Experimental and Numerical Study of Polymorphism in Crystallization Processes

Polymorphism, which is exhibited in more than half of the active pharmaceutical ingredients, has a direct impact on the stability, bioavailability and processability of the product. Despite extensive studies on polymorphism in the field of crystal engineering, the control of polymorphism is still one of the most challenging tasks in pharmaceutical manufacturing. The aim of this work is to crystallize the desired polymorph with the help of process modeling and process analytical technologies. First, we investigated the crystallization properties of imatinib mesylate, including polymorphism characterization, solubility measurement, polymorphic transformation and kinetic parameter estimation, as they are the fundamental information for the model-based process design and control of crystallization process and were lacking in the literature. Subsequently, the capability of in-situ Raman spectroscopy in measuring solution concentration and solids concentration was proved. The analytical models were developed with several pre-processing methods and multivariable analysis techniques and compared based on the root mean squared errors. Thereafter, the impacts of relative kinetics of the two polymorphs on the polymorphic outcome were studied numerically in batch and MSMPR (mixed suspension and mixed product removal) crystallizers. The optimal operating conditions for harvesting the desired polymorph were analyzed in both modes of operations. Lastly, the effects of the operating conditions in batch and MSMPR crystallization on the product polymorphism, process yield, and crystal size were investigated. The effectiveness of continuous seeding strategy in altering the steady-state condition of MSMPR crystallization and its implementation was also proved and discussed. In conclusion, this work is concerned with studying the polymorphism phenomenon in crystallization processes experimentally and numerically, providing insights into the design, optimization and control of batch and continuous crystallization processes