A Versatile Compact Parahydrogen Membrane Reactor

Abstract

We introduce a Spin Transfer Automated Reactor (STAR) that produces continuous parahydrogen induced polarization (PHIP), which is stable for hours to days. We use the PHIP variant called signal amplification by reversible exchange (SABRE), which is particularly well suited to produce continuous hyperpolarization. The STAR is operated in conjunction with benchtop (1.1 T) and high field (9.4 T) NMR magnets, highlighting the versatility of this system to operate with any NMR or MRI system. The STAR uses semipermeable membranes to efficiently deliver parahydrogen into solutions at nano to milli Tesla fields, which enables ¹ H, ¹³ C, and ¹⁵ N hyperpolarization on a large range of substrates including drugs and metabolites. The unique features of the STAR are leveraged for important applications, including continuous hyperpolarization of metabolites, desirable for examining steady-state metabolism in vivo, as well as for continuous RASER signals suitable for the investigation of new physics.

Keywords: NMR; RASER; fluidics; hyperpolarization; parahydrogen.

Figure 1.

Schematic of SABRE in a cross-section of the Spin Transfer Automated Reactor (STAR). Para and Ortho hydrogen exchange across the membrane occurs between the outer gas annulus and inner liquid annulus. Of the SABRE complex, only equatorial ligands are, where X=IMes (1,3 - bis(2,4,6 - trimethylphenyl) imidazole-2-ylidene) and Y=pyridine in the axial plane. The J-couplings represent the necessary scalar couplings for spin transfer from the para-hydrides to the target substrate.

Figure 2.

Mode of operation of STAR, where a solution is injected into the fluid path and subsequently pumped in a closed loop, cycling through the pump, tube-in-tube reactors, benchtop NMR and system reservoir. In one standard configuration, the p-H₂ pressure is 100 psi and the N₂ pressure is 90 psi.

Figure 3.

Continuous STAR-SABRE polarization observed for both (a) pyridine and (b) pyrazine; sample composition for both spectra shown is 60 mM substrate + 3 mM IMes catalyst. Data is acquired in flow at 2 mL/min with p-H₂ pressure of 90 psi at 100 sccm. B_pol=6.5 mT.

Figure 4.

¹⁵N hyperpolarization using SABRE-SHEATH in the STAR system. HP [¹⁵N₃] metronidazole spectrum with the STAR system at 2.0 mL/min, 100 psi p-H₂ at 250 sccm. Light red overlay is the spectrum achieved with a standard bubbling mode. Sample composition for both spectra is 60 mM Mnz + 3 mM IMes catalyst. Table inset: Calculated polarization levels for each corresponding ¹⁵N nuclei in metronidazole, based on [¹⁵N] pyridine reference spectra (SI section 6).

Figure 5.

¹³C hyperpolarization using SABRE-SHEATH in the STAR system, detected at 1.1 T in a Magritek benchtop Spinsolve. Hyperpolarized [¹³C₂]-pyruvate spectrum with the STAR system at 2 mL/min. Light blue overlay is the spectrum achieved with a standard bubbling mode. Sample composition for both spectra is 24 mM [¹³C₂]-pyruvate + 30 mM DMSO + 3 mM IMes catalyst. Table inset: Calculated polarization levels for each corresponding ¹³C nuclei in pyruvate, based on benzene the reference spectra (SI section 6).

Figure 6.

RASER physics and corresponding results acquired with the STAR system. (a) Mode of operation of a RASER, where a continuously pumped polarized population inversion is coupled to photons in an NMR LC circuit. (b) Buildup of RASER effects observed where a RASER threshold is observed at ~0.5% polarization as the pressure is ramped from 0 to 90 psi. The FIDs shown inset are shown for an acquisition time of 3 s after a 90° initialization pulse, with the magnitude of each FID scaled for visualization of the relative time buildup of the RASER burst.

Figure 7.

Continuous RASER signal acquired with the STAR system at both 1.1 T and 9.4 T. In both cases the sample composition is 60 mM pyrazine + 3 mM IMes in CD₃OD. (a-c) 1.1 T pyrazine RASER (a) Continuous detection of a RASER from pyrazine protons with a total acquisition time of 157.3 s and a dwell time of 1200 μs. (b) Zoom of a single region of the pyrazine RASER time domain. (c) Calibration of the magnetic field drift using a quadratic fit and (d) corresponding drift-corrected Fourier transform of the full 157.2 s observed RASER, yielding the theoretically lowest possible FWHM of 7.7 mHz. (e-f) 9.4 T pyrazine RASER (e) Continuous detection of a RASER action with a total acquisition time of 1000 s, with an inset zoom of 100 s of the RASER time domain. (f) Corresponding FFT of the pyrazine RASER showing a frequency comb with a spacing of 0.42 Hz with chaotic substructure.