At present, 40% of all leading compounds that emerge from drug discovery are not developed further due to their poor solubility. Currently, drug molecules are almost exclusively made into a medicine using a crystalline drug which has an inherent solubility disadvantage due to the lattice energy associated with its crystalline state that needs to be overcome before dissolution occurs. The amorphous state, where the molecules are completely disordered and hence the cohesive energy is smaller, is a potential alternative state for drug-molecule formulations. Given that the amorphous state is higher in energy, such drug formulations are currently perceived to be high risk, as it is not possible, using the existing technology and understanding, to predict their stability against recrystallisation reliably. In addition, there is still no comprehensive understanding of the physics of the amorphous state in general and the factors governing devitrification (the crystallisation process from the amorphous phase) even though this area of research has been the focus of very intense activities over the past decades. Unforeseen stability issues due to recrystallisation could lead to enormous costs for pharmaceutical companies if such formulations fail during the later stage clinical trials or, even more catastrophically, once the product is on the market. However, the improvement of solubility in the amorphous state would be sufficient to permit greater than 50% of poorly soluble leading compounds to be selected as candidates for the drug-development pipeline. This would permit an extensive range of hitherto untested chemistries to move through to the clinic to address unmet therapeutic needs for patient benefit. Here, we aim to develop a better understanding of structural changes occurring in organic amorphous formulations of drugs, with the ultimate goal of improving their efficacy and stability. This proposal is developed around the ability to quantify directly terahertz and/or picosecond-nanosecond inter-molecular dynamics that govern the crystallisation in organic amorphous systems. The majority of experimental evidence will be gathered by means of terahertz time-domain spectroscopy (THz-TDS) and low-frequency Raman spectroscopy but will be complemented by theoretical and simulational studies, and other experimental techniques as necessary. There are two ultimate goals of the proposed work: 1) To develop an analytical method that can be used to quantify the likelihood of structural changes, ultimately culminating in crystallisation, occurring in amorphous materials over extended periods. Furthermore, to allow a systematic optimisation of amorphous drug formulations and their storage conditions with respect to their stability against structural changes. 2) To provide high-quality experimental data to stimulate and support the development of theory aimed at better understanding the fundamental physics of non-equilibrium organic solids. If successful, the terahertz or Raman methods could be implemented for drug-development activities almost immediately, as such turn-key equipment is now commercially available and, once we are able to develop the detailed understanding as outlined in this proposal, they can be operated and the data interpreted by technicians, much like any other analytical technique today. The lab-based measurements proposed here could further remove the requirement for costly and time-consuming measurements at central facilities, such as neutron sources, for similar analysis, and thus free up this critical resource for other research activities.

'Watching paint dry' is a metaphor for a boring and pointless activity. In reality, the drying of liquids is a complex process and the imperturbable appearance to the eye can hide a wealth of dynamics occurring inside the liquid. The effect of these internal processes is to change the distribution of materials in the deposit left after drying. We are all familiar with the coffee-ring effect, where split coffee dries to form a ring of solids at the edge of the spill - of little use if you are trying to coat a surface uniformly. This project is all about the drying of droplets, either in air or on a surface; one isolated droplet, two droplets merging or many droplets in a spray. We seek to understand how drops dry and how to control where the particles or molecules in the drop end up after the drop evaporates. When do you get a solid particle or a hollow particle? A round one or a spiky one? A uniform particle or one with shells? Or on a surface: a coffee-ring or a pancake? A uniform deposit, a layered one or a bull's eye? Are particles crystalline or amorphous, are different components mixed or separated? There are a myriad of possibilities for controlling the microstructure and properties of the final particle or film. Drying is complicated for three main reasons. First, many transport processes (evaporation, heat flow, diffusion, convection) occur simultaneously and are strongly coupled. For example, in a small droplet of alcohol and water evaporating on a surface, the liquid inside the drop will flow around in a doughnut pattern tens of times each second. Second, the conditions in a drying droplet are often far from equilibrium. For example, a small water droplet in air or on a smooth clean surface can be cooled to -35 degrees C without freezing. So to understand drying one needs to understand the properties of fluids far from equilibrium. It is generally not possible to predict the final outcome of drying from the properties of simple solutions near equilibrium. Third, drops do not dry in isolation. They may merge or bounce, coalesce or chase each other across a surface. The evaporation of one droplet affects its neighbours. Moving droplets change the flow of air around other droplets, coupling the motion of droplets. Why does anyone care, beyond the intellectual fascination with the bizarre outcomes of droplet drying? Drying of droplets turns out to be a rather important process in practical applications: spray painting, graphics printing, inkjet manufacturing, crop spraying, coating of seeds or tablets, spray cooling, spray drying (widely used in food, pharmaceutical and personal care products), drug inhalers and disinfection, to give a few examples. The physics and chemistry underlying all these applications is the same, but if manifests itself in different ways and the desired outcome varies between applications. The first challenge addressed by this project is one of measurement: how do you work out what is going on in a droplet that is less than a tenth of a millimetre across and may dry in less than a second? We have already developed sophisticated measurement tools but will need to extend these further. Another challenge is one of modelling: to understand the drying process we need a theoretical framework and computer models to explain - and predict - experimental observations. We will begin looking at the fundamental processes occurring in single drops in air and on a surface and then explore what happens when drops interact or coalesce. This fundamental understanding will be fed into improved models of arrays, clouds or sprays of droplets that are encountered in most practical applications (such as spray coating, spray drying, inhalers or inkjet manufacturing). We will use an Industry Club to engage with companies from a range of different sectors. This Club will provide a forum for sharing problems, ideas and solutions and for disseminating the knowledge generated in the project.

A vital challenge for modern engineering is the modelling of the multiscale complex particle-liquid flows at the heart of numerous industrial and physiological processes. Industries dependent on such flows include food, chemicals, consumer goods, pharmaceuticals, oil, mining, river engineering, construction, power generation, biotechnology and medicine. Despite this large range of application areas, industrial practice and processes and clinical practice are neither efficient nor optimal because of a lack of fundamental understanding of the complex, multiscale phenomena involved. Flows may be turbulent or viscous and the carrier fluid may exhibit complex non-Newtonian rheology. Particles have various shapes, sizes, densities, bulk and surface properties. The ability to understand multiscale particle-liquid flows and predict them reliably would offer tremendous economic, scientific and societal benefits to the UK. Our fundamental understanding has so far been restricted by huge practical difficulties in imaging such flows and measuring their local properties. Mixtures of practical interest are often concentrated and opaque so that optical flow visualisation is impossible. We propose to overcome this problem using the technique of positron emission particle tracking (PEPT) which relies on radiation that penetrates opaque materials. We will advance the fundamental physics of multiscale particle-liquid flows in engineering and physiology through an exceptional experimental and theoretical effort, delivering a step change in our ability to image, model, analyse, and predict these flows. We will develop: (i) unique transformative Lagrangian PEPT diagnostic methodology for engineering and physiological flows; and (ii) innovative Lagrangian theories for the analysis of the phenomena uncovered by our measurements. The University of Birmingham Positron Imaging Centre, where the PEPT technique was invented, is unique in the world in its use of positron-emitting radioactive tracers to study engineering processes. In PEPT, a single radiolabelled particle is used as a flow follower and tracked through positron detection. Thus, each component in a multiphase particle-liquid flow can be labelled and its behaviour observed. Compared with leading optical laser techniques (e.g. LDV, PIV), PEPT has the enormous and unique advantage that it can image opaque fluids, and fluids inside opaque apparatus and the human body. To make the most of this and image fast, complex multiphase and multiscale flows in aqueous systems, improved tracking sensitivity and accuracy, dedicated new radiotracers and simultaneous tracking of multiple tracers must be developed, and new theoretical frameworks must be devised to analyse and interpret the data. By delivering this, we will enable multiscale complex particle-liquid flows to be studied with unprecedented detail and resolution in regimes and configurations hitherto inaccessible to any available technique. The benefits will be far-reaching since the range of applications of PEPT in engineering and medicine is extremely wide. This multidisciplinary Programme harnesses the synergy between world-leading centres at Birmingham (chemical engineering, physics), Edinburgh (applied maths) and King's College London (PET chemistry, biomedical engineering) to develop unique PEPT diagnostic tools, and to study experimentally and theoretically outstanding multiscale multiphase flow problems which can only be tackled by these tools. The advances of the Programme include: a novel microPEPT device designed to image microscale flows, and a novel medical PEPT validated in small animals for translation to humans. The investigators' combined strengths and the accompanying wide-ranging industrial collaborations, will ensure that this Programme leads to a paradigm-shift in complex multiphase flow research.

Formulation engineering is concerned with the manufacture and use of microstructured materials, whose usefulness depends on their microstructure. For example, the taste, texture and shine of chocolate depends on the cocoa butter being in the right crystal form - when chocolate is heated and cooled its microstructure changes to the unsightly and less edible 'bloomed' form. Formulated products are widespread, and include foods, pharmaceuticals, paints, catalysts, structured ceramics, thin films, cosmetics, detergents and agrochemicals, with a total value of £180 bn per year. In all of these, material formulation and microstructure control the physical and chemical properties that are essential to the product function. The research issues that affect different industry sectors are common: the need is to understand the processing that results in optimal nano- to micro structure and thus product effect. Products are mostly complex soft materials; structured solids, soft solids or structured liquids, with highly process-dependent properties. The CDT fits into Priority Theme 2 of the EPSRC call: Design and Manufacture of Complex Soft Material Products. The vision for the CDT is to be a world-leading provider of research and training addressing the manufacture of formulated products. The UK is internationally-leading in formulation, with many research and manufacturing sites of national and multinational companies, but the subject is interdisciplinary and thus is not taught in many first degree courses. A CDT is thus needed to support this industry sector and to develop future leaders in formation engineering. The existing CDT in Formulation Engineering has received to date > £6.5 million in industry cash, has graduated >75 students and has 46 currently registered. The CDT has led the field; the new National Formulation Centre at CPI was created in 2016, and we work closely with them. The strategy of the new Centre has been co-created with industry: the CDT will develop interdisciplinary research projects in the sustainable manufacture of the next generation of formulated products, with focus in two areas (i) Manufacturing and Manufacturability of New Materials for New Markets 'M4', generating understanding to create sustainable routes to formulated products, and (ii) 'Towards 4.0rmulation': using modern data handling and manufacturing methods ('Industry 4.0') in formulation. We have more than 25 letters from companies offering studentships and >£9 million of support. The research of the Centre will be carried out in collaboration with a range of industry partners: our strategy is to work with companies that are are world-leading in a number of areas; foods (PepsiCo, Mondelez, Unilever), HPC (P+G, Unilever), fine chemicals (Johnson Matthey, Innospec), pharma (AstraZeneca, Bristol Myers Squibb) and aerospace (Rolls-Royce). This structure maximises the synergy possible through working with non-competing groups. We will carry out at least 50 collaborative projects with industry, most of which will be EngD projects in which students are embedded within industrial companies, and return to the University for training courses. This gives excellent training to the students in industrial research; in addition to carrying out a research project of industrial value, students gain experience of industry, present their work at internal and external meetings and receive training in responsible research methods and in the interdisciplinary science and engineering that underpin this critical industry sector.