Solid-state NMR: a uniquely powerful analytical tool and interactions

Nuclear magnetic resonance (NMR) spectroscopy is used to elucidate the structure of a wide range of samples, providing detailed information on atomic-level structure and dynamics. Within the NMR field, solid-state NMR is a rapidly growing area, providing unique insights into the structure and dynamics of both inorganic and organic molecules, and has applications in, for example, pharmaceuticals,  and biological systems

Because it provides detailed information about a sample in its native state without the need for special sample preparation, solid-state NMR can be used to study crystalline, amorphous, and composite materials, as well as suspensions and mixed samples with liquid or even gas components. It is particularly useful for studying complex systems that are difficult to characterize using other methods.

“Solid-state NMR is a very powerful tool that provides valuable insight into the structure and dynamics of molecules in a site-specific manner,” says Prof. Brown. “Its main advantage is that it can be applied to insoluble systems and doesn’t require long-range order to yield atomic resolution information. This means it is highly complementary to techniques such as solution-NMR and x-ray crystallography.”

Solid-state NMR: Important advances

As noted above, Prof. Brown’s main research interests center around pharmaceuticals and plant cell walls, where he and his colleagues are advancing solid-state MAS NMR techniques.

“For solid-state characterization, the gold standard would be single crystal X-ray diffraction, but there are many examples where you cannot actually get a crystal structure, and in those cases, you're relying on other techniques,” he reveals. “A lot of our work in the field of NMR crystallography brings together experimental characterization via solid-state NMR and complementary techniques such as diffraction with density-functional theory calculations, where you have a structural model from experiment or crystal structure prediction.”

Prof. Brown has found that solid-state NMR can provide valuable insights into the molecular structure, conformation, and dynamics of the studied material – but the group’s experimental techniques enhance elucidation further.  “Solid-state NMR spectra exhibit broader linewidths compared to solution state NMR,” he explains. “For our solid-state NMR research in pharma and on plant cells, we rely on MAS, which eliminates anisotropic interactions and boosts both the sensitivity and resolution.”

“Quadrupolar nuclei is an area of interest for myself and also many of my colleagues in the UK who are looking at inorganic materials, energy and battery applications,” he explains. “Faster MAS frequencies are another area of continuing development. In solid-state NMR, we pack the sample into small rotors and rely on them spinning very fast. The technology of making the rotors ever smaller, allowing them to spin to faster frequencies brings multiple advantages across different application fields.”

Pharmaceutical analysis

Within the pharmaceutical space, Prof. Brown says that solid-state MAS NMR is playing an increasingly more important role in pharmaceutical research.

“Everyone is aware of drug discovery, and everyone knows about the concept of clinical trials. But there’s a very important stage between those two, where promising compounds have been identified and need to be made into a form that can be taken by the patient,” he says. Currently, the preferred method is via tablet, a dose form that solid-state NMR is perfectly placed to analyze.

“You've identified a molecule that's beneficial once it gets into the bloodstream, and the conventional solid-state tablet is still the most widely used method for getting it into the bloodstream – but solid-state NMR analysis is essential for following its stability,” he says. “With a paracetamol tablet, for example, you want to know the actual solid-state forms of that API and how they change in humidity, plus the effect of the other ingredients in that tablet that are called excipients. That’s where solid-state NMR comes in: it’s very well suited to looking at these components.”

More specifically, Prof. Brown’s team is looking to characterize solid-state forms of APIs. This includes polymorphs, (where an API can have multiple crystalline forms), co-crystals and salts,  and amorphous dispersions that can be part of a drug formulation. Importantly, the solid-state structure and dynamics of each of these can impact drug stability, solubility and bioavailability, and can affect the efficacy or toxicity of medications. “I’ve always been interested in hydrogen bonding, which is one of the key intermolecular interactions that drive why a particular solid-state form or polymorph is chosen,” he says. “Solid-state NMR, and particularly proton methods, are really well suited to looking at hydrogen bonding.”

Prof. Brown has partnered with large pharma companies to characterize APIs that will ultimately be formulated as solid dose tablet form.  “Working with pharmaceutical companies is something that's always been an important part of my research as an independent PI,” he says. “It is through collaboration with industry that we have developed advanced 2D NMR techniques to one, identify different forms of pharmaceutical ingredients and two, to determine the interactions between molecules to better understand supramolecular assembly.”

For example, recent work  on Lorlatinib, an API used in the treatment of lung cancer, has shown that NMR crystallography analysis that brings together X-ray diffraction, calculation of NMR parameters and experimental MAS NMR, yields insight into the specific hydrogen-bonding interactions that drive the crystal packing – information that was previously unavailable to the drug’s developers.

Supporting new biofuel research

For his research on plant cell walls, in collaboration with Ray and Paul Dupree at the University of Warwick and the University of Cambridge, respectively, Prof. Brown applies 2D double quantum NMR to plant cell walls to analyze 13C labeled samples. The aim of the research is to learn how to make more efficient plant biofuels, thereby improving green infrastructure. “We are using 13C labeling to discover how different biopolymers interact with each other, which should enable the development of enzymes that break down the biopolymers into smaller sugars that are more usable for biofuels,” he says.

One of the barriers to breaking down insoluble biopolymers into forms that are better biofuels has been the lack of knowledge as to how these biopolymers interact. “There can be many different biopolymers within the plant, such as cellulose, mannan and xylan, and very little is known about how these biopolymers interact with each other,” Prof. Brown says. “In NMR analysis, sugars are difficult to look at, because the carbon chemical shifts are quite close together – using high field instruments and 13C enriched samples prepared by our Cambridge collaborators allows us to spread them out into a 2D spectrum, and that is key to our work.”

One of the team’s published findings was that xylan changes from a three-fold to a two-fold arrangement when it interacts with cellulose as compared to in solution.  “It was there we saw a big change in the experimental carbon-13 chemical shifts – and this was backed up by DFT calculations. The experimental observations proved the hypothesis that Paul Dupree had theorized was happening,” Prof. Brown reveals.

In further work, published in 2022,  solid-state NMR played an important role in adding to the understanding of the structure and functional differences between the various plant cell wall hemicelluloses, with a specific focus on β-galactoglucomannan (β-GGM). These results highlight the need to consider the contribution of multiple hemicelluloses in the functional study of plant cell walls.

It is high-field solid-state NMR that has allowed the researchers to gather this extremely high-level information about the atomic structure of plant cell walls. “The 1 GHz NMR spectrometer has given us exquisite atomic-level detail on the structure and dynamics,” Prof. Brown says. “There's so much information because different peaks correspond to distinct carbon atoms in the different biopolymers. We can then use that information to see which biopolymers are close together in space to others.”

Exciting capabilities for collaboration

In 2025, a 1.2 GHz Avance™ NMR spectrometer from Bruker will be installed at Warwick as the first 1.2 GHz instrument in the UK.  This and a second 1.2 GHz system in Birmingham will be open to scientists from around the country.

“The NRF NMR facilities at Warwick have always been part of a bigger national community, and the 1.2 GHz spectrometer is no exception – we are hosting the instrument as a resource for the whole country to support expansion of the UK’s fundamental research infrastructure,” says Prof. Brown. “Together with Birmingham, we have established a joint industry advisory board and a high-level oversight group for 1.2 GHz NMR in the UK.”

New NMR techniques are driving the field forwards, Prof. Brown asserts. “We are dealing with such complex systems where, the more you do, the more you realize you don’t know. There are examples where diffraction doesn’t work and microscopy is limited,” he says. “The insight you get from methods like solid-state NMR is invaluable – and that’s why I think the capability that these high field instruments can deliver is so exciting.”

About Steven Brown

Professor Steven Brown applies high-field solid-state Magic Angle Spinning (MAS) nuclear magnetic resonance (NMR), in particular 2D double-quantum NMR to two particular research areas of interest, pharmaceuticals and the biochemistry of plant cell walls.

Much of his pharmaceutical work has been in partnership with major pharma companies, such as AstraZeneca, GSK and Pfizer, and is focused on the characterization of active pharmaceutical ingredients (APIs) as delivered to patients in solid dose forms. His research on plant cell walls is in collaboration with Ray and Paul Dupree analyzing carbon-13 (¹³C) labelled samples to reveal structural and dynamic information on the individual biopolymers and how they interact with each other.

Solid-State NMR at the University of Warwick

The multi-PI (Principal Investigator) group across the physics and chemistry departments at the University of Warwick focuses on a wide range of solid-state NMR research interests encompassing the development of multinuclear solid-state NMR methodology and pulse-sequences, combined with calculations, and application to pharmaceuticals, supramolecular chemistry, materials science and biological solids.

“We’re actually a group of five PIs each with their own areas of specialty,” Prof. Brown says. “It’s unusual for NMR to have such levels of shared activity, but it means that between us we cover most of the applications of solid-state NMR.”

A total of nine magnets for solid-state NMR, from 2.3 Tesla up to 23.5 Tesla, together with a large array of probes for MAS, as well as for static NMR and double rotation NMR, are located in the Magnetic Resonance Centre at the university.

The university hosts the UK High-Field Solid-State NMR National Research Facility (NRF) which welcomed its first users in 2010 and of which Prof. Brown is the Director. The NRF comprises an 850 MHz and a 1 GHz Bruker system,  with a 1.2 GHz system planned for installation in 2025, all of which are available for the wider UK research community to use.

The University of Warwick is also a member of PANACEA (Pan-European solid-state NMR Infrastructure for Chemistry-Enabling Access) consortium,  which aims to expand access to NMR spectrometers for other academics and industries across Europe.

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