Study of freeze-dried quercetin–cyclodextrin binary systems by DSC, FT-IR, X-ray diffraction and SEM analysis

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Abstract

The inclusion behavior of 2-hydroxypropyl β-cyclodextrin (HPβCD) and β-cyclodextrin (βCD), in solution and solid-state was studied towards a poorly water-soluble bioflavonoid, quercetin (QURC), chemically 3,3′,4′,5′,7-pentahydroxy flavone. Drug-cyclodextrin solid systems were prepared by freeze-drying. Phase solubility study was used to evaluate the complexation in solution, of two cyclodextrins, i.e., βCD and HPβCD. The stoichiometry and stability constants of QURC-βCD (1:1 and 402 M−1) and QURC-HPβCD (1:1 and 532 M−1) complexes were calculated by phase solubility method. The formation of inclusion complexes with βCD and HPβCD in the solid-state were confirmed by infrared spectroscopy, differential scanning calorimetry, X-ray diffractometry, and scanning electron microscopy (SEM).

Introduction

Flavonoids have a broad pharmacological profile such as antilipoperoxidant [1] and anti-inflammatory [2] properties and the ability to exert anticancer and chemopreventive activities [3], [4]. Quercetin, 3,3′,4′,5′-7-pentahydroxy flavone, a polyphenolic flavonoid, extremely hydrophobic in nature, is a component of onion. Quercetin shows several biological effects including a strong inhibitory effect on the growth of several human and animal cancer cell lines [5], [6] and enhances the antiproliferative effect of cisplatin both in vitro and in vivo [7]. In spite of this wide spectrum of pharmacological properties, its use in pharmaceutical field is limited by its low aqueous solubility. In recent years, cyclodextrin complexation has been successfully used to improve solubility, chemical stability and bioavailability of a number of poorly soluble compounds. The β-cyclodextrin (βCD) is α-1,4-linked cyclic oligosaccharide composed of seven d-glucopyranose units with a relatively hydrophobic central cavity [8]. However, it is known that the application of β-cyclodextrin in the pharmaceutical field is limited by its rather low aqueous solubility, which led to a search for more soluble derivatives of cyclodextrins [8], [9]. Recently, various hydrophilic, hydrophobic and ionic cyclodextrin derivatives have been successfully utilized to extend physicochemical properties and inclusion capacity of natural cyclodextrin [10], [11]. Hydrophilic cyclodextrins can modify the rate of drug release for the enhancement of drug absorption across biological barriers. Amorphous cyclodextrins such as 2-hydroxypropyl β-cyclodextrin is useful for inhibition of polymorphic transition and crystallization rates of poorly water-soluble drugs during storage, which can consequently maintain the higher dissolution characteristics and oral bioavailability of the drugs [12].

In the present study solubilization of quercetin was achieved by complexation with natural β-cyclodextrin and its 2-hydroxypropyl derivative. The stoichiometry and stability constant of the complexes were determined by evaluating drug-cyclodextrin interactions in solution using phase solubility analysis. Drug-cyclodextrin solid systems were prepared by method of freeze-drying. Additional information on the complexing efficacies of the two cyclodextrins toward quercetin was obtained by differential scanning calorimetry, FT-IR, powder X-ray diffractometry and scanning electron microscopy (SEM).

Section snippets

Materials

Quercetin (QURC) was purchased from S.D. Fine Chemicals (Mumbai, India) β-cyclodextrin and 2-hydroxypropyl β-cyclodextrin were kindly provided by S.A. Chemicals (Mumbai, India). All other reagents and solvents used were of analytical grade.

Phase solubility studies

Solubility measurements were performed according to Higuchi and Connors [13]. Excess amounts of drug were added to 10 ml of water or aqueous solution of CDs (0.003–0.015 M concentration range) in 25 ml stoppered conical flasks and shaken at 25±0.5 °C. At

Solubility studies

Phase solubility diagrams of QURC-βCD and QURC-HPβCD are shown in Fig. 1, Fig. 2, respectively. Phase solubility diagrams obtained with βCD and HPβCD showed a linear relationship between the amount of QURC solubilized and the concentration of cyclodextrin in solution (AL type diagram). According to Higuchi and Connors theory [13], this may be attributed to the formation of soluble 1:1 QURC-cyclodextrin inclusion complexes. Stability constant obtained for QURC was in the rank order of HPβCD (532 M

Conclusions

Through complexation with the two cyclodextrins, βCD and HPβCD, the aqueous solubility of QURC has been improved substantially (up to 10-fold) in neutral aqueous solutions. All the data obtained from FT-IR, DSC, X-ray diffraction and SEM studies showed that it is possible to obtain an inclusion complex with a stoichiometry of 1:1, in the solid-state and in aqueous solution, with an overall complexing ability that is slightly greater for the HPβCD derivative. Thus, βCD and its derivatives may be

Acknowledgements

The authors are grateful to Indian Institute of Technology (IIT), Mumbai and Tata Institute of Fundamental Research (TIFR), Mumbai for help in performing characterization studies. Financial support from University Grants Commission (UGC), Government of India, New Delhi is gratefully acknowledged.

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