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Experimental set-up of high-resolution 1H solid-state NMR by wPMLG_NM200010E

1H, in principle, is very useful nucleus to investigate atomic-resolution structures and dynamics due to its high abundance (>99%) and gyromagnetic ratio (600 MHz at 14.1T). In fact 1H is the first choice of nucleus in solution NMR. On the other hand, 1H NMR of rigid solids is much less common. This is because 1H solid-state NMR gives very broad (~50 kHz) and featureless spectra (Fig 1a) due to strong 1H-1H dipolar coupling, which is dynamically averaged out in solution. Magic angle spinning (MAS) removes the broadening to the first order, but is not enough to achieve high resolution 1H NMR at moderate MAS rate (Fig 1b). Tremendous efforts were made to overcome this issue from the early dates of solid-state NMR towards high-resolution 1H NMR [1]. Most of them combine MAS with sophisticated 1H pulses which is dubbed CRAMPS (combined rotation and multiple pulse spectroscopy). Nowadays very fast MAS > 60 kHz can be used to achieve high-resolution 1H solid-state NMR (Fig 1c) [2]. However, the traditional CRAMPS is still useful as that can be performed with very conventional solid-state NMR equipment, for example 4 mm MAS probe with a 400 MHz spectrometer. Moreover, wPMLG at moderate MAS rate often overwhelms fast MAS in terms of resolution. In this note, we will describe tutorial guidance to optimize experimental parameters for CRAMPS.

2D homonuclear correlation 1H solid-state NMR by wPMLG_NM200011E

Multidimensional correlation NMR spectroscopies, which provides inter-nuclear proximity/connectivity, play a crucial role to probe the atomic resolution structures. Especially, 1H-1H homonuclear correlation spectroscopy is quite useful source of information because of high abundance (>99%) and gyromagnetic ratio, thus resulting in strong inter nuclear interactions. Thanks to the development of high resolution 1H solid-state NMR, now it is feasible to observe 1H-1H correlation high resolution solid-state NMR [1]. There are two distinctive categories; 1) single quantum (SQ)/SQ correlation and 2) double quantum (DQ)/SQ correlations. In this note we introduce 2D 1H SQ/ 1H SQ and 1H DQ/ 1H SQ correlation spectroscopy to probe the internuclear proximity using high-resolution 1H solid-state NMR techniques.

A 1H Solid State NMR Application for Pharmaceutical Development by using Ultra Fast MAS: Drug-Polymer Intermolecular Interaction on Solid Dispersions_NM190003E

The low oral bioavailability of a drug due to its poor aqueous solubility is a major challenge for pharmaceutical development. Solid dispersion (SD), where the amorphous drug is dispersed into the polymer matrix, is one of the useful approaches to improve the aqueous solubility. However, thermodynamically unstable nature of an amorphous drug increases its susceptibility to recrystallize upon storage, which, in turn, reduces its solubility and dissolution. Therefore, design of thermodynamically stable SD is required.

Overtone solid-state NMR spectroscopy on Nitrogen-14_NM180002E

15N NMR is widely used because of the importance of nitrogen in chemistry, materials, biology, environment, etc. However, very low abundance of 15N (<0.4%) results in poor sensitivity and thus makes observation time-consuming. On the other hand, the rest of nitrogen atoms are also NMR sensitive nucleus of 14N. Despite the high abundance of 14N (>99%), it's application is rather limited due to the huge quadrupolar interactions and its spin quantum number I = 1.

X-ray, Electron and NMR Crystallography to Structural Determination of Small Organic Molecules

Here we present the recent development at RIKEN CLST-JEOL collaboration laboratory to explore the molecular structures of low-molecular weight pharmaceutical compounds in natural abundance (without any isotopic labeling); the recent progress in fast magic angle spinning (MAS) technology in solid-state nuclear magnetic resonance (ssNMR) and in ultra high sensitivity camera in transmission electron microscopy (TEM) paves a new way to answer problems in the pharmaceutical industry and sciences. 1) Crystalline polymorphs and 2) salt/cocrystal are two major concerns in terms of quality control, stability, and intellectual property. To identify the crystalline form, powder X-ray diffraction and 13C cross-polarization MAS ssNMR are widely used methods, however, the former is sometimes not suitable for mixture analysis and latter fails to distinguish crystalline forms with similar molecular conformations. To solve these issues, we use electron diffraction (ED) and 1H fast MAS NMR. The crystalline form can be determined from nano- to micro-meter sized single crystals using ED, since electron interactions are 4 to 5 order stronger than X-ray interactions. 1H NMR also gives suitable information to molecular packing since 1H is located at the surface of the crystals. The salt/cocrystal issue, where hydrogen plays a key role, is a serious problem, since single crystal X-ray diffraction (SCXRD) cannot determine the hydrogen atom position precisely. Here we determine the internuclear distances between 1H and 15N using ssNMR at fast MAS conditions, while the global structure is obtained through SCXRD, answering the salt/cocrystal questions.

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