Predictive Design of Polymer-Based Amorphous Solid Dispersion

已知包含溶解在聚合物中的药物的无定形固体分散体增强水溶性差的药物的溶解性能和生物利用度。然而，由于无定形形式的固有不稳定性，导致活性成分的物理不稳定性和重结晶，使产品失活，因此这些方法在市售产品中的应用受到限制。因此，设计稳定的分散体系是开发基于聚合物的无定形分子分散体的主要挑战。该项目的目的是开发和测试应用对分布函数分析来揭示局部短程结构的方法，并评估预测稳定、亚稳或不稳定配方的能力。具体而言，该项目将开发工具，通过在已知溶解度范围内控制短程包装，提供对结构-工艺-性能相互作用的深入了解，以实现对无定形材料和配方系统的更具预测性的设计。此外，该项目将提供实验数据，以促进开发用于药物-聚合物溶解度预测的先进基团贡献方法。该项目的目的是开发和测试应用对分布函数分析来揭示局部短程结构的方法，并评估预测稳定、亚稳或不稳定配方的能力。具体而言，该项目将开发工具，通过在已知溶解度范围内控制短程包装，提供对结构-工艺-性能相互作用的深入了解，以实现对无定形材料和配方系统的更具预测性的设计。此外，该项目将提供实验数据，以促进开发用于药物-聚合物溶解度预测的先进基团贡献方法。- 该项目将涉及利用熔融淬火，冷冻干燥和喷雾干燥制备无定形材料，并利用一套物理分析方法，以及X射线散射生成PDF。- PDF分析将与CMAC国家设施中可用的其他技术相结合，包括DSC、溶解、纳米CT、成像光谱、AFM和ToF-SIMS，以提供对分子分散体的均匀性、结构、物理组成和性能的前所未有的洞察。将利用多变量数据分析来识别相组成的早期变化，标志着不稳定的开始。从这些良好表征的系统中确定的溶解度和相组成数据将直接有助于利用帝国理工学院的合作者正在开发的新型gSAFT框架进行溶解度预测的开发和测试。（图10）。

Amorphous solid dispersions comprising drug dissolved in polymers are known to enhance the dissolution performance and bioavailability of poorly water soluble drug. The exploitation of these approaches in marketed products has however been limited because of the inherent instability of the amorphous form, leading to physical instability and recrystallisation of the active ingredient rendering the product inactive. Thus, designing stable dispersed systems is a major challenge in the development of polymer based amorphous molecular dispersions. The aim of this project is to develop and test approaches for applying pair distribution function (PDF) analysis to reveal local short-range structure, and assess the ability to predict stable, metastable or unstable formulations. Specifically the project will develop tools that provide insight into structure-process-property interactions towards more predictive design of amorphous materials and formulated systems through control of short range packing within known solubility ranges. In addition, the project will provide experimental data to contribute to the development of advanced group contribution methods for drug-polymer solubility prediction. The aim of this project is to develop and test approaches for applying pair distribution function (PDF) analysis to reveal local short-range structure, and assess the ability to predict stable, metastable or unstable formulations. Specifically the project will develop tools that provide insight into structure-process-property interactions towards more predictive design of amorphous materials and formulated systems through control of short range packing within known solubility ranges. In addition, the project will provide experimental data to contribute to the development of advanced group contribution methods for drug-polymer solubility prediction. - The project will involve preparation of amorphous materials utilising melt-quench, lyophilisation and spray drying and exploit a suite of physical analysis methods in addition to x-ray scattering for PDF generation. - PDF analysis will be with combined with other techniques available in the CMAC National Facility including DSC, dissolution, nano-CT, imaging spectroscopies, AFM and ToF-SIMS to provide an unprecedented insight into the homogeneity, structure, physical composition and performance of molecular dispersions. Multivariate data analysis will be utilised to identify early changes in phase composition marking the onset of instability.- Solubility and phase composition data determined from these well characterised systems will then contribute directly to the development and testing of solubility predictions utilising the novel gSAFT framework being developed by collaborators at Imperial College (C. Adjiman).