UBC Theses and Dissertations

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UBC Theses and Dissertations

Leveraging novel process analytical technologies to access chiral small molecule drug precursors via dynamic crystallization Kukor, Andrew


Dynamic crystallizations can drive the formation of enantiopure solid phases but require significant process understanding to achieve the necessary levels of control. Phase-specific data that sheds light on the solution and solid phases of crystallizations can facilitate this understanding and enable the development of such dynamic crystallizations. Building off previous work in the Hein Lab, this Thesis explores the development of two new phase-specific analytical tools for monitoring crystallizations and their application to dynamic crystallization development. A filter modification for Mettler-Toledo’s EasySampler probe is presented. This filter is capable of selectively sampling the solution phase of crystallizations, and its efficacy is demonstrated in a variety of crystallization tests. A complementary solid phase tool is developed using a webcam to monitor the turbidity of solutions, providing a solid phase monitoring tool and allowing automated solubility and nucleation measurements to be performed. These two tools were used in combination to investigate, optimize, and demonstrate the dynamic crystallizations of two unique small molecule drug precursors, each of which is currently isolated via crystallization. The first molecule was discovered to form an undesired racemic solid phase. As such, a multi-well continuous crystallization setup with dissolution, crystallization and inline racemization was used to kinetically control its dynamic crystallization. Based on this success, the crystallization of a second molecule was investigated in partnership with Genentech. Mechanistic understanding was achieved using our novel process analytical technology tools and traditional offline sampling, allowing a similar inline racemization approach to that used with the first molecule to be applied and optimized for the second molecule’s crystallization.

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Attribution-NonCommercial-NoDerivatives 4.0 International