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

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.