Traditionally, crystallization has been achieved in batch processes that suffer from non-uniform process conditions across the reactors such as temperature, important in temperature-driven crystallization, and concentration, important in evaporation-driven crystallization. Traditional batch processes also suffer from poorly controlled mixing of the reagents, important in precipitation and antisolvent-driven crystallization. Consequently, crystal growth can vary across the reactors, giving rise to polydisperse crystal size distribution (CSD). This reduces reproducibility of the crystallization process and increases difficulty in obtaining accurate kinetics data.

Microfluidic systems offer a unique toolset for studying the growth kinetics of crystal systems because of well-defined laminar flow profiles and online optical access for measurements. The short length scale in microfluidic devices also allows for better control over the process parameters, such as the temperature, and the contact mode of the reagents, creating uniform process conditions across the reactor channel. Thus, these devices have the potential to generate a more uniform size distribution and more accurate kinetics data. In addition, microfluidic systems decrease waste, provide safety advantages, and require only minute amounts of reactants, which is most important when dealing with expensive materials such as pharmaceutical drugs. Some of these advantages have been demonstrated for evaporation-driven batch crystallization of macromolecules in microfluidic devices [1, 2], but so far not for continuous crystallization.

We have developed microfluidic based continuous microcrystallizers for small organic molecules by using soft lithography techniques. A key issue for achieving continuous crystallization in microsystems is to eliminate heterogeneous crystallization – irregular and uncontrolled formation and growth of crystals at the channel surface, and aggregation of crystals, which ultimately clogs the reactor channel. We have designed and fabricated microcrystallizers that introduces the reagents to the reactor channel in a controlled manner preventing heterogeneous nucleation and aggregation. We have used optical microscopy for in situ characterization of the crystal size distribution and measurement of the crystallization kinetics. We have used Glycine as the model system for our studies and have determined the growth kinetics of the different polymorphs of Glycine. In addition, we have also integrated a Raman spectroscopy tool with the microcrystallizer in order to distinguish between the different polymorphs in situ.

1. Hansen, C.L., et al., A robust and scalable microfluidic metering method that allows protein crystal growth by free interface diffusion. Proceedings of the National Academy of Sciences of the United States of America, 2002. 99(26): p. 16531-16536.

2. Zheng, B., et al., A droplet-based, composite PDMS/glass capillary microfluidic system for evaluating protein crystallization conditions by microbatch and vapor-diffusion methods with on-chip X-ray diffraction. Angewandte Chemie-International Edition, 2004. 43(19): p. 2508-2511.