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Toward continuous crystallization of Urea-Barbituric acid: a polymorphic co-crystal system

journal contribution
posted on 23.10.2015 by Keddon Powell, Giulia Bartolini, Kate E. Wittering, Ali N. Saleemi, Chick C. Wilson, Chris Rielly, Zoltan Nagy
Pharmaceutical co-crystals are multicomponent molecular systems typically formed through hydrogen bonding of a co-former molecule with the active pharmaceutical ingredient (API). Just as many single component molecular structures can exhibit polymorphism due to the geometry of hydrogen bond donors and acceptors, the same is true for pharmaceutical co-crystals. In this study, the selective cocrystallization of the desired polymorphic form of urea-barbituric acid (UBA) co-crystals (forms I and III) is demonstrated, applying a novel periodic mixed suspension mixed product removal (PMSMPR) crystallizer cascade. The process was monitored using an integrated process analytical technology (PAT) array consisting of Raman spectroscopy, attenuated total reflectance ultraviolet/visible (ATRUV/ vis) spectroscopy, focused beam reflectance measurement (FBRM), particle vision microscopy (PVM), and an in-house developed commercial crystallization process informatics system (CryPRINS) software tool to determine when a “state of controlled operation” (SCO) was achieved. Three different start-up strategies were employed and their ability to produce selectively a particular polymorphic form of UBA was evaluated. The experimental conditions for producing pure UBA form I were optimized, but pure UBA form III remained elusive. Off-line characterization of the UBA polymorphs was carried out using Powder X-ray Diffraction (PXRD) and Raman spectroscopy.


This paper was funded by the EPSRC (EP/I033459/1) and the Centre for Continuous Innovation in Continuous Manufacturing and Crystallization (CMAC) for the financial support of this work and the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. [280106-CrySys] (for equipment and financial support).



  • Aeronautical, Automotive, Chemical and Materials Engineering


  • Chemical Engineering

Published in

Crystal Growth and Design


POWELL, K.A., 2015. Toward continuous crystallization of Urea-Barbituric acid: a polymorphic co-crystal system. Crystal Growth and Design, 15(10), pp 4821–4836.


© American Chemical Society


AM (Accepted Manuscript)

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This paper is in closed access until 2nd Sept 2016.






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