Seventh Street Development Group, Kure Beach, North Carolina 28449, United States.
School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
Mol Pharm. 2022 Feb 7;19(2):378-391. doi: 10.1021/acs.molpharmaceut.1c00519. Epub 2021 Aug 11.
In this Perspective, the authors examine the various factors that should be considered when attempting to use miscible amorphous API-excipient mixtures (amorphous solid dispersions and coamorphous systems) to prevent the solid-state crystallization of API molecules when isothermally stored for long periods of time (a year or more) . After presenting an overview of a variety of studies designed to obtain a better understanding of possible mechanisms by which amorphous API undergo physical instability and by which excipients generally appear to inhibit API crystallization from the amorphous state, we examined 78 studies that reported acceptable physical stability of such systems, stored below under "dry" conditions for one year or more. These results were examined more closely in terms of two major contributing factors: the degree to which a reduction in diffusional molecular mobility and API-excipient molecular interactions operates to inhibit crystallization. These two parameters were chosen because the data are readily available in early development to help compare amorphous systems. Since - = 50 K is often used as a rule of thumb for the establishing the minimum value below required to reduce diffusional mobility to a period of years, it was interesting to observe that 30 of the 78 studies still produced significant physical stability at values of - < 50 K (3-47 °C), suggesting that factors besides diffusive molecular mobility likely contribute. A closer look at the - < 50 systems shows that hydrogen bonding, proton transfer, disruption of API-API self-associations (such as dimers), and possible π-π stacking were reported for most of the systems. In contrast, five crystallized systems that were monitored for a year or more were also examined. These systems exhibited - values of 9-79, with three of them exhibiting - < 50. For these three samples, none displayed molecular interactions by infrared spectroscopy. A discussion on the impact of relative humidity on long-term crystallization in the glass was included, with attention paid to the relative water vapor sorption by various excipients and effects on diffusive mobility and molecular interactions between API and excipient.
在这篇观点文章中，作者研究了在试图使用可混溶性无定形 API-赋形剂混合物（无定形固体分散体和共无定形系统）来防止 API 分子在等温储存很长时间（一年或更长时间）时发生固态结晶时应考虑的各种因素。在介绍了各种旨在更好地了解无定形 API 经历物理不稳定性的可能机制以及赋形剂通常似乎抑制 API 从无定形状态结晶的机制的研究概述之后，作者检查了 78 项研究，这些研究报告了此类系统在“干燥”条件下储存一年或更长时间低于以下温度时的可接受物理稳定性。根据两个主要贡献因素更仔细地检查了这些结果：降低扩散分子迁移率和 API-赋形剂分子相互作用的程度以抑制结晶。选择这两个参数是因为在早期开发中，数据很容易获得，以帮助比较无定形系统。由于 - = 50 K 通常被用作将扩散迁移率降低到数年的最小值的经验法则，因此观察到 78 项研究中有 30 项仍在 - < 50 K（3-47°C）的值下产生显著的物理稳定性是很有趣的，这表明除了扩散分子迁移率之外，可能还有其他因素起作用。仔细研究 - < 50 系统表明，对于大多数系统，报告了氢键、质子转移、破坏 API-API 自组装（如二聚体）以及可能的 π-π 堆积。相比之下，还检查了五个监测了一年或更长时间的结晶系统。这些系统的 - 值为 9-79，其中三个系统的 - < 50。对于这三个样品，通过红外光谱均未显示分子相互作用。还讨论了相对湿度对玻璃中长期结晶的影响，注意了各种赋形剂的相对水蒸气吸附以及对扩散迁移率和 API 与赋形剂之间分子相互作用的影响。
