SONOCRYSTALLISATION IN CONTINUOUS FLOW MICROCHANNEL CONTACTORS

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.

Impact on economy. The UK is the third largest exporter of pharmaceuticals in the world (12.5billion in 2005). The pharmaceutical industry will be one of the main beneficiaries from this work, by accessing a novel technology for the manufacture of pharmaceutical ingredients. The final product can be obtained more efficiently and with better quality. The proposed approach will help reduce risk and capital cost associated with scaling up from laboratory to production, since scale up by replication of the laboratory units would eliminate costly redesign and pilot plant experiments. This can result to shortening of the development time from laboratory to commercial production. All the above will give a significant competitive advantage to the UK pharmaceutical industry, assisting it to remain at the forefront of pharmaceutical innovation worldwide. The work can also benefit equipment manufacturers, by introducing innovative products, placing the UK as a leading supplier of ultrasonic flow microprocessing equipment. The research proposed can lead to technology which is applicable to other (nano)particle manufacturing companies ranging from pigments to photofunctional materials, thus benefiting in the longer term other manufacturing industries. Impact on knowledge. This work will assist research and development laboratories involved in particle manufacture, both in industry and academia to better understand, predict and optimize crystallization processes. Crystallization is a complex phenomenon that, despite several experimental and theoretical developments, still remains puzzling, so that no accurate theory can substitute for empirical investigation. Micro-structured continuous flow reactors offer unequalled experimentation conditions to explore this process, since small scales consent excellent control of flow patterns, transport phenomena and kinetic pathways. Impact on society. The health and quality of life of the wider public will benefit through the provision of new/improved drugs, which the proposed techniques will enable. Should this technology become established and readily available, it will contribute in many areas of chemical manufacturing to finding faster, safer, more efficient, cleaner and cheaper process solutions, benefiting the society through the use of these technological advances for green and sustainable chemical manufacture. Impact on people. The project will result in highly trained researchers with professional skills in a wide range of areas, including chemical reactor engineering, microreaction technology, crystallization, sonocrystallisation, ultrasound science, flow processing. It will develop their ability to work independently and in a team, expose them to interdisciplinary research and facilitate acquiring transferable skills that will enhance their learning process and broaden their horizons. These will make them valuable assets to R&D departments of particle technology of pharmaceutical but also high-tech nanomaterial manufacture companies. To make our results available to beneficiaries we will: - Disseminate them through publications in scientific and trade journals and presentations at international conferences. Communication will be enhanced by webinars though targeted websites. - Document the modelling procedures and computational tools that we will develop (after IPR protection) to design insonated crystallization units, making our expertise available to the wider crystallization community. - Organize a workshop involving researchers, industry and relevant stakeholders to present, discuss and advertise this technology and facilitate its commercial application and exploitation. - Involve pharmaceutical industry and engage with UCL Advances and UCL Business to evaluate the technology on systems of relevance to pharmaceutical companies, foster knowledge transfer, and explore potential exploitation routes.