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Extensive sequential polymorphic interconversion in the solid-state : two hydrates and ten anhydrous phases of hexamidine diisethionate.

Edkins, Katharina and McIntyre, Garry J and Wilkinson, Clive and Kahlenberg, Volker and Toebbens, Daniel M. and Griesser, Ulrich J. and Bruening, Juergen and Schmidt, Martin U. and Steed, Jonathan W. (2019) 'Extensive sequential polymorphic interconversion in the solid-state : two hydrates and ten anhydrous phases of hexamidine diisethionate.', Crystal growth & design., 2019 (19). pp. 7280-7289.


Crystal polymorphism and solvent inclusion is a dominant research area in the pharmaceutical industry and continues to unveil complex systems. Here, we present the solid-state system of hexamidine diisethionate (HDI), an antiseptic drug compound forming a dimorphic dihydrate as well as ten anhydrous polymorphs. The X-ray and neutron crystal structures of the hydrated crystal forms and related interaction energies show no direct interaction between the cation and water but very strong interactions between cation and anion, and anion and water. This is observed macroscopically as high stability of the hydrate against dehydration by temperature and humidity. The anhydrous polymorphs reveal a rare case of sequential and reversible polymorphic transformations, which are characterized by thermal analysis and variable-temperature powder X-ray diffraction (PXRD). While most transitions are accompanied by significant structural changes, the low-energy transitions can only be detected as slight changes in the reflection positions with temperature. HDI thus represents a model compound to investigate polymorphic transitions with small structural changes.

Item Type:Article
Full text:(AM) Accepted Manuscript
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Publisher statement:This document is the Accepted Manuscript version of a Published Work that appeared in final form in Crystal Growth & Design, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see
Date accepted:No date available
Date deposited:28 October 2019
Date of first online publication:22 October 2019
Date first made open access:22 October 2020

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