Development of Automated Parallel CO2 Supercritical Fluid Chromatography for Use in Continuous Flow Chemical Synthesis

There has been a significant shift in focus within the scientific community over the previous few years towards practices that are more environmentally accessible and sustainable, driven largely by increased awareness of the impacts of current practice, governmental legislation and increasing costs of waste disposal (most especially solvents). In the chemistry world there are increasing demands for greater efficiencies, lower solvent use, lower energy consumption and improved processes. Wasteful and time-consuming practices are no longer acceptable, forcing chemists to be more responsible for their actions. The EPSRC has acknowledged the importance of this shift and is actively promoting it through the creation of a series of 'Grand Challenges' including Dial-a-Molecule (100% efficient synthesis) and CO2Chem (utilising CO2 for chemical synthesis).

Unusually, although computer-aided processes and electronic automation have been shown to be effective in other sectors at increasing efficiency and minimising costs, chemistry as a science has been slow on the uptake of new technology designed to assist chemists in routine tasks. In the traditional research environment, this can be seen most clearly by the lack of computer assistance in even the most ordinary of tasks such as titrations, crystallisations, extractions or distillations. When looking at more complex activities such as the identification, optimisation and analysis of new reactions, the situation is even worse. This must change if we are to move chemistry forward. Our research group has consistently pioneered novel methods in chemical synthesis and we are well positioned to deliver a new vision that will lead the way in addressing the present constraints and limitations of how we work in the laboratory today. Our vision of the Lab of the Future is one that breaks away from inefficient traditions and pushes the boundaries of what is possible in chemical synthesis by combining modern-day computing power with the most useful of software developments in order to intelligently combine synthesis procedures.

During the last few years there has been a significant amount of effort expended in the development of new flow synthesis enabling tools, most notably in the area of enhancing reaction capability. At the same time new in-line detection methods are being developed, with desktop NMR spectrometers and in-line miniature MS detectors providing extensive chemical structure data rapidly for compounds produced in flow. Despite the increase in these new enabling tools coming onto the market, there has been little focus on essential continuous downstream processing tools such as work-up cycles and chromatography.

In situations where compounds having similar chemical properties need to be separated, chromatography is usually the method of choice. Researchers are easily able to use semi-preparative and preparative HPLC to separate compounds reasonably quickly. The use of manual column chromatography and semi-automated flash chromatography is commonplace. However for multi-component, complex mixtures there exist no solutions for in-line continuous separation of compounds, especially on an R&D scale.

There are huge conveniences to being able to chromatograph compounds in-line (e.g. in a continuous flow multistep reaction sequence) and it is additionally attractive in terms of many benefits and economies that can be obtained. At the current time, however, there exist no devices that can conveniently achieve this in the research environment; the basis of our proposal therefore is to meet such a need: to design, build and develop the first parallel column SFC separation device for use in-line, at the R&D scale of synthesis, in flow chemistry applications. Utilising CO2 supercritical fluid chromatography enables rapid separations in a sustainable and environmentally friendly manner while fulfilling an unmet need in downstream processing.

Functional materials such as pharmaceuticals, food preservatives, polymers, paints and pigments are playing an increasingly important role in modern society. As demands for these compounds grow, new methods are being sought for their creation that conform to the present world's requirements for the efficient use of materials while remaining environmentally sustainable. Continuous flow chemical synthesis has received attention as a means by which to achieve the realisation of this ambitious goal. There currently exists a need in flow synthesis, however, for a method that is capable of separating complex product mixtures continuously so that, for example, reactors may be connected in series to achieve efficient continuous synthesis processes. The proposed Parallel Column Supercritical Chromatography (SFC) unit will meet this need by enabling rapid continuous separations while aligning with the national strategy of sustainability.

Currently used batch separation methods for synthesis (e.g. semi-preparative HPLC and flash chromatography) utilise hazardous and toxic eluent solvents with little attention given to the environmental effects of solvent discharge. In addition these solvents are expensive, considerably increasing the operating costs of any chemical manufacturing operation be it lab-sized or on an industrial scale. Using a non-toxic, non-flammable and inexpensive eluent compound such as CO2 will lower these operating costs considerably and not pose a risk if discharged. Our unique design incorporates an efficient recycle loop that we calculate will allow for the reuse over 95% of the feed CO2 supply thus reducing environmental impacts and operating costs even further.

Additionally, further downstream processing is usually required for compounds separated using traditional separation techniques. Energy-intensive processes such as vacuum evaporation are commonly used to remove eluent solvents after chromatography. These procedures act as bottle-necks in any chemical process, consuming considerable amounts of researcher time, both by requiring researchers to monitor tools and creating lengthy pauses between synthesis steps. The proposed SFC unit includes product and waste cyclones that will facilitate instant collection of eluting compounds simply through the release of pressure, enabling skilled researchers to spend more time on other, less routine tasks aimed at advancing progress. For those laboratories in academia and industry that are focussed on drug discovery, this benefit will accelerate developmental progress and potentially enable drug candidates to be brought to the market more quickly.

As a group, we are committed to using open-source computer software and hardware whenever we can; the proposed project is no different. All significant developments made during this project, such as those arising during the design and coding of complex neural networking controls, will be fed back into the open-source community for others to use. The PDRA and graduate students who will be working on this project will gain significant experience in developing multifaceted, self-optimising algorithms, experience that they will take to other sectors when the project reaches completion. This will facilitate the growth of a new breed of control systems where efficiencies are rapidly optimised through intelligent computer control in a wide range of applications, lowering operating costs for businesses and improving environmental effects.

During the final year of this project, we will develop a bench-top SFC unit to the point of commercialisation in collaboration with our UK-based partner companies such as Vapourtec. In addition to prioritising the sourcing of parts, materials and machine-shop hours from Cambridge-based suppliers, this will aid the development of the nascent flow chemistry industry in the UK while supporting local small businesses.