Periodic Reporting for period 2 - APPFlow (Active Pharmaceutical Production in Flow)
Berichtszeitraum: 2021-01-01 bis 2023-06-30
APPFlow (Active Pharmaceutical Production in Flow) trained three Early Stage Researchers (ESRs) in innovative research centred on flow chemistry, an area that is essential for the pharmaceutical and fine chemical industries in Europe. APPFlow is a European Industrial Doctorate (EID) scheme and the three ESRs have worked towards obtaining a PhD (awarded by Queen’s University, Belfast) while collaborating closely with industrial collaborators (Arran Chemical Company and the Almac Group).
The production of active pharmaceutical ingredients (APIs) and many other fine chemicals still relies on batch operations. Many modern efficient synthetic routes require hazardous reagents and conditions, which are dangerous to scale using batch reactions, for example, reactions that use highly reactive intermediates or flammable gases. Continuous operation allows much smaller reactors to be used, which makes the hazards associated with using dangerous conditions much easier to manage and therefore utilise on an industrial scale. APPFlow aims to develop safer and more efficient processes for the production of important chemicals. This is positive for society, as it means that these important chemicals are produced in a more sustainable manner, producing less waste, and requiring less energy.
The programme has delivered the following:
• industry relevant training that resulted in three ESRs with skills and knowledge in cutting-edge sciecne, related to the production of fine chemicals and APIs
• innovative multidisciplinary research projects, producing knowledge that will benefit the European community as a whole.
• ESRs with research expertise and transferable skills that are highly attractive to employers in industry and academia
The production of active pharmaceutical ingredients (APIs) and many other fine chemicals still relies on batch operations. Many modern efficient synthetic routes require hazardous reagents and conditions, which are dangerous to scale using batch reactions, for example, reactions that use highly reactive intermediates or flammable gases. Continuous operation allows much smaller reactors to be used, which makes the hazards associated with using dangerous conditions much easier to manage and therefore utilise on an industrial scale. APPFlow aims to develop safer and more efficient processes for the production of important chemicals. This is positive for society, as it means that these important chemicals are produced in a more sustainable manner, producing less waste, and requiring less energy.
The programme has delivered the following:
• industry relevant training that resulted in three ESRs with skills and knowledge in cutting-edge sciecne, related to the production of fine chemicals and APIs
• innovative multidisciplinary research projects, producing knowledge that will benefit the European community as a whole.
• ESRs with research expertise and transferable skills that are highly attractive to employers in industry and academia
ESR1 studied chemistry involving highly reactive reagents and intermediates. Their work has explored the chemistry of organomagnesium and organolithium reagents in addition and C-H functionalization applications. The exothermic reactions and pyrophoric reagents present safety concerns and practical challenges upon scale-up in batch, and continuous flow protocols have been developed for both. Lastly the ESR explored Ritter synthesis of amides employing solid-supported Bronsted acid catalysts under. Here, placing the acid on a solid support significantly simplifies the work-up procedure, obviating the need to quench any acid. Manuscripts are in preparation for all three areas of study and we anticipate these will be published in the first half of 2024.ESR2 studied oxidation chemistry, examining the oxidation of alkenes to epoxides and alcohols to carbonyl compounds. These reactions used a homogeneous manganese catalyst and an organic peroxide (peracetic acid). The reactions are very fast and exothermic, therefore heat management is important in order to ensure safe operation and to avoid runaway reactions. Continuous flow is therefore the ideal way to develop a process which would be scalable for industrial exploitation. We designed and developed of a continuous flow process for carrying out these oxidation reactions, which used low loadings of an inexpensive catalyst. The peracetic acid was generated in situ and telescoped directly into the epoxidation reaction, which reduces the risks associated handling and storing this oxidant. The epoxidation study has been published (Org. Process Res. Dev. 2023, 27, 2, 262–268) and a manuscript on the oxidation of alcohols has been prepared and will be published in 2024.ESR3 developed flow processes associated with reduction chemistry, examining the catalytic reduction of nitrile compounds, an important class of model substrates. The project studied transfer hydrogenation methods and those also those that utilise hydrogen gas. The utilisation of pyrophoric materials (e.g. metal hydrides) and flammable gases pose significant challenges for scaling these in batch mode. The use of flow reactors enables smaller reactors to be used and the hazards can be more easily managed. ESR3 studied the catalytic transfer hydrogenation of benzonitrile to benzylamine using a palladium on carbon catalyst with triethylammonium formate as reducing agent. This system had previously only been studied under batch conditions. It was found that solvent choice was critical in overcoming rapid catalyst deactivation, which was important for developing a practical flow system. A 15-fold increase in catalyst productivity was observed in flow compared to batch. More details can be found in the published article (React. Chem. Eng., 2023,8, 1559-1564). This project also examined the use of H2 gas and therefore there was the need for pressurised flow systems. The reductive amination of nitriles was carried out with heterogeneous catalysts in fixed-bed reactor system. The flow system also used an in-line separator to improve the efficiency of product isolation. Finally, the system was shown to be applicable to the synthesis of API type compounds and a manuscript detailing these studies has been prepared and will be published in 2024.The ESRs disseminated their findings at a number of relevant international and regional conferences. The completion of the projects and writing of journal articles was slowed by the global pandemic, but all of the articles should be published in 2024, and these will be compiled on the ITN website.
Innovative research was carried out in the APPFlow EID, producing results which will help researchers in academia and industry develop more sustainable methods for the manufacturing of fine chemicals, such as APIs. The move from batch to continuous processing is not a small undertaking and the three ESRs in APPFlow have contributed valuable knowledge to this area. The ESRs studied important classes of chemical reactions, which present challenges for industry. APPFlow has demonstrated flow methods which will help chemists and engineers design industrial processes, which are difficult to implement due to dangers associated with issues such as flammable reagents and exothermic reactions. The results in these research projects demonstrate how to overcome fundamental problems such as reactor blocking, catalyst instability and product isolation. The APPFlow training programme has produced researchers with the optimal combination of research excellence and transferable skillsets to best address future economic and societal challenges. The ESRs availed of scientific and complimentary skills training at Queen’s University Belfast. This has ranged from technical training (e.g. analytical chemistry) to transferable areas such as writing and presentation skills. Furthermore, all of the ESRs have completed a course and obtained a recognised, accredited qualification from the Chartered Management Institute (CMI). This CMI course focused on leadership, project management and entrepreneurial practice. Carrying out research in industrial laboratories and receiving industrially relevant training from Arran Chemical Company and Almac Group colleagues has produced ESRs which are highly employable and sought after by the growing pharmaceutical manufacturing sector. Dissemination of results from APPFlow projects (at conferences and in initial journal articles) has already led to new projects and collaborations for both the academic and industry partners. The impact will continue to grow, as the ESRs continue their industrial careers and the remainder of their APPFlow work is published in leading scientific journals.