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.
Highlights
Time and resource constraints increasingly often necessitate early decision-making to accelerate or stop pre-clinical drug discovery programs
(hereafter, referred to as 298 °K samples), a linear curve was found (AL-type systems). This suggests the formation of a first-order complex between CCB and HP-β-CD
It is known that the efficiency of the solubilization of drugs in HP-β-CD can be significantly improved by the formation of a 1:2 complex and become much more useful to prepare formulations
Summary
Time and resource constraints increasingly often necessitate early decision-making to accelerate or stop pre-clinical drug discovery programs. Discovery drug candidates may be potent inhibitors of new targets, but all too often exhibiting poor pharmaceutical and pharmacokinetic properties that have limited in vivo exposure, often making early assessment of in vivo efficacy and target safety very challenging. In the pre-clinical setting, one of the biggest problems for oral drug delivery is the solubility and dissolution rate-limited absorption. When such an issue is encountered, enabling formulations are often used to help solubilize compounds. Cyclodextrin (CD) inclusion is a technique widely used in the pharmaceutical industry to enhance drug solubility [1,2,3]. The mechanistic nature and driving forces remain fragmentary for some critical characteristics of the inclusion complexes, which include the stoichiometric ratios of the complexes, the inclusion efficiency or the complex stability and the role of cyclodextrin self-aggregation in the complex formation [4,5]
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