SONOCRYSTALLISATION IN CONTINUOUS FLOW MICROCHANNEL CONTACTORS

Lead Research Organisation: University College London
Department Name: Chemical Engineering

Abstract

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.

Planned Impact

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.
 
Description Continuous flow sonocrystallization devices for the production of crystals by the aid of ultrasound were designed, commissioned and investigated. It was shown that ultrasound equipped continuous millireactors are capable of controlling crystallization (in terms of crystal size and production rate) of pharmaceutical components and have the potential to produce crystals in a reproducible and controllable way, which is beneficial for pharmaceuticals production. We have employed a multidisciplinary approach which combined acoustic modelling with crystallization experiments that helped identified critical parameters and phenomena during continuous sonocrystallization. In particular. we demonstrated that transient cavitation of bubbles is a significant mechanism for enhancing nucleation of crystals. We produced smaller crystals with narrow size distribution, as compared with conventional crystallization and commercially available products.
Exploitation Route We have provided the potential to bring about a change in pharmaceuticals production by combining the benefits offered by continuous flow processing and sonocrystallisation. The principal beneficiary of this work will be the pharmaceutical industry. The knowledge gained from this research and its dissemination can help scientists and engineers involved in the manufacture of pharmaceuticals to understand this novel procedure, facilitate its penetration to process development and turn it into a core pharmaceutical engineering technology. Other manufacturing industries that rely on particle technology (e.g. adipic acid manufacture) can also use our findings to improve their manufacturing processes.
Sectors Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description This project has been in close engagement with GSK, one of the biggest pharmaceutical companies in the world. The outcome of our research has a potential impact to their processes, specifically in ultrasound aided crystallization processes for the production of pharmaceutical crystals. The laboratory sonocrystallization devices that we have designed and evaluated in this project, can help reduce the 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. Our devices can be employed by other UK pharmaceutical companies, assisting them to remain at the forefront of pharmaceutical innovation.
First Year Of Impact 2015
Sector Chemicals,Education,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description AFPAC14, Surrey, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Our talk included a very emerging topic for the audience. Some experts about sonocrystallization put useful comments on the research topic which helped significantly on future activities.
Year(s) Of Engagement Activity 2014
URL http://afpac14.iopconfs.org/home
 
Description AFPAC15, Villa Clythia, Fréjus, France 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Our talk was very interesting for most of the audience who work on different applications of ultrasound. Fruitful discussions with experts of ultrasound helped us in finding new directions for future activities.
Year(s) Of Engagement Activity 2015
URL https://intranet.sfa.asso.fr/archives/J87-AFPAC2015/
 
Description AFPAC16, Surrey, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Several questions were raised from different groups in/outside the UK working on sonocrystallization. It has been revealed that our model for the effect of ultrasound on nucleation could be useful for others in different universities working on the same topic.
Year(s) Of Engagement Activity 2016
URL http://afpac2016.iopconfs.org/home
 
Description AIChE 2014, "Characterization of Residence Time Distribution in Micro Coiled Flow Inverters" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A couple of professionals from industry showed interest about the outcome of our research, since it has the potential to be used in large-scale industrial plants.

L. Gargiulo, S. Kuhn, A. Gavriilidis, L. Mazzei, "Characterization of Residence Time Distribution in Micro Coiled Flow Inverters", AIChE Annual Meeting, Atlanta, USA, November 2014.
Year(s) Of Engagement Activity 2014
URL http://www.aiche.org/conferences/aiche-annual-meeting/2014
 
Description BACG 2016 "Adipic Acid Primary Nucleation Kinetics from Probability Distributions in Droplet-Based Systems under Stagnant and Flow Conditions" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation of our work in the 12th International Workshop of the Crystal Growth of Organic Material & 47th Annual British Association of Crystal Growth Conference, BACG 2016, Leeds, 26-30 June 2016.
Year(s) Of Engagement Activity 2016
 
Description BACG 2016 "Ultrasound Particle Engineering" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation in the 12th International Workshop of the Crystal Growth of Organic Material & 47th Annual British Association of Crystal Growth Conference, BACG 2016, Leeds, 26-30 June 2016.
Year(s) Of Engagement Activity 2016
 
Description BACG Annual Conference: "Continuous-Flow Sonocrystallization in Milliscale devices" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Oral Presentation: G. Valitov, A. Gavriilidis, L. Mazzei, "Continuous-Flow Sonocrystallization in Milliscale devices" BACG Annual Conference, 27 - 30 June, 2017 University of Manchester, Manchester, UK.
Year(s) Of Engagement Activity 2017
 
Description ECCE10, "Experimental and Numerical Investigation of Continuous Sonocrystallisation of Adipic Acid in a Straight Millichannel" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact More than 50 people attended the talk which was accepted as a keynote of the conference. The outcome of the research was very interesting for a couple of group from outside of the UK, including Belgium and Italy.
Keynote presentation
R. Jamshidi, D. Rossi, L. Gargiulo, S. R. Haqshenas, L. Mazzei, S. Kuhn, N. Saffari, A. Gavriilidis, "Experimental and Numerical Investigation of Continuous Sonocrystallisation of Adipic Acid in a Straight Millichannel", ECCE10, 10th European Conference of Chemical Engineering, Nice, France, 27 September - 1 October 2015.
Year(s) Of Engagement Activity 2015
URL http://www.ecce2015.eu/
 
Description IChemE PTSIG 2016 "Nanoparticle and Microparticle Production in Flow" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact This was a presentation to the Institution of Chemical Engineers working group on particle technolofy. It sparked questions and discussions afterwards, and we were invited to give a seminar to the University of Surrey
Year(s) Of Engagement Activity 2017
 
Description ISIC19, "Adipic Acid Nucleation Kinetics from Probability Distributions in Drop-based Systems" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation
D. Rossi, L. Mazzei, S. Kuhn, M. Ardid Candel, A. Jones, A. Gavriilidis, "Adipic Acid Nucleation Kinetics from Probability Distributions in Drop-based Systems", 19th International Symposium on Industrial Crystallization, Toulouse, France, September 2014.
Year(s) Of Engagement Activity 2014
URL http://inpact.inp-toulouse.fr/ISIC2014/EFCE_award.html
 
Description Keynote Talk - Micro and Millifluidic Separation Processes 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Keynote Lecture by A Gavriilidis, L. Mazzei, A. Radhakrishnan, & G. Valitov, on "Micro and Millifluidic Separation Processes" at IMRET 2018, 15th International Conference on
Micro Reaction Technology; Karlsruhe, Germany.
Year(s) Of Engagement Activity 2018