Benchtop NMR analysis of piperazine-based drugs hyperpolarised by SABRE

Tennant, Thomas, Hulme, Matthew, Robertson, Thomas, Sutcliffe, Oliver and Mewis, Ryan (2020) Benchtop NMR analysis of piperazine-based drugs hyperpolarised by SABRE. Magnetic Resonance in Chemistry, 58 (12), 1151-1159. (doi:10.1002/mrc.4999).

Abstract

Piperazine‐based drugs, such as N‐benzylpiperazine (BZP), became attractive in the 2000s due to possessing effects similar to amphetamines. Herein, BZP, in addition to its pyridyl analogues, 2‐, 3‐, and 4‐pyridylmethylpiperazine (2‐PMP, 3‐PMP, and 4‐PMP respectively) was subjected to the hyperpolarisation technique Signal Amplification By Reversible Exchange (SABRE) in order to demonstrate the use of this technique to detect these piperazine‐based drugs. Although BZP was not hyperpolarised via SABRE, 2‐PMP, 3‐PMP, and 4‐PMP were, with the ortho‐ and meta‐pyridyl protons of 4‐PMP showing the largest enhancement of 313‐fold and 267‐fold, respectively, in a 1.4‐T detection field, following polarisation transfer at Earth's magnetic field. In addition to the freebase, 4‐PMP.3HCl was also appraised by SABRE and was found not to polarise, however, the addition of increasing equivalents of triethylamine (TEA) produced the freebase, with a maximum enhancement observed upon the addition of 3 equivalents of TEA. Further addition of TEA led to a reduction in the observed enhancement. SABRE was also employed to polarise 4‐PMP.3HCl (~20% w/w) in a simulated tablet to demonstrate the forensic application of the technique (138‐fold enhancement for the ortho‐pyridyl protons). The amount of 4‐PMP.3HCl present in the simulated tablet was quantified via NMR using D2O as a solvent and compared well to complimentary gas chromatography–mass spectrometry data. Exchanging D2O for CD3OD as the solvent utilised for analysis resulted in a significantly lower amount of 4‐PMP.3HCl being determined, thus highlighting safeguarding issues linked to drug abuse in relation to determining the amount of active pharmaceutical ingredient present.

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Contributors

Author: Thomas Robertson

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