Cryogen-free 400-MHz nuclear magnetic resonance spectrometer as a versatile tool for pharmaceutical process analytical technology

The discovery of new ceramic materials containing Ba-La-Cu oxides in 1986 that exhibited superconducting properties at high temperatures in the range of 35 K or higher, recognized with the Nobel Prize in Physics in 1987, opened a new world of opportunities for nuclear magnetic resonance (NMRs) and magnetic resonance imaging (MRIs) to move away from liquid cryogens. This discovery expands the application of high temperature superconducting (HTS) materials to fields beyond the chemical and medical industries, including electrical power grids, energy, and aerospace. The prototype 400-MHz cryofree HTS NMR spectrometer installed at Amgen's chemistry laboratory has been vital for a variety of applications such as structure analysis, reaction monitoring, and CASE-3D studies with RDCs. The spectrometer has been integrated with Amgen's chemistry and analytical workflows, providing pipeline project support in tandem with other Kinetic Analysis Platform technologies. The 400-MHz cryofree HTS NMR spectrometer, as the name implies, does not require liquid cryogens refills and has smaller footprint that facilitates installation into a chemistry laboratory fume hood, sharing the hood with a process chemistry reactor. Our evaluation of its performance for structural analysis with CASE-3D protocol and for reaction monitoring of Amgen's pipeline chemistry was successful. We envision that the HTS magnets would become part of the standard NMR and MRI spectrometers in the future. We believe that while the technology is being developed, there is room for all magnet options, including HTS, low temperature superconducting (LTS) magnets, and low field benchtop NMRs with permanent magnets, where utilization will be dependent on application type and costs. High temperature superconducting (HTS) ceramic materials provide magnets with liquid cryogen-free working environment, no need of oxygen sensors and exhaust ventilation system, reducing the magnet footprint compared to low temperature superconducting (LTS) magnets, reducing long-term maintenance costs, and enabling installation at smaller facilities. In this mini review, we describe the work successfully done with the prototype 400-MHz HTS cryogen-free spectrometer, installed in the fume hood of a chemistry laboratory, for structure elucidation, reaction monitoring, and computer-assisted 3D structure elucidation (CASE 3D). image