Analytical Instrument Documents

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.

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.

Applications concerning Polymers using the SpiralTOF.

Applications concerning Polymers, Materials & Chemistry using the SpiralTOF.

Applications for Life Science using the SpiralTOF.

Applications concerning MALDI MS Imaging using the SpiralTOF.

Various applications on the topics of Materials and Chemistry for the AccuTOF GC Series

Publication containing various applications pertaining to Environment, Food, Flavor, & Fragrance.

Notebook containing various articles and application notes pertaining to the AccuTOF DART.

The ROSY (Relaxation Ordered SpectroscopY) is a method in which the 13C CPMAS spectrum of a mixture is classified by a longitudinal relaxation time of 1H, and the 13C CPMAS spectrum is displayed separately for each substance. In solution NMR, each peak in the 1H spectrum has its own longitudinal relaxation time. In solid-state NMR, however, spin diffusion occurs due to the dipolor interaction between 1H, and all 1H have the same longitudinal relaxation in the domain within a certain distance. The 13C spectrum can be separated for each domain by using this difference in relaxation time of 1H. The longitudinal relaxation time (T1H) obtained by the saturation recovery method as shown in Fig.1a is usually used to separate the 13C spectrum of the mixture. The size of the domain that can be separated by this method is about 100 nm. To separate domains smaller than this, a measurement using the relaxation time at rotational flame (T1ρH) obtained by the spinlock method as shown in Fig.1b is effective. The domain size that can be separated by T1ρH is about several nm, and it is possible to determine the phase separation structure of block copolymers and the molecular compatibility.