Prediction of Structure and Stability of Amorphous Pharmaceuticals

无定形药物的结构和稳定性预测

• 批准号: 2746941
• 金额: --
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2746941
• 关键词: Prediction; Structure; Stability; Amorphous; Pharmaceuticals

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.

专注于无定形活性药物成分和微晶无定形系统的结构和稳定性预测。它将筛选一系列API，配制成无定形材料并确定其固态结构，以填充无定形药物的新数据库。随后将使用数据驱动的方法来确定无定形稳定性指数。API分子库将涵盖分子大小、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、小规模热方法将用于制备无定形样品库，并根据需要使用其他方法。过程条件将得到控制和记录，在标准化样品制备和数据收集/简化方法中测试的所得样品将优化测量数据质量。对关键材料、工艺、设备和建模信息的元数据要求将为今后的比较研究提供背景。XRPD、DSC将提供所有样品的主要表征，并使用X射线对分布函数、光谱学、热分析、断层扫描、显微镜和AFM分析局部、本体和表面结构，并使用关键物理特性补充上述分子数据。还将捕获来自分子的计算输出。加速稳定性研究将在相关条件下评估每个样品的结晶开始时间，提供响应数据以训练ASI。AMDB将用于训练和基准ML模型以开发ASI。这一非晶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，快速指示替代稳定策略的需求。PDF已用于识别纳米晶4和储存期间的非晶变化。我们将使用先进的散射和建模来研究选定的API中分子结构、分子间堆积和稳定性之间的关系。新的结构细化方法允许MD衍生模型与实验PDF的拟合，从而实现模型细化。- 描述无定形API和mc-A的全面、公平的结构和物理化学数据;-无定形固体的独特APDB结构-性质数据库;-基于分子结构预测无定形行为的验证ML的ASI;- 预测可开发性模型，以选择基于ASI的配方系统的属性。在提供基本理解和新工具，通过研究非晶态，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，英国及欧洲行业在维持其于全球经济中的竞争地位方面面临严峻挑战，而COVID-19只会使我们所面临的挑战成为焦点。《2020年欧洲制药战略》的目标是“确保欧洲各地的患者在任何情况下都能迅速获得新的药物和疗法，减少药物短缺”。这一点应该得到确保，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。我们通过我们的研究，更好地利用HME和增材制造等工艺以及药物的预测性数字设计方法来解决这一问题。我们还提供了一个训练有素的PDRA和博士生熟练的国家的最先进的科学和高度发达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的人才队伍。