Compact Nuclear Magnetic Resonance Research Articles

Benchtop NMR Coupled with Chemometrics: A Workflow for Unveiling Hidden Drug Ingredients in Honey-Based Supplements.

Recently, benchtop nuclear magnetic resonance (NMR) spectrometers utilizing permanent magnets have emerged as versatile tools with applications across various fields, including food and pharmaceuticals. Their efficacy is further enhanced when coupled with chemometric methods. This study presents an innovative approach to leveraging a compact benchtop NMR spectrometer coupled with chemometrics for screening honey-based food supplements adulterated with active pharmaceutical ingredients. Initially, fifty samples seized by French customs were analyzed using a 60 MHz benchtop spectrometer. The investigation unveiled the presence of tadalafil in 37 samples, sildenafil in 5 samples, and a combination of flibanserin with tadalafil in 1 sample. After conducting comprehensive qualitative and quantitative characterization of the samples, we propose a chemometric workflow to provide an efficient screening of honey samples using the NMR dataset. This pipeline, utilizing partial least squares discriminant analysis (PLS-DA) models, enables the classification of samples as either adulterated or non-adulterated, as well as the identification of the presence of tadalafil or sildenafil. Additionally, PLS regression models are employed to predict the quantitative content of these adulterants. Through blind analysis, this workflow allows for the detection and quantification of adulterants in these honey supplements.

Analysis of complex mixtures with benchtop nuclear magnetic resonance: Solvent suppression with T2 and diffusion filters.

Benchtop nuclear magnetic resonance (NMR) spectrometers are being employed in a wide variety of applications from undergraduate teaching and research in academia to quality control and process monitoring in industrial settings. Incorporating benchtop NMR in some of these applications presents opportunities for new practical uses of the technology and challenges that truly test the capabilities of compact NMR spectrometers. For instance, the use of protonated solvents in manufacturing or process monitoring requires separating and quantitating the analyte signals of interest from the strong (overwhelming) response from the solvents. Furthermore, due to the lower field strength available with permanent magnet spectrometers, the NMR spectra of complex mixtures can be more difficult to analyze due to partial or complete signal overlap. To address some of these challenges and to extend the range of applications of benchtop NMR, we investigate NMR techniques that enable quantitative analysis of different components in mixtures. These pulse sequences can be used to suppress one or multiple solvent peaks, to filter out signals by spin-spin relaxation time (T2), or to separate signal components by a molecule's diffusion coefficient (NMR diffusometry). In this paper, we discuss quantitative analysis of excipients in buffers for therapeutic proteins to highlight the usefulness of these NMR pulse sequences in the analysis of complex samples with benchtop NMR spectrometers.

Decreasing Magnetic-Field Inhomogeneity by Inlaying the RF Coil Into a Tubular Bracket

The homogeneous magnetic field is highly desired for achieving high-resolution nuclear magnetic resonance (NMR) spectra. Inevitably, however, nonzero magnetic susceptibility (non-ZMS) structures near the detection region, such as radio-frequency (RF) coils and brackets among others, accentuate the magnetic field inhomogeneity ( <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\beta $ </tex-math></inline-formula> ) and broaden NMR spectral lines. In this study, we discover that when cylindrical sensors are perpendicular to the applied magnetostatic field, inlaying the RF coil into a tubular bracket that coaxially overlays the tube can reduce <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\beta $ </tex-math></inline-formula> within the detection region of this RF coil. This inlay depth can be optimized by enforcing magnetic dipole fields induced by the RF coil to equal those of the materials replaced by this RF coil. Based on this mechanism, we have developed an inlaid-coil sensor for a lab-built compact NMR spectrometer, which is merely additionally installed with a tubular Teflon bracket. Simulated results demonstrate that, as this depth approaches the optimal theoretical value, <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\beta $ </tex-math></inline-formula> within the detection region gradually decreases, supporting our identification of such a mechanism. Furthermore, experimental results reveal that the inlaid-coil sensor can acquire higher-resolution NMR spectra than the bracketless sensor can, validating the compensation mode based on this mechanism. This approach can achieve magnetostatic-field compatibility among different materials inside cylindrical sensors perpendicular to the imposed magnetostatic field. Hopefully, our study can help provide a guide for the magnetostatic-field design of complex cylindrical sensors in emerging NMR technologies such as microsystems, hyperpolarization, and in situ detection.

Fast quantification of water content in glycols by compact 1H NMR spectroscopy

Glycols are key chemicals for many applications in different fields of activities. Being highly hydroscopic, glycols contain usually water. The presence of water, even in tiny amounts, can affect their chemical and physical properties. Therefore, the accurate determination of water content is essential for any intended applications. In this context, a novel method using low-field Nuclear Magnetic Resonance (NMR) spectroscopy is introduced. The proposed approach offers a straightforward, fast, low-cost, and versatile solution for water quantification in glycols without the need for reagents or calibration data. It is demonstrated by quantifying the water concentration up to 11 wt% in aqueous ethylene glycol (EG) and triethylene glycol (TEG) mixtures with the help of lineshape analysis of the corresponding proton spectra. The limit of detection, achieved within 1 min of measuring time, was 0.05 wt% for water in EG and 0.15 wt% in TEG. The excellent agreement between the NMR results and those from the Karl-Fischer titration indicates that the proposed NMR-based approach has a great potential to be used as an alternative to the Karl-Fischer method. In addition, it is expected that the same methodology can be applied for water quantification in more complex glycolic solutions and other mixtures.

A compact magnetic resonance system with inside-out sensor for soil moisture measurement

Accurate measurement of soil moisture parameters plays a vital role in promoting agricultural production. Nuclear magnetic resonance (NMR) measuring instruments have become increasingly compact, especially in low field applications. However, NMR soil moisture measurement instruments still have problems with portability. We report on a compact NMR measuring instrument that focuses on the circuit’s design and construction. The instrument includes an inside-out sensor, NMR spectrometer, radio frequency power amplifier, low-noise preamplifier, and duplexer. They are integrated into a slim 3D-printed cylinder. The integrated NMR instrument is portable and user-friendly and can reduce the influence of nonideal factors, such as transmission line effects and electromagnetic interference. We conducted different soil moisture experiments with the prototype using Carr–Purcell–Meiboom–Gill pulse sequence to obtain the corresponding transverse relaxation time (T 2) decay curves. Then, the T 2 1D spectrum distributions were obtained by inverse Laplace transformation. Finally, the results reveal that the area of long T 2 component decreases as the soil moisture content decreases.

Evaluation of a hydrogen signal detection method using a compact NMR sensor for the measurement of ion concentrations in culture medium

AbstractIn recent years, the demand for highly nutritious and functional vegetables has been increasing in the agricultural sector. In order to cultivate highly functional vegetables, it is necessary to adjust the nutrients in the soil, such as potassium ions, to an optimal state. Therefore, there is a need for a sensor that can measure soil ion concentration in real time in the field. In this report, we aim to develop an ion concentration sensor using Nuclear Magnetic Resonance (NMR). Since the sensor observes atomic specific behavior, it has the potential to measure the concentration of each ion species in soil where multiple ions exist. In this study, we aim to realize compact NMR and to establish a method for NMR measurement of water ahead of ion measurement. Using an NMR measurement system of our own design, we measured water and air. As a result, NMR signal spectra were obtained only when measuring water under resonance conditions, and resonance frequency of hydrogen atoms were successfully measured. We have established an NMR signal measurement method for measuring ion concentrations using a small NMR sensor that can be installed in the agriculture.

Analyses on Critical Current Density and Magnetic Fields of a REBCO Annular Plate Excited by Flux Pump With Thermal Switch

With development of high temperature superconducting (HTS) magnets composed by HTS tapes, it attracts extensive interest in high-magnetic field and at low temperature. In this paper, a RE-Ba-Cu-O (REBCO, RE is rare earth) annular plate model is proposed with two holes. An exciting coil is located in one hole and magnetic field is generated in another hole by a flux pump with thermal switch. Principle of flux accumulation in REBCO annular plate is presented, the flux accumulation is numerically analyzed to verify its feasibility at 77 K. Results show that REBCO annular plate can be excited by flux pump with thermal switch so that the closed-loop operation can realize. The method may extend to HTS magnet staked by those REBCO annuli, which has promising application as persistent current mode (PCM) in compact nuclear magnetic resonance (NMR) magnets.

Compact low-field NMR spectroscopy and chemometrics applied to the analysis of edible oils

Compact nuclear magnetic resonance (NMR) spectroscopy combined with chemometric tools opens new perspectives for NMR use. This work compares the potential of 43, 60 and 400 MHz NMR spectroscopy for quality control of edible oils. Partial least squares regression (PLSR) and support vector regression (SVR) models built on the three NMR devices had equivalent performances for fatty acids and iodine value, and the models built with the low field spectra were equivalent to the high field. Moreover, performances for calibration indicated that most of the models built with medium/or high-resolution fields presented reproducibility values lower than the minimum accepted by the American Oil Chemists' Society (AOCS). Compared to classical methods, this new approach allows the application of medium resolution devices as a sample screening tool in analytical laboratories since it allows the spectrum obtention in a few seconds, without the need for sample preparation or the use of deuterated solvents.

Screening Metal-Organic Frameworks for Separation of Binary Solvent Mixtures by Compact NMR Relaxometry.

Metal–organic frameworks (MOFs) have great potential as an efficient alternative to current separation and purification procedures of a large variety of solvent mixtures—a critical process in many applications. Due to the huge number of existing MOFs, it is of key importance to identify high-throughput analytical tools, which can be used for their screening and performance ranking. In this context, the present work introduces a simple, fast, and inexpensive approach by compact low-field proton nuclear magnetic resonance (NMR) relaxometry to investigate the efficiency of MOF materials for the separation of a binary solvent mixture. The mass proportions of two solvents within a particular solvent mixture can be quantified before and after separation with the help of a priori established correlation curves relating the effective transverse relaxation times T2eff and the mass proportions of the two solvents. The new method is applied to test the separation efficiency of powdered UiO-66(Zr) for various solvent mixtures, including linear and cyclic alkanes and benzene derivate, under static conditions at room temperature. Its reliability is demonstrated by comparison with results from 1H liquid-state NMR spectroscopy.

Automatic Shimming Method Using Compensation of Magnetic Susceptibilities and Adaptive Simplex for Low-Field NMR

During the past several decades, inexpensive compact nuclear magnetic resonance (NMR) instruments have been widely used for on-site detections of chemical identity and sample analyses in industrial applications. In general, via shim coils and control strategies, automatic search shimming methods are capable of improving the magnetic field uniformity so that optimized signals can be acquired and particularly suited for rapid detections in compact NMR instruments. However, because these methods inherently endure the inefficiency in multidimensional shims and the sensitivity of starting points, it is time-consuming to obtain acceptable results in a field infected with distortions and strays. Here, two remedies that improve the shimming speed for the search shimming method are proposed. First, analyzing and compensating for magnetic susceptibility effects, we relocate starting points closely to optima and reduce the complexity of global exploration. Second, modifying the simplex movement with adaptive scale factors and gradient-like centroid, we have improved the convergence of the simplex shimming algorithm in a multidimensional search space. Via theoretical analyses and lab experiments, we find that the proposed shimming method outperforms regular shimming methods in terms of handling complex magnetic fields and reducing shimming times and hope that our study can help further improve NMR shimming methods in the future.

Attempts at the Characterization of In-Cell Biophysical Processes Non-Invasively-Quantitative NMR Diffusometry of a Model Cellular System.

In the literature, diffusion studies of cell systems are usually limited to two water pools that are associated with the extracellular space and the entire interior of the cell. Therefore, the time-dependent diffusion coefficient contains information about the geometry of these two water regions and the water exchange through their boundary. This approach is due to the fact that most of these studies use pulse techniques and relatively low gradients, which prevents the achievement of high b-values. As a consequence, it is not possible to register the signal coming from proton populations with a very low bulk or apparent self-diffusion coefficient, such as cell organelles. The purpose of this work was to obtain information on the geometry and dynamics of water at a level lower than the cell size, i.e., in cellular structures, using the time-dependent diffusion coefficient method. The model of the cell system was made of baker’s yeast (Saccharomyces cerevisiae) since that is commonly available and well-characterized. We measured characteristic fresh yeast properties with the application of a compact Nuclear Magnetic Resonance (NMR)-Magritek Mobile Universal Surface Explorer (MoUSE) device with a very high, constant gradient (~24 T/m), which enabled us to obtain a sufficient stimulated echo attenuation even for very short diffusion times (0.2–40 ms) and to apply very short diffusion encoding times. In this work, due to a very large diffusion weighting (b-values), splitting the signal into three components was possible, among which one was associated only with cellular structures. Time-dependent diffusion coefficient analysis allowed us to determine the self-diffusion coefficients of extracellular fluid, cytoplasm and cellular organelles, as well as compartment sizes. Cellular organelles contributing to each compartment were identified based on the random walk simulations and approximate volumes of water pools calculated using theoretical sizes or molar fractions. Information about different cell structures is contained in different compartments depending on the diffusion regime, which is inherent in studies applying extremely high gradients.

Application of benchtop low-field NMR spectrometers in the refining industry: A multivariate calibration approach for rapid characterization of crude oils.

High-field nuclear magnetic resonance (NMR) has proven to be a valuable tool to analyze petroleum products but has never acquired widespread acceptance in routine work in oil refinery due to the high cost. The advent of compact, reliable, and affordable cryogen-free low-field benchtop NMR spectrometers suggest a possible role of such instrument for a variety of uses in refining spanning from routine lab work applications to online analysis. In this work, we report the development of a novel benchtop NMR application to estimate the API gravity, sulfur content, total acidity number (TAN), and distillation yields of crude petroleum from 60 MHz 1 H NMR spectra and partial least square (PLS) regression models. The results obtained on a dataset of over 170 crude oil samples and tested with external validation set show performances in terms of root mean square standard error of prediction (RMSEP) matching the analytical methods' ASTM precision. This novel benchtop NMR and multivariate analysis application can thus be used in typical refinery laboratories to provide within minutes and without physical distillation, reliable estimates of the most important properties usually measured on the crude petroleum during refining. The method proves to be a fast, cheaper alternative to the current analytical options providing readily available data for managing crude oil and has high potential to be further exploited for online application.

Taking compact NMR to monitoring real reactions in large-scale chemical industries-General considerations and learnings from a lab-scale test case.

The considerations for use of compact nuclear magnetic resonance in a large-scale industrial environment clearly differ from those in academic and educational settings and even from those in smaller companies. In the first part of this article, these differences will be discussed along with the additional requirements that need to be fulfilled for successful applicability in different use cases. In the second part of the article, outcomes from different research activities aiming to fulfill these requirements will be presented with a focus on an online reaction-monitoring study on a lab-scale nucleophilic chlorination reaction.

Formation of uniform magnetic flux distribution for NMR magnets using HTS bulk magnets activated by pulsed-field magnetization

Nuclear magnetic resonance (NMR) magnets generally need an extremely uniform magnetic field in the space where the specimens will be placed. Although high temperature superconducting bulk magnets can obtain an intense magnetic field of more than 3 T, the field distribution is intrinsically characterized to be inhomogeneous, showing steep gradient. Aiming at the practical application of compact and portable NMR magnets, the authors have developed magnet systems capable of generating uniform magnetic fields in a narrow space between face-to-face settled magnetic poles, targeting to obtain a uniform magnetic field between the poles. Here, the authors modified the shape of magnetic field distribution from convex to concave by attaching a ferromagnetic iron plate on one of the pole surfaces, and then settled them face to face with a gap of 70 mm. The uniformity of the magnetic field in the x-y plane was experimentally measured and estimated along various z-axis directions. The best uniformity of 463 ppm at 1.25 T was obtained in the experimental evaluation in the x-y plane of 4 × 4 mm2 at z = 0.5 mm from the iron plate surface. The value of uniformity along the z-direction range was extended from 0.8 mm to a depth of 1.1 mm. These results show that the possible space of NMR signal detection or the available sample size can be enlarged.

Generation of Uniform Magnetic Field between Face-to-Face HTS Bulk Magnets

Aiming to develop the compact nuclear magnetic resonance devices, the authors have been developing the uniform magnetic fields in the space between the face-to-face magnetic poles which contain HTS bulk magnets. The authors deformed the original convex shape of the magnetic field distribution to concave by attaching a ferromagnetic iron plate of 20 mm and 100 mm in diameter on one of the pole surfaces. The magnetic field distribution precisely measured along x-axis changed from concave to convex with increasing distance from the magnetic pole surface, which suggested the presence of magnetically flat region. From the results of mapping on the field uniformity data, we have succeeded in obtaining the field uniformity under 500ppm in the space of 4 x 4 x 0.8 mm3 when the magnetic poles emitting concave and convex field distributions were settled face-to-face with various gaps 30-70 mm. This performance exceeded the target value of 1,500ppm which is necessary to detect the NMR signals.

Synthesis of α-fluoro-α,β-unsaturated esters monitored by 1D and 2D benchtop NMR spectroscopy.

For optimization and control of pharmaceutically and industrially important reactions, chemical information is required in real time. Instrument size, handling, and operation costs are important criteria to be considered when choosing a suitable analytical method apart from sensitivity and resolution. This present study explores the use of a robust and compact nuclear magnetic resonance (NMR) spectrometer to monitor the stereo-selective formation of α-fluoro-α,β-unsaturated esters from α-fluoro-β-keto esters via deprotonation and deacylation in real time. These compounds are precursors of various pharmaceutically active substances. The real-time study revealed the deprotonation and deacylation steps of the reaction. The reaction was studied at temperatures ranging from 293 to 333K by interleaved one-dimensional 1 H and 19 F and two-dimensional 1 H-1 H COSY experiments. The kinetic rate constants were evaluated using a pseudo first-order kinetic model. The activation energies for the deprotonation and deacylation steps were determined to 28±2 and 63.5±8kJ/mol, respectively. This showed that the deprotonation step is fast compared with the deacylation step and that the deacylation step determines the rate of the overall reaction. The reaction was repeated three times at 293K to monitor the repeatability and stability of the system. The compact NMR spectrometer provided detailed information on the mechanism and kinetics of the reaction, which is essential for optimizing the synthetic routes for stepwise syntheses of pharmaceutically active substances.

Flexible automation with compact NMR spectroscopy for continuous production of pharmaceuticals

Modular plants using intensified continuous processes represent an appealing concept for the production of pharmaceuticals. It can improve quality, safety, sustainability, and profitability compared to batch processes; besides, it enables plug-and-produce reconfiguration for fast product changes. To facilitate this flexibility by real-time quality control, we developed a solution that can be adapted quickly to new processes and is based on a compact nuclear magnetic resonance (NMR) spectrometer. The NMR sensor is a benchtop device enhanced to the requirements of automated chemical production including robust evaluation of sensor data. Beyond monitoring the product quality, online NMR data was used in a new iterative optimization approach to maximize the plant profit and served as a reliable reference for the calibration of a near-infrared (NIR) spectrometer. The overall approach was demonstrated on a commercial-scale pilot plant using a metal-organic reaction with pharmaceutical relevance.Graphical abstract

Low-Field, Benchtop NMR Spectroscopy as a Potential Tool for Point-of-Care Diagnostics of Metabolic Conditions: Validation, Protocols and Computational Models

Novel sensing technologies for liquid biopsies offer promising prospects for the early detection of metabolic conditions through omics techniques. Indeed, high-field nuclear magnetic resonance (NMR) facilities are routinely used for metabolomics investigations on a range of biofluids in order to rapidly recognise unusual metabolic patterns in patients suffering from a range of diseases. However, these techniques are restricted by the prohibitively large size and cost of such facilities, suggesting a possible role for smaller, low-field NMR instruments in biofluid analysis. Herein we describe selected biomolecule validation on a low-field benchtop NMR spectrometer (60 MHz), and present an associated protocol for the analysis of biofluids on compact NMR instruments. We successfully detect common markers of diabetic control at low-to-medium concentrations through optimised experiments, including α-glucose (≤2.8 mmol/L) and acetone (25 µmol/L), and additionally in readily accessible biofluids, particularly human urine. We present a combined protocol for the analysis of these biofluids with low-field NMR spectrometers for metabolomics applications, and offer a perspective on the future of this technique appealing to ‘point-of-care’ applications.

Non-destructive analysis of polymers and polymer-based materials by compact NMR

Low-field nuclear magnetic resonance (NMR) based on permanent magnet technologies is currently experiencing a considerable growth of popularity in studying polymer materials. Various bulk properties can be probed with compact NMR tabletop instruments by placing the sample of interest inside the magnet. Contrary to this, compact NMR sensors with open geometries give access to depth-dependent properties of polymer samples and objects of different sizes and shapes truly non-destructively by performing measurements in the inhomogeneous stray-field outside the magnet system. Some of the sensors are also portable being thus well suited for onsite measurements. The gain of both bulk and depth-dependent microscopic properties are important for establishing improved structure-property relationships needed for the rational design of new polymer formulations. Selected recent applications will be presented to illustrate this potential of compact NMR.

Laser Source for a Compact Nuclear Magnetic Resonance Gyroscope

Vertical-cavity surface-emitting lasers (VCSELs) of 895 nm spectral range, with fixed direction of output polarization have been developed. These lasers provide single-mode output power of over 1 mW at an operational temperature of 60°С, at orthogonal polarization suppression ratio (OPSR) about 20 dB. The designed VCSELs were used in a laser source for a perspective compact nuclear magnetic resonance gyroscope. The designed laser source provides precise tuning of wavelength to the Cs133 D1 spectral line, and formation of collimated output beam.