Nucleation Kinetics during Suspension Crystallization of Proteins

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Protein crystallization is an important step along the process chain of protein production. It is applied for purification of protein solutions and for producing protein formulations with high stability and long shelf life. Despite of its high potential and relevance for industries in the biotechnological, pharmaceutical and food branch, there are only few other than empirical approaches available for the design of such processes.In suspension crystallization processes the produced particle size distribution is determined by nucleation and growth of the crystals. In technical crystallizers nucleation takes place either due to primary and, in particular, due to secondary mechanisms. A typical secondary mechanism is the creation of nuclei by collision of already existing crystals with stirrer blades. For low molecular substances 3 secondary nucleation mechanisms are discussed in the literature: shear nucleation, contact nucleation and attrition. It is the aim of the first part of this proposal to prove or disapprove the existence of these mechanisms for protein crystallization, and if applicable to identify the relevant influencing parameters.It is the aim of the second part of this proposal to come to a mechanistic and quantitative description of attrition during protein crystallization. Protein crystals are mechanically less stable than non-protein crystals because of their rather weak intracrystalline interactions. Therefore, protein crystals should be more prone to attrition than those. In the project it shall be searched for a quantitative model like description of attrition which takes into account the mechanical load on the crystals as well as their mechanical strength. A model, which has already been developed for low-molecular crystals, shall be scrutinized with regard to its applicability for attrition nucleation of protein crystals.The aimed at qualitative mechanistic description of nucleation mechanisms and the quantitative knowledge about nucleation kinetics in technical protein crystallizers shall make possible a considerable improvement of quality and efficiency of protein crystallization processes.