(624d) Dynamics Is the Key to Achieving Fully Continuous Crystallization

Conventional stirred tank reactor designs are incapable of maintaining a uniform reaction environment as solids physically and chemically interact with the surrounding multiphase mixture. These challenges are exacerbated in crystallization as temperature and concentration gradients can form on length scales ranging from a single crystal to the entire body of the reactor. A distribution of thermodynamics and kinetics leads to a polydisperse particle size and potentially variable morphology. This work aims to develop a scalable continuous crystallization platform designed to ripen in-situ generated seeds into monodisperse crystals. By leveraging ultrafast heat and mass transfer, it is possible to operate in a previously unattainable kinetically-limited regime.

Segmented flow microfluidics offers a variety of in situ methods to generate crystals and study their growth pathways. Confining the crystallization mixture to 2 μL droplets at flow rates ranging from 0.05 to 0.5 mL/min allows for residence times ranging from seconds to hours thereby capturing the entire life span of a single crystal. Minimizing the Biot number in the design (Bi << 1) ensures scalable isothermal step changes across the phase diagram as the system alternates between nucleation, growth, and dissolution modes. Furthermore, the modular design of the crystallizer allows for adjustable flow paths that take advantage of varying curvature to induce Dean vortices for mixing.

Periodically shifting between a series hot and cold temperatures (5 - 100 °C) creates a dynamic environment where crystals can be selectively ripened according to how the square wave form of the temperature profile aligns with growth and dissolution kinetics. With reactor length scales on the order of millimeters, amplitudes ranging from 15 to 45 °C at duty cycles ranging from 0 (isothermal growth) to 1 (complete dissolution) were implemented to generate supersaturation ratios ranging from 2 to 50. By monitoring liquid phase concentration with in situ UV Vis in flow and pairing it with yields and particle size distributions determined from optical microscopy, experimental data was fit to parametric kinetic model equations provided by CrySyst LLC, which was then used to predict distributions of more complicated wave forms. This continuous bottom-up technique is a precise approach to generate high-quality monodisperse products as each microdroplet experiences identical crystallization environments.