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Minimizing polymorphic risk through cooperative computational and experimental exploration

Taylor, Christopher R.; Mulvee, Matthew T.; Perenyi, Domonkos S.; Probert, Michael R.; Day, Graeme M.; Steed, Jonathan W.

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Christopher R. Taylor

Matthew T. Mulvee

Domonkos S. Perenyi

Michael R. Probert

Graeme M. Day


We combine state-of-the-art computational crystal structure prediction (CSP) techniques with a wide range of experi-mental crystallization methods to understand and explore crystal structure in pharmaceuticals and minimize the risk of unanticipated late-appearing polymorphs. Initially, we demonstrate the power of CSP to rationalize the difficulty in ob-taining polymorphs of the well-known pharmaceutical isoniazid and show that CSP provides the structure of the recently discovered, but unsolved, Form III of this drug despite there being only a single known form for almost 70 years. More dramatically, our blind CSP study predicts a significant risk of polymorphism for the related iproniazid. Employing a wide variety of experimental techniques, including high-pressure experiments, we experimentally obtained the first three known non-solvated crystal forms of iproniazid, all of which were successfully predicted in the CSP procedure. We demonstrate the power of CSP methods and free energy calculations to rationalize the observed elusiveness of the third form of iproniazid, the success of high-pressure experiments in obtaining it, and the ability of our synergistic computa-tional-experimental approach to “de-risk” solid form landscapes.


Taylor, C. R., Mulvee, M. T., Perenyi, D. S., Probert, M. R., Day, G. M., & Steed, J. W. (2020). Minimizing polymorphic risk through cooperative computational and experimental exploration. Journal of the American Chemical Society, 142(39), 16668-16680.

Journal Article Type Article
Online Publication Date Sep 8, 2020
Publication Date Sep 30, 2020
Deposit Date Sep 11, 2020
Publicly Available Date Sep 18, 2020
Journal Journal of the American Chemical Society
Print ISSN 0002-7863
Electronic ISSN 1520-5126
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 142
Issue 39
Pages 16668-16680


Published Journal Article (Advance online version) (3.4 Mb)

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Copyright Statement
Advance online version This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium,<br /> provided the author and source are cited.

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