Scale-up of solvent-free synthesis

Lead Research Organisation: Queen's University of Belfast
Department Name: Sch of Chemistry and Chemical Eng


Solvents are traditionally assumed to be essential for most chemical reactions to proceed at an acceptable rate and in a controlled way. They are correspondingly ubiquitous in chemical processes, but simultaneously generate enormous amounts of waste, deplete fossil resources and require large amounts of energy to produce, purify and recycle. Finding cleaner and more sustainable ways of manufacturing chemicals and materials is a priority goal globally for the foreseeable future. Therefore, innovative thinking to come up with new types of processes which do not need solvents, and which can be scaled up to industrial production levels, is now critically important. 'Mechanochemistry' is a way of inducing chemical reactions simply by grinding solids together, and it is now attracting attention as an alternative general approach to traditional solvent-intensive methods. It has recently emerged that by using surprisingly simple, energy-efficient grinding apparatus such as ball mills, many reactions between solids can actually be performed, at least on small scales, often
within a few minutes and without any added solvent. However, a critical issue now is how to scale-up this mechanochemical synthesis to industrially-applicable levels. This project aims to provide a step-change in this area by enabling such chemistry to be done on larger scales so making it more applicable to industrial implementation. This project is highly interdisciplinary, bringing together experts in chemistry, chemical engineering, mechanical engineering and pharmaceutical processing. The project is structured in order to: 1) gain greater knowledge and understanding of how such chemistry works and thus how to optimise it, and 2) explore how it can be used to provide new types of chemical reactions and chemistry and processes. A recently-formed university spin-out company will act a vehicle to maximise the commercial impact of this research.

Planned Impact

Professor James (PI) is dedicated not only to innovative and challenging work of a fundamental nature but also to realizing tangible impact from that work.
In 2012 founded a spin-out company, MOF Technologies ( based on IP arising from an EPSRC-sponsored project (GR/T23145/01, 'Solventless synthesis of metal organic frameworks,' £113K, 2005-2008). To our knowledge, this is the only company world-wide which has the necessary IP rights to compete with BASF in the commercial manufacture of metal-organic frameworks (MOFs). MOF Technologies is an excellent vehicle through which to demonstrate synthesis by extrusion in a commercial context. The company produces and markets MOFs by solvent-free synthesis and this project therefore matches very well with its commercial goals (see Statement of Support). It is keen to license IP arising from this project from Queen's University Belfast (who will own the IP). It already supplies MOFs to two distributors (i.e. it is establishing routes to market) and is in discussions for quantities as large as 200 kg. It has also identified commercial opportunities for mechanochemical synthesis of products other than MOFs. Furthermore, it currently has more than 70 significant links to chemical, distribution and engineering companies. Therefore, it would be able to pursue ventures in collaboration with a range of more established companies and/or establish sub-licensing agreements in line with its existing business model. Since Professor James is CTO of MOF Technologies there will be effective communication between the academic and industrial partners. Also, promoting researcher mobility, the PDRA will be formally seconded into the company for up to six months during the project to transfer his/her hands-on expertise and tailor the methods towards the company goals, effectively as an informal Knowledge Transfer Partnership. Specifically, this work will range from optimization of the developed extrusive synthetic methods with regard to product quality, process cost and scale, up to devising new extrusive synthesis methods for alternative products not investigated in the pure research phase.
We will also organize up to five industrial visits to the lab for one-to-one clinics to demonstrate the process, potentially tailored specifically to a company's particular materials of interest. We will provide up to six summer studentships over the grant period for undergraduates and potentially school students in order to provide them with potentially career-determining experience of the research environment, to improve their comprehension of academic literature and the potential applications of fundamental research, and to enhance their laboratory skills, communication skills (through group presentations) and confidence.
We will naturally seek to disseminate the results in high-profile journals such as Angewandte Chemie International Edition and Journal of the American Chemical Society. As well as academic meetings, trade fairs will be used to disseminate the work and network more directly with potential end-users, specifically: RSC Faraday Meeting on Mechanochemistry, May 2014, Montreal, education and integration of PDRA; InformEx 2015 or 2016 (venue tba, global trade fair to network with end-users); 249th ACS National Meeting & Exposition, March 2015, Denver, Program Theme: Chemical Resources: Extraction, Refining and Conservation; ACS Gordon Conference on Green Chemistry 2016, venue tba), 9th INCOME International Conference on Mechanochemistry 2016 venue tba). The PI has a good track record of dissemination through the media (~25 articles since 2002,e.g. C&E News, BBC, Chemistry World) and these avenues will also be actively pursued.
We will also set up a dedicated web page to publicize the project to the general public and to interact with industrialists. We will also commission a professional video for dissemination via the web site, conferences and YouTube.


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Crawford DE (2016) Efficient continuous synthesis of high purity deep eutectic solvents by twin screw extrusion. in Chemical communications (Cambridge, England)

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Crawford DE (2016) Recent Developments in Mechanochemical Materials Synthesis by Extrusion. in Advanced materials (Deerfield Beach, Fla.)

Description This has been a highly successful project. We have found that the highly efficient, solvent-free chemical manufacturing can be done for the first time by using our twin screw extrusion techniques. During this project we have successfully demonstrated its effectiveness across a broad range of types of chemical reactions and processes not previously explored. Effectively, this demonstrates that our method of performing chemical synthesis is not only potentially far more efficient and economical than conventional methods, but also has much broader applications than our original results showed. There is clear potential for this technique to be adopted quite widely within chemical industries (see below for further details) and for it to become a truly transformative manufacturing technique. We have also used related (non-extrusion) equipment at the University of Warwick to gain greater insight into rheological changes which occur during reactions in extruders which may ultimately be used for the more efficient optimisation of extrusion conditions. Collaborators at the University of Limerick have also helped us to understand the basic processes which are critical to reactions occurring under these conditions, specifically effective wetting of one reactant by the other. Over the course of the project we have made considerable advances. We are now internationally recognised as the leaders in this emerging approach to synthesis. In particular, world-leading research groups from The Universities of Liverpool, Aachen and Leicester have visitied us to undertake collaborative work which have so far lead to three research papers and a further one is currently at draft stage. In all cases we have demonstrated how synthesis by extrusion is a unique way to provide continuous chemical synthesis without the use of solvents. This significantly improves the scalability, economics and environmental impact of the synthesis and makes commercialisation more realistic. We have published 11 papers from the project to date inlcuding papers given 'Hot paper' status and papers in the very top chemistry journals (such as Angewandte Chemie). Despite the recent nature of this work these papers have attracted to date more than 130 citations. I am invited to give typically 5-6 presentations on this topic per year, in some cases as keynote or plenary speaker at major international conferences. Regarding patents, to date one patent has been granted and is licensed to spin-out company MOF Technologies who are demonstrating the commercialisation of this method of synthesis to great success (MOF Technologies provided the active material for the first commercial application of MOF materials by Decco Post Harvest Inc.). A further patent on the synthesis of different commercially important products has passed a patentability assessment and is now being drafted. We have also learned how to 'telescope' multiple chemical reactions into a single extrusion process which demonstrates a way to gain further efficiciency in chemical manufacturing. Finally we have begun to move into potentially more challenging work in attempting to demonstrate delamination of layered materials again with some success, and we have begun to engage with global companies regarding their adoption of these methods (please see below). In terms of key findings, within the last year we have shown the we can manufacture certain thin-later materials using the extrusion technique. We are currently considering whether to patent, publish academically or both. Further experimental work is required on this which should be complete by end of 2019.
Exploitation Route The next milestone we are working toward is for a globally recognised manufacturer to apply our methods to their own processes. We currently have interest from two multinational chemicals companies who have expressed a wish to fund research into the application of this approach to the manufacture of their own products and we are engaging with them enthusiastically during the coming year. 2019 update: We have secured a CASE PhD studentship with Johnson Matthey to take the technique into the area of pharmaceutical manufacturing. Therefore, the anticipated move toward working with a large industrial partner is progressing as hoped.
Sectors Chemicals,Manufacturing, including Industrial Biotechology

Description We are in the process of patenting the synthesis of organic materials by our new extrusion technique, following a positive initial patentability assessment. The products are used commercially. Our method improves considerably on exisiting methods for these materials in terms of avoiding hazardous and highly toxic solvents and in terms of economy. We are engaging wwith the Research and Enterprise Directorate and QUB to identify potential licensees once the patent application has been submitted. We are also in discussion with a global chemicals company about potential joint work on applying synthesis by extrusion to a number of their commercial products. We are in further initial discussion with an international oil and gas company on applying synthesis by extrusion to other active materials. In the last yuear we have filed a patent application for the synthesis of dye materials using the extrusion techniques devloped in this project. We have also engaged a 'deal maker' who has provided a report identifying relevant areas of application and potential industrial conbtacts as end-users. The report is helpful and we will now move the to the next step of making these contacts. Also, a CASE PhD studentship has been secured with Johnson Matthey to further develop the work done in the direction of pharmaceutical synthesis. The project will begin October 2019. A PhD studentship has been secured (120K) fully-funded by a multinational company to explore twin screw extrusion for the solvent-free synthesis of polymer precursors.
First Year Of Impact 2021
Sector Chemicals
Impact Types Economic

Description Synthesis of APIs by Twin Screw Extrusion
Amount £108,000 (GBP)
Organisation Johnson Matthey 
Sector Private
Country United Kingdom
Start 09/2019 
End 10/2023
Description Continuous Solventless Synthesis of porous organic cages by twin screw extrusion 
Organisation University of Liverpool
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution We have hosted and trained a visiting PDRA for two weeks in the use of twin screw extrusion for the synthesis of novel materials developed at Liverpool, specifically porous organic cages. We have held discussions with the PI Prof. Andy Cooper subsequently and are drafting a paper.
Collaborator Contribution Provided PDRA visit for two weeks and held discussion of results.
Impact The work was successful and showed that such compounds were amenable to this type of synthesis for the first time. We are drafting a joint paper and considering a patent application as well as potential follow-up work. The project is significant in demonstrating an economic and scalable way to make these materials and so makes their application more realistic.
Start Year 2017
Description Continuous solvent-free enzyme-catalysed synthesis by twin screw extrusion 
Organisation RWTH Aachen University
Department Department of Chemistry
Country Germany 
Sector Academic/University 
PI Contribution We hosted and trained two visiting researchers to conduct synthesis by extrusion and co-wrote the two resulting papers. The visitors were rom a world-leading group in organic synthesis (Professor Carsten Bolm).
Collaborator Contribution The partners conducted the bulk of the synthesis and analysis under our guidance and co-wrote the resulting paper.
Impact Publication 1: Mechanoenzymatic peptide and amide bond formation; By:Hernandez, JG (Hernandez, Jose G.); Ardila-Fierro, KJ (Ardila-Fierro, Karen J.); Crawford, D (Crawford, Deborah); James, SL (James, Stuart L.); Bolm, C (Bolm, Carsten); GREEN CHEMISTRY, Volume: 19 Issue: 11 Pages: 2620-2625 DOI: 10.1039/c7gc00615b. Published: JUN 7 2017. Publication 2: Papain-catalysed mechanochemical synthesis of oligopeptides by milling and twin-screw extrusion: application in the Juliá-Colonna enantioselective epoxidation; by Karen J. Ardila-Fierro, Deborah E. Crawford, Andrea Körner, Stuart L. James, Carsten Bolma and José G. Hernández; GREEN CHEMISTRY, 2018, DOI: 10.1039/C7GC03205F.
Start Year 2017
Description Lice cycle analysis of synthesis by extrusion 
Organisation Technion - Israel Institute of Technology
Country Israel 
Sector Academic/University 
PI Contribution We have collaborated on an analysis which compares the environmental impact of a pharmaceutical by the conventional solvent-based method versus the solvent-free extrusion method developed under the EPSRC project. We provided expertise and numerical data from experiments to enable the analysis to be done.
Collaborator Contribution They conducted the life cycle analysis.
Impact published paper: Mechanochemistry Can Reduce Life Cycle Environmental Impacts of Manufacturing Active Pharmaceutical Ingredients Or Galant, Giacomo Cerfeda, Aaron S. McCalmont, Stuart L. James, Andrea Porcheddu, Francesco Delogu, Deborah E. Crawford, Evelina Colacino, and Sabrina Spatari* ACS Sustainable Chem. Eng. 2022, 10, 4, 1430-1439
Start Year 2019
Description Synthesis of deep eutectic solvents by extrusion 
Organisation University of Leicester
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint research was conducted (visit of PDRA from Leicester to QUB, and of PI and PDRA from QUB Leicester) to explore improved synthesis of Deep Eutectic Solvents enabled by the extrusion techniques being developed in this project. The work was successful and lead to a publication (DOI: 10.1039/C5CC09685E). Further collaborative work is planned and a grant application to EPSRC.
Collaborator Contribution Provided time and expertise (1 week PDRA time), 2 days Professor time and expertise in Deep Eutectic Solvents.
Impact Efficient continuous synthesis of high purity deep eutectic solvents by twin screw extrusion D. E. Crawford,a L. A. Wright,b S. L. James*a and A. P. Abbott*b Show Affiliations Chem. Commun., 2016, Advance Article DOI: 10.1039/C5CC09685E
Start Year 2015
Description Use of resonant acoustic mixer for chemical synthesis 
Organisation University of Edinburgh
Department School of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution PDRA visited Edinburgh (3 days) to explore the use of a resonant acoustic mixer for chemical synthesis. This type of equipment has not been used for chemical synthesis previously to our knowledge. Results were positive and a publication is planned.
Collaborator Contribution Provided access to equipment, discussion of system and results.
Impact none yet.
Start Year 2015
Description Johnson Matthey 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact A visit to the Johnson Matthey Technology Research Centre to present and discuss our work on synthesis by extrusion and how it might relate to future joint work.
Year(s) Of Engagement Activity 2017