Prediction of Structure and Stability of Amorphous Pharmaceuticals

重点研究了非晶活性药物成分和微晶非晶体系的结构和稳定性预测。它将筛选一系列api，配制成非晶态材料并确定其固态结构，以填充非晶态药物的新数据存储库。它随后将使用数据驱动的方法来确定非晶稳定性指数。API分子库将涵盖大小，结构复杂性和生物制药特性以及来自选定mc-A系统的数据。材料将与测量和计算的分子数据相关，包括从文献中挖掘的数据。自动化，小规模的热方法将用于制备非晶样品库与其他方法的需要。过程条件将被控制和记录，所得到的样品将在标准化的样品制备和数据收集/还原方法中进行测试，以优化测量数据质量。关键材料、工艺、设备和建模信息的元数据需求将为未来的比较研究提供背景。XRPD、DSC将通过x射线对分布函数、光谱学、热成像、断层扫描、显微镜和原子力显微镜分析，对所有样品的局部、整体和表面结构进行初步表征，并提供关键的物理性质，以补充上述分子数据。分子的计算输出也将被捕获。加速稳定性研究将评估每个样品在相关条件下结晶开始的时间，为训练ASI提供响应数据。AMDb将用于训练和测试ML模型，以开发ASI。这个非晶态稳定性的数字开发指南将允许用户预测给定分子的结晶阻力，快速指示对替代稳定策略的需求。pdf已用于指纹存储过程中的纳米晶化和非晶态变化。我们将使用先进的散射和建模来研究选定原料药的分子结构、分子间堆积和稳定性之间的关系。新的结构细化方法允许将MD衍生模型拟合到实验PDF中，从而实现模型的细化。必要时将使用用于时间分辨研究的sssnmr、同步加速器和中子的国际设施。-描述非晶API和mc-A的全面、公平的结构和物理化学数据；-独特的非晶固体APDb结构-性能数据库；-验证基于ML的ASI预测基于分子结构的无定形行为；-基于ASI的可发展性预测模型，用于选择配方系统的特性。在为研究非晶态提供基本理解和新工具的过程中，DDMAP将为新材料、新产品和新制造创造机会。制药业是英国最大的制造业出口部门。然而，英国和欧洲工业在保持其在全球经济中的竞争地位方面面临严峻挑战，新冠肺炎疫情只是让我们面临的挑战变得更加突出。2020年“欧洲制药战略”旨在“确保欧洲各地的患者在任何情况下都能在其国家迅速获得新药和疗法，并减少药物短缺”。应确保这一点，同时提供解决方案，允许个性化医疗，打击伪造产品，并减少相关制造的环境足迹。通过我们的研究，我们能够更好地利用HME和增材制造等工艺，并结合药物的预测性、数字化设计方法来解决这个问题。我们还培养了一批训练有素的PDRA和博士生，他们精通最先进的科学，具有高度发展的多学科和协作能力，准备成为这个令人兴奋的领域的未来领导者。

Focus on structure and stability prediction of amorphous active pharmaceutical ingredient and microcrystalline amorphous systems. It will screen a range of APIs, formulate as amorphous materials and determine their solid-state structure in order to populate a new data repository for amorphous pharmaceuticals. It will subsequently use data-driven approaches to determine an Amorphous Stability Index.The API molecule library will cover size, structural complexity and biopharmaceutical properties plus data from select mc-A systems. Materials will be related with measured and calculated molecular data including data mined from literature. Automated, small scale thermal methods will be used to prepare amorphous sample libraries with other methods as needed. Process conditions will be controlled and recorded and the resultant samples tested in Standardised sample preparation and data collection/reduction approaches will optimise measurement data quality. Metadata requirements for key material, process, equipment, and modelling information will give context for future comparative studies. XRPD, DSC will provide primary characterisation of all samples with analysis of local, bulk and surface structure using X-ray pair distribution function, spectroscopy, thermal, tomography, microscopy and AFM with key physical properties complement molecular data from above. Calculated outputs from molecular will also be captured. Accelerated stability studies will assess time to onset of crystallisation for each sample under relevant conditions giving response data to train the ASI.The AMDb will be used to train and benchmark ML models to develop the ASI. This digital development guide for amorphous stability will allow users to predict resistance to crystallisation for given molecules, rapidly indicating the need for alternative stabilisation strategies.PDF has been used to fingerprint nanocrystallinity4 and amorphous changes during storage. We will use advanced scattering and modelling to investigate the relationship between molecular structure, intermolecular packing and stability in selected APIs. New structure refinement methods allow fits of MD derived models to experimental PDF enabling model refinement. International facilities for ssNMR, synchrotron and neutron for time-resolved studies will be used when required.Deliverables:-Comprehensive, FAIR structural and physicochemical data describing amorphous API and mc-A;-Unique APDb structure-property database for amorphous solids;-Validated ML based ASI to predict amorphous behaviour based on molecular structure;-Predictive developability model to select properties of formulated systems based on ASI.In delivering the fundamental understanding and new tools for investigating amorphous state, DDMAP will create opportunities for novel materials, products and manufacturing. Pharma is the UK's largest manufacturing export sector. However, the UK and European industries face serious challenges to maintain their competitive position in the global economy and COVID-19 has only served to throw a spotlight on the challenge facing us. The "Pharmaceutical strategy for Europe" 2020 aims to "make sure that patients across Europe have new medicines and therapies in their countries quickly and under all circumstances and that there are fewer shortages of medicines". This should be ensured while at a same time delivering solutions allowing for personalised medicine, combating falsified products, and reducing the environmental footprint of related manufacturing. We address this by enabling the greater exploitation of processes such as HME and additive manufacturing coupled with predictive, digital design methodologies for pharmaceuticals through our research. We also deliver a talented cohort of trained PDRA and doctoral students skilled in state-of-the-art science and with highly developed multidisciplinary and collaborative abilities, primed to be the future leaders in this exciting area.