Benchtop Nuclear Magnetic Resonance Spectroscopy: An Emerging Tool in Regulated Assays

Nuclear magnetic resonance (NMR) spectroscopy is a valuable tool for scientists to determine primary (atom connectivity), secondary (spatial arrangements) and tertiary molecular structures , purities, and other essential parameters of diverse chemical species.^1,2

Traditionally, the industry has been dominated by superconducting, high-field spectrometers. Although these instruments offer excellent sensitivity and peak dispersion, their cost and maintenance expenses are prohibitive for many users. They also occupy significant space, often requiring a dedicated room.  

Using rare earth magnets arranged in a highly homogeneous Halbach-based array has facilitated the production of cryogen-free benchtop NMR instruments. These devices feature miniaturized electronics and an embedded computer for direct data acquisition and processing.  

Benchtop NMR technology has substantially improved the accessibility, affordability, and automatability of this vital technique. Since approximately 80% of conventional high-field NMR instruments are owned by only eight countries, increased access to the analytical capabilities offered by these spectrometers has become crucial.³

Approximately 76% of end-users rely on NMR for qualitative and structural elucidation purposes, particularly in academia, government research, pharmaceuticals, biotechnology, and contract research organizations (CROs).³

From a logistical standpoint, the enhanced accessibility of benchtop NMR spectrometers allow non-experts to utilize NMR technology on their workbench directly. This has significant implications for quality assurance and quality control (QA/QC) assays and applications, expanding the technique’s applicability.

Historically, analytical techniques like gas chromatography (GC) and high-performance liquid chromatography (HPLC) have been extensively used for various analytical assays.^4–6

Their widespread usage has prompted standardization organizations such as the United States Pharmacopeia – National Formulary (USP–NF) and European Pharmacopoeia (Ph. Eur.) to develop and publish numerous standardized methods for use with these instruments, promoting their presence in almost every analytical laboratory.

Conversely, due to accessibility concerns associated with traditional NMR spectrometers, the development of equivalent methods using NMR spectroscopy has lagged behind these other techniques.

Out of the >5000 monograph methods currently published in the USP–NF and Ph. Eur., only a surprisingly low 22 methods employ NMR (<0.4%!).

In addition to its structural elucidation capabilities, NMR is also a powerful quantitative tool. However, the limited accessibility of NMR instruments across various industries has resulted in a dearth of standardized test methods for this analytical approach.  

In recent years, efforts have been made to establish the equivalence between benchtop NMR spectroscopy and high-field NMR spectroscopy, which is required by standardized testing methods.  

The focus has been on demonstrating the capabilities of this technology in assays traditionally relying on GC or HPLC while emphasizing the advantages of NMR spectroscopy, such as shorter run times, simplified data acquisition, and minimal solvent volumes.

For instance, one project involves lithium analysis, where direct sampling and assaying of brine ponds using ⁷Li NMR significantly reduce the sample preparation necessary for other techniques like atomic absorption spectroscopy (AAS).⁹

Another example involves quantifying the substructures of lignin polymers through a phosphitylation reaction, followed by analysis using ³¹P NMR.¹⁰ It is crucial to analyze the phosphitylated products within a few hours to prevent decomposition, and benchtop NMR instrumentation facilitates this task.

The instruments have also been successfully employed following several published USP monograph methods, including but not limited to chitosan, hydroxypropyl betadex, parabens, polyoxyl 10 oleyl ether (Oleth-10), and polyoxyl 20 cetostearyl ether (Ceteareth-20).^{11,12,13,14,15}

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References and further reading

1. Keeler, J. in Understanding NMR Spectroscopy, 2nd ed.; John Wiley & Sons Ltd: Chichester, West Sussex, England, 2010.
2. Claridge, T. D. W. in High-Resolution NMR Techniques in Organic Chemistry, 1st ed.; Elsevier: Amsterdam, Netherlands, 1999.
3. SDI Global Assessment Report 2019.
4. Liang, Y.-Z.; Xie, P.; Chan, K. J. Chromatogr. B 2004, 812, 53–70.
5. Lehotay, S. J.; De Kok, A.; Hiemstra, M.; Van Bodegraven, P. J. AOAC Int. 2005, 88, 595–614.
6. Pita-Calvo, C.; Guerra-Rodríguez, M. E.; Vázquez, M. J. Agric. Food Chem. 2017, 65, 690–703.
7. The United States Pharmacopeia – The National Formulary. Rockville, MD, USA.
8. The European Pharmacopeia. Strasbourg, France.
9. Araneda, J. F.; Hui, P.; Leskowitz, G. M.; Riegel, S. D.; Mercado, R.; Green, C. Analyst 2021, 146, 882–888.
10. Araneda, J. F.; Burton, I. W.; Paleologou, M.; Riegel, S. D.; Leclerc, M. C. Can. J. Chem. 2022, 100, 799–808.
11. https://www.nanalysis.com/request-usp-monographs-chitosan
12. https://www.nanalysis.com/request-usp-monographshydroxypropyl-betadex
13. https://www.nanalysis.com/usp-paraben
14. https://www.nanalysis.com/request-usp-nf-polyoxyl-10-oleyl-ether
15. https://www.nanalysis.com/request-usp-monographs-polyoxyl-20- cetostearyl-ether

Nanalysis Scientific Corp

Nanalysis Scientific Corp. is a public company (TSXV:NSCI, FRA:1N1, OTC:NSCIF). The company is a global manufacturer and seller of compact Nuclear Magnetic Resonance (NMR) spectrometers. The Nanalysis 60 MHz was the first portable, high-resolution 60 MHz benchtop NMR spectrometer released on the market in 2013. These instruments are notable for their ease of use, low-maintenance, accessibility, affordability and automatability.  

Recently, Nanalysis introduced the 100 MHz spectrometer, representing the highest resolution instrument available on the market.  Designed with flexibility in mind, the instruments can be configured as traditional NMR spectrometers or programmed as analyzers for specific industrial applications (oil and gas, chemical, pharma, biotech, food science, atomic agencies, cannabis, mining). With global sales network, manufacturing, product development and corporate headquarters located in Calgary, Alberta, Canada, Nanalysis has sold instruments in over 45 countries, allowing the expansion of the North American sales team. Nanalysis’ product line has been widely recognized, including being named Company of the Year in Global Portable NMR in the prestigious Frost & Sullivan award for three consecutive years. 

Nanalysis expanded its portfolio of magnetic resonance technology acquiring RS2D and their superior Cam4™ technology offering their high-field NMR PulseTM console (200-600 MHz), preclinical MRI and MR product line. RS2D, founded in 2004, designs and manufactures a suite of magnetic resonance products powered by the versatile Cam4™ which will soon power all our spectrometers, including MRI consoles and the Pulse™ NMR console suitable for 200-600 MHz instruments. These are powered by innovative software packages, PRim and SPINit , for MRI and NMR, respectively. In 2011, RS2D helped pioneer preclinical imaging with the first rodent MRI system made from a superconducting cryogen-free. *Investors, please see Nanalysis scientific LinkedIn page

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