SONOCRYSTALLISATION IN CONTINUOUS FLOW MICROCHANNEL CONTACTORS

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Crystallization from solution is a core technology in major sectors of the chemical process and allied industries. It is widely employed in the manufacture of pharmaceuticals during the intermediate and final stages of purification and separation. The process defines drug chemical purity and physical properties: crystal morphology, size, size distribution, habit or shape and degree of perfection. Variations in crystal characteristics are responsible for a wide range of pharmaceutical formulation problems, related for instance to bioavailability, a principal pharmacokinetic property, and the chemical and physical stability of drugs in their final dosage forms. In the pharmaceutical sector up to 90% of active ingredients are produced as crystals. The technical sophistication of crystal products is always rising, placing ever greater demands on the knowledge, skill and ingenuity of researchers to develop novel materials and devise viable processes for their manufacture. The increasing environmental constraints and need for sustainability place additional pressure on these processes.To attain these ambitious goals, researchers need to devise innovative process solutions in manufacturing technology. The complexity of this challenge cannot be met by single individuals, because innovation at this level requires interdisciplinary research that integrates methods, skills and strengths of different disciplines. In line with this winning strategy, we intend to bring about a sizable step change in pharmaceuticals manufacturing through a new technology that combines and exploits the benefits of continuous flow processing, microreaction technology and ultrasound engineering. To do so, we will build on the complementary expertise of the team members, basing the work on strong fundamental foundations that will ensure a deep level of understanding of the physicochemical phenomena (and their interaction) taking place during flow sonocrystallisation. Chemical engineers have used ultrasound to manipulate crystal synthesis, but often barriers posed by limited understanding of ultrasound technology have reduced the impact of these endeavours. One unique feature of this research project is that we will - for the first time - design crystallizers with integrated ultrasound capability based on properly constructed models of ultrasound physics and using fluid dynamic tools that will enable us to obtain within the reactor the desired ultrasonic field. This will ensure control and reproducibility. Another unique aspect of this work is using continuous flow microreactors to repartition the synthesis in stages and intensify the process, enhancing control and efficiency even further. The research will entail experimental and theoretical investigations on crystal formation, growth, agglomeration and disruption. Ultrasound can affect these processes in different ways, for example through cavitation or streaming. These can be adjusted by proper manipulation of suitable variables such as the ultrasound power. The effect of ultrasound will be studied by targeted experiments, so that insight into the various processes is gained. Ultrasound generators operate remotely and therefore are suitable for contained, sterile environments. Thus, the crystallisation processes can potentially be controlled at the flick of a switch.