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

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

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6262-6266
Number of pages5
JournalCrystal Growth and Design
Volume22
Issue number10
Early online date20 Sep 2022
DOIs
Publication statusPublished - 5 Oct 2022
Externally publishedYes

Cite this