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Integral Role of Water in the Solid-State Behavior of the Antileishmanial Drug Miltefosine

Hall, Amy V.; Gostick, Isobel E.F.; Yufit, Dmitry S.; Marchant, Gloria Y.; Kirubakaran, Preyanthiny; Madu, Shadrack J.; Li, Mingzhong; Steel, Patrick G.; Steed, Jonathan W.

Integral Role of Water in the Solid-State Behavior of the Antileishmanial Drug Miltefosine Thumbnail


Authors

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Dr Amy Hall amy.v.hall@durham.ac.uk
Leverhulme Early Career Fellow

Isobel E.F. Gostick

Gloria Y. Marchant

Preyanthiny Kirubakaran

Shadrack J. Madu

Mingzhong Li



Abstract

Miltefosine is a repurposed anticancer drug and currently the only orally administered drug approved to treat the neglected tropical disease leishmaniasis. Miltefosine is hygroscopic and must be stored at subzero temperatures. In this work, we report the X-ray structures of miltefosine monohydrate and methanol solvate, along with 12- and 14-carbon chain analogue hydrates and a solvate. The three hydrates are all isostructural and are conformational isomorphs with Z′ = 2. Water bridges the gap between phosphocholine head groups caused by the interdigitated bilayer structure. The two methanol solvates are also mutually isostructural with the head groups adopting a more extended conformation. Again, the solvent bridges the gap between head groups in the bilayer. No anhydrous form of miltefosine or its analogues were isolated, with dehydration resulting in significantly reduced crystallinity. This arises as a result of the integral role that hydrogen-bond donors (in the form of water or solvent molecules) play in the stability of the zwitterionic structures.

Citation

Hall, A. V., Gostick, I. E., Yufit, D. S., Marchant, G. Y., Kirubakaran, P., Madu, S. J., …Steed, J. W. (2022). Integral Role of Water in the Solid-State Behavior of the Antileishmanial Drug Miltefosine. Crystal Growth and Design, 22(10), 6262-6266. https://doi.org/10.1021/acs.cgd.2c00843

Journal Article Type Article
Online Publication Date Sep 20, 2022
Publication Date Oct 5, 2022
Deposit Date Oct 25, 2022
Publicly Available Date Mar 28, 2024
Journal Crystal Growth and Design
Print ISSN 1528-7483
Electronic ISSN 1528-7505
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 22
Issue 10
Pages 6262-6266
DOI https://doi.org/10.1021/acs.cgd.2c00843

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Copyright Statement
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.





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