Continuous-Flow Tubular Crystallization in Slugs Spontaneously Induced by Hydrodynamics

Abstract

A novel continuous crystallizer design is described with the potential to provide improved control of crystal properties, improved process reproducibility, and reduced scale-up risk. Liquid and gas are introduced into one end of the tube at flow rates selected to spontaneously generate alternating slugs of liquid and gas that remain stable while cooling crystallization occurs in each liquid slug. Mixing within each stable self-circulating slug is maximized by controlling the slug aspect ratio through specification of liquid and gas flow rates. The crystallizer is designed so that nucleation and growth processes are decoupled to enhance the individual control of each phenomenon. Coaxial or radial mixers combine liquid streams to generate seed crystals immediately upstream of the growth zone where nucleation is minimized, and crystal growth is controlled by the varying temperature profile along the length of the tube. The slug-flow crystallizer design is experimentally demonstrated to generate large uniform crystals of L-asparagine monohydrate in less than 5 min.

Reducing the Induction Time Using Ultrasound and High-Shear Mixing in a Continuous Crystallization Process

“…However, studies often focused on components with relatively fast nucleation kinetics [2,5,7,10]. This leaves the nucleation of molecules with slow nucleation kinetics as one of the key challenges for tubular crystallizers.…”

“…Another challenge is fouling, which eventually leads to clogging. Whilst multiple solutions to fouling are suggested in literature, they often add a lot of complexity and can only limit fouling to a certain degree [10,13,14]. A general rule to minimize fouling is to work at low supersaturations; however, this decreases nucleation rates even more, highlighting the need to enhance nucleation at low supersaturations.…”

Design of a Continuous Tubular Cooling Crystallizer for Process Development on Lab‐Scale

“…Therefore, a parent crystal or tablet is fixed on a rotating shaft. Seed crystals [34,35] Liquid-liquid slug flow…”

“…Seed crystals of paracetamol were subsequently grown in a tubular growth section [31,32]. In order to minimize axial dispersion [33,34] and to prevent clogging of tubular devices [34], the application of a gas-liquid slug flow is under investigation for continuous cooling crystallization. Jiang et al reported on a slug-flow device which was used as a growth section for the L-asparagine monohydrate (water) system.…”

Separation Units and Equipment for Lab-Scale Process Development

“…Thus, an efficient particle fluidization is crucial for robust operation. Pulsating flow by piston movement (e.g., COBC) [47] and gas-liquid slug flow [95][96][97] is under discussion to facilitate particle transport in plug flow crystallization. For helically coiled tubes, there is evidence that Dean vortices enhance particle fluidization and reduce scaling of surfaces, e.g., in membrane filtration processes [100].…”