溶剂-药物相互作用对药物溶剂化物去溶剂化的影响,The Journal of Physical Chemistry B

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溶剂-药物相互作用对药物溶剂化物去溶剂化的影响
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2022-01-07 , DOI: 10.1021/acs.jpcb.1c07655
Yannis Vasilopoulos ₁ , Jan Heyda ₂ , Jan Rohlíček ₃ , Eliška Skořepová _{1,

3} , Vítek Zvoníček ₄ , Miroslav Šoóš ₁

Affiliation

在药物制造中，基于溶剂的方法用于活性药物成分 (API) 的结晶。通常，溶剂与 API 相互作用，导致形成新的固体化合物，即溶剂化物。当加热时发生去溶剂化时，可能会导致形成具有显着不同物理化学性质的新固体形式。因此，在这项工作中，我们通过结合原位粉末 X 射线衍射 (PXRD)、全原子分子动力学 (MD) 模拟和宏观固态反应动力学建模来研究去溶剂化动力学。布鲁顿酪氨酸激酶抑制剂依鲁替尼 (IBR) 的氟苯 (FB) 溶剂化物用作模型系统。虽然宏观固态建模提供了有关去溶剂化动力学的信息，MD模拟用于追踪晶格内的单个FB分子。通过 MD 模拟获得的受限溶剂扩散的活化能与宏观固态反应动力学建模的结果非常吻合。此外，MD 模拟提供了有关纳米级 IBR-FB 相互作用的详细信息。揭示的机制是溶剂分子的扩散，由药物的明显的开闭门构象变化控制，触发整个晶格的去溶剂化。

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Impact of Solvent–Drug Interactions on the Desolvation of a Pharmaceutical Solvate

In drug manufacturing, solvent-based methods are used for the crystallization of active pharmaceutical ingredients (APIs). Often, the solvent interacts with the API resulting in the formation of a new solid compound, the solvate. When desolvation occurs upon heating, it might result in the formation of new solid forms with significantly different physicochemical properties. Therefore, in this work, we study the desolvation kinetics by combining in situ powder X-ray diffraction (PXRD), all-atom molecular dynamics (MD) simulations, and macroscopic solid-state reaction kinetics modeling. The fluorobenzene (FB) solvate of Bruton’s tyrosine kinase inhibitor Ibrutinib (IBR) was used as a model system. While the macroscopic solid-state modeling provides information about the desolvation kinetics, the MD simulations were used to trace individual FB molecules inside the crystal lattice. The activation energy of confined solvent diffusion, obtained by MD simulations, agrees well with results of the macroscopic solid-state reaction kinetics modeling. In addition, MD simulations provided detailed information about the IBR–FB interactions at the nanoscale. The mechanism revealed is that the solvent molecules diffusion, controlled by distinct open-close gating conformational changes of the drug, triggers the desolvation throughout the crystal lattice.

更新日期：2022-01-20

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