Temperature Dependence of the Complexation Mechanism of Celecoxib and Hydroxyl-β-cyclodextrin in Aqueous Solution

Pharmaceutics

Po-Chiang Chiang²  Yue Shi¹ 

[1] Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; E-Mail:;Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA

关键词: molecular dynamics simulation;    transition state;    hydroxypropyl-β-cyclodextrin;    celecoxib;    solubilization;    complexation;   

DOI  :  10.3390/pharmaceutics6030467

来源: mdpi

【 摘 要 】

Hydroxypropyl-β-cyclodextrin (HP-β-CD) is commonly used as a complexation reagent to solubilize compounds with poor aqueous solubility to improve in vivo dosing. However, the degree of solubility enhancement was often limited by the formation of only a 1:1 complex and a low complexation constant (K). Such a limitation can be significantly improved by the formation of 1:2 complexes in some cases. Despite the understanding of the solubility advantage of the formation of the 1:2 complexes, there is no systematic understanding that could drive for the formation of 1:2 complexes. Thus, in most cases, the formation of 1:2 complexes was limited by observation bases. In this study, we pioneer the usages of molecular dynamics (MD) simulation to understand the phenomena of a model drug of celecoxib (CCB) and HP-β-CD. It has been reported that celecoxib (CCB) forms 1:1 complexes with cyclodextrin in solution; however, some data suggest the existence of a 1:2 complex. The simulation results suggest that a transition state of CCB and HP-β-CD may exit at a higher temperature of CCB and HP-β-CD; a model drug, such as celecoxib (CCB), that is known to form 1:1 complexes can achieve a higher degree of complexation (1:2) and obtain much improved solubility when the same amount of cyclodextrin was used and demonstrated in vitro. The simulation results of CCB and HP-β-CD could be a model system that may provide important insights into the inclusion mechanism.

【 授权许可】

CC BY   
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