Several literature publications have described the potential application of active pharmaceutical ingredient (API)–polymer phase diagrams to identify appropriate temperature ranges for processing amorphous solid dispersion (ASD) formulations via the hot-melt extrusion (HME) technique. However, systematic investigations and reliable applications of the phase diagram as a risk assessment tool for HME are non-existent. Accordingly, within AbbVie, an HME risk classification system (HCS) based on API–polymer phase diagrams has been developed as a material-sparing tool for the early risk assessment of especially high melting temperature APIs, which are typically considered unsuitable for HME. The essence of the HCS is to provide an API risk categorization framework for the development of ASDs via the HME process. The proposed classification system is based on the recognition that the manufacture of crystal-free ASD using the HME process fundamentally depends on the ability of the melt temperature to reach the API’s thermodynamic solubility temperature or above. Furthermore, we explored the API–polymer phase diagram as a simple tool for process design space selection pertaining to API or polymer thermal degradation regions and glass transition temperature-related dissolution kinetics limitations. Application of the HCS was demonstrated via HME experiments with two high melting temperature APIs, sulfamerazine and telmisartan, with the polymers Copovidone and Soluplus. Analysis of the resulting ASDs in terms of the residual crystallinity and degradation showed excellent agreement with the preassigned HCS class. Within AbbVie, the HCS concept has been successfully applied to more than 60 different APIs over the last 8 years as a robust validated risk assessment and quality-by-design (QbD) tool for the development of HME ASDs.

中文翻译：

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用于非晶固体分散体配方开发的热熔挤出风险评估分类系统

一些文献出版物描述了活性药物成分 (API)-聚合物相图的潜在应用，以确定通过热熔挤出 (HME) 技术加工无定形固体分散体 (ASD) 制剂的适当温度范围。然而，不存在将相图作为 HME 风险评估工具的系统调查和可靠应用。因此，在 AbbVie 内部，基于 API-聚合物相图的 HME 风险分类系统 (HCS) 已被开发为一种材料节省工具，用于对通常被认为不适合 HME 的特别高熔点 API 进行早期风险评估。HCS 的本质是通过 HME 流程为 ASD 的开发提供 API 风险分类框架。所提出的分类系统基于这样一种认识，即使用 HME 工艺制造无晶体 ASD 从根本上取决于熔体温度达到 API 的热力学溶解度温度或更高的能力。此外，我们探索了 API-聚合物相图作为一种简单的工具，用于与 API 或聚合物热降解区域和玻璃化转变温度相关的溶解动力学限制相关的工艺设计空间选择。HME 的应用通过使用两种高熔点 API（磺胺美拉嗪和替米沙坦）以及聚合物 Copovidone 和 Soluplus 的 HME 实验得到证实。对所得 ASD 在残余结晶度和降解方面的分析表明与预先指定的 HCS 类别非常一致。在艾伯维，b D) 用于开发 HME ASD 的工具。