Our vision is to use continuous photochemistry and electrochemistry to transform how fine chemicals, agrochemicals and pharmaceuticals are manufactured in the UK. We aim to minimize the amount of chemicals, solvents and processing steps needed to construct complex molecules. We will achieve this by exploiting light and/or electricity to promote more specific chemical transformations and cleaner processes. By linking continuous photochemistry and electro-chemistry with thermal flow chemistry and environmentally acceptable solvents, we will create a toolkit with the power to transform all aspects of chemical synthesis from initial discovery through to chemical manufacturing of high-value molecules. The objective is to increase efficiency in terms of both atoms and energy, resulting in lower cost, low waste, low solvent footprints and shorter manufacturing routes. Historically photo- and electro-chemistry have been under-utilised in academia and industry because they are perceived to be complicated to use, difficult to scale up and engineer into viable processes despite their obvious environmental, energy and cost benefits. We will combine the strategies and the skills needed to overcome these barriers and will open up new areas of science, and deliver a step-change (i) providing routes to novel molecular architectures, hard to reach or even inaccessible by conventional methodologies, (ii) eliminating many toxic reagents by rendering them unnecessary, (iii) minimizing solvent usage, (iv) promoting new methodologies for synthetic route planning. Our proposal is supported by 21 industrial partners covering a broad range of sectors of the chemistry-using industries who are offering £1.23M in-kind support. Therefore, we will study a broad range of reactions to provide a clear understanding of the most effective areas for applying our techniques; we will evaluate strategies for altering the underlying photophysics and kinetics so as to accelerate the efficiency of promising reactions; we will transform our current designs of photochemical and electrochemical reactors, with a combination of engineering, modelling and new fabrication techniques to maximize their efficiency and to provide clear opportunities for scale-up; we will exploit on-line analytics to accelerate the optimisation of continuous photochemical and electrochemical reactions; we will design and build a new generation of reactors for new applications; we will identify the most effective strategies for linking our reactors into integrated multi-step continuous processes with minimized waste; we will demonstrate this integration on at least one synthesis of a representative pharmaceutical target molecule on a larger scale; we will apply a robust series of sustainability metrics to benchmark our approaches against current manufacturing.

Our Hub research is driven by the societal need to produce medicines and materials for modern living through novel manufacturing processes. The enormous value of the industries manufacturing these high value products is estimated to generate £50 billion p.a. in the UK economy. To ensure international competitiveness for this huge UK industry we must urgently create new approaches for the rapid design of these systems, controlling how molecules self-assemble into small crystals, in order to best formulate and deliver these for patient and customer. We must also develop the engineering tools, process operations and control methods to manufacture these products in a resource-efficient way, while delivering the highest quality materials. Changing the way in which these materials are made, from what is called "batch" crystallisation (using large volume tanks) to "continuous" crystallisation (a more dynamic, "flowing" process), gives many advantages, including smaller facilities, more efficient use of expensive ingredients such as solvents, reducing energy requirements, capital investment, working capital, minimising risk and variation and, crucially, improving control over the quality and performance of the particles making them more suitable for formulation into final products. The vision is to quickly and reliably design a process to manufacture a given material into the ideal particle using an efficient continuous process, and ensure its effective delivery to the consumer. This will bring precision medicines and other highly customisable projects to market more quickly. An exemplar is the hubs exciting innovation partnership with Cancer Research UK. Our research will develop robust design procedures for rapid development of new particulate products and innovative processes, integrate crystallisation and formulation to eliminate processing steps and develop reconfiguration strategies for flexible production. This will accelerate innovation towards redistributed manufacturing, more personalisation of products, and manufacturing closer to the patient/customer. We will develop a modular MicroFactory for integrated particle engineering, coupled with a fully integrated, computer-modelling approach to guide the design of processes and materials at molecule, particle and formulation levels. This will help optimise what we call the patient-centric supply chain and provide customisable products. We will make greater use of targeted experimental design, prediction and advanced computer simulation of new formulated materials, to control and optimise the processes to manufacture them. Our talented team of scientists will use the outstanding capabilities in the award winning £34m CMAC National Facility at Strathclyde and across our 6 leading university spokes (Bath, Cambridge, Imperial, Leeds, Loughborough, Sheffield). This builds on existing foundations independently recognised by global industry as 'exemplary collaboration between industry, academia and government which represents the future of pharmaceutical manufacturing and supply chain R&D framework'. Our vision will be translated from research into industry through partnership and co-investment of £31m. This includes 10 of world's largest pharmaceutical companies (eg AstraZeneca, GSK), chemicals and food companies (Syngenta, Croda, Mars) and 19 key technology companies (Siemens, 15 SMEs) Together, with innovation spokes eg Catapult (CPI) we aim to provide the UK with the most advanced, integrated capabilities to deliver continuous manufacture, leading to better materials, better value, more sustainable and flexible processes and better health and well-being for the people of the UK and worldwide. CMAC will create future competitive advantage for the UK in medicines manufacturing and chemicals sector and is strongly supported by industry / government bodies, positioning the UK as the investment location choice for future investments in research and manufacturing.

The combination of electricity with chemical reactions has a long history. The ability to use a single electron from an electric current in order to trigger a chemical reaction is an exciting concept, especially from the perspective of sustainability. Electrons are one of the cleanest possible chemical reagents (i.e. there is no waste generated from their use) with photons of light representing a complementary alternative. It is surprising therefore that organic chemistry, the branch of chemistry involved with creating molecules for society, such as pharmaceuticals, crop-protection agents, dyes, pigments, flavours, fragrances and polymers does not often use such electro-chemical methods at both the discovery and manufacture stages. One of the key reasons for this lack of adoption is that often the applied current, or the energy of the electron, is not properly tuned to the reaction system. This can lead to undesired reactions and impure reaction profiles. However, there have been some recent pioneering developments in the field that may permit broadening of the application of this electro-organic chemistry. The developments are two-fold and concern the chemistry and the reactor design. 1) With regards to the chemistry, several examples now exist where complex reaction processes can be triggered by appropriate choice of electrolyte and careful planning of the chemical reactants. Furthermore, it has recently been proven that catalytic systems can be sustained by the input of electrons, with such processes giving rise to complex and interesting molecules of the kind that could feature in 'molecules for society'. 2) With regards to the reactor design, the development and advancement of continuous flow chemistry (chemistry in pipes and tubing circuits rather than beakers and flasks) has permitted the lowering of the electric current and thus allows more sensitive 'surgical incisions' to be made in the reaction process, thus reducing the undesired reactions and propensity to yield impure reaction profiles. This proposal looks to work in an area of catalysis known as organo-catalysis, where a small amount of an organic molecule is used to accelerate the rate of reactions (this is in contrast to a precious metal-based system). Here the electro-chemistry approach will help to sustain and maintain the catalytic cycle. Notably, in all other organo-catalytic processes of this type an equal amount of an addition chemical is needed to maintain the catalytic activity. This chemical is purely sacrificial in nature and is thus extremely wasteful. A preliminary hit from the UK has already demonstrated that organo-catalytic reactions can be sustained using electro-chemical methods. This proposal aims to greatly diversify the application of this observation. The combination of an organo-catalytic, electro-chemical and continuous flow approach will serve to amplify the sustainability of the processes that we use to deliver these industrially useful reactions.