Desolvation Processes in Channel Solvates of Niclosamide.

The antiparasitic drug niclosamide (NCL) is notable for its ability to crystallize in multiple 1:1 channel solvate forms, none of which are isostructural. Here, using a combination of time-resolved synchrotron powder X-ray diffraction and thermogravimetry, the process-induced desolvation mechanisms of methanol and acetonitrile solvates are investigated. Structural changes in both solvates follow a complicated molecular-level trajectory characterized by a sudden shift in lattice parameters several degrees below the temperature where the desolvated phase first appears. Model fitting of kinetic data obtained under isothermal heating conditions suggests that the desolvation is rate-limited by the nucleation of the solvent-free product. The desolvation pathways identified in these systems stand in contrast to previous investigations of the NCL channel hydrate, where water loss by diffusion initially yields an anhydrous isomorph that converts to the thermodynamic polymorph at significantly higher temperatures. Taking the view that each solvate lattice is a unique "pre-organized" precursor, a comparison of the pathways from different starting topologies to the same final product provides the opportunity to reevaluate assumptions of how various factors (e.g., solvent binding strength, density) influence solid-state desolvation processes.

Dehydration of Niclosamide Monohydrate Polymorphs: Different Mechanistic Pathways to the Same Product.

Many active pharmaceutical ingredients (APIs) can crystallize as hydrates or anhydrates, the relative stability of which depends on their internal structures as well as the external environment. Hydrates may dehydrate unexpectedly or intentionally, though the molecular-level mechanisms by which such transformations occur are difficult to predict a priori. Niclosamide is an anthelmintic drug on the World Health Organization's "List of Essential Medicines" that crystallizes in two monohydrate forms: HA and HB. Through complementary time-resolved synchrotron powder X-ray diffraction and thermogravimetric kinetic studies, we demonstrate that the two monohydrates dehydrate via distinctly different solid state pathways yet yield the same final anhydrate phase. Water loss from HA via diffusion yields an isomorphous desolvate intermediate which can rearrange to at least two different polymorphs, only one of which exhibits long-term stability. In contrast, dehydration of HB proceeds via a surface nucleation process where simultaneous water loss and product formation occur with no detectable crystalline intermediates. Comparative analysis of the two systems serves to highlight the complex relationship between lattice structure and solid state dehydration processes.