Computational approach to elucidate the formation and stabilization mechanism of amorphous formulation using molecular dynamics simulation and fragment molecular orbital calculation
Computational approach to elucidate the formation and stabilization mechanism of amorphous formulation using molecular dynamics simulation and fragment molecular orbital calculation
复制标题
利用分子动力学模拟和碎片分子轨道计算阐明无定形制剂的形成和稳定机制的计算方法
DOI：
10.1016/j.ijpharm.2022.121477
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发表时间：
2022
影响因子：
5.8
通讯作者：
Moribe Kunikazu
中科院分区：
文献类型：
--
作者：
Ma Xiaohan;Higashi Kenjirou;Fukuzawa Kaori;Ueda Keisuke;Kadota Kazunori;Tozuka Yuichi;Yonemochi Etsuo;Moribe Kunikazu
α-糖基芦丁（rutin - g）由黄酮醇骨架和糖基组成，是一种很有前途的无定形配方添加剂。在我们之前的研究中，实验方法表明模型药物卡马西平（CBZ）和芦丁- g的黄酮醇骨架之间的相互作用稳定了无定形制剂。本文采用计算方法研究了CBZ/芦丁- g非晶配方的形成和稳定机理。采用分子动力学（MD）模拟方法得到了CBZ/芦丁- g非晶配方。均方根偏差分析表明，加入芦丁- g抑制了CBZ在冷却过程中的平移运动。在冷却过程中对原子距离的监测表明，CBZ的羧胺氧与芦丁- g的羟基氢优先与黄酮醇骨架形成氢键，而不是糖基。然后用片段分子轨道（FMO）方法计算模拟的非晶态配方。多重相互作用的定量评价表明，cbz -糖基团的氢键能高于cbz -黄酮醇骨架，而cbz -黄酮醇骨架的π型相互作用能高于cbz -糖基团。结合MD模拟和FMO计算的计算方法提供了难以用实验方法检测到的各种相互作用的信息，有助于理解非晶配方的形成和稳定机制。
α-Glycosyl rutin (Rutin-G) consists of a flavonol skeleton and sugar groups and is a promising additive for amorphous formulations. In our previous study, experimental approaches suggested an interaction between the model drug carbamazepine (CBZ) and flavonol skeleton of Rutin-G that stabilizes amorphous formulations. In the present study, the formation and stabilization mechanisms of CBZ/Rutin-G amorphous formulation were investigated using a computational approach. The CBZ/Rutin-G amorphous formulation was obtained via molecular dynamics (MD) simulation, which mimicked the melt-quenching method. Root mean square deviation analysis revealed that the translational motion of CBZ during the cooling process was suppressed by adding Rutin-G. Monitoring the atomic distance during the cooling process revealed that hydrogen bonds via carboxamide oxygen of CBZ with hydroxyl hydrogen of Rutin-G were preferentially formed with flavonol skeletons than sugar groups. The simulated amorphous formulation was then calculated using fragment molecular orbital (FMO) method. The quantitative evaluation of multiple interactions revealed that the hydrogen bond energy was higher in CBZ-sugar groups than in CBZ-flavonol skeleton, while the π-type of interaction energy was higher in CBZ-flavonol skeleton than in CBZ-sugar groups. The computational approach combining MD simulation and FMO calculation provides information on various interactions that are difficult to detect using experimental approaches, which helps understand the formation and stabilization mechanism of amorphous formulations.