A hybrid in-silico/in-vitro approach for integrated design and optimisation of large-molecule crystallisation

用于大分子结晶集成设计和优化的混合硅内/体外方法

• 批准号: 2744720
• 金额: --
• 依托单位: Imperial College London
• 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-2744720
• 关键词: hybrid; silico; vitro; approach; integrated

The proposed PhD project, carried out in collaboration with AstraZeneca, will investigate a hybrid in-silico/in-vitro approach for integrated design and optimisation of large-molecule crystallisation, with particular focus on seeding. The following general aims of the products are further explained below. Each step will also include a relevant literature review to examine research progress in each area.Develop understanding of the population balance model formulation and solution methods -investigate complex mechanisms, such as two-step nucleation or heterogeneous seeding, and their mathematical modelling. Identify when methods and assumptions are applicable and when their inaccuracy or other limitations make their implementation infeasibleDevelop large molecule crystallisation models - use the gained knowledge of appropriate crystallisation mechanisms and mathematical methods, along with data-driven techniques to build crystallisation process models with varying complexity and assumptions. In the absence of data from the industrial partner AstraZeneca, the model will be based on lysozyme, previously used as a representative molecule for protein crystallisation (Durbin & Feher 1986).Carry out laboratory work supporting model development and validation efforts - the data will be used for mechanism identification and parameter estimation. Additionally, familiarisation with crystallisation equipment will reveal obstacles in the implementation of the model to a laboratory and industrial setting.Investigate optimisation approaches and control strategies with regards to operational conditions such as seeding and supersaturation trajectory, aiming to extend them to more complex large molecule systems exhibiting phenomena such as polymorphism and achieving a target size distribution.

拟议的PHD项目是与阿斯利康合作进行的，将研究一种混合的硅胶/体外方法，用于集成设计和优化大分子结晶，特别是种子。下面将进一步解释这些产品的以下总体目标。每一步还将包括相关的文献综述，以检查每个领域的研究进展。发展对种群平衡模型公式和求解方法的理解-研究复杂的机制，如两步成核或异质播种，及其数学模型。确定方法和假设何时适用，以及它们的不准确或其他限制何时使其无法实施开发大分子结晶模型-使用获得的适当结晶机制和数学方法的知识，以及数据驱动技术来构建具有不同复杂性和假设的结晶过程模型。在没有来自工业合作伙伴阿斯利康的数据的情况下，该模型将基于以前作为蛋白质结晶的代表性分子的溶菌酶(Durbin&Feher 1986)。开展支持模型开发和验证工作的实验室工作--数据将用于机制识别和参数估计。此外，熟悉结晶设备将揭示在实验室和工业环境中实施该模型的障碍。研究关于操作条件的优化方法和控制策略，如种子和过饱和轨迹，旨在将其扩展到更复杂的大分子系统，表现出多态现象并实现目标尺寸分布。