Benchtop NMR analysis of piperazine‐based drugs hyperpolarised by SABRE

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 D 2 O as a solvent and compared well to complimentary gas chromatography-mass spectrometry data. Exchanging D 2 O for CD 3 OD 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.

Recent Applications of Benchtop Nuclear Magnetic Resonance Spectroscopy

“…Solvent suppression based on gradient pulse sequence [97,107] Homo-decoupling method using different pure-shift methods [108] Addition of salts as chemical shift agents to peptide sample [109] Hyperpolarization methods (SABRE) [110][111][112][113][114] Figure 11 shows that spectral resolution can be increased using various pulse sequences and the homo-decoupling method, which is another technique commonly used in high-field NMR spectroscopy. Moreover, benchtop NMR spectrometers with gradient coils can be used to increase signal sensitivity through the programming of various pulse sequences [108].…”

“…In this study, improved resolution resulted in more accurate quantitative analysis, which allowed the researchers to better understand peptide reaction kinetics. Although they are not universally applicable to all samples, hyperpolarization methods can be used for the enhancement of low-field NMR signals [110][111][112][113][114]. Hyperpolarization generates a population distribution that is significantly larger than that dictated by the Boltzmann distribution at thermal equilibrium.…”

“…Among the hyperpolarization methods such as dynamic nuclear polarization, spin-exchange optical pumping, and parahydrogen-induced polarization (PHIP), PHIP is the one most commonly used to enhance the sensitivity of benchtop NMR spectroscopy. In particular, the reversible exchange (SABRE) method, a non-hydrogenation PHIP technique, has been exclusively used, as it does not Although they are not universally applicable to all samples, hyperpolarization methods can be used for the enhancement of low-field NMR signals [110][111][112][113][114]. Hyperpolarization generates a population distribution that is significantly larger than that dictated by the Boltzmann distribution at thermal equilibrium.…”

Benchtop nuclear magnetic resonance spectroscopy in forensic chemistry

“…The potential of benchtop NMR for uncovering drug falsification was demonstrated by Assemat et al [12] in their analysis of the most common falsified medicines: erectile dysfunction and anti-malarial medicines. Fifteen seized falsified erectile dysfunction samples and nine [48] Abbreviations: ANPP, 4-anilino-N-phenethylpiperidine; CBD, cannabidiol; COSY, correlation spectroscopy; HMBC, heteronuclear multiple bond correlation; HSQC, heteronuclear single quantum coherence; NMR, nuclear magnetic resonance; NPP, N-phenethyl-4-piperidinone; THC, Δ 9 -tetrahydrocannabinol; TOCSY, total correlation spectroscopy.…”

Organic Reaction Monitoring of a Glycine Derivative Using Signal Amplification by Reversible Exchange-Hyperpolarized Benchtop Nuclear Magnetic Resonance Spectroscopy

“…PHIP using benchtop NMR is a PHIP-based experiment using benchtop NMR that monitors changes in the hydrogenation process of a small amount of material. , However, the disadvantage is that the material cannot be reused, because the hydrogenated material does not return to the starting material (e.g., unsaturated carbon). To overcome the shortcoming of this technology, the suggested method is benchtop NMR using SABRE. − SABRE delivers para -hydrogen’s spin order to the material, but the structure of the material does not change, so it can be used in the next reaction. Some significant studies on reaction monitoring using SABRE and benchtop NMR have been reported .…”