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.

Continuous-flow solution crystallization is an approach to manufacture pharmaceutical crystals with improved control of product characteristics, simplified post-crystallization operations, higher production rate flexibility, and reduced capital costs and footprint. An indirect ultrasonication-assisted nucleation process is designed to vary seed generation rate during operation independent of mass flow rate, by varying the ultrasonication power. The ultrasonication probe is pressed against a tube to generate a spatially localized zone within the tube inside of a temperature bath for the generation of crystal nuclei without heating or contaminating the supersaturated solution. This nucleation design is integrated into a continuous slug-flow crystallization process to generate uniform-sized product crystals within each slug at a high supersaturation level and a short residence time of ~8.5 min, without inducing significant secondary nucleation. By increasing size uniformity, the indirect ultrasonication-assisted slug-flow crystallizer has potential as a final crystallization step to produce crystals for direct compression tableting without having any possibility of metal contamination.

This review of recent research advances in continuous-flow crystallization includes a five-step general design procedure, generally applicable process intensification strategies, and practical insights.

The evolution of particle shape is an important consideration in many industrial crystallizations. This article describes the design of temperature-cycling experiments (between alternating positive and negative supersaturations) to substantially change crystal shape with only a small number of cycles. The growth and dissolution of monosodium glutamate crystals of varying shapes were monitored using in-process attenuated total reflection−Fourier transform infrared spectroscopy (ATR-FTIR), focused beam reflectance measurement (FBRM), particle vision and measurement (PVM), and off-line optical microscopy. The growth and dissolution kinetics were estimated in a multidimensional population balance model based on solute concentration and crystal dimension measurements. This model fitted the experimental data with a limited number of parameters of small uncertainty. In addition, with the estimated kinetic parameters, the model predicted the crystal size and shape distribution in a different temperature-cycling experiment reasonably well. In contrast to previous studies that have estimated kinetics along multiple crystal axes in mixed-tank crystallizers, this study implements dissolution terms in the multidimensional population balance model along multiple axes.