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

拟议中的博士项目将与阿斯利康合作开展，将研究一种集成设计和优化大分子结晶的硅/体外混合方法，特别关注播种。下面将进一步解释这些产品的一般目的。每个步骤还将包括相关文献综述，以检查每个领域的研究进展。发展对种群平衡模型公式和解决方法的理解-研究复杂的机制，如两步成核或异质播种，以及它们的数学模型。确定什么时候方法和假设是适用的，什么时候它们的不准确性或其他限制使它们的实施不可行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。由于缺乏来自工业合作伙伴阿斯利康的数据，该模型将基于溶菌酶，以前用作蛋白质结晶的代表性分子（Durbin & Feher 1986）。开展实验室工作，支持模型开发和验证工作-数据将用于机制识别和参数估计。此外，对结晶设备的熟悉将揭示在实验室和工业环境中实施模型的障碍。研究关于播种和过饱和轨迹等操作条件的优化方法和控制策略，旨在将其扩展到更复杂的大分子系统，展示多态性等现象，并实现目标尺寸分布。

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.