Preparing active pharmaceutical ingredients (APIs) by designing methods with the concept of “green production” is challenging. In this study, an efficient mechanochemical salinization method was developed to prepare trelagliptin succinate (TRE-S), the first once-weekly oral treatment drug for type II diabetes. Trelagliptin (TRE), trelagliptin ethanol solvate (TRE-Et), trelagliptin methanol solvate (TRE-Me), and TRE-S were prepared and characterized via different analytical techniques. Various trelagliptin solid forms were assessed to verify the efficacy of forming TRE-S by the milling method. Intriguingly, TRE-S could be obtained by milling trelagliptin solvates and succinic acid (SA) with a mole ratio of 1 : 1. However, only amorphous solid forms were obtained by milling the mixture of TRE and SA. Liquid-assisted grinding of TRE and SA with ethanol or methanol could also prepare TRE-S. We have attempted to unearth the reaction mechanism for the formation of TRE-S via the ball-milling method. This work illustrates that similar intermolecular interactions in crystals and any factor inducing proton transfer have a vital role in the formation of API salts by mechanochemistry.

中文翻译：

---

固体化学成分对海藻糖素的直接盐化作用机理及其成盐机理

通过具有“绿色生产”概念的设计方法来制备活性药物成分（API）具有挑战性。在这项研究中，开发了一种有效的机械化学盐化方法来制备琥珀酸曲拉格汀（TRE-S），这是第一种每周一次的II型糖尿病口服治疗药物。制备了Trelagliptin（TRE），trelagliptin乙醇溶剂化物（TRE-Et），trelagliptin甲醇溶剂化物（TRE-Me）和TRE-S，并通过不同的分析技术。评估了各种曲拉格列汀固体形式，以验证通过研磨方法形成TRE-S的功效。有趣的是，可以通过研磨海藻糖蛋白溶剂化物和琥珀酸（SA）的摩尔比为1：1来获得TRE-S。但是，通过研磨TRE和SA的混合物只能得到无定形固体形式。用乙醇或甲醇对TRE和SA进行液体辅助研磨也可以制备TRE-S。我们试图通过球磨法揭示出形成TRE-S的反应机理。这项工作表明，在晶体中类似的分子间相互作用以及任何诱导质子转移的因素在通过机械化学形成API盐中都起着至关重要的作用。