基于计算药剂学探究L-缬氨酸对加巴喷丁稳定性影响的机制  

Investigation on Mechanism of the Effect of L-Valine on Gabapentin Stability Based on Computational Pharmacy

作　　者：王嘉新 杨理想 许莹 王浩[1] 栾瀚森[1] WANG Jiaxin;YANG Lixiang;XU Ying;WANG Hao;LUAN Hansen(National Pharmaceutical Engineering Research, China State Institute of Pharmaceutical Industry, Shanghai 201203;School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093;School of Pharmacy, Fudan University, Shanghai 201203)

机构地区：[1]中国医药工业研究总院药物制剂国家工程研究中心,上海201203 [2]上海理工大学医疗器械与食品学院,上海200093 [3]复旦大学药学院,上海201203

出　　处：《中国医药工业杂志》2019年第6期638-645,共8页Chinese Journal of Pharmaceuticals

基　　金：上海市科学技术委员会科研计划项目(18DZ2290500)

摘　　要：本研究旨在探讨L-缬氨酸(L-Val)对加巴喷丁(1)稳定性的影响,并阐述其机制。通过不同方式(如物理混合、研磨和流化床处理)向1原料药中加入L-Val,并考察不同体系在高温下的稳定性。采用扫描电镜和显微拉曼光谱对不同方法得到的1/L-Val体系进行表征。应用量子化学密度泛函理论结合计算药剂学对L-Val与1分子间的相互作用进行计算模拟。结果表明L-Val能有效抑制3,3’-亚戊基丁内酰胺(2)的生成。将1和L-Val溶液采用流化床工艺处理,可提高1稳定性。通过扫描电镜和显微拉曼光谱观察表明,经流化床喷入L-Val溶液处理的1,在1晶体表面会形成L-Val的覆盖层。经计算机模拟得知,1能通过氢键与L-Val结合形成稳定的复合物,且形成复合物后的过渡态自身缩合能垒由147.86 kJ/mol升高至524.12 kJ/mol,抑制了1自身环合生成2。The aim of this paper was to investigate the effect of L-valine(L-Val) on the stability of gabapentin(1), and explain the mechanism. The 1/L-Val systems prepared differently by physical mixing, grinding and fluidizedbed were stored under high temperature conditions to investigate the stability through determining the content changes of gabapentin-lactam(2), the resulting product of intramolecular condensation. The surface properties of free 1 and different1/L-Val systems were characterized by scanning electron microscopy(SEM) and laser confocal micro-Raman(LCMRaman). The quantum chemical density functional theory was combined with computational pharmaceutics to simulate and calculate the interaction between L-Val and 1. The experimental results showed that L-Val could inhibit the formation of 2 effectively. The stability of complex of 1 and L-Val prepared by fluidized-bed process was significantly improved.The results of SEM and LCM-Raman revealed that L-Val sprayed in the fluidized-bed could form a coating layer on the surface of 1. According to the computer simulation results, a stable complex, 1/L-Val complex, could be formed by hydrogen bonding, and the self-condensation energy barrier of the transition state of complex was significantly improved from 147.86 kJ/mol to 524.12 kJ/mol. The results showed that 1 could form a stable complex with 2 through hydrogen bonding, thereby the formation of 2 was inhibited and the stability of 1 was improved.

关 键 词：加巴喷丁 L-缬氨酸 稳定性 氢键 复合物 能垒 计算药剂学 

分 类 号：R971[医药卫生—药品]