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.

Chromonics are a fascinating class of lyotropic liquid crystals. They are usually formed in water from plate-like molecules, which self-assemble into aggregate stacks (rods or layers), which in turn self-organise to form liquid crystals. Chromonics are very poorly understood. Researchers are just beginning to understand how self-assembly is influenced by the interactions between molecules and how the process can be controlled by use of additives (such as small molecules or salt). Moreover, many known chromonic materials are based on industrial dyes, which are very difficult to purify; and this hampered some of the early investigations into phases and phase behaviour. Despite these difficulties it is beginning to be recognised that chromonic systems are far more common than once thought. Formation of stacked aggregates in dilute solution and/or chromonic mesophases at higher concentrations, have been widely reported in aqueous dispersions of many formulated products such as pharmaceuticals and dyes used in inkjet printing. Recently, there has been greatly enhanced interest in chromonics materials as functional materials for fabricating highly ordered thin films, as biosensors, and chromonic stacks have also been used to aid in the controllable self-assembly of gold nanorods. This proposal seeks to develop a novel class of chromonic molecules: nonionic chromonics based on ethylenoxy groups. Here, we will design new chromonic phases demonstrating novel structures (such as hollow water-filled columns and layered brick-like phases), which can be used for future applications. We will also investigate and control the self-assembly process, in a class of materials that can be purified, that are not influenced as strongly by salt (compared to most industrial dyes), where structural changes can be easily engineered by minor changes to a synthetic scheme, and where addition of other solvents can lead to major changes in both self assembly and phase behaviour. We will also use state-of-the-art modelling and theory, which has recently been shown to provide new insights into self-assembly in chromonics, to help design new materials. Here, the use of quantitative and semi-quantitative molecular modelling provides for the possibility of "molecular engineering" new phases. To accomplish our goals for this project we will bring together synthetic organic chemistry to design and make new materials; state-of-the-art physical organic measurements to characterise both the nature of self-assembly and the novel chromonic phases formed; and state-of-the-art modelling/theory to predict, explain and help control the chromonic aggregation.

'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.

This application requests funds to continue and develop the EngD in Formulation Engineering which has been supported by EPSRC since 2001. The EngD was developed in response to the needs of the modern process industries. Classical process engineering is concerned with processing materials, such as petrochemicals, which can be described in thermodynamic terms. However, modern process engineering is increasingly concerned with production of materials whose structure (micro- to nano- scale) and chemistry is complex and a function of the processing it has received. For optimal performance the process must be designed concurrently with the product, as to extract commercial value requires reliable and rapid scale-up. Examples include: foods, pharmaceuticals, paints, catalysts and fuel cell electrodes, structured ceramics, thin films, cosmetics, detergents and agrochemicals. In all of these, material formulation and microstructure controls the physical and chemical properties that are essential to its function. The Centre exploits the fact that the science within these industry sectors is common and built around designing processes to generate microstructure:(i) To optimise molecular delivery: for example, there is commonality between food, personal care and pharmaceuticals; in all of these sectors molecular delivery of actives is critical (in foods, to the stomach and GI tract, to the skin in personal care, throughout the body for the pharmaceutical industry);(ii) To control structure in-process: for example, fuel cell elements and catalysts require a structure which allows efficient passage of critical molecules over wide ranges of temperature and pressure; identical issues are faced in the manufacture of structured ceramics for investment casting;(iii) Using processes with appropriate scale and defined scale-up rules: the need is to create processes which can efficiently manufacture these products with minimal waste and changeover losses.The research issues that affect widely different industry sectors are thus the same: the need is to understand the processing that results in optimal nano- to microstructure and thus optimal effect. Products are either structured solids, soft solids or structured liquids, with properties that are highly process-dependent. To make these products efficiently requires combined understanding of their chemistry, processing and materials science. Research in this area has direct industrial benefits because of the sensitivity of the products to their processes of manufacture, and is of significant value to the UK as demonstrated by our current industry base, which includes a significant number of FMCG (Fast Moving Consumer Goods) companies in which product innovation is especially rapid and consumer focused. The need for, and the added value of, the EngD Centre is thus to bring together different industries and industry sectors to form a coherent underpinning research programme in Formulation Engineering. We have letters of support from 19 companies including (i) large companies who have already shown their support through multiple REs (including Unilever, P+G, Rolls Royce, Imerys, Johnson Matthey, Cadbury and Boots), (ii) companies new to the Centre who have been attracted by our research skills and industry base (including Bayer, Akzo Nobel, BASF, Fonterra (NZ), Bristol Myers Squibb and Pepsico).