Impact case study database

Context

Nuclear magnetic resonance is one of the most important and powerful analytical tools used by chemists, and finds application in a wide range of other fields. It is able to determine, for example, the composition of a mixture, the structures of complex molecules, and the mobilities of these molecules in solution. However, to direct the complex and precisely-timed sequences of radiofrequency and magnetic field pulses that are used in an NMR spectrometer to measure these different properties of substances is a science in itself. The impact described in this case relates to the development and commercial exploitation of two such families of pulse sequences developed at Manchester, known respectively as DOSY and pure shift NMR, that are able to analyse complex mixtures in a unique manner. They have proved vital to industrial research and product development and has led to a significant shift in practice and capacity in industrial research.

Pathway to impact

The initial impetus for our developments came from an industrial collaboration with Pfizer Global Research, and led to dedicated processing software, which was initially shared widely but informally with other users. The subsequent development of DOSY software, both open source and licensed for the proprietary operating system of the major NMR manufacturer Varian (subsequently Agilent), gave both the opportunity to exploit the intellectual property generated, and an effective vehicle for disseminating the results to a wide range of users, including many industrial research organisations. Key contributors to this impact were the Department policy of maintaining shared high-resolution NMR facilities, and the assistance of UMIP (University of Manchester Intellectual Property management agent) in negotiating the licensing of DOSY software.

In parallel to licensing proprietary code, the researchers made open-source DOSY processing code available through the DOSY Toolbox (and very recently through the General NMR Analysis Toolbox, GNAT, which has had >1,200 downloads since its release in October 2018). UoM’s development of pure shift NMR, initially as an adjunct to DOSY but now very widely used in its own right, has been the subject of several workshops at international conferences (EUROMAR, SMASH); a September 2017 workshop held in Manchester attracted 66 delegates, 11 from abroad and 8 from industry. The workshop materials have been downloaded from the researchers’ website over 1,000 times.

In collaboration with the major NMR equipment manufacturer Bruker, the researchers integrated pure shift and DOSY experimental techniques into their commercial software, with the result that many of these experiments are now available on all Bruker spectrometers in a dedicated University of Manchester section of the Bruker user library. The researchers also assisted the other major manufacturer, JEOL, to implement our methods in their software.

Reach and significance of impact

This work has changed the way that NMR is used in the chemical industries, including pharmaceuticals, agrochemicals and food. It led to the discovery of a new flavour ingredient that generated sales well in excess of GBP100,000,000 in the REF period, was key to maintaining sales of a fungicide worth >GBP100,000,000, and has supported growth in a billion-dollar scientific instrument market.

The principal impacts associated with DOSY and pure shift NMR in this period are:

Driving growth and innovation at NMR instrument manufacturers

The integration of UoM’s DOSY and pure shift NMR techniques into major manufacturers Bruker and JEOL’s spectrometers has brought both companies significant benefits. Bruker and JEOL both include the techniques in their standard offerings of NMR experiments on current-generation, high-resolution spectrometers [A, B]. Bruker specifically highlight that “… processing software for diffusion experiments is now an essential part of our Dynamics Centre software suite”, and that “… pure shift methods have become an indispensable part of our standard experiment library and are used routinely by our customers” [A]. The improvements in analytical problem-solving for NMR spectrometer customers achieved by DOSY and pure shift methods have also brought financial benefits to Bruker and JEOL. Bruker confirm, “ *the wide uptake of usage will definitely have contributed to our global NMR sales (around $400 million per year)*” [A], whilst JEOL say that the techniques “ have contributed to our instrumentation global annual sales of $900M” [B].

Bruker and JEOL both acknowledge the significant advantages that adopting DOSY and pure shift techniques bring to their customers [A, B]. As Bruker note, these techniques “ have significantly improved the ability of our end users to analyse mixture samples efficiently, and in extremis to solve otherwise intractable analytical problems” [A]. For Bruker, DOSY NMR techniques have spurred them to further technical innovation including special probes (DiffBB and BBO) with 17 T m^-1 gradient strength and −40 to 150 °C temperature ranges, as well as a new amplifier (GREAT60), all of which further enhance the usefulness of UoM’s DOSY techniques [A].

Changing practice in the food, pharmaceutical, and agrochemical industries

UoM’s DOSY and pure shift techniques are now used widely across the chemical industries. They have made significant contributions to the way many companies in the food, pharmaceutical and agrochemical industries perform chemical analysis and characterisation. This change derives from the need in the chemical industries to solve analytical problems with increased speed, precision and detail. A Senior Technical Expert in Crop Protection at international agrochemicals giant Syngenta emphasises the importance of NMR to industry, saying “ Chemical analysis is important throughout the research and development process and this importance is growing because modern environmental and safety regulations demand identification and quantification of molecules at lower and lower levels. NMR remains Syngenta’s primary method of structure elucidation” [C]. Pharmaceutical company Arcinova’s Head of Drug Product and Scientific Direction confirms, “… it is evident that molecular level characterisation of both drug substances and drug products is pivotal throughout pharmaceutical development for optimisation purposes and also for reducing the time to commercialisation” [D]

DOSY NMR experiments are available to all researchers at Syngenta’s Jealott’s Hill International Research Centre, their largest R&D site, with >800 active researchers [C]. Specific impacts of DOSY and pure shift at Syngenta include:

• Identifying a xenobiotic metabolite in a highly impure sample, by separating metabolite resonances from contaminants; this was required to maintain multi-million pound sales of a key fungicide product [C]

• Measuring diffusion, in multiple solvents, of a fungicide with sales >GBP100,000,000, helping to “… *optimize and reduce waste from the production process of this fungicide.*” [C]

• “Understanding of how a crop protection product partitioned within a spray mix”, crucial to understanding the mechanism of action of the formulation and previously impossible [C]

Both large and small pharmaceutical companies have also embraced the use of DOSY and pure shift methods. Small pharmaceutical company Arcinova, for example, has fully integrated the techniques into their work, saying “ The techniques developed at Manchester are routinely implemented in our own Laboratories and, as a SME [Small and Medium-sized Enterprise] , we have recently invested >£200,000 in upgrades to our magnetic resonance instrumentation for enabling the highest quality data generation and processing”. [D] Specific impacts of DOSY and pure shift at Arcinova include:

• Characterising monomer, dimer and trimer impurities in a pharmaceutical product used for advanced cancer treatment, since commercialised and now used globally [D]

• Assessing physical stability of a liposomal product to determine whether it met technical requirements for use in humans; this product is now commercially available [D]

The international pharmaceutical giant AstraZeneca has also integrated DOSY and pure shift NMR techniques into their research, describing them as representing “… *a step function improvement in our ability to analyse our samples by NMR.*” [E]. The methods are widely used in the AstraZeneca analysis toolbox, and are “… *playing an important part in the development of both small and medium sized drugs (e.g. oligonucleotides)*” [E]. The benefits to AstraZeneca’s business are characterised by a Principal Scientist in Pharmaceutical Technology & Development, who says “ *…the understanding that is derived from these experiments helps expedite the drug development process, ultimately allowing us to deliver medicines to patients more effectively.*” [E].

Mestrelab Research, who produce the NMR processing software Mnova, illustrate the breadth of uptake across the chemical industries. Mestrelab‘s software, which has 150,000 users globally, incorporates specific processing algorithms for DOSY and pure shift NMR experiments [F]. Mestrelab‘s Managing Director credits the UoM NMR techniques with contributing to their software’s success, saying, “ *We have no doubt that incorporating processing for pure shift and DOSY methods has contributed to establishing a market-leading position for our Mnova software.*” [F]

Delivering financial benefits to the chemical industries

Alongside the more general benefits derived from the enhanced problem-solving that DOSY and pure shift techniques provide, companies have developed new products directly from their use. As an example, Givaudan, a major international flavours and fragrances company, used DOSY to discover a compound that only occurred in trace amounts in food extracts. This compound positively influences taste perception and is widely applicable to a range of flavour products; sales between 2014 and 2018 generated CHF120,000,000 (approximately GBP100,000,000) [G]. Givaudan emphasise the value of these NMR techniques for companies, stating “ We are optimistic that the newly developed DOSY techniques and the newly deveped (sic) processing toolbox will also help us in finding the next “golden bullet” and can give Givaudan a clear competitive advantage.” [G].