Among the most inefficient and least reproducible steps in the manufacture of most active pharmaceutical ingredients are multiple batch crystallizations, which motivate the development of new continuous-flow crystallization technologies. A novel continuous-flow 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 crystal size, shape, and distribution within each slug are monitored in real-time by employing in-situ video microscopy through a transparent wall 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. Our continuous-flow crystallizer design increases the process productivity by nearly two orders of magnitude compared to the existing batch crystallizers used in the pharmaceutical industry.

Continuous-flow tubular crystallization in slugs spontaneously induced by hydrodynamics

248th National Meeting (2014)

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