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Selective detection of active pharmaceutical ingredients in tablet formulations using solid-state NMR spectroscopy

Highlights: • Selective detection of 1H signals of API in a tablet formulation is proposed. • 1H signals of excipients are suppressed. • 1H signals in the vicinity of nuclei (here 14N) which only appear in API are excited. • 1H{14N} magnetization is diffused to 1Hs in API crystals by RFDR recoupling.

Dynamic Transformation Between Covalent Organic Frameworks And Discrete Organic Cages

We propose a dynamic covalent chemistry (DCC)-induced linker exchange strategy for the structural transformation between covalent organic frameworks (COFs) and cages for the first time. Studies have shown that the COF-to-cage and cage-to-COF transformations were realized by using borate bonds and imine bonds, respectively, as linkages. Self-sorting experiments suggested that borate cages and imine COFs are thermodynamic minimum compounds. This research builds a bridge between discrete and polymeric organic scaffolds and broadens the knowledge of chemistry and materials for porous materials science.

Azoxystrobin amine: A novel azoxystrobin degradation product from Bacillus licheniformis strain TAB7

Azoxystrobin (AZ) is a broad-spectrum synthetic fungicide widely used in agriculture globally. However, there are concerns about its fate and effects in the environment. It is reportedly transformed into azoxystrobin acid as a major metabolite by environmental microorganisms. Bacillus licheniformis strain TAB7 is used as a compost deodorant in commercial compost and has been found to degrade some phenolic and agrochemicals compounds. In this article, we report its ability to degrade azoxystrobin by novel degradation pathway. Biotransformation analysis followed by identification by electrospray ionization-mass spectrometry (MS), high-resolution MS, and nuclear magnetic resonance spectroscopy identified methyl (E)-3-amino-2-(2-((6-(2-cyanophenoxy)pyrimidin-4-yl)oxy)phenyl)acrylate, or (E)-azoxystrobin amine in short, and (Z) isomers of AZ and azoxystrobin amine as the metabolites of (E)-AZ by TAB7. Bioassay testing using Magnaporthe oryzae showed that although 40 μg/mL of (E)-AZ inhibited 59.5 ± 3.5% of the electron transfer activity between mitochondrial Complexes I and III in M. oryzae, the same concentration of (E)-azoxystrobin amine inhibited only 36.7 ± 15.1% of the activity, and a concentration of 80 μg/mL was needed for an inhibition rate of 56.8 ± 7.4%, suggesting that (E)-azoxystrobin amine is less toxic than the parent compound. To our knowledge, this is the first study identifying azoxystrobin amine as a less-toxic metabolite from bacterial AZ degradation and reporting on the enzymatic isomerization of (E)-AZ to (Z)-AZ, to some extent, by TAB7. Although the fate of AZ in the soil microcosm supplemented with TAB7 will be needed, our findings broaden our knowledge of possible AZ biotransformation products.

Understanding hydrogen-bonding structures of molecular crystals via electron and NMR nanocrystallography

Understanding hydrogen-bonding networks in nanocrystals and microcrystals that are too small for X-ray diffractometry is a challenge. Although electron diffraction (ED) or electron 3D crystallography are applicable to determining the structures of such nanocrystals owing to their strong scattering power, these techniques still lead to ambiguities in the hydrogen atom positions and misassignments of atoms with similar atomic numbers such as carbon, nitrogen, and oxygen. Here, we propose a technique combining ED, solid-state NMR (SSNMR), and first-principles quantum calculations to overcome these limitations. The rotational ED method is first used to determine the positions of the non-hydrogen atoms, and SSNMR is then applied to ascertain the hydrogen atom positions and assign the carbon, nitrogen, and oxygen atoms via the NMR signals for 1H, 13C, 14N, and 15N with the aid of quantum computations. This approach elucidates the hydrogen-bonding networks in L-histidine and cimetidine form B whose structure was previously unknown.

Selective detection of active pharmaceutical ingredients in tablet formulations using solid-state NMR spectroscopy

Atomic-level characterization of active pharmaceutical ingredients (API) is crucial in pharmaceutical industry because APIs play an important role in physicochemical properties of drug formulations. However, the analysis of targeted APIs in intact tablet formulations is less straightforward due to the coexistence of excipients as major components and different APIs at dilute concentrations (often below 10 ​wt% loading). Although solid-state (ss) NMR spectroscopy is widely used to investigate short-range order, polymorphism, and pseudo-polymorphism in neat pharmaceutical compounds, the analysis of complex drug formulations is often limited by overlapped signals that originate from structurally different APIs and excipients. In particular, such examples are frequently encountered in the analysis of 1H ssNMR spectra of pharmaceutical formulations. While the high-resolution in 1H ssNMR spectra can be attained by, for example, high magnetic fields accompanied by fast magic-angle spinning (MAS) approaches, the spectral complexity associated with the mixtures of compounds hinders the accurate determination of chemical shifts and through-space proximities. Here we propose a fast MAS (70 ​kHz) NMR experiment for the selective detection of 1H signals associated with an API from a severely overlapped NMR spectrum of a tablet formulation. Spectral simplification is achieved by combining (i) symmetry-based dipolar recoupling (SR412) rotational-echo saturation-pulse double-resonance (RESPDOR) with phase-modulate (PM) saturation pulses, (ii) radio frequency-driven recoupling (RFDR), and (iii) double-quantum excitation using Back-to-Back (BaBa) pulse sequence elements. First, 1H sites in close proximities to 14N nuclei of an API are excited using a PM-S-RESPDOR sequence, and simultaneously, the other unwanted 1H signals of excipients are suppressed. Then, 1H magnetization transfer to adjacent 1H sites in the API is achieved by spin diffusion process using a RFDR sequence, which polarizes to 1H sites within the crystalline API regions of the drug formulation. Next, a PM-S-RESPDOR-RFDR sequence is combined with a Back-to-Back (BaBa) sequence to elucidate local-structures and 1H–1H proximities of the API in a dosage form. The PM-S-RESPDOR-RFDR-BaBa experiment is employed in one- (1D) and two-dimensional (2D) versions to selectively detect the 1H ssNMR spectrum of l-cysteine (10.6 ​wt% or 0.11 ​mg) in a commercial formulation, and compared with the spectra of neat l-cysteine recorded using a standard BaBa experiment. The 2D 1H double-quantum−single-quantum (DQ-SQ) spectrum of the API (l-cysteine)-detected pharmaceutical tablet is in good agreement with the 2D 1H DQ-SQ spectrum obtained from the pure API molecule. Furthermore, the sensitivity and robustness of the experiment is examined by selectively detecting 1H{14N} signals in an amino acid salt, l-histidine.H2O.HCl.

Development of 19F‐detected 1,1‐ADEQUATE for the characterization of polyfluorinated and perfluorinated compounds

Polyfluorinated and perfluorinated compounds in the environment are a growing health concern. 19F‐detected variants of commonly employed heteronuclear shift correlation experiments such as heteronuclear single quantum correlation (HSQC) and heteronuclear multiple bond correlation (HMBC) are available; 19F‐detected experiments that employ carbon–carbon homonuclear coupling, in contrast, have never been reported. Herein, we report the measurement of the 1JCC and nJCC coupling constants of a simple perfluorinated phthalonitrile and the first demonstration of a 19F‐detected 1,1‐ADEQUATE experiment.

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