Elsevier

Journal of Molecular Structure

Volume 1118, 15 August 2016, Pages 307-315
Journal of Molecular Structure

Host-guest inclusion systems of daidzein with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD): Preparation, binding behaviors and water solubility

https://doi.org/10.1016/j.molstruc.2016.04.040Get rights and content

Highlights

  • Host-guest inclusion complexes of daidzein with HP-β-CD and SBE-β-CD were prepared and extensively characterized.

  • Binding behaviors of inclusion complexes were elucidated and inclusion modes were proposed.

  • Water solubility of daidzein was increased significantly by inclusion complexation with HP-β-CD and SBE-β-CD.

Abstract

Daidzein is an isoflavone of naturally abundance existing in plants and foods which has attracted much attention for its significant benefits on human health. However, its application was severely limited by its poor solubilities, instability and low bioavailability. To overcome these drawbacks, inclusion complexes of daidzein with two cyclodextrin (CD) derivatives, i.e., 2-hydropropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) were prepared and characterized both in solution and solid state by 1D and 2D NMR, XRD, SEM and elemental analyses. Fluorescence spectroscopy and the Job plot were used to demonstrate a mainly 1:1 inclusion mode between daidzein and CDs. Their thermal stabilities were evaluated with TG and DSC experiments. Moreover, water solubility of daidzein was significantly improved by inclusion complexation with CDs. These results might suggest valuable approaches to developments of new pharmaceutical formulations of daidzein.

Introduction

Daidzein (4′,7-dihydroxy-isoflavone, Fig. 1) is an isoflavone of natural abundance mainly from leguminous plants and soybean products. It possesses many biological activities which are important to human health such as prevention of cardiovascular diseases [1] and menopausal symptoms [2], antidiabetes [3], [4], antioxidant activities [5], [6], [7], [8], bone protection [9], [10] and antitumor activities, especially to human hepatic [11], prostate [12], and colon cancer cells [13]. Furthermore, daidzein has exhibited varies estrogen-depended health benefits through its metabolite S-equol produced by intestinal bacteria [14], [15]. However, the application of daidzein has been severely hindered by its low water solubility, poor stabilities, poor oral absorption, unfavorable metabolism, uterine estrogenicity and low bioavailability [16], [17].

Cyclodextrins (CDs) are a series of cyclic oligosaccharides consisting of d-glucose units linked by α-1,4-glucosidic bonds, usually produced from starch in the presence of cyclodextrin glucosyl transferase (CGTase). The most common CDs are α-, β-, and γ-CD, which consists of 6, 7 and 8 d-glucose monomers respectively. CDs have many virtues such as solubilization, stabilization, removing odors, enhancing bioavailability and donating targeted-delivering properties of drugs [18], [19]. They have hydrophobic central cavities and hydrophilic external walls, which endow them with the salient ability of forming inclusion complexes with numerous guest molecules. In our group, the preparation and properties of inclusion complexes of CDs with natural products including mangiferin [20], 3-tigloyl-azadirachtol [21], artemether [22], [23], scutellarein [24], norathyriol [25] were successfully conducted in recent years. In most cases, the inclusion complexation of CDs significantly enhanced water solubility, stability and bioavailability of the guest compounds.

β-CD is the most frequently used one owing to its readily availability and cheapness among CDs. However, pharmaceutical application of native β-CD is usually hampered by its relatively low water solubility [26] and hemolytic effects [27], [28]. Thus β-CD derivatives such as methyl-β-cyclodextrin (M-β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) were developed to overcome such drawbacks of β-CD [29], [30], [31]. Particularly, the latter two have underwent rigorous safety tests and been applied to several drugs and lots of pre- and clinical chemical entities [32]. They are both chemically modified on the hydroxyl groups of β-CD (Fig. 2) and have superior pharmaceutical properties such as excellent water solubility and much lower toxicities. Recently, conjugates [33], [34] and complexes [35], [36], [37], [38], [39] of daidzein with biocompatible carbohydrate units were established to improve the physiochemical properties of daidzein. However, SBE-β-CD has not been used except the reported β- and γ-CD, M-β-CD and HP-β-CD, and it was not so extensively studied when concerning HP-β-CD. In this paper, we reported the preparation and extensive characterization of inclusion complexes of daidzein with HP-β-CD and SBE-β-CD. The binding behaviors, thermal stability and water solubility of the inclusion complexes were elucidated. This could provide a useful approach to novel daidzein-based formulations with higher thermal stability, water solubility and bioavailability.

Section snippets

Materials

Daidzein (MW: 254.24, >98%) was purchased from Aladdin Industrial Corporation in Shanghai, China. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD, average MW: 1541) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD, average MW: 1451) were purchased from Xi'an Deli Biochem Co. Ltd in Shaanxi, China. Other chemical reagents were of analytical grade. All experiments were carried out using ultrapure water.

Preparation of solid inclusion complexes and physical mixtures of daidzein/HP-β-CD and daidzein/SBE-β-CD

Solid inclusion complexes of daidzein/HP-β-CD and daidzein/SBE-β-CD were prepared by suspension method [40]

Stoichiometry

The stoichiometry of daidzein/CD complexes in solution was obtained from the Job plot with fluorescence spectroscopy. As showed in Fig. 3(A), the plot of daidzein/HP-β-CD showed a maximal peak at the molar fraction of 0.5, which indicated a 1:1 inclusion complexation between the host (HP-β-CD) and the guest (daidzein). However, a shoulder at about 0.66 was observed in addition to the maxima at 0.5 concerning the inclusion complex of daidzein/SBE-β-CD from Fig. 3(B), which indicated mixed

Conclusions

In summary, daidzein/HP-β-CD and daidzein/SBE-β-CD inclusion complexes were successfully prepared and were characterized by spectral titration, NMR, XRD, DSC and SEM. The binding behaviors of daidzein with CDs were extensively elucidated. The stability constants were also obtained. The water solubility of daidzein was significantly improved by inclusion complexation with CDs. This indicated that inclusion complexes of daidzein/HP-β-CD and daidzein/SBE-β-CD might be novel promising formulations

Acknowledgments

This work was financially supported by National Natural Science Foundation of China (No. 21362016) and Kunming University of Science and Technology. The authors would also like to thank Mr. Congtao Yu and Mr. Pin Lv for assistance on NMR and elemental analyses.

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