This work develops a mechanistic understanding and a simplified model to understand changes in drug release profiles of an active pharmaceutical ingredient in a long-acting parenteral polymer formulation from changes in its microstructure determined using X-ray computed tomography (XRCT) imaging. The system studied is an implant composed of a solid dispersion of crystalline drug microdomains embedded in a polymer matrix and fabricated by hot melt extrusion. We conduct material characterization of these devises using microCT and introduce, for the first time, imaging of such pharmaceutical devices by means of nanoCT, showing finer structures that cannot be captured by ordinary CT methods. We propose a simplified theoretical mechanistic model that estimates the drug release by extracting relevant microscopic features that modulate the release rate from microCT images to construct an idealized geometry. Using this analysis, we found that although the primary mechanism of resistance was originating from submicrometer features, which are below the resolution of the microCT, the main features that determine changes in diffusivity as a result of different process conditions were microscale pore volume and pore connectivity distributions. The parameters were extracted from the microCT images and in conjunction with the theory were able to explain changes in experimental drug release under different process conditions. These results demonstrate that the modeling strategy can explain the dominant release mechanism and estimate drug release of formulations, even when the equations are simplified due to many assumptions and a lack of subscale information. The proposed approach, due to its simplicity and reliance on the widely employed microCT technique, holds promise for guiding formulation development by providing a rapid initial assessment of batch consistency and process parameter selection before embarking upon lengthy and costly clinical trials.

中文翻译：

---

微观结构图像表征从长效肠胃外药物释放的理论模型和机理

这项工作发展了一种机理理解和简化的模型，以通过使用X射线计算机断层扫描（XRCT）成像确定的微观结构变化来了解长效肠胃外聚合物制剂中活性药物成分的药物释放曲线变化。所研究的系统是一种植入物，该植入物由结晶药物微区的固体分散体组成，该固体分散体嵌入聚合物基质中，并通过热熔挤出制造。我们使用microCT对这些装置进行材料表征，并首次通过nanoCT引入此类药物设备的成像，显示出普通CT方法无法捕获的更精细的结构。我们提出了一种简化的理论机理模型，该模型通过提取相关的微观特征来估计药物释放，这些特征可以调节microCT图像的释放速率，从而构建理想的几何结构。使用此分析，我们发现尽管阻力的主要机理源自亚微米级特征（低于microCT的分辨率），但决定不同工艺条件导致的扩散率变化的主要特征是微米级孔体积和孔连通性分布。从microCT图像中提取参数，并与理论相结合能够解释在不同过程条件下实验性药物释放的变化。这些结果表明，即使由于许多假设和缺乏子量表信息而简化了方程式，该建模策略也可以解释主要的释放机理并估计制剂的药物释放。所提出的方法，由于其简单性和对广泛使用的microCT技术的依赖，通过在进行冗长而昂贵的临床试验之前提供批次一致性和工艺参数选择的快速初始评估，为指导配方开发提供了希望。