Abstract Amorphous solid dispersions (ASD) are state-of-the art enabling formulations for poorly water-soluble active pharmaceutical ingredients (APIs). Depending on the relative humidity (RH), temperature, and API content, ASDs are often metastable against crystallization of the API or even against the formation of API hydrates in the ASD. Knowing the conditions at which API crystals or API hydrate formation may occur in ASDs therefore is an important prerequisite for developing a suitable formulation strategy for APIs. ASDs containing hydrate-forming APIs (carbamazepine/polyvinylpyrrolidone, carbamazepine/hydroxypropylmethylcellulose acetate succinate, and theophylline/polyvinylpyrrolidone) were investigated in this work. The influence of polymer type, RH, API content, and water sorption on the ASD stability was determined via phase diagrams predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These predictions were successfully validated by long-term stability tests at 295 K and 0%, 58%, 76%, 86%, and 93% RH. Hydrate crystals are formed above their critical RH. Thus, ASDs with carbamazepine (critical RH 65% at 295 K) as well as theophylline (critical RH 58% RH) showed hydrate crystals at 76%, 86% and 93% RH, no matter which polymer was used for preparing the ASD.

中文翻译：

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聚合物基药物制剂中的水合物形成

摘要 无定形固体分散体 (ASD) 是最先进的用于难溶于水的活性药物成分 (API) 的制剂。根据相对湿度 (RH)、温度和 API 含量，ASD 通常对 API 结晶或什至对 ASD 中 API 水合物的形成具有亚稳态。因此，了解在 ASD 中可能发生 API 晶体或 API 水合物形成的条件是开发合适的 API 配方策略的重要先决条件。在这项工作中，研究了含有形成水合物的 API（卡马西平/聚乙烯吡咯烷酮、卡马西平/羟丙基甲基纤维素乙酸琥珀酸酯和茶碱/聚乙烯吡咯烷酮）的 ASD。聚合物类型、RH、API含量的影响，和水吸附对 ASD 稳定性的影响是通过使用扰动链统计关联流体理论 (PC-SAFT) 预测的相图确定的。这些预测已通过 295 K 和 0%、58%、76%、86% 和 93% RH 的长期稳定性测试成功验证。水合物晶体在其临界相对湿度以上形成。因此，无论使用哪种聚合物制备 ASD，含有卡马西平（295 K 下的临界 RH 65%）和茶碱（临界 RH 58% RH）的 ASD 在 76%、86% 和 93% RH 下都显示出水合物晶体。