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

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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.