Levenstein, MA orcid.org/0000-0002-2309-3743, Wayment, L, Scott, CD et al. (8 more authors) (2020) Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray Diffraction. Analytical Chemistry, 92 (11). pp. 7754-7761. ISSN 0003-2700
Abstract
Understanding the transitions between polymorphs is essential in the development of strategies for manufacturing and maximizing 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 analysis 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 regarding 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 American Chemical Society. This is an author produced version of an article published in Analytical Chemistry. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Inorganic Chemistry (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Mechanical Engineering (Leeds) > Institute of Engineering Thermofluids, Surfaces & Interfaces (iETSI) (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 03 Jun 2020 10:58 |
Last Modified: | 04 May 2021 00:38 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acs.analchem.0c00860 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:161413 |