Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder XRD

• Mark Alan Levenstein^{1, 2}
• Lois E Wayment^{3, 4, 5}
• C. Daniel Scott^{3, 6}
• Ruth A Lunt^{3, 4}
• Pierre-Baptiste Flandrin³
• Sarah Day⁵
• Chiu Tang⁵
• Chick C. Wilson³
• Fiona C. Meldrum²
• Nikil Kapur¹
• Karen Robertson³

• ¹School of Mechanical Engineering, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK
• ²School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK
• ³Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
• ⁴CMAC Future Manufacturing Hub, University of Bath, Claverton Down, Bath BA2 7AY, UK
• ⁵Diamond Light Source, Harwell Campus, Didcot, Oxfordshire OX11 0DE, UK
• ⁶Centre for Sustainable Chemical Technologies, University of Bath, Claverton Down, Bath BA2 7AY, UK

Understanding the transitions between polymorphs is essential in the development of strategies for manufacturing and max-imizing the efficiency of pharmaceuticals. However, this can be extremely challenging: crystallization can be influenced by subtle changes in environment such as temperature and mixing intensity or even imperfections in the crystallizer walls. Here, we highlight the importance of in situ measurements in understanding crystallization mechanisms, where a segmented flow crystallizer was used to study the crystallization of the pharmaceuticals urea:barbituric acid (UBA) and carbamazepine (CBZ). The reactor provides highly reproducible reaction conditions, while in situ synchrotron powder X-ray diffraction (PXRD) enables us to monitor the evolution of this system. UBA has two polymorphs of almost equivalent free-energy and so is typically obtained as a polymorphic mixture. In situ PXRD uncovered a progression of polymorphs from UBA III to the thermodynamic polymorph UBA I, where different positions along the length of the tubular flow crystallizer correspond to different reaction times. Addition of UBA I seed crystals modified this pathway such that only UBA I was observed throughout, while transformation from UBA III into UBA I still occurred in the presence of UBA III seeds. Information re-garding the mixing-dependent kinetics of the CBZ form II to III transformation was also uncovered in a series of seeded and unseeded flow crystallization runs, despite atypical habit expression. These results illustrate the importance of coupling controlled reaction environments with in situ XRD to study the phase relationships in polymorphic materials.

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