Atomic-level structure of the amorphous drug atuliflapon NMR crystallography.

We determine the complete atomic-level structure of the amorphous form of the drug atuliflapon, a 5-lipooxygenase activating protein (FLAP) inhibitor, chemical-shift-driven NMR crystallography. The ensemble of preferred structures allows us to identify a number of specific conformations and interactions that stabilize the amorphous structure. These include preferred hydrogen-bonding motifs with water and with other drug molecules, as well as conformations of the cyclohexane and pyrazole rings that stabilize structure by indirectly allowing for optimization of hydrogen bonding.

Improvements in Resolution of ¹H NMR of solids.

Magic angle spinning (MAS) in 1H NMR has allowed progress from featureless spectra in static samples to linewidths of a few hundreds of Hertz for powdered solids at the fastest spinning rates available today (100-150 kHz). While this is a remarkable improvement, this level of resolution is still limiting to the widespread use of 1H NMR for complex systems. This review will discuss two recent alternative strategies that have significantly improved 1H resolution, when combined with fast MAS.

Barriers to resolution in H NMR of rotating solids.

The role of H solid-state NMR in structure elucidation of solids is becoming more preponderant, particularly as faster magic-angle spinning rates (MAS) become available which improve H detected assignment strategies. However, current H spectral resolution is still relatively poor, with linewidths of typically a few hundred Hz, even at the fastest rates available today. Here we detail and assess the factors limiting proton linewidths and line shapes in MAS experiments with five different samples, exemplifying the different sources of broadening that affect the residual linewidth.

Pure Isotropic Proton NMR Spectra in Solids using Deep Learning.

The resolution of proton solid-state NMR spectra is usually limited by broadening arising from dipolar interactions between spins. Magic-angle spinning alleviates this broadening by inducing coherent averaging. However, even the highest spinning rates experimentally accessible today are not able to completely remove dipolar interactions.

Bayesian probabilistic assignment of chemical shifts in organic solids.

A prerequisite for NMR studies of organic materials is assigning each experimental chemical shift to a set of geometrically equivalent nuclei. Obtaining the assignment experimentally can be challenging and typically requires time-consuming multidimensional correlation experiments. An alternative solution for determining the assignment involves statistical analysis of experimental chemical shift databases, but no such database exists for molecular solids.

Theory and simulations of homonuclear three-spin systems in rotating solids.

The homonuclear dipolar coupling is the internal spin interaction that contributes the most to the line shapes in magic-angle-spinning (MAS) H NMR spectra of solids, and linewidths typically extend over several hundred Hertz, limiting the H resolution. Understanding and reducing this contribution could provide rich structural information for organic solids. Here, we use average Hamiltonian theory to study two- and three-spin systems in the fast MAS regime.

Pure Isotropic Proton Solid State NMR.

Resolution in proton solid state magic angle sample spinning (MAS) NMR is limited by the intrinsically imperfect nature of coherent averaging induced by either MAS or multiple pulse sequence methods. Here, we suggest that instead of optimizing and perfecting a coherent averaging scheme, we could approach the problem by parametrically mapping the error terms due to imperfect averaging in a -space representation, in such a way that they can be removed in a multidimensional correlation leaving only the desired pure isotropic signal. We illustrate the approach here by determining pure isotropic H spectra from a series of MAS spectra acquired at different spinning rates.

Structure determination of an amorphous drug through large-scale NMR predictions.

Knowledge of the structure of amorphous solids can direct, for example, the optimization of pharmaceutical formulations, but atomic-level structure determination in amorphous molecular solids has so far not been possible. Solid-state nuclear magnetic resonance (NMR) is among the most popular methods to characterize amorphous materials, and molecular dynamics (MD) simulations can help describe the structure of disordered materials. However, directly relating MD to NMR experiments in molecular solids has been out of reach until now because of the large size of these simulations.

Machine Learning Classification of One-Chiral-Center Organic Molecules According to Optical Rotation.

In this study, machine learning algorithms were investigated for the classification of organic molecules with one carbon chiral center according to the sign of optical rotation. Diverse heterogeneous data sets comprising up to 13,080 compounds and their corresponding optical rotation were retrieved from Reaxys and processed independently for three solvents: dichloromethane, chloroform, and methanol. The molecular structures were represented by chiral descriptors based on the physicochemical and topological properties of ligands attached to the chiral center.

Fast remote correlation experiments for H homonuclear decoupling in solids.

In H MAS spectra, the residual homogeneous broadening under MAS is due to a combination of higher-order shifts and splittings. We have recently shown how the two-dimensional anti-z-COSY experiment can be used for the removal of the splittings. However, this requires spectra with high resolution in the indirect dimension (t), leading to experiment times of hours.

Homonuclear Decoupling in H NMR of Solids by Remote Correlation.

The typical linewidths of H NMR spectra of powdered organic solids at 111 kHz magic-angle spinning (MAS) are of the order of a few hundred Hz. While this is remarkable in comparison to the tens of kHz observed in spectra of static samples, it is still the key limit to the use of H in solid-state NMR, especially for complex systems. Here, we demonstrate a novel strategy to further improve the spectral resolution.