Formulation processing of organic crystalline compounds can have a significant effect on drug properties, such as dissolution rate or tablet strength/hardness. Transmission electron microscopy has the potential to resolve the atomic lattice of these crystalline compounds and, for example, identify the defect density on a particular crystal face, provided the sensitivity of these crystals to irradiation by high energy electrons can be overcome. Here, we acquire high-resolution (HR) lattice images of the compound furosemide using two different methods: low-dose HRTEM and bright-field (BF) STEM scanning moiré fringes (SMFs). Before acquiring HRTEM images of furosemide, a model system of crocidolite (asbestos) was used to determine the electron flux/fluence limits of low-dose HR imaging for our scintillator based, CMOS electron camera by testing a variety of electron flux and total electron fluence regimes. An electron flux of 10 e- /(Å2 s) and total fluence of 10 e- /Å2 was shown to provide sufficient contrast and SNR to resolve 0.30 nm lattice spacings in crocidolite at 300 kV. These parameters were then used to image furosemide which has a critical electron fluence for damage of ≥ 10 e- /Å2 at 300 kV. The resulting HRTEM image of a furosemide crystal shows only a small portion of the total crystal exhibiting lattice fringes, likely due to irradiation damage during acquisition close to the compound's critical fluence. BF-STEM SMF images of furosemide were acquired at a lower electron fluence (1.8 e- /Å2 ), while still indirectly resolving high resolution details of the (001) lattice. Several different SMFs were observed with minor variations in the size and angle, suggesting strain due to defects within the crystal. Overall BF-STEM SMFs appear to be more useful than BF-STEM or HRTEM (with a CMOS camera) for imaging the crystal lattice of very beam sensitive materials since a lower electron fluence is required to reveal the lattice. BF-STEM SMFs may thus prove useful in improving the understanding of crystallization pathways in organic compounds, degradation in pharmaceutical formulations and the effect of defects on the dissolution rate of different crystal faces. Further work is however required to quantitatively determine properties such as the defect density or the amount of relative strain from a BF-STEM SMF image. This article is protected by copyright. All rights reserved.

中文翻译：

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通过透射电子显微镜和扫描莫尔条纹对有机药物晶体进行高分辨率成像


有机结晶化合物的制剂加工会对药物特性产生显着影响，例如溶出速率或片剂强度/硬度。透射电子显微镜有可能解析这些晶体化合物的原子晶格，例如，只要可以克服这些晶体对高能电子辐射的敏感性，就可以识别特定晶面上的缺陷密度。在这里，我们使用两种不同的方法获取化合物呋塞米的高分辨率 (HR) 晶格图像：低剂量 HRTEM 和明场 (BF) STEM 扫描莫尔条纹 (SMF)。在获取呋塞米的 HRTEM 图像之前，使用青石棉（石棉）模型系统通过测试各种电子通量和总电子注量来确定我们基于闪烁体的 CMOS 电子相机的低剂量 HR 成像的电子通量/注量限制政权。 10 e- /(Å2 s) 的电子通量和 10 e- /Å2 的总注量可提供足够的对比度和信噪比，以在 300 kV 下解析青石棉中 0.30 nm 的晶格间距。然后使用这些参数对呋塞米进行成像，呋塞米在 300 kV 下的损伤临界电子注量为 ≥ 10 e- /Å2。所得的呋塞米晶体的 HRTEM 图像仅显示整个晶体的一小部分表现出晶格条纹，这可能是由于在接近化合物临界注量的采集过程中的辐射损伤造成的。呋塞米的 BF-STEM SMF 图像是在较低的电子注量 (1.8 e- /Å2 ) 下获得的，同时仍然间接解析 (001) 晶格的高分辨率细节。观察到几种不同的 SMF，尺寸和角度略有变化，表明由于晶体内的缺陷而产生应变。 总体而言，对于对光束非常敏感的材料的晶格进行成像，BF-STEM SMF 似乎比 BF-STEM 或 HRTEM（使用 CMOS 相机）更有用，因为显示晶格所需的电子注量较低。因此，BF-STEM SMF 可能有助于增进对有机化合物结晶途径、药物制剂降解以及缺陷对不同晶面溶解速率的影响的理解。然而，需要进一步的工作来定量确定 BF-STEM SMF 图像的缺陷密度或相对应变量等特性。本文受版权保护。版权所有。