Physical Chemistry, Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., Osaka, 561-0825, Japan.
Bioanalysis, Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., Osaka, 561-0825, Japan.
J Pharm Sci. 2023 Jan;112(1):158-165. doi: 10.1016/j.xphs.2022.07.004. Epub 2022 Jul 11.
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 C-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.
巴洛沙韦马索利是一种新型的流感病毒帽依赖性内切酶抑制剂。本研究旨在鉴定其多晶型物及其与晶体工程的关系。蒸发法筛选得到了晶型 I-III 和溶剂化物晶型 IV 和 V。加热能够使晶型 III 转化为晶型 II，但不能使晶型 I 和 II 相互转化。在不同溶剂中通过搅拌使晶型 I-III 发生溶剂化转变，得到了晶型 I。这些结果表明晶型 I 是稳定的晶型。然而，在 50%乙腈水溶液中进行磁力搅拌后，所有晶型都转化为晶型 II，而该晶型不能从水或乙腈中获得。在 50%乙腈水溶液中的混悬液表现出一种新的 X 射线衍射图谱，如图 VI 所示。通过固态 C-核磁共振对混悬液的测量表明，晶型 II 和 VI 的光谱相似。根据这些结果，我们得出结论，药物与水和乙腈形成溶剂化物，并在环境条件下迅速去溶剂化时自发转化为晶型 II。本研究阐明了在特定溶剂中意外收敛到亚稳形式的机制，并为巴洛沙韦马索利的晶体工程做出了贡献。
