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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.


While biotechnology-based medicines are listed at the top shares in pharmaceutical market, the traditional low-molecular weight drugs are still very important for daily treatment, for example adult diseases. These low-molecular weight active pharmaceutical ingredients (APIs) can typically be crystallized in several different forms, i.e. crystalline polymorphs, depending on the crystallization conditions. Since the solubility and stability are largely affected by the crystalline form, it is very important to control and monitor the crystalline form in view point of quality control from development to production stages [1, 2, 3]. When the crystals with large enough size (~100 μm) is available, single crystal X-ray diffraction (SCXRD) gives distinct answer to crystalline forms with atomic resolution. However, most of the low-molecular weight drugs are provided in micro-crystalline forms with various formulation including tablets, pills, powders. As these formulations involve the excipient, it is crucial to determine crystalline form from micro-crystals in mixture. Powder X-ray diffraction (PXRD) and 13C cross-polarization magic angle spinning nuclear magnetic resonance (CPMAS NMR) are two major methods to identify the crystalline form. As the experimental patterns/spectra gives finger prints of each crystalline form, the comparison of patterns/spectra between drug and standard form gives, in most cases, clear answer to the crystalline from in it. However, both methods still have practical problems. PXRD sometimes fails to identify the crystalline form as many diffraction patters from API and excipient are overlapped to each other. On the other hand, 13C CPMAS which is sensitive to molecular conformation is suitable method for mixture analysis as most signals from excipient appear at the positions different from those from API, avoiding the overlapping of signals. However, 13C CPMAS is rather insensitive to molecular packing as carbon atoms are buried inside the molecules and located far from the molecular surface. Thus, the 13C CPMAS fails to identify the crystalline forms with similar molecular conformations. Moreover, the sensitivity to crystalline form is less than PXRD.

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