title: Temperature Dependence of the Complexation Mechanism of Celecoxib and Hydroxyl-β-cyclodextrin in Aqueous Solution.
abstract: 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.
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Chiang.pochang@gene.com.
authors.forename: Po-Chiang
authors.initials: PC
authors.lastname: Chiang
authors.affiliation: Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA. shiyue8638@gmail.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Hisun-Pfizer, Shanghai 200041, China. Yong.Cui@hisun-pfizer.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cui