Final Report Summary - MICRO-THERAPY (Eco Friendly Tuneable Microwave continuous Flow Reactor for the Synthesis of Lecucettamines in Therapeutic Activity Against Alzheimer's Disease)
The four-year MICRO-THERAPY is a fully integrated interdisciplinary proposal which will develop a new area of competence in the three partners, Liverpool John Moores University, University of Rennes1 and ManRos Therapeutics. It brings together a powerful set of partners covering fully the three key aspects - microwave engineering, chemistry and biology to create new technology and sustainable technical and scientific expertise applicable to the bio-pharmaceutical industry. The proposed research programme is unique in terms of generating a tuneable, multipurpose, microwave, continuous, atmospheric pressure, flow reactor for the efficient conduct of various chemical reactions for the synthesis of Leucettamines to be used against Alzheimer’s disease. Unlike the restricted batch reactors a continuous microwave reactor has the potential to operate at high production rates simply by virtue of offering continuous throughput and, more significantly, by being easy to replicate allowing scale up the process for bulk production at commercial rates. In addition the system will operate for the first time with tuneable frequency microwaves in the range 2.45 – 8GHz in order to optimise the process to produce higher yields with reduced separation costs. This is unlike current microwave synthesis where the source is only operated at one fixed frequency of 2.45GHz and is therefore not necessary have the optimum operating frequency to suit various chemicals reactions at different temperatures. The timeliness of MICRO-THERAPY is a response to demand for new ways to produce chemicals for the therapeutic activities against Alzheimer’s disease. However, such a reactor also has scope fore much wider application
The main objectives of this project are:
1. To use the project to develop new cross-disciplinary expertise through the recruitment of experienced researchers to work particularly at LJMU and UR1, but also incorporating expertise at MRT thereby providing new training and development opportunities for young and experienced researchers at the partners, blending an expanding knowledge base and unique skills to produce key proficiencies.
2. To specifically develop a multipurpose prototype reactor for the synthesis of bulk quantities of chemicals on a continuous basis by using novel atmospheric pressure, continuous microwave flow reactor.
3. To select the reaction time, flow rate, microwave power and frequency within the operating range 2.45 to 8GHz to produce chemicals with high yield, low waste and using low power in comparison with the conventional techniques.
• Scientific and Technology Objectives
(i) Scientific Objectives
• To specifically develop and implement a new design for a tuneable microwave flow reactor for improved chemical synthesis of key bio-pharmaceutical compounds.
• To optimise the reaction time, flow rate, microwave power and frequency (within the operating range 2.45 to 8GHz) to produce chemicals with high yield and purity, thereby minimising waste and requiring the minimum of product extraction.
• To research self-tuning of microwave sources to operate at various frequencies ranging from 2.45 to 8 GHz and where power levels are modulated to maintain optimisation.
• To characterise the effects of microwave frequency and power applied to the various chemicals that will give the best speed of reaction and yields.
• To specifically extend this to a multipurpose prototype reactor for the synthesis of bulk quantities of chemicals on a continuous basis by using a novel atmospheric pressure, continuous, tuneable microwave flow reactor.
• To use solvent free chemistry wherever possible to avoid waste disposal problems.
• To use the reactor to investigate, in depth, four chemical reactions. By using the data from these reactions to obtain an explanation of the mechanism of their particular microwave assisted chemistry.
(ii) Technological Objectives
• To measure the dielectric properties of various pure chemicals and related mixtures across a range of frequencies 2.45 GHz to 8 GHz, noting the effect of temperature. Measurements to be made at atmospheric pressure.
• Design and build a continuous microwave reactor in which a single cavity will be use for all frequencies in the range of 2.45 to 8 GHz allowing multimode resonance conditions to be maintained at all times. In this system coupling waveguides will be use to allow any of the microwave sources to be easily attached to the cavity.
• Design and build an automated microwave sensor plasma monitoring system in which software analysis will identify the salient parameter of each sensor (based on temporal analysis, spectrum analysis and responses times), which will be used to give an insight to the chemical reactions.
• To achieve a step change in efficient use of resources (energy, chemicals and solvents).
(iii) Knowledge Transfer Objectives
Knowledge transfer provides a significant beneficial outcome for this project. Key to this is the recruitment of two experienced researchers. The need for two researchers is based on expected workload and the required complement of prior knowledge and skills. The design of a microwave cavity and associated hard and software requires specialist knowledge and a suitably experienced microwave engineer is most unlikely to have the depth of knowledge of chemical synthesis required. Equally, the design and optimaisation of the panel of chemical reactions is non-trivial and requires extensive experience of organic chemistry, which will be the province of the experienced chemist. However, such as chemist would not have the in-depth knowledge of microwave technology. consequently, the two experienced researchers will complement each other and provide mutual input to enable the project to remain on course.
The MICRO-THERAPY Fellows and designated staff have worked together to:
• Develop and test the engineering and chemical parameters of the microwave flow reactor leading to an industrial prototype capable of operating at various frequencies and variable power.
• Improve understanding by six existing specific LJMU and UR1 researchers of their respective scientific areas and also of cognate areas.
• Produce documentation of protocols, construction designs, testing and results throughout development of microwave reactor, as a basis for retaining and extending the new knowledge gained during MICRO-THERAPY.
• Design routes for synthesis based on the likely advantages of microwave promoted reactions and demonstrate how to conduct reaction optimisation procedures using studies of reaction kinetics.
• Write literature reviews for in-house and external use on subjects within their areas of expertise to enhance knowledge at Liverpool and Rennes.
• Contribute to the content of the MICRO-THERAPY website.
• Deliver seminars within BEST Research Institute and the Pharmacy and Biological Science research centre (two industrial applications seminars), UR1 (two interdisciplinary seminars) and industrial workshops at MRT.
• Contribute to the annual Open Day for public awareness of engineering and science
• Participate in one workshop/Open Days targeted at local industry to raise awareness of new technology in SMEs in Merseyside and Normandy regions.
• Contribute to publications in the scientific literature.
The final results was led to various outcomes and in some cases exceeded the project technical aims and objectives in terms of the development for the first time a true microwave flow reactor with the capabilities of producing high added value chemicals for Therapeutic Activity Against Alzheimer's Disease. The system has proven to compatible with conventional systems such as CEM, Anton Parr, Milestone in which will create a step change in the industry. It is also achieved beyond the project expectation a real time sensor system which can identify the products contents without the need for the typical instrumentation of HPLC, IR, NMR, MS, GC-MS...etc.
Summary of results;
1. Developed new cross disciplinary expertise through the experienced researchers to work at LJMU and UR1 and provide new training opportunities for both young and experienced researchers at LJMU, UR1 and MRT, blending unique skills to produce key proficiencies. At present the partners have their own particular expertise, but only limited experience of the cognate areas in this project. Cross fertilisation will result in much deeper understanding and hence the possibility for further rapid development in this area. The project offers the opportunity for training and for the development of deep specialist skills so that both new workers and experienced researchers can gain additions to their tool-kit of techniques and whilst broadening their portfolio of broad generic skills.
2. Developed a novel tuneable microwave flow reactor and ancillary equipment, including facilities for on-line measurement of key parameters such as flow, temperature with heat inputs and heat transfer rates for improved synthesis of key bio-pharmaceutical compounds.
3. Managed to optimise the reaction time, flow rate, microwave power and frequency (within the operating range 2.45 to 8GHz) to produce chemicals with high yield and purity, thereby minimising waste and requiring the minimum of product extraction and other downstream processing steps.
4. Managed to specifically extend this to a multipurpose prototype reactor for the synthesis of bulk quantities of chemicals on a continuous basis by using a novel atmospheric pressure, continuous, tuneable, microwave flow reactor.
5. Achieved to use solvent free chemistry wherever possible to avoid waste disposal problems.
6. Achieved to develop real-time, self-tuning, computer control strategies to optimise the rates and yields of reactions by matching the microwave frequency and power to the variable chemical reaction conditions.
7. Achieved a step change in efficient use of resources (energy, chemicals and solvents).
8. Managed to use the reactor to investigate, in depth, four exemplar chemical reactions. By using the data from these reactions to obtain an explanation of the mechanism of their particular microwave assisted chemistry.
9. Prepared all documentation about the prototype; assess intellectual property potential and initiate future development in collaboration with industry by developing a website to publicise MICRO-THERAPY, to increase networking and collaborative opportunities with academia and industry in Europe.
10. Although the focus in MICRO-THERAPY is on the pharmaceutical industry, obvious further developments could include: renewable energy for the production of biofuel from waste using the microwave flow reactor, industrial treatments of water, waste water and recycled water.
11. Achieved most of the transfer knowledge planned activities.
The networks of European researchers and our existing links with industrial partners reinforced during MICRO-THERAPY to enhance future research projects at LJMU and UR1. The MICRO-THERAPY website provided publicity about the research innovation, output from the project and links with European laboratories. After working in this interdisciplinary, industrially orientated project at the boundaries of engineering, chemistry and biology, the experienced researchers will be very good candidates for industrial, research or academic positions in Europe within this subject area, including Marie Curie re-integration Fellowships.
Project website: http://www.ljmu.ac.uk/BLT/BEST/RFM/microtherapy/index.htm
For the list of all publications, please see the attached publication file.
The main objectives of this project are:
1. To use the project to develop new cross-disciplinary expertise through the recruitment of experienced researchers to work particularly at LJMU and UR1, but also incorporating expertise at MRT thereby providing new training and development opportunities for young and experienced researchers at the partners, blending an expanding knowledge base and unique skills to produce key proficiencies.
2. To specifically develop a multipurpose prototype reactor for the synthesis of bulk quantities of chemicals on a continuous basis by using novel atmospheric pressure, continuous microwave flow reactor.
3. To select the reaction time, flow rate, microwave power and frequency within the operating range 2.45 to 8GHz to produce chemicals with high yield, low waste and using low power in comparison with the conventional techniques.
• Scientific and Technology Objectives
(i) Scientific Objectives
• To specifically develop and implement a new design for a tuneable microwave flow reactor for improved chemical synthesis of key bio-pharmaceutical compounds.
• To optimise the reaction time, flow rate, microwave power and frequency (within the operating range 2.45 to 8GHz) to produce chemicals with high yield and purity, thereby minimising waste and requiring the minimum of product extraction.
• To research self-tuning of microwave sources to operate at various frequencies ranging from 2.45 to 8 GHz and where power levels are modulated to maintain optimisation.
• To characterise the effects of microwave frequency and power applied to the various chemicals that will give the best speed of reaction and yields.
• To specifically extend this to a multipurpose prototype reactor for the synthesis of bulk quantities of chemicals on a continuous basis by using a novel atmospheric pressure, continuous, tuneable microwave flow reactor.
• To use solvent free chemistry wherever possible to avoid waste disposal problems.
• To use the reactor to investigate, in depth, four chemical reactions. By using the data from these reactions to obtain an explanation of the mechanism of their particular microwave assisted chemistry.
(ii) Technological Objectives
• To measure the dielectric properties of various pure chemicals and related mixtures across a range of frequencies 2.45 GHz to 8 GHz, noting the effect of temperature. Measurements to be made at atmospheric pressure.
• Design and build a continuous microwave reactor in which a single cavity will be use for all frequencies in the range of 2.45 to 8 GHz allowing multimode resonance conditions to be maintained at all times. In this system coupling waveguides will be use to allow any of the microwave sources to be easily attached to the cavity.
• Design and build an automated microwave sensor plasma monitoring system in which software analysis will identify the salient parameter of each sensor (based on temporal analysis, spectrum analysis and responses times), which will be used to give an insight to the chemical reactions.
• To achieve a step change in efficient use of resources (energy, chemicals and solvents).
(iii) Knowledge Transfer Objectives
Knowledge transfer provides a significant beneficial outcome for this project. Key to this is the recruitment of two experienced researchers. The need for two researchers is based on expected workload and the required complement of prior knowledge and skills. The design of a microwave cavity and associated hard and software requires specialist knowledge and a suitably experienced microwave engineer is most unlikely to have the depth of knowledge of chemical synthesis required. Equally, the design and optimaisation of the panel of chemical reactions is non-trivial and requires extensive experience of organic chemistry, which will be the province of the experienced chemist. However, such as chemist would not have the in-depth knowledge of microwave technology. consequently, the two experienced researchers will complement each other and provide mutual input to enable the project to remain on course.
The MICRO-THERAPY Fellows and designated staff have worked together to:
• Develop and test the engineering and chemical parameters of the microwave flow reactor leading to an industrial prototype capable of operating at various frequencies and variable power.
• Improve understanding by six existing specific LJMU and UR1 researchers of their respective scientific areas and also of cognate areas.
• Produce documentation of protocols, construction designs, testing and results throughout development of microwave reactor, as a basis for retaining and extending the new knowledge gained during MICRO-THERAPY.
• Design routes for synthesis based on the likely advantages of microwave promoted reactions and demonstrate how to conduct reaction optimisation procedures using studies of reaction kinetics.
• Write literature reviews for in-house and external use on subjects within their areas of expertise to enhance knowledge at Liverpool and Rennes.
• Contribute to the content of the MICRO-THERAPY website.
• Deliver seminars within BEST Research Institute and the Pharmacy and Biological Science research centre (two industrial applications seminars), UR1 (two interdisciplinary seminars) and industrial workshops at MRT.
• Contribute to the annual Open Day for public awareness of engineering and science
• Participate in one workshop/Open Days targeted at local industry to raise awareness of new technology in SMEs in Merseyside and Normandy regions.
• Contribute to publications in the scientific literature.
The final results was led to various outcomes and in some cases exceeded the project technical aims and objectives in terms of the development for the first time a true microwave flow reactor with the capabilities of producing high added value chemicals for Therapeutic Activity Against Alzheimer's Disease. The system has proven to compatible with conventional systems such as CEM, Anton Parr, Milestone in which will create a step change in the industry. It is also achieved beyond the project expectation a real time sensor system which can identify the products contents without the need for the typical instrumentation of HPLC, IR, NMR, MS, GC-MS...etc.
Summary of results;
1. Developed new cross disciplinary expertise through the experienced researchers to work at LJMU and UR1 and provide new training opportunities for both young and experienced researchers at LJMU, UR1 and MRT, blending unique skills to produce key proficiencies. At present the partners have their own particular expertise, but only limited experience of the cognate areas in this project. Cross fertilisation will result in much deeper understanding and hence the possibility for further rapid development in this area. The project offers the opportunity for training and for the development of deep specialist skills so that both new workers and experienced researchers can gain additions to their tool-kit of techniques and whilst broadening their portfolio of broad generic skills.
2. Developed a novel tuneable microwave flow reactor and ancillary equipment, including facilities for on-line measurement of key parameters such as flow, temperature with heat inputs and heat transfer rates for improved synthesis of key bio-pharmaceutical compounds.
3. Managed to optimise the reaction time, flow rate, microwave power and frequency (within the operating range 2.45 to 8GHz) to produce chemicals with high yield and purity, thereby minimising waste and requiring the minimum of product extraction and other downstream processing steps.
4. Managed to specifically extend this to a multipurpose prototype reactor for the synthesis of bulk quantities of chemicals on a continuous basis by using a novel atmospheric pressure, continuous, tuneable, microwave flow reactor.
5. Achieved to use solvent free chemistry wherever possible to avoid waste disposal problems.
6. Achieved to develop real-time, self-tuning, computer control strategies to optimise the rates and yields of reactions by matching the microwave frequency and power to the variable chemical reaction conditions.
7. Achieved a step change in efficient use of resources (energy, chemicals and solvents).
8. Managed to use the reactor to investigate, in depth, four exemplar chemical reactions. By using the data from these reactions to obtain an explanation of the mechanism of their particular microwave assisted chemistry.
9. Prepared all documentation about the prototype; assess intellectual property potential and initiate future development in collaboration with industry by developing a website to publicise MICRO-THERAPY, to increase networking and collaborative opportunities with academia and industry in Europe.
10. Although the focus in MICRO-THERAPY is on the pharmaceutical industry, obvious further developments could include: renewable energy for the production of biofuel from waste using the microwave flow reactor, industrial treatments of water, waste water and recycled water.
11. Achieved most of the transfer knowledge planned activities.
The networks of European researchers and our existing links with industrial partners reinforced during MICRO-THERAPY to enhance future research projects at LJMU and UR1. The MICRO-THERAPY website provided publicity about the research innovation, output from the project and links with European laboratories. After working in this interdisciplinary, industrially orientated project at the boundaries of engineering, chemistry and biology, the experienced researchers will be very good candidates for industrial, research or academic positions in Europe within this subject area, including Marie Curie re-integration Fellowships.
Project website: http://www.ljmu.ac.uk/BLT/BEST/RFM/microtherapy/index.htm
For the list of all publications, please see the attached publication file.