Investigation of molecular aggregation mechanism of glipizide/cyclodextrin complexation by combined experimental and molecular modeling approaches  

作　　者：Tianhe Huang Qianqian Zhao Yan Su Defang Ouyang 

机构地区：[1]State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macao

出　　处：《Asian Journal of Pharmaceutical Sciences》2019年第6期609-620,共12页亚洲药物制剂科学（英文）

基　　金：supported by the University of Macao Research Grants(MYRG2016-00038-ICMS-QRCM and MYRG2016-00040-ICMS-QRCM);in part at the High-Performance Computing Cluster(HPCC)which is supported by Information and Communication Technology Office(ICTO)of the University of Macao

摘　　要：Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of waterinsoluble drugs.However,the aggregation mechanism of drug-cyclodextrin complexes is still unclear.This research aimed to investigate the molecular aggregation mechanism of glipizide/cyclodextrin complexation by the combination of experimental and modeling methods.Binding free energies between glipizide and cyclodextrins from modeling calculations were higher than those by the phase solubility diagram method.Both experimental and modeling results showed that methylated-β-cyclodextrin exhibited the best solubilizing capability to glipizide.Size-measurement results confirmed the aggregation between glipizide and all four cyclodextrins in high concentrations.Glipizide/γ-cyclodextrin and glipizide/β-cyclodextrin complexes showed stronger aggregation trend than HP-β-cyclodextrin and methylated-β-cyclodextrin.The substituted groups in the rim of HP-β-cyclodextrin and methylated-β-cyclodextrin lead to weak aggregation.This research provided us a clear molecular mechanism of glipizide/cyclodextrin complexation and aggregation.This research will also benefit the formulation development of cyclodextrin solubilization.Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of waterinsoluble drugs. However, the aggregation mechanism of drug-cyclodextrin complexes is still unclear. This research aimed to investigate the molecular aggregation mechanism of glipizide/cyclodextrin complexation by the combination of experimental and modeling methods. Binding free energies between glipizide and cyclodextrins from modeling calculations were higher than those by the phase solubility diagram method. Both experimental and modeling results showed that methylated-β-cyclodextrin exhibited the best solubilizing capability to glipizide. Size-measurement results confirmed the aggregation between glipizide and all four cyclodextrins in high concentrations. Glipizide/γ-cyclodextrin and glipizide/β-cyclodextrin complexes showed stronger aggregation trend than HP-β-cyclodextrin and methylated-β-cyclodextrin. The substituted groups in the rim of HP-β-cyclodextrin and methylated-β-cyclodextrin lead to weak aggregation. This research provided us a clear molecular mechanism of glipizide/cyclodextrin complexation and aggregation. This research will also benefit the formulation development of cyclodextrin solubilization.

关 键 词：GLIPIZIDE CYCLODEXTRIN MOLECULAR modeling AGGREGATION MOLECULAR MECHANISM 

分 类 号：O62[理学—有机化学]