Study On Advanced Crystallization Control Strategy Based On Modeling And Process Analytical Technology

In the pharmaceutical industry,the polymorphic purity of active pharmaceutical ingredients is crucial for drug consistency evaluation.As the crystal nucleation and growth are influenced by multiple variables in the crystallization process,the traditional polymorph control approaches usually fail to inhibit the polymorph transformation in the scaling up process.Additionally,it’s always challenging to control the impurity in the cooling crystallization of heat sensitive materials because of the degradation.Based on the process analytical technology and crystallization modeling approach,this thesis presents a comprehensive study on the development and application of advanced crystallization control approaches for robust process design and operation for impurity rejection and polymorph control in the solution crystallization.First,the thermodynamics and kinetics of reactive crystallization process of clopidogrel hydrogen sulfate involving polymorph nucleation and transformation were studied based on online monitoring and analysis using ATR-FTIR and FBRM.Multiple trajectories of nucleation were revealed,and the transformation path was determined as that “oil/gel phase → Ⅰ form(metastable form)→Ⅱ form(patented form)”.The relationship between the nucleated polymorphic form and the solvent hydrogen bond donor ability,as well as the correlation between polymorphic form and supersaturation,were attempted to establish quantitively.This work can provide guidelines for solvent selection and supersaturation design for precise polymorph control.Supersaturation control(SSC)is a simple yet very effective feedback control strategy for crystallization processes.The benefits of SSC on product properties(large size crystals or high purity)have been extensively investigated.While most of the applications using SSC have been reported for batch cooling crystallization,a novel feedback control strategy by the semi-batch implementation for cooling crystallization is proposed in this thesis,in which the supersaturation is specified by manipulating the feed flow rate of the concentrated solution rather than temperature.A combined mode of SSC strategy was also proposed based on batch and semi-batch implementations.A comparison of these three scenarios is presented through numerical simulations in MATLAB-Simulink,which enables the identification of optimal operation modes of cooling crystallizers for various types of crystallization systems.Based on the integration of software,hardware,and sensors,an innovative hierarchical intelligent control system was developed,and proof-of-concept experimental demonstrations were also presented to support the simulation results.This thesis introduces the application of a novel SSC approach for impurity rejection in the crystallization of heat-sensitive materials.The effectiveness of the semibatch operation was demonstrated for the cooling crystallization of acetylsalicylic acid by thorough simulation study as well as experimental investigations.Both analyses revealed the superiority of semi-batch SSC for the crystallization of heat-sensitive materials.The semi-batch SSC implementation was also applied for the thermodynamic polymorph control in the enantiotropic system.The system is presented through the case study of para-aminobenzoic acid crystallization from ethanol.According to the literature,the β form cannot be easily obtained in batch cooling crystallization,but the semi-batch setup was able to produce it consistently and without yield limitations due to the transition temperature.The principle of the Quality by Control was also employed as a direct design approach,which reduced the complex multilevel control strategy to a simple controlled charging of the crystallizer.In a broader context,the advanced crystallization control approaches are generally applicable for a broad variety of polymorphic systems and heat-sensitive materials in laboratory study as well as industrial manufacturing.