy persued in this project is using the two- phase interface in microreactors as a heterogeneous nucleation site. In this regard micro- bubbles are introduced in the system to control the location of the nucleation site and particle aggregates and to limit wall interactions. The velocity of the bubbles determines the residence time and using a gas phase enables a straight forward separation, see Figure 1.

2. Experimental study

2.1. Nucleation section

For designing the nucleation section, in the first step, the generation of micro-bubbles (i.e. nitrogen as an inert gas) in capillaries is studied. The total bubble surface area per unit volume of the reactor is related to the bubble diameter and the number of bubbles present in the reactor volume. Bubble diameter, bubble velocity and bubble generation frequency were extracted from the images captured by the high-speed camera using an inhouse-generated Matlab script. Using this information, the bubble surface area available as a heterogeneous nucleation site is further calculated and the effect of gas and liquid flowrate is investigated, see Figure 2.

This is followed by a systematic study of nucleation of an organic compound (i.e. cooling crystallization of paracetamol) using the developed system employing microbubbles. The particle size distribution is measured at the outlet of the channel subjected to the microbubble residence time and the nucleation and growth kinetics are extracted.

The continuous crystallization experiments provided proof that the micro-bubbles act as a heterogeneous nucleation site. An enhanced nucleation rate compared to the operation without bubbles was observed, and the presence of micro-bubbles results in the formation of more crystals, which indicates that nucleation is faster than without bubbles, i.e. the metastable zone width is reduced, see Figure 3. Furthermore, quantifying the crystal yield showed an increase by more than a factor of 2 in the presence of micro-bubbles.

2.2. Growth section

Further on a growth section is added to the nucleation section which is kept at the constant temperature equal to the outlet of nucleation section to allow formed nuclei to grow. Sample is collected at the outlet of the growth section for further analysis of particle size distribution, see Figure 4.

4. Conclusions

A decoupled crystallization set-up consisting of different nucleation and growth sections is designed using microreactors. Nucleation is enhanced using microbubbles acting as heterogeneous nucleation sites providing lower surface energy interface for the nucleation to start. Further a growth part is added to allow the formed nuclei grow within the constant temperature growth section.

In case of the continuous crystallization of paracetamol the results allow the conclusion that the low-energy heterogeneous surface introduced by the bubbles promotes crystal nucleation. In addition, adding micro-bubbles enables the continuous crystallization for long operating times, as the bubbles act as carriers for the formed crystals and effectively prevent wall deposition and thus clogging.

References

[1] Gunther, K. F. Jensen, Multiphase microfluidics: from flow characteristics to chemical and materials synthesis, Lab Chip , 2006, 6, 1487–1503

[2] S. Flowers, R.L. Hartman, Particle Handling Techniques in Microchemical Processes, Challenges 2012, 3, 194-211

[3] Wu, S. Kuhn, Strategies for solids handling in microreactors. Chim Oggi. 2014; 32(3):62-66.

[4] Fatemi, Z. Dong, T. Van Gerven, S. Kuhn, Microbubbles as Heterogeneous Nucleation Sites for Crystallization in Continuous Microfluidic Devices. Langmuir (2018). doi:10.1021/acs.langmuir.8b03183