RESEARCH | APPFlow

OUR RESEARCH VISION

Moving from batch to continuous chemical processing is now an important goal for the pharmaceutical industry. However, the production of advanced intermediates for fine chemicals and APIs has primarily relied on traditional batch processing. In contrast to bulk chemicals, API intermediates can be complex molecules and are prepared via multi-step synthesis.

Continuous operation allows much smaller reactors to be used, which makes the hazards associated with using dangerous conditions (such as high pressures) much easier to manage. The use of small reactors also greatly improves mass transfer and improves efficiency of catalytic reactions using gases (such as H2 or O2) which often become limited by gas-liquid transfer when carried out using larger batch reactors. Small flow reactors also have superior heat transfer and this not only improves efficiency but also safety which is of paramount importance.

APPFlow will address the central challenge of complex API synthesis by bringing together a unique team of chemists and chemical engineers from academia with industrial partners from Arran and Almac Group.

APPFlow will develop Early Stage Researchers (ESRs) in innovative research through a focussed training plan centred on flow chemistry, essential for the changing pharmaceutical and fine chemical industries in Europe. The training programme and research proposed in APPFlow tackles the problems associated with the production of advanced intermediates en-route to Active Pharmaceutical Ingredients (APIs) in the pharma-industry. Moving from batch to continuous chemical processing is now an important goal for the pharmaceutical industry. The bulk chemical industry has long relied on continuous-flow processes due to the superior safety and efficiency of such processes. Such commodity, building-block chemicals are produced on a massive scale (millions of tons) and benefits arising from continuous flow processing are key in delivering industrially viable processes. However, the production of advanced intermediates for fine chemicals and APIs has primarily relied on traditional batch processing. In contrast to bulk chemicals, API intermediates can be complex molecules and are prepared via multi-step synthesis. The use of simple batch reactors arises from the fact that the production of these intermediates often involves a wide variety of reactions and simple stirred tank reactors offer a great deal of versatility and flexibility. However, such batch reactors also have some important limitations. Many modern efficient synthetic routes require hazardous reagents and conditions, which are dangerous to scale using batch reactions, for example, oxidation, Curtius and hydrogenation reactions.

The programme will train 3 ESRs who will gain state-of-the-art knowledge in a number of valuable areas such as synthetic organic chemistry, catalytic chemistry, chemical engineering, process design and economics. At the end of the APPFlow programme, the ESRs will possess a multidimensional perspective to research, enabling them to address problems with a holistic approach. The ESRs will also develop a range of transferable “soft” managerial skills that will widen their potential career opportunities and ability to contribute to a range of different sectors.

Projects

ESR1 Project: “Selective Hydrogenation Reactions using Hydrogen Gas and Heterogeneous Catalysts” Reductive transformations are important in the synthesis of many APIs and the use of hydrogen gas and an effective catalyst is the most sustainable method for carrying out such transformations. This project will examine the hydrogenation of nitrile and nitro functionalised molecules; substrates which can be challenging to reduce in a selective manner. The project will utilise continuous flow approaches (with heterogeneous catalysts) in order to improve safety, product selectivity and catalyst lifetime.

ESR2 Project: “High Energy / Reactive Intermediates for Synthetic Transformations”

Reactive intermediates pose a challenge for synthetic chemistry. High sensitivity to water and air make performing the reactions difficult, thermal runaway and undesired reactivity are commonplace, and scale-up creates serious safety risks. This project will explore the chemistry of nitroalkanes and related molecules under continuous flow conditions to tackle these challenges and create safe, robust and high-yielding transformations.

ESR3 Project: “Catalytic Selective Oxidation Reactions”

Oxidation reactions are often problematic in the synthesis of APIs and many methods exploit unsustainable reagents in super stoichiometric quantities. This project will examine catalytic approaches along with sustainable oxidants (e.g. H2O2) to prepare a range of useful products (e.g. sulfoxides, sulfones, epoxides, aldehydes, ketones and carboxylic acids). The use of continuous flow operation has the potential to not only enable more scalable processes to be developed, but also improve selectivity as continuous product removal can greatly reduce the degree of over-oxidation.

APPFlow Reseach Programme

APPFlow is a European Industrial Doctorate (EID) programme having industrial co-ownership from project conception, through execution to full realization. APPFlow will demonstrate the value of integrating industry into doctoral training programmes by realizing industrially-informed academically-excellent research goals, translating that research into commercial output and generating PhD graduates with high employability and broad career opportunities. Over the course of the 3-year project, the ESRs will carry out a series of secondments (typically 6-8 months in length), so that over the course of the project, the ESRs will spend 50% of their time on-site at the Arran Chemical Company. Therefore, ESRs will not only pursue PhD-level research in a traditional academic setting but also benefit from an industrial setting and the associated unique learning opportunities and growth of experience/expertise.

All 3 projects involve aspects of fundamental chemistry, chemical engineering as well as industrial/business drivers, which will require the participants to work together and share knowledge. The APPFlow partners will exploit their combined expertise in engineering, organic chemistry, catalysis, economic assessment and industrial application, to move beyond the state of the art and develop new solutions to chemical problems as shown below. The ESRs will be subject to all expertise as shown in the figure below and training developed around these themes. The wider breadth of training that the ESRs will receive will provide them with a unique perspective and associated skills-set that will allow them to go on and make a significant impact across the European community.

The 3 projects are inherently linked and although individual ESRs will be assigned to one project, they will all work closely together. This is the most efficient approach and will benefit all the participants and ESRs. All 3 projects involve different areas of chemistry and so it is important that ESRs can develop a detailed knowledge of the chemistry for their project.

Training Programme

An important aspect of APPFlow is ensuring that the ESRs obtain training in a wide range of important areas. Each ESR will develop a ‘Personal Career Development Plan’ (PCDP) in conjunction with their supervisors. The PCDP will include:

Formal Training: yearly record of module choices, dates attended, assessment requirements, dates completed
Supervision: yearly record of supervision sessions, dates, summaries of key points
Scholarly Activities: conferences and seminars attended, papers presented
Research Logbook: research focus/research questions, timetable, achievements
Skills Development: areas where some training might be required, and plans for acquiring training
Industrial secondment: record of activities completed, training attended, achievements and experience gained.
Mobility: to detail short term secondment outside the main industrial placement, and conference attendance, scientific visits etc (including secondments to the Almac Group for further training).

Outreach: a list of communication and dissemination activities to be undertaken by the ESR, brought together in a ‘Communication and public engagement strategy’.

Future Plans: career planning and desired future experience

The training objectives can be broken down into 3 key headings and will be carried out at all sites across the network:

1) core research skills – these will add to their existing graduate experience and qualifications, to ensure that they can efficiently and safely operate in the laboratory and commercial environment they will be placed in. This will be delivered to them as a fundamental aspect of the project itself under the mentorship of their experienced supervisors.

2) advanced/additional research skills – the addition of these further skills will be a considerable part of the attraction for the ESR in seeking to be part of the APPFlow project. They will include contemporary synthetic methods using alternative non-conventional batch routes, engineering in the case of the design and building of flow rigs that can be transferable into a manufacturing setting at Arran, economic assessment and thinking to align the ESR on what is important in process flow design, managerial skills to address this multifunctional project. The skills they will develop, both in the academic and industrial setting, will enhance their employability and prove to be of significant value for their future career, in whichever sector they should choose. This training will be delivered by all of the project partners, giving the full breadth of exposure.

3) transferable skills – these wider skills will shift the focus away from the pure scientific expertise of the ESRs and seek to provide them with a more rounded skill-set that would be attractive to employers from any area. Skills and awareness in areas such as IP management, project management, gender equality, research ethics and grant writing will be delivered again by all partners in the consortium and supported by Almac.

Project Descriptions