In this work, a chemical (and physical) evaluation of cryogenic milling to manufacture amorphous solid dispersions (ASDs) is provided to support novel mechanistic insights in the cryomilling process. Cryogenic milling devices are considered as reactors in which both physical transitions (reduction in crystallite size, polymorphic transformations, accumulation of crystallite defects, and partial or complete amorphization) and chemical reactions (chemical decomposition, etc.) can be mechanically triggered. In-depth characterization of active pharmaceutical ingredient (API) (content determination) and polymer (viscosity, molecular weight, dynamic vapor sorption, Fourier transform infrared spectroscopy, dynamic light scattering, and ANS and thioflavin T staining) chemical decomposition demonstrated APIs to be more prone to chemical degradation in case of presence of a polymer. A significant reduction of the polymer chain length was observed and in case of BSA denaturation/aggregation. Hence, mechanochemical activation process(es) for amorphization and ASD manufacturing cannot be regarded as a mild technique, as generally put forward, and one needs to be aware of chemical degradation of both APIs and polymers.

中文翻译：

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通过低温研磨制备非晶态固体分散体：与活性药物成分和载体有关的化学和物理问题。

在这项工作中，提供了对低温研磨以制造无定形固体分散体（ASD）的化学（和物理）评估，以支持低温研磨过程中的新颖机械原理。低温铣削设备被视为反应器，可以机械地触发物理转变（晶粒尺寸减小，多晶型转变，晶粒缺陷积累以及部分或完全非晶化）和化学反应（化学分解等）。活性药物成分（API）和聚合物的深度表征（粘度，分子量，动态蒸气吸附，傅立叶变换红外光谱，动态光散射，以及ANS和thioflavin T染色）的化学分解表明，如果存在聚合物，API更易于化学降解。在BSA变性/聚集的情况下，观察到聚合物链长度的显着减少。因此，如通常所提出的，用于非晶化和ASD制造的机械化学活化过程不能被视为温和的技术，并且需要意识到API和聚合物的化学降解。