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

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–H···O, C–H···F, and C–H···π interactions. The 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.