Baloxavir Marboxil Shows Anomalous Conversion of Crystal Forms from Stable to Metastable through Formation of Specific Solvate Form

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Baloxavir marboxil is a novel cap-dependent endonuclease inhibitor of influenza. This study aimed to identify its polymorphs and their relationship with crystal engineering. Polymorph screening by evaporation gave forms I–III and solvate forms IV and V. Heating enabled the conversion of form III to form II, but did not enable that of forms I and II. The solvent-mediated transformation of the forms I–III by magnetic stirring in various solvents resulted in the formation of form I. These results indicate that form I is the stable form. However, all crystal forms transformed to form II after magnetic stirring in a 50% acetonitrile aqueous solution, which was not obtained from water or acetonitrile. The suspension in a 50% acetonitrile aqueous solution exhibited a novel X-ray diffraction pattern as shown in form VI. The measurement of the suspension by solid-state 13C-nuclear magnetic resonance revealed that the spectra of forms II and VI were similar. From these results, we conclude that the drug forms a solvate with both water and acetonitrile and spontaneously transforms to form II upon rapid desolvation under ambient conditions. This study elucidates the mechanism of unexpected convergence to a metastable form in a specific solvent and contributes to the crystal engineering of baloxavir marboxil.