Protons represent the most NMR-sensitive nucleus in pharmaceutical compounds. Therefore, proton-detected solid-state NMR techniques under fast magic angle spinning are among the few solutions to overcome the challenge of low sensitivity to analyze natural abundant drug substances and products. In this study, we report the structural characterization of crystal polymorphs of a commercial drug molecule, posaconazole, with a relatively large molecular weight of 700.8 g·mol-1 and at the natural abundance. The enhanced sensitivity and resolution at 100 kHz MAS enables the exploration of the distinct intermolecular packing in posaconazole forms I, III, and γ. These results demonstrate that proton-detected homo- and heteronuclear correlation methods can probe the structural details of pharmaceutical polymorphism.

In solid dosage formulations, probing intermolecular interactions between active pharmaceutical ingredients (APIs) and polymeric excipients, which have a mechanistic impact on physical stability as well as bioavailability, remains a challenge. In recent years, solid-state NMR spectroscopy has been demonstrated to be a powerful tool to provide structural details with an atomic resolution of therapeutic organic compounds and formulation products. However, conventional 13C-detected techniques often suffer from poor resolution and low sensitivity due to the disordered structure of certain materials such as amorphous pharmaceuticals and 13C natural abundance, hindering in-depth investigations. In this study, we utilize the magic angle spinning (MAS) technique with ultrafast speeds (UF-MAS: νR = 60 and 110 kHz) and demonstrate the enabled methods with 1H detection to study the amorphous molecular complex of rafoxanide and povidone in the solid state. The downfield shift of the RAF amide proton, resolved under UF-MAS, and its correlations with aliphatic protons of PVP, serve as strong evidence of the existence of intermolecular hydrogen bonding. Two-dimensional (2D) 1H-detected 1H{13C} and 1H-1H correlation experiments, interestingly, exhibit distinct API-polymer interactions in the spray-dried amorphous solid dispersions (ASDs), utilizing aqueous and organic cosolvents and organic solvents mixtures. The rich intermolecular interactions in the aqueously prepared ASDs presumably contribute to the physical stability, and the interactions are retained in the solution state to maintain supersaturation for an enhanced dissolution profile. This study presents the first application of UF-MAS NMR characterization of therapeutic solid dosages at a spinning frequency of 110 kHz and uncovers the molecular mechanisms of solvent-mediated pharmaceutical dispersions.

Magic angle spinning (MAS) NMR is a powerful method for the study of pharmaceutical compounds, and probes with spinning frequencies above 100 kHz enable an atomic-resolution analysis of sub-micromole quantities of fully protonated solids. Here, we present an ultrafast NMR crystallography approach for structural characterization of organic solids at MAS frequencies of 100-111 kHz. We assess the efficiency of 1H-detected experiments in the solid state and demonstrate the utility of 2D and 3D homo- and heteronuclear correlation spectra for resonance assignments. These experiments are demonstrated for an amino acid, U-13C,15N-histidine, and also for the significantly larger, natural product Posaconazole, an antifungal compound investigated at natural abundance. Our results illustrate the power for characterizing organic molecules, enabled by exploiting the increased 1H resolution and sensitivity at MAS frequencies above 100 kHz.

A new (19)F anisotropic-isotropic shift correlation experiment is described that operates with ultrafast MAS, resulting in good resolution of isotropic (19)F shifts in the detection dimension. The new experiment makes use of a recoupling sequence designed using symmetry principles that reintroduces the (19)F chemical shift anisotropy in the indirect dimension. The situations in which the new experiment is appropriate are discussed, and the (19)F shift anisotropy parameters in poly(difluoroethylene) (PVDF) are measured. In addition, similar recoupling sequences are shown to be effective for measuring (1)H-(19)F distances via the heteronuclear dipolar interaction. This is demonstrated by application to a recently synthesized zirconium phosphonate material that contains one-dimensional chains linked by H-F hydrogen bonds.

There is considerable interest in the measurement of proton ((1)H) chemical shift anisotropy (CSA) tensors to obtain deeper insights into H-bonding interactions which find numerous applications in chemical and biological systems. However, the presence of strong (1)H/(1)H dipolar interaction makes it difficult to determine small size (1)H CSAs from the homogeneously broadened NMR spectra. Previously reported pulse sequences for (1)H CSA recoupling are prone to the effects of radio frequency field (B1) inhomogeneity. In the present work we have carried out a systematic study using both numerical and experimental approaches to evaluate γ-encoded radio frequency (RF) pulse sequences based on R-symmetries that recouple (1)H CSA in the indirect dimension of a 2D (1)H/(1)H anisotropic/isotropic chemical shift correlation experiment under ultrafast magic angle spinning (MAS) frequencies. The spectral resolution and sensitivity can be significantly improved in both frequency dimensions of the 2D (1)H/(1)H correlation spectrum without decoupling (1)H/(1)H dipolar couplings but by using ultrafast MAS rates up to 70 kHz. We successfully demonstrate that with a reasonable RF field requirement (<200 kHz) a set of symmetry-based recoupling sequences, with a series of phase-alternating 270°0-90°180 composite-180° pulses, are more robust in combating B1 inhomogeneity effects. In addition, our results show that the new pulse sequences render remarkable (1)H CSA recoupling efficiency and undistorted CSA lineshapes. Experimental results on citric acid and malonic acid comparing the efficiencies of these newly developed pulse sequences with that of previously reported CSA recoupling pulse sequences are also reported under ultrafast MAS conditions.

A new proton anisotropic-isotropic shift correlation experiment is described which operates with ultrafast MAS, resulting in good resolution of isotropic proton shifts in the detection dimension. The new experiment makes use of a recoupling sequence designed using symmetry principles which reintroduces the proton chemical shift anisotropy in the indirect dimension. The experiment has been used to measure the proton shift tensor parameters for the OH hydrogen-bonded protons in tyrosine·HCl and citric acid at Larmor frequencies of up to 850 MHz.