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.

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., Li, M., Steel, P. G., & 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: Oct 25, 2022
• 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
• Public URL: https://durham-repository.worktribe.com/output/1188208