Issue 48, 2021

Exploring the solid form landscape of the antifungal drug isavuconazole: crystal structure analysis, phase transformation behavior and dissolution performance

Abstract

Isavuconazole (ISV) is a systemic antifungal agent and is used to treat invasive aspergillosis, mucormycosis and candidiasis. Although both oral and intravenous dosage forms of this drug exist on the market, the crystal structure and physicochemical properties of ISV as well as possible alternative solid forms are yet unexplored in the literature. In the present work, the solid form landscape of isavuconazole including solvate, polymorph and salt screening was studied systematically. The solid-state properties of the initial crystalline ISV and newly obtained forms (ISV monohydrate, two amorphous forms obtained by different means and two pharmaceutical salts with p-toluenesulfonic acid and phosphoric acid) were described for the first time. The structures of all crystalline forms were solved based on single crystal X-ray diffraction data, and the packing forces in the considered solids were studied using different theoretical approaches. The transformation pathways between the ISV solid forms were investigated experimentally and rationalized based on DFT computations and non-covalent interaction analysis. It was observed that crystalline isavuconazole does not transform into the hydrate upon dissolution, in contrast to other solid forms. The amorphous and salt forms of ISV were found to demonstrate a spring-like increase of the drug concentration in pharmaceutically relevant buffer media. The tableting of the pharmaceutical salts leads to slower phase transformation into the ISV hydrate and prolonged drug supersaturation.

Graphical abstract: Exploring the solid form landscape of the antifungal drug isavuconazole: crystal structure analysis, phase transformation behavior and dissolution performance

Supplementary files

Article information

Article type
Paper
Submitted
07 अक्तूबर 2021
Accepted
18 नवम्बर 2021
First published
18 नवम्बर 2021

CrystEngComm, 2021,23, 8513-8526

Exploring the solid form landscape of the antifungal drug isavuconazole: crystal structure analysis, phase transformation behavior and dissolution performance

A. P. Voronin, N. A. Vasilev, A. O. Surov, A. V. Churakov and G. L. Perlovich, CrystEngComm, 2021, 23, 8513 DOI: 10.1039/D1CE01353J

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements