Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

The pharmaceutical industry is the UK's third largest exporting sector, annually contributing £17bn to exports, and investing £4.5bn in UK research and development. The pharmaceutical industry is, however, dogged by a high failure rate (around 97%) of drug candidates, often late in the drug discovery process. A reduction in the failure rate of drug candidates would revolutionise the pharmaceutical industry (for example, a reduction in the rate of failure to even 94% would double the number of successful drugs). The drug discovery process often begins with the screening of many (typically at least hundreds of thousands) molecules for a required biological function. Unfortunately, the active molecules identified in the high-throughput screening process are not optimised drug molecules; instead, these molecules (known as "leads") are starting points for optimisation to give final drug molecules. There is now a clear link between the physical properties of drug candidates and their probability of successfully negotiating the development process to yield marketed medicines. In turn, the properties of drug candidates are often dependent on those of lead molecules. Unfortunately, enhancement of corporate screening collections of molecules is hampered by the poor availability of large numbers of compounds with appropriate lead-like physical properties. A recent analysis of 4.6 million commercially available compounds revealed that less than 1% had optimal lead-like properties. Furthermore, emerging synthetic methods are not, in large part, addressing this deficiency: in 2009 papers in key synthetic organic chemistry journals, only 1.8% of prepared compounds (249 from 13454) had lead-like properties. The development of robust synthetic methods for preparing diverse and novel lead-like molecules remains a significant and unmet academic challenge. This project will realise a new approach to synthetic chemistry - lead-oriented synthesis - which will focus on the preparation of large numbers of diverse small molecules with lead-like physical properties. The project will specifically focus on the development of a systematic approach to the synthesis of diverse families of novel molecular scaffolds with designed 'lead-like' properties. Crucially, specific methods will only be optimised when it has been established that the requirements of lead-oriented synthesis are directly addressed. The project will involve the identification, optimisation and demonstration of the power of a toolkit of reactions that enable the synthesis of large numbers of diverse, lead-like molecules. Realising the full value of the research will require not only the successful execution of the approach, but the definition of a mechanism by which the technology can be made commercially available to end-users (in the pharmaceutical, and other discovery-based, industries). We have engaged, and will continue to engage, with end-users to ensure that the outputs of the project meet their specific requirements. The systematic approach will address the poor availability of lead-like compounds to end-users; will improve the physical properties of starting points and, hence, drug candidates; and will increase the probability of drug candidates negotiating the development process to become marketed medicines.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Crystallization from solution is a core technology in major sectors of the chemical process and allied industries. It is widely employed in the manufacture of pharmaceuticals during the intermediate and final stages of purification and separation. The process defines drug chemical purity and physical properties: crystal morphology, size, size distribution, habit or shape and degree of perfection. Variations in crystal characteristics are responsible for a wide range of pharmaceutical formulation problems, related for instance to bioavailability, a principal pharmacokinetic property, and the chemical and physical stability of drugs in their final dosage forms. In the pharmaceutical sector up to 90% of active ingredients are produced as crystals. The technical sophistication of crystal products is always rising, placing ever greater demands on the knowledge, skill and ingenuity of researchers to develop novel materials and devise viable processes for their manufacture. The increasing environmental constraints and need for sustainability place additional pressure on these processes.To attain these ambitious goals, researchers need to devise innovative process solutions in manufacturing technology. The complexity of this challenge cannot be met by single individuals, because innovation at this level requires interdisciplinary research that integrates methods, skills and strengths of different disciplines. In line with this winning strategy, we intend to bring about a sizable step change in pharmaceuticals manufacturing through a new technology that combines and exploits the benefits of continuous flow processing, microreaction technology and ultrasound engineering. To do so, we will build on the complementary expertise of the team members, basing the work on strong fundamental foundations that will ensure a deep level of understanding of the physicochemical phenomena (and their interaction) taking place during flow sonocrystallisation. Chemical engineers have used ultrasound to manipulate crystal synthesis, but often barriers posed by limited understanding of ultrasound technology have reduced the impact of these endeavours. One unique feature of this research project is that we will - for the first time - design crystallizers with integrated ultrasound capability based on properly constructed models of ultrasound physics and using fluid dynamic tools that will enable us to obtain within the reactor the desired ultrasonic field. This will ensure control and reproducibility. Another unique aspect of this work is using continuous flow microreactors to repartition the synthesis in stages and intensify the process, enhancing control and efficiency even further. The research will entail experimental and theoretical investigations on crystal formation, growth, agglomeration and disruption. Ultrasound can affect these processes in different ways, for example through cavitation or streaming. These can be adjusted by proper manipulation of suitable variables such as the ultrasound power. The effect of ultrasound will be studied by targeted experiments, so that insight into the various processes is gained. Ultrasound generators operate remotely and therefore are suitable for contained, sterile environments. Thus, the crystallisation processes can potentially be controlled at the flick of a switch.

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.