Doctor of Philosophy
Chemical and Biochemical Engineering
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.
Summary for Lay Audience
Crystallization is the process by which the atoms or molecules form solid crystals from a saturated solution or a gas phase. In the pharmaceutical industry, more than 90% of small molecular drugs are delivered in crystalline form and over 80% drug products involve at least one crystallization step. The operation conditions during the crystallization process have significant effects on the product properties, such as crystal size distribution, purity and polymorphism. Polymorphism, which is exhibited in more than half of the active pharmaceutical ingredients, refers to the different arrangements of molecules in solid-state and has a direct impact on the stability, bioavailability and processability of the drug products. 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.
This work is concerned with studying the polymorphism phenomenon in crystallization processes experimentally and numerically, providing insights into the process design and optimization. At first, the investigation of the imatinib mesylate properties, was conducted experimentally and thoroughly, in the aspects of characterization, solubility, polymorphic transformation, and nucleation and growth rates. These properties are the fundamental and necessary information for the process design and control. Then, Raman spectroscopy, a process analytic technology, was applied for in-situ monitoring of the solution concentration and slurry density of each polymorph during the crystallization process. Subsequently, the impact of relative kinetics of the two polymorphs on the polymorphic outcome was studied numerically in batch and MSMPR (mixed suspension and mixed product removal) crystallizers. The optimal operating conditions for harvesting the desired polymorph were investigated in both modes of operations. The influence of each manipulated variable on the crystal properties was also studied.
Lin, Mengxing, "Experimental and Numerical Study of Polymorphism in Crystallization Processes" (2020). Electronic Thesis and Dissertation Repository. 7380.
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