Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray Diffraction

Mark A. Levenstein, Mark A. Levenstein, Lois Wayment, C. Daniel Scott, C. Daniel Scott, Ruth Lunt, Ruth Lunt, Pierre Baptiste Flandrin, Sarah J. Day, Chiu C. Tang, Chick C. Wilson, Fiona C. Meldrum, Nikil Kapur, Karen Robertson

Research output: Contribution to journalArticlepeer-review

11 Citations (SciVal)


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.

Original languageEnglish
Pages (from-to)7754-7761
Number of pages8
JournalAnalytical Chemistry
Issue number11
Early online date4 May 2020
Publication statusPublished - 2 Jun 2020

ASJC Scopus subject areas

  • Analytical Chemistry


Dive into the research topics of 'Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray Diffraction'. Together they form a unique fingerprint.

Cite this