发现和选择性制备活性药物成分γ-氨基丁酸（GABA）多晶型物的绿色机械化学策略,ACS Sustainable Chemistry & Engineering

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发现和选择性制备活性药物成分γ-氨基丁酸（GABA）多晶型物的绿色机械化学策略
ACS Sustainable Chemistry & Engineering ( IF 8.4 ) Pub Date : 2020-11-05 , DOI: 10.1021/acssuschemeng.0c04707
Lingyu Wang ₁ , Guangxu Sun ₂ , Keke Zhang ₁ , Menghui Yao ₁ , Yingdi Jin ₃ , Peiyu Zhang ₃ , Songgu Wu ₁ , Junbo Gong ₁

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这项研究利用机械化学策略发现了药物的新多晶型物，同时实现了无需使用大量溶剂即可选择性制备各种多晶型物的方法。值得注意的是，在实践中，机械化学方法是一种独特的绿色高效方法。一方面，在最后一次发现γ-氨基丁酸（GABA）多晶型物约20年之后，我们通过机械化学研磨法鉴定了一种新的GABA多晶型物（III型）。形式III目前仅可通过研磨获得，其晶体结构也通过晶体结构预测（CSP）方法确定。另一方面，通过引入痕量具有不同氢键供体/受体（α/β）能力的溶剂，我们可以在研磨过程中实现对三种GABA多晶型物的选择性控制，传统的基于解决方案的方法无法访问。从不同多晶型物在研磨条件下稳定性关系的变化，研究了痕量溶剂定向多晶型产物的机理。随着研磨的进行，晶体尺寸减小并且表面效果变得显着，使得表面稳定性将主导整体稳定性。具有不同α和β值的溶剂在晶体表面的吸附将影响各种GABA多晶型物的表面稳定性。因此，具有较高稳定性的多晶型物能够在研磨条件下存活。从不同多晶型物在研磨条件下稳定性关系的变化，研究了痕量溶剂定向多晶型产物的机理。随着研磨的进行，晶体尺寸减小并且表面效果变得显着，使得表面稳定性将主导整体稳定性。具有不同α和β值的溶剂在晶体表面的吸附将影响各种GABA多晶型物的表面稳定性。因此，具有较高稳定性的多晶型物能够在研磨条件下存活。从不同多晶型物在研磨条件下稳定性关系的变化，研究了痕量溶剂定向多晶型产物的机理。随着研磨的进行，晶体尺寸减小并且表面效果变得显着，使得表面稳定性将主导整体稳定性。具有不同α和β值的溶剂在晶体表面的吸附将影响各种GABA多晶型物的表面稳定性。因此，具有较高稳定性的多晶型物能够在研磨条件下存活。具有不同α和β值的溶剂在晶体表面的吸附将影响各种GABA多晶型物的表面稳定性。因此，具有较高稳定性的多晶型物能够在研磨条件下存活。具有不同α和β值的溶剂在晶体表面的吸附将影响各种GABA多晶型物的表面稳定性。因此，具有较高稳定性的多晶型物能够在研磨条件下存活。

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Green Mechanochemical Strategy for the Discovery and Selective Preparation of Polymorphs of Active Pharmaceutical Ingredient γ-Aminobutyric Acid (GABA)

This study exploited a mechanochemical strategy to discover new polymorphs of a drug and meanwhile realize the selective preparation of various polymorphs without using bulk solvents. It is worth noting that in practice, the mechanochemical approach is a unique green and highly efficient method. On the one hand, about 20 years after the last discovery of the γ-aminobutyric acid (GABA) polymorph, we identified a new GABA polymorph (Form-III) by mechanochemical milling. Form-III is available exclusively by milling at present, and its crystal structure is also determined by crystal structure prediction (CSP) methods. On the other hand, through introducing a trace amount of solvents with different hydrogen bond donor/acceptor (α/β) abilities, we can achieve selective control of three GABA polymorphs during the milling process, which is not accessible by the traditional solution-based method. The mechanism of trace solvent-directed polymorphic outcomes was investigated from the change of the stability relationship between different polymorphs under milling conditions. As the milling proceeds, the crystal size decreases and the surface effect becomes significant so that the surface stability will dominate the overall stability. The adsorption of solvents with different α and β values on the crystal surface will affect the surface stability of various GABA polymorphs. Consequently, the polymorph with higher stability is able to survive under milling conditions.

更新日期：2020-11-16

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