This proposal will establish a national multidisciplinary centre for research into crystals and powders and the challenges presented by their industrial manufacture, properties and use. Powders, particles, crystals and the molecules they are made of are important in the chemical and pharmaceutical industries as intermediate stages and final products in the manufacture of a range of materials from drugs to inks and pigments to paints to computer screens. Crucially, the structure and properties of crystals, particles and powders control the ease of manufacture, function and performance of the final product and it is therefore important to be able to make these materials reproducibly. Firstly, by understanding the ways in which the molecules, which make up the crystal pack together. Many molecules can adopt several distinct crystal forms by packing together in different ways, which can dramatically affect physical properties despite the fact the same molecule is present. It is vital to control this during crystal formation since the wrong form could for example, affect the amount of drug released by a tablet into the body after it is swallowed. Secondly as the crystal grows its size (micrometres or millimetres), shape, or morphology (flat or round) is critical for some applications especially when many crystal particles come together in a powder and impact on the ease with which the material is subsequently manufactured into a paint or ink for example. These challenges are critical as currently manufacturers struggle with crystal formation and control of their particle and powder properties due to the traditional batch methods they employ. To tackle these problems the Centre aims to revolutionise current processes by researching exciting new continuous methods of crystal formation and particle and powder production applicable to current but importantly also future products such as nanomaterials. In addition the Centre will explore how established methods for molecule synthesis are best integrated with continuous crystallisation processes and how continuously manufactured crystals are isolated, dried and transferred into subsequent formulation and final product manufacturing stages whilst preserving their carefully optimised properties. To maximize these technology changes the Centre must also understand the impact that such a transformation will have on the way companies approach this aspect of their business. This will ensure that the maximum economic potential is effectively exploited. To achieve this the Centre consists of a multidisciplinary team of 14 outstanding researchers from 7 leading Universities covering the country from Glasgow, to Edinburgh, to Cambridge, to Bath. In addition industrial support, interest and input (2 million) will be provided from 3 major pharmaceutical companies and many small technology driven companies within the UK. This provides a combination of academic and industrial expertise ranging from chemistry and chemical engineering to pharmacy and systems management capable of powerfully attacking the issues from many angles. The Centre's aim is to deliver new continuous manufacturing technologies with improved performance in a range of areas. Control of crystal formation and particle and powder properties is critical, however a key goal will also be the development of simpler and faster technologies. Such a combination will permit quicker product development and cheaper, cleaner and greener manufacturing processes. The Centre will deliver these technologies to the UK chemical and pharmaceutical industry thus maintaining this sector at the international forefront of product development and manufacture with obvious national economic benefits in terms of jobs and income. National and international benefits will also arise through better and new medicines and improved and new consumer products, which will assist the global community.

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.

Industrial inkjet technology involves the generation, manipulation and deposition of very small drops of liquid (typically 20-50 um diameter) under digital control. The UK is recognised internationally as a leader in this area. Inkjet technology already dominates the desktop printing market. In commercial printing, it is rapidly becoming established for short-run applications and has, in only a few years, conquered a market previously occupied by conventional screen-printing equipment, where its great flexibility and inherent scalability give significant advantages. If higher printing speeds and greater quality can be achieved, then it will also be able to move into large-volume commercial printing. Apart from these printing applications, novel opportunities for inkjet deposition are also beginning to be exploited commercially in the manufacturing of high-value, high precision products (e.g. flat-panel displays, printed/plastic electronics, photovoltaic cells for power generation). By extending the existing benefits of inkjet methods (e.g. flexible, digital, non-contact, additive) to attain the speed, coverage and material diversity of conventional printing and manufacturing systems, we can transform inkjet from its present status as a niche technology into a group of mainstream processes, with the UK as a major player. But in order for this transformation to happen, we need a much better understanding of the science underlying the formation and behaviour of very small liquid drops at very short timescales, and to widen the range of materials which can be manipulated in this way, especially to allow fluids with high solids content (i.e. colloidal fluids) to be deposited. This cross-disciplinary programme of research is strongly supported by a consortium of nine UK-based companies and will bring together established research groups from three major UK universities to study three themes focused on key aspects of the industrial inkjet process: the formulation, rheology and jetting behaviour of colloidal printing fluids; understanding and controlling dynamic micro-scale drop impact, spreading and fixing; and development and validation of an advanced process model for industrial inkjet. Within these themes we aim to: develop a theoretical and practical understanding of how to make stable high solid-content colloids suitable for inkjet deposition, and how they behave in an inkjet system and on the substrate; explore post-impact processes that determine the structure and functionality of the printed features, including surface morphology, chemistry and surface treatment, fluid dynamics of wetting and the interaction of successively printed materials; and develop a set of models, validated by precise measurements and underlying physical theory, to describe all aspects of the formation and ultimate fate of ink drops. Industrial beneficiaries will include companies in the fields of inkjet printing and digital manufacturing, as well as other companies involved in the precise manipulation of small liquid droplets: examples of sectors include pharmaceuticals, agrochemicals, combustion, coating application, materials processing, and particle technology. Academic beneficiaries, apart from researchers working directly on inkjet technology, will include those in the fields of rheology, fluid mechanics, microfluidics, materials science and surface engineering.

This proposal is to establish a Doctoral Training Centre embedded within the EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation. The Centre tackles a core issue in the manufacture of fine chemicals and pharmaceuticals - an important sector for the UK - and has strong support from industry including major companies from the Pharma sector (GSK, AstraZeneca, Novartis). We will enable manufacturers to shift their production processes from traditional batch methods, which can be expensive, inefficient and limited in their control, to continuous methods that offer solutions to each of these issues. The Centre can potentially make a huge impact on the UK's manufacturing efficiency in a £multi-billion sector. Although the EPSRC Centre does have a limited cohort of PhD students at the moment, there is no provision for 2012 onwards. As the largest of the current EPSRC Centres, achieving a critical mass of researchers across the core disciplines is a key goal as we establish a world class research activity. It is also important for our industry partners that the UK can meet their needs for trained people in this area and embed continuous processing in their manufacturing plants. We will establish a unique and tailored training and research programme that meets these needs. The proposed DTC will add an extra dimension to the EPSRC Centre, training 3 cohorts of PhD students with the skills, knowledge and understanding to help meet the challenges of continuous manufacturing. Recruiting 45 students over 3 intakes in 2012/13/14 the DTC will mark a step change in activity in this field. We will attract the very best PGR students and equip them to become future leaders who will be influential in implementing this transformational change. The research will contribute to opportunites for new products that can be brought more quickly to market, using more reliable, energy-efficient and profitable manufacturing routes. The Centre involves a multidisciplinary team across 7 universities who will contribute to the DTC including expertise in pharmaceutical sciences, chemical engineering, chemistry, operations management and manufacturing. Thus, the embedded DTC will provide students with a unique programme of training across disciplines, using a combination of modules and research activities. . Students will register in a host institution and will follow a 1+3 year model. Year 1 will comprise intensive formal training delivered in 10 residential courses across the universities, including transferable skills and group project work, allowing the cohort to gain identity and build team spirit and fellowship. Elective specialist elements will then develop knowledge in preparation for PhD research, along with exploratory cross-disciplinary mini-projects. Assessment of modules and projects will be by a combination of presentations and reports. Years 2-4 will focus on multidisciplinary, co-supervised PhD research projects, allowing the student to work with academics from across the Centre. Further transferable skills training and cohort building activities will include an annual two-week Summer School, and networking opportunities with other cohorts. The proposed DTC has captured the imagination of our industrial collaborators with 5 additional companies having added their support to the creation of this DTC. In addition to substantial cash contributions they are offering training, site visits, project input, mentoring and short-term industrial placements. We will create a national community of highly skilled researchers in continuous manufacturing and crystallisation, building the scale and quality of research to enhance the international reputation of our Centre and make a real difference to the manufacture of high-value products, such as pharmaceuticals. The training of 45 high quality DTC PhD students will make a major contribution towards this goal.

Manufacture of nanometre particulate form products in suspensions is becoming increasingly important to the pharmaceutical, speciality chemical, and functional material industries. For instance, nano-processing is now used as an effective drug-delivery method for solid form hydrophobic pharmaceuticals due to the dramatically increased drug solubility and bioavailability at nano-scale. The biggest challenge to nano-processing under industrial conditions has been highlighted as the difficulty in achieving consistency in product quality as characterised by particle size distribution. The objective of this proposed research is to investigate on-line characterisation and process modelling techniques that can be applied under industrial operational conditions. The research on on-line sensing will focus on photon correlation spectroscopy and acoustic spectroscopy for real-time particle sizing. The work will tackle the key challenge posed by multiple scattering and particle-particle interactions, which are known to be the cause leading to incorrect measurement at high solid concentrations. High solid concentration is not only the economically viable range for commercial manufacture of nanoparticles (a much larger reactor would be required to process the same amount of particles in low concentration), but also technically essential for producing ultra-fine particles for many processes. The on-line real-time measurement will provide invaluable data to the development of process models using population balance equations. The focus will be on quantitatively deriving models for particle breakage and aggregation to be used in the population balance equations, as well as intelligent interpretation of the data to improve the qualitative understanding of the process. The process chosen for investigation is wet nano-milling, a very important operation for processing nanoparticles in the pharmaceutical, agrochemical and materials industries.