Category Archives: Application

NMR Studies of Protic Ionic Liquids

Overbeck, Viviane, and Ralf Ludwig. “NMR Studies of Protic Ionic Liquids.” In Annual Reports on NMR Spectroscopy, 95:147–90. Elsevier, 2018.

https://doi.org/10.1016/bs.arnmr.2018.05.002.

This review presents recent developments in the application of nuclear magnetic resonance (NMR) spectroscopy for studying the structure and dynamics of ionic liquids. We in particular focus on protic ionic liquids which are characterized by strong hydrogen bonding and proton transfer. Thus, the most relevant NMR-active nucleus is the proton, which undergoes rapid exchange on the NMR time scale. Also, other nuclei are considered if they provide information beyond simple characterization of this unique liquid material. We addressed several NMR techniques which are traditionally or just recently used in the field of ionic liquids research: relaxation time experiments, pulsed-field gradient NMR, fast-field-cycling NMR, electrophoretic NMR, and solid state NMR. Also, novel experiments such as dynamic nuclear polarization NMR are discussed.

High-Field Solid-State NMR with Dynamic Nuclear Polarization #DNPNMR

Lee, D., S. Hediger, and G.D. Paëpe, High-Field Solid-State NMR with Dynamic Nuclear Polarization, in Modern Magnetic Resonance, G.A. Webb, Editor. 2017, Springer International Publishing: Cham. p. 1-17.

https://doi.org/10.1007/978-3-319-28275-6_73-1

Microwave-induced dynamic nuclear polarization (DNP) can produce hyperpolarization of nuclear spins, leading to substantial signal enhancement in NMR. This chapter discusses the contemporary application of DNP for solid-state NMR spectroscopy at high magnetic fields. The main mechanisms and polarizing agents that enable this hyperpolarization are presented, along with more practical aspects such as the effect of decreasing sample temperature and analyzing the absolute sensitivity gain from these experiments. Examples of the exploitation of DNP for studies of biomolecules, biominerals, pharmaceuticals, self-assembled organic nanostructures, and mesoporous materials are given as is an outlook as to the future of this powerful technique.

Dynamic nuclear polarization for sensitivity enhancement in modern solid-state NMR #DNPNMR

Lilly Thankamony, A.S., et al., Dynamic nuclear polarization for sensitivity enhancement in modern solid-state NMR. Prog Nucl Magn Reson Spectrosc, 2017. 102-103(Supplement C): p. 120-195.

https://www.ncbi.nlm.nih.gov/pubmed/29157490

The field of dynamic nuclear polarization has undergone tremendous developments and diversification since its inception more than 6 decades ago. In this review we provide an in-depth overview of the relevant topics involved in DNP-enhanced MAS NMR spectroscopy. This includes the theoretical description of DNP mechanisms as well as of the polarization transfer pathways that can lead to a uniform or selective spreading of polarization between nuclear spins. Furthermore, we cover historical and state-of-the art aspects of dedicated instrumentation, polarizing agents, and optimization techniques for efficient MAS DNP. Finally, we present an extensive overview on applications in the fields of structural biology and materials science, which underlines that MAS DNP has moved far beyond the proof-of-concept stage and has become an important tool for research in these fields.

Static DNP-NMR Spectroscopy to Characterize Active Pharmaceutical Ingredients #DNPNMR

Dynamic Nuclear Polarization in general is no new method, but the focus of modern applications has initially been on bio-macromolecules under magic-angle-spinning (MAS) conditions.

One application that came out-of-the-blue was using DNP-NMR spectroscopy to study surface materials by DNP-NMR spectroscopy (for example Lafon et al., 2011) opening up a complete new research area within material science that traditionally struggled with very low signal-to-noise (S/N) ratios.

Even the application of DNP-NMR spectroscopy to study small molecules was not immediately evident, but as demonstrated in Rossini et al, 2012 DNP offers the possibility to record 13C correlation spectra of unlabeled molecules such as glucose in just 16 hours. Without DNP this experiment would require months of spectrometer time.

The majority of the DNP-NMR experiments that have been reported in recent years use gyrotron-based DNP-NMR systems and MAS-DNP probes operating at about 100 K. Alternatively, there is a small group of researchers that use DNP systems based on a solid-state microwave source. These systems have are typically limited by their output power, which ranges between >80 mW at 263 GHz (400 MHz 1H NMR) to < 200 mW at 197 GHz (300 MHz 1H NMR). At lower frequencies the output power increases and > 500 mW can be reached for systems operating at 95 GHz. A comprehensive overview of low-power DNP-NMR systems can be found in Siaw et al., 2016.

Because of the limited output power, DNP experiments are performed at temperatures < 20 K, which requires cooling with liquid helium (very common for example in EPR experiments) and can be cost-effective when using a cryostat (e.g. at 10 K the consumption is about 0.5 l/hr). Furthermore, with the increasing popularity of cryogen-free systems some cryostats don’t require any liquid cryogens anymore for cooling. The main advantage is the reduced cost since a solid-state source based DNP-NMR system typically comes at a 10th of the cost of a gyrotron-based system.

At first sight it seems as if the applications of static DNP are very limited. However, when I was at ENC this year I listened to a talk by David A. Hirsh entitled “35Cl Dynamic Nuclear Polarization Solid-State NMR of Active Pharmaceutical Ingredients”. David is a graduate student in the group of Rob Schurko, University of Windsor and gave a very nice talk on using DNP-NMR spectroscopy to characterize Active Pharmaceutical Ingredients (API) using 35Cl solid-state NMR spectroscopy. Since 35Cl is a quadrupole nucleus the corresponding NMR spectra are typically very broad. MAS does only have a small effect, mainly on the center transition, and traditionally wide-line spectra of static solids are recorded.

To overcome sensitivity issues, the group has developed pulse sequences such as WURST-CPMG or BRAIN-CP to rapidly record broad 35Cl patterns even at moderate magnetic field strengths (e.g. 9.4 T, 400 MHz 1H NMR). However, recording a single spectrum often requires several hours of signal averaging to achieve a sufficiently high signal-to-noise (S/N) ratio. With the aid of DNP these acquisition times can be dramatically reduced to just minutes. In his talk at ENC David described using a grytron-based DNP-NMR system, equipped with a MAS-DNP probe head in his experiments. Polarizing the sample is done while the rotor is spinning, but the rotor is stopped prior to recording the wide-line NMR spectrum. 

This experiment seems to be ideally suited for a low-power DNP-NMR system for static solids, using a cryostat for sample cooling. This would greatly simplify the experiment because starting and stopping the rotor is not required anymore. Because the experiment is performed at much lower temperatures, there will be an additional boost in sensitivity and multi-dimensional correlation experiments should be possible, experiments that are close to impossible to perform without the aid of DNP.

In recent years the NMR community has witnessed the transition of DNP-NMR spectroscopy from an exotic method with a limited number of applications to a method with more and more applications. High-field DNP-NMR spectroscopy either based on a gyrotron or using a low-power solid-state source is still a very young method with many possibilities and I’m very excited to see what other applications lie in the future. I am however convinced that DNP-NMR spectroscopy will find their way into many more labs in the future and that the method will become an integral part of the NMR toolbox.

DNP visiting scientist positio at NHMFL

From the Ampere Magnetic Resonance List

A visiting scientist position is available at the U.S. National High Magnetic Field Laboratory (NHMFL) in Tallahassee Florida as part of a major initiative on Dynamic Nuclear Polarization (DNP) including magic-angle spinning (MAS) DNP, dissolution DNP and Overhauser solution DNP. The position will be focused primarily on but not limited to MAS DNP. A Bruker 600MHz DNP system has recently been installed and a 600MHz field-sweepable wide-bore magnet will be delivered soon to the NHMFL. The visiting scientist is expected to develop independent and collaborative research in chemical, biological and material applications of DNP as well as DNP instrumentation and technology. The scientist will work within a team of faculty and engineers through the NMR, EMR and AMRIS programs and in collaboration with users of the NHMFL facilities. 

Minimum qualifications include a Ph.D. in Chemistry, Physics, Biology or a related discipline. Experience in DNP is expected. To apply, please send a CV, a cover letter describing your experience and research interests, and contact information for three references to 

Zhehong Gan 

National High Magnetic Field Laboratory 

1800 E. Paul Dirac Dr., Tallahassee, FL 32310, USA 

Email: gan@magnet.fsu.edu

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Dynamic nuclear polarization enhanced NMR spectroscopy for pharmaceutical formulations

Rossini, A.J., et al., Dynamic nuclear polarization enhanced NMR spectroscopy for pharmaceutical formulations. J Am Chem Soc, 2014. 136(6): p. 2324-34.

http://www.ncbi.nlm.nih.gov/pubmed/24410528

Dynamic nuclear polarization (DNP) enhanced solid-state NMR spectroscopy at 9.4 T is demonstrated for the detailed atomic-level characterization of commercial pharmaceutical formulations. To enable DNP experiments without major modifications of the formulations, the gently ground tablets are impregnated with solutions of biradical polarizing agents. The organic liquid used for impregnation (here 1,1,2,2-tetrachloroethane) is chosen so that the active pharmaceutical ingredient (API) is minimally perturbed. DNP enhancements (epsilon) of between 40 and 90 at 105 K were obtained for the microparticulate API within four different commercial formulations of the over-the-counter antihistamine drug cetirizine dihydrochloride. The different formulations contain between 4.8 and 8.7 wt % API. DNP enables the rapid acquisition with natural isotopic abundances of one- and two-dimensional (13)C and (15)N solid-state NMR spectra of the formulations while preserving the microstructure of the API particles. Here this allowed immediate identification of the amorphous form of the API in the tablet. API-excipient interactions were observed in high-sensitivity (1)H-(15)N correlation spectra, revealing direct contacts between povidone and the API. The API domain sizes within the formulations were determined by measuring the variation of epsilon as a function of the polarization time and numerically modeling nuclear spin diffusion. Here we measure an API particle radius of 0.3 mum with a single particle model, while modeling with a Weibull distribution of particle sizes suggests most particles possess radii of around 0.07 mum.

DNP-Enhanced MAS NMR of Bovine Serum Albumin Sediments and Solutions

Ravera, E., et al., DNP-Enhanced MAS NMR of Bovine Serum Albumin Sediments and Solutions. J Phys Chem B, 2014.

http://www.ncbi.nlm.nih.gov/pubmed/24460530

Protein sedimentation sans cryoprotection is a new approach to magic angle spinning (MAS) and dynamic nuclear polarization (DNP) nuclear magnetic resonance (NMR) spectroscopy of proteins. It increases the sensitivity of the experiments by a factor of approximately 4.5 in comparison to the conventional DNP sample preparation and circumvents intense background signals from the cryoprotectant. In this paper, we investigate sedimented samples and concentrated frozen solutions of natural abundance bovine serum albumin (BSA) in the absence of a glycerol-based cryoprotectant. We observe DNP signal enhancements of epsilon approximately 66 at 140 GHz in a BSA pellet sedimented from an aqueous solution containing the biradical polarizing agent TOTAPOL and compare this with samples prepared using the conventional protocol (i.e., dissolution of BSA in a glycerol/water cryoprotecting mixture). The dependence of DNP parameters on the radical concentration points to the presence of an interaction between TOTAPOL and BSA, so much so that a frozen solution sans cryoprotectant still gives epsilon approximately 50. We have studied the interaction of BSA with another biradical, SPIROPOL, that is more rigid than TOTAPOL and has been reported to give higher enhancements. SPIROPOL was also found to interact with BSA, and to give epsilon approximately 26 close to its maximum achievable concentration. Under the same conditions, TOTAPOL gives epsilon approximately 31, suggesting a lesser affinity of BSA for SPIROPOL with respect to TOTAPOL. Altogether, these results demonstrate that DNP is feasible in self-cryoprotecting samples.

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