During drug development control of polymorphism, particle properties and impurities are critical for ensuring a good quality, reproducible, and safe medicine. A wide variety of analytical techniques are employed in demonstrating the regulators control over the drug substance and product manufacturing, storage, and supply. Transmission electron microscopy (TEM) offers the opportunity to analyze in detail pharmaceutical systems at a length scale and limit of detection not readily achieved by many traditional techniques. However, the use of TEM as a characterization tool for drug development is uncommon due to possible damage caused by the electron beam. This work outlines the development of a model, using molecular descriptors, to predict the electron beam stability of active pharmaceutical ingredients (API). For a given set of conditions and a particular imaging or analytical mode, the total number of electrons per unit area, which causes observable damage to a sample in the TEM, can be defined as the critical fluence (C_F). Here the C_F of 20 poorly water-soluble APIs were measured using selected area electron diffraction. Principal component analysis was used to select the most influential molecular descriptors on C_F, which were shown to be descriptors involving the degree of conjugation, the number of hydrogen bond donors and acceptors, and the number of rotatable bonds. These were used to generate several multiple linear regression models. The model that provided the best fit to the measured C_F data included the ratio of the number of conjugated carbons to nonconjugated carbons, the ratio of the number of hydrogen bond donors to acceptors, and the ratio of the number of hydrogen bond acceptors to donors. Using this model, the C_F of the majority of the compounds was predicted within ±2 e^–/Ų. Molecules with no hydrogen bond acceptors did not fit the model accurately possibly due to the limited sample size or the influence of other parameters not included in this model, such as intermolecular bond energies. The model presented can be used to support pharmaceutical development by quickly assessing the stability of other poorly soluble drugs in TEM. Provided that the model suggests that the API is relatively stable to electron irradiation, TEM offers the prospect of determining the presence of crystalline material at low levels at length scales and limits of detection unobtainable by other techniques. This is particularly so for amorphous solid dispersions.

中文翻译：

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致力于开发一种预测方法，以评估药物分子在透射电子显微镜下的电子束不稳定性

在药物开发过程中，控制多态性，颗粒性质和杂质对于确保高质量，可重现和安全的药物至关重要。在证明监管机构对原料药和产品的生产，储存和供应进行控制时，采用了多种分析技术。透射电子显微镜（TEM）提供了机会，可以对许多传统技术难以轻易达到的长度范围和检测极限进行详细的制药系统分析。但是，由于电子束可能造成损坏，因此将TEM用作药物开发的表征工具并不常见。这项工作概述了使用分子描述符来预测活性药物成分（API）的电子束稳定性的模型的开发。C _F）。在这里，使用选定的区域电子衍射测量了20种水溶性差的API的C _F。主成分分析用于选择C _F上最具影响力的分子描述子，这些描述子涉及共轭程度，氢键供体和受体的数量以及可旋转键的数量。这些被用来生成多个多元线性回归模型。提供最适合所测C _F的模型数据包括共轭碳与非共轭碳的比例，氢键供体与受体的比例以及氢键受体与供体的比例。使用该模型，该Ç _˚F大多数化合物的混合物±2e的内预测^- / A ²。没有有限氢键受体的分子可能无法准确拟合模型，这可能是由于样本量有限或该模型中未包含的其他参数（例如分子间键能）的影响所致。提出的模型可用于通过快速评估TEM中其他难溶性药物的稳定性来支持药物开发。如果该模型表明API对电子辐照相对稳定，则TEM可以确定在低水平下以低水平存在晶体物质的存在以及其他技术无法获得的检测极限。对于无定形固体分散体尤其如此。