Progress of Pharmaceutical Continuous Crystallization

Perspectives on process monitoring of industrial systems

Process intensification (PI) is a strategy aimed at transforming conventional chemical processes into more economical, productive and green processes. Its fundamental concept hinges upon the volume reduction of processing equipment resulting in enhanced mixing and heat/mass transfer as well as a multitude of other benefits. To date, the focus of PI has been on processes mainly involving gas/liquid systems. Solids handling applications have been more limited as fouling and blockages can occur due to large concentrations of solids in smaller equipment sizes. Appropriately designed equipment is therefore a key consideration for intensifying industrially-relevant solids handling processes. In this review paper, we highlight a number of solid processing applications including precipitation, separation, granulation and milling, etc. where PI has been demonstrated. Much effort has been directed at reactive crystallization and precipitation in various intensified technologies, exploiting their enhanced mixing capabilities to produce uniformly distributed nano-particles. Generally, the objective in many of these processes has focused on transforming solids handling in batch processes into continuous ones with processing time reduction and improved energy efficiency. The review highlights the considerable opportunity for further development of multifunctional technologies in solids handling applications such as granulation and drying, the subject of a European Commission-funded HORIZON 2020 project.

https://www.eprints.ncl.ac.uk/file_store/production/237752/C9A42596-EAB3-43AC-AA17-4C8C3D12DC62.pdf

A review of process intensification applied to solids handling

Recent progress of continuous crystallization

Continuous-flow solution crystallization is an approach to manufacture pharmaceutical crystals with improved control of product characteristics, simplified postcrystallization operations, higher production rate flexibility, and reduced capital costs and footprint. An indirect ultrasonication-assisted nucleation process is designed to vary the 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-a...

Indirect Ultrasonication in Continuous Slug-Flow Crystallization

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...

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Ernesto Jimenez

Papers

Continuous-Flow Tubular Crystallization in Slugs Spontaneously Induced by Hydrodynamics