Solvates and Polymorphs of Baloxavir Marboxil: Crystal Structure and Phase Transformation Study

Abstract

Baloxavir marboxil (BXM) is an influenza cap-dependent endonuclease (CEN) inhibitor for the treatment of influenza A and B infections. In this work, systematic crystallization screening of BXM produced three forms (forms I, II, and III) and four solvates (methyl acetate solvate S MA , 2-methyltetrahydrofuran solvate S 2-THF , 1,4-dioxane solvate S DIOX , and tetrahydrofuran solvate S THF ). A new methyl acetate solvate (S MA ) was discovered, and the crystal structures of two isostructural channel solvates (S MA and S 2-THF ) were solved by single-crystal X-ray diffraction for the first time. The crystal structures of form I, form II, S MA , and S 2-THF show that there is no significant conformational difference and the molecular packing patterns were changed due to the introduction of solvent molecules. In addition, all interactions in form I, form II, S MA , and S 2-THF are weak intermolecular interactions, including C−HThe stability, thermal properties, and phase transformation relationships of the seven solid forms were studied by various methods. Form I is the thermodynamically stable phase, followed by form II. Solvates are unstable due to the lack of strong intermolecular interactions between solvents and host molecules. Desolvation studies of the four solvates indicated that they are sensitive to the modes of desolvation. The detailed solid form landscape of BXM was summarized to deepen our understanding of the crystallization behavior under different conditions and to guide the industrial process.

Exploring the Structural Landscape for a Thrombopoietin Receptor Agonist Avatrombopag Maleate: An Innovative Trihydrate Forms with Improved Solubility Found

“…Exploring new solid forms for active pharmaceutical ingredients (APIs), including polymorphic forms, solvates, and cocrystals, is essential to overcome challenges throughout the processes of its synthesis, purification, pharmaceutical formulation, and subsequent storage. The solid form can significantly influence its solubility, powder property, stability, mechanical property, bioavailability, etc. − Solvates were often formed in the recrystallizing process in solution, in which solvent is inserted in the crystal lattice at fixed stoichiometry. When the solvent escapes from crystal lattice, solvates transform into other solvent-free polymorphic forms, which is a very important method for screening new forms. ,− In summary, polymorphism is recognized as an intrinsic characteristic of the crystalline state.…”

“…The solid form can significantly influence its solubility, powder property, stability, mechanical property, bioavailability, etc. − Solvates were often formed in the recrystallizing process in solution, in which solvent is inserted in the crystal lattice at fixed stoichiometry. When the solvent escapes from crystal lattice, solvates transform into other solvent-free polymorphic forms, which is a very important method for screening new forms. ,− In summary, polymorphism is recognized as an intrinsic characteristic of the crystalline state. It is widely acknowledged that the diversity of solid forms identified for a given substance is directly proportional to the duration and intensity of the research efforts dedicated to their discovery…”