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Minimizing Polymorphic Risk Through Cooperative Computational and Experimental Exploration

preprint
submitted on 23.06.2020 and posted on 25.06.2020 by Christopher R. Taylor, Matthew T. Mulvee, Domonkos S. Perenyi, Michael R. Probert, Graeme Day, Jonathan Steed

We combine state-of-the-art computational crystal structure prediction (CSP) techniques with a wide range of experimental 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 obtaining 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 computational-experimental approach to “de-risk” solid form landscapes.

Funding

A Supramolecular Gel Phase Crystallisation Strategy

Engineering and Physical Sciences Research Council

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MATERIALS CHEMISTRY HIGH END COMPUTING CONSORTIUM

Engineering and Physical Sciences Research Council

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HIGH END COMPUTING MATERIALS CHEMISTRY CONSORTIUM

Engineering and Physical Sciences Research Council

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History

Email Address of Submitting Author

g.m.day@soton.ac.uk

Institution

University of Southampton

Country

United Kingdom

ORCID For Submitting Author

0000-0001-8396-2771

Declaration of Conflict of Interest

No conflicts of interest.

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in Journal of the American Chemical Society

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