(646d) Segmented Flow Crystallization of Paracetamol Via Microdroplet Cooling

Efficiently controlling particle size, quality, and polymorphism challenges every branch of crystallization. Traditional top-down synthesis methods rely on cumbersome, highly sensitive processes resulting in wasted material, excessive solvents, and numerous unit operations to achieve the desired particle size distribution. Alternatively, continuous bottom-up crystallization is a precise approach to generate high-quality monodisperse products as each microdroplet experiences identical crystallization environments.

Segmented flow microfluidics offers a high throughput continuous platform to study crystal nucleation, growth, and dissolution. In situ UV-vis spectroscopy captures the liquid phase changes that occur throughout the phase change, while microscopy and laser diffraction highlight the quality of the solid products formed. Nucleation rate can be tuned according to ultrasonication energy input into the system spanning the fast generation of fines (sonics) to the slow formation of large particles (silent).

This work details the design, construction, and implementation of a continuous segmented flow crystallizer. Since solute solubility tends to be highly temperature-dependent, operating at low Reynolds and Biot numbers facilitates the isothermal step changes required to quickly span the phase diagram of cooling crystallization. Microdroplet flow crystallization is a scalable process that opens the door to directly controlling the formation of crystals from nucleation to harvesting.