Article pubs.acs.org/jced
Solubility of Naringenin in Ethanol and Water Mixtures Peipei Zhang,† Rong Lin,‡ Guangde Yang,† Jiye Zhang,†,* Li Zhou,† and Tingting Liu† †
School of Pharmacy and ‡Department of Pharmacology, School of Medicine, Xi’an Jiaotong University, Xi’an 710061, P. R. China ABSTRACT: The solubility of naringenin in the binary system of ethanol and water was measured by an ultraviolet spectrophotometer at 288 nm (the maximum absorption wavelength) from (283.15 to 323.15) K. The increasing solubility was correlated with the increasing temperature and the increasing mole fraction of ethanol in the solvent system. In the investigated experimental temperature range, the course of naringenin dissolving in the binary system was endothermic. The calculated solubility of naringenin showed good consistency with the experimental values. outer and inner walls of the flasks, circulated water was filled, the temperature of which was maintained by a thermostat (uncertainty of ± 0.1 K). A 5 mL sample of each water, absolute ethanol, and ethanol + water mixtures was added into the flasks, respectively. An excess amount of naringenin was then added into the solvents. The suspensions were stirred by magnetic stirrers for 4 h. When equilibrium was attained, the stirrers were stopped. Then about 1 mL of the suspensions was removed from the upper part of the mixture and filtered. The filtered solutions were poured into volumetric flasks and diluted to appropriate concentrations for UV analysis. The mole fraction solubility of the solute (x1) in the ethanol and water mixtures was calculated by eq 1. The solvent composition x2 is defined by eq 2.
1. INTRODUCTION Solubility evaluation is very important for the pharmaceutical product design, because the drug solubility affects the drug efficacy directly, as well as its future developments and formulation optimizations, influencing the pharmacokinetic properties, such as release, transport, and absorption.1−4 In recent years, natural compounds, especially the polyphenols and flavonoids, have been shown to have antioxidant, antiatherogenic, and normolipidemic effects.5,6 Naringenin, (C15H12O5, CAS 480-41-1) 4″,5,7-trihydroxyflavanone is an aglycon of naringin, a dihydroflavone compound, which has been reported to have the ability of reducing plasma cholesterol levels demonstrated in vivo,7,8 as well as ApoE (Apolipoprotein E) secretion demonstrated extensively in vitro.8,9 More recently, Shulman and co-workers have indicated that naringenin inhibits hepatitis C virus replication, while others have demonstrated its potential in the treatment of hyperlipidemia and diabetes.6 However, the clinical potential of naringenin is restricted because of its low oral bioavailability.2 The solubility of naringenin could be enhanced by complexation with an FDA (US Food and Drug Administration) approved excipient6 β-cyclodextrin, but the solubility data of naringenin is rarely available in the literature. In our study, the solubility of naringenin in the binary system of ethanol and water from (283.15 to 323.15) K was measured by an ultraviolet spectrophotometer.
m1/M1 m1/M1 + m2 /M 2 + m3 /M3
(1)
x2 =
m2 /M 2 m2 /M 2 + m3 /M3
(2)
where m1, m2, and m3 are the mass of the naringenin, ethanol, and water, respectively, M1, M2, and M3, respectively, represent the molecular weight of naringenin, ethanol, and water. The concentrations of naringenin in the diluted solutions were assayed by using an ultraviolet spectrophotometer; the absorbance of the standard and sample was measured at 288 nm, which is the maximum absorption wavelength of naringenin. To estimate the amount of naringenin in the solution, a calibration curve was prepared by using standard solutions in the appropriate concentration range. The solubility of the solute (x1) in the binary solvent mixtures was measured in triplicate, and the mean values were adopted and the precision of the analysis method was estimated to be less than 1.0%.
2. EXPERIMENTAL SECTION 2.1. Materials and Apparatus. Naringenin (C15H12O5, CAS 480-41-1) was supplied by Shaanxi Jiahe Phytochem Co., Ltd. (Shaanxi, China) with minimum purity of 98.0 % (mass fraction). Other reagents used, like ethanol, were of analytical grade. The ethanol in the experiment had a minimum purity of 98.0 % (mass fraction), and redistilled deionized water was used throughout. Absorbance measurements were conducted on a SP-752 UV−vis spectrophotometer (Shanghai Spectrum Instrument Co., Ltd., Shanghai, China). 2.2. Sample Preparation and Analysis. Specially designed 10 mL dual-wall flasks were utilized. Between the © 2013 American Chemical Society
x1 =
Received: December 31, 2012 Accepted: August 21, 2013 Published: September 4, 2013 2402
dx.doi.org/10.1021/je4000718 | J. Chem. Eng. Data 2013, 58, 2402−2404
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Table 1. Experimental Mole Fraction Solubilities of Naringenin (x1) in the Binary Solvent System of Ethanol and Water (x2) at Temperature from (283.15 to 323.15) K and at Pressure P = 0.1 MPaa Including the Small Discrepancy between the Experimental Data and the Calculated Values 106 x1
T/K
X2 = 0
283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15
0.397 0.463 0.662 0.927 1.125 1.876 2.542 3.508 4.038 102 x1
104 x1
(x1 − x1calc) x1/100 0.3792 0.1323 0.0517 −0.0149 −0.2048 −0.0046 0.0042 0.0616 −0.0287
T/K
X2 = 0.6
(x1 − x1calc) x1/100
283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15
0.451 0.470 0.512 0.608 0.681 0.757 0.855 0.922 1.062
0.0419 −0.0260 −0.0514 0.0112 0.0138 0.0066 0.0158 −0.0227 0.0052
103 x1
(x1 − x1calc) x1/100
X2 = 0.2
X2 = 0.4
−0.0969 0.0207 0.0791 0.0488 −0.0530 −0.0576 0.0062 0.0330 −0.0117
0.995 1.403 1.887 2.316 2.660 3.377 4.590 6.039 7.401 102 x1
1.577 1.693 2.142 2.556 3.072 3.255 3.665 4.241 5.070 102 x1
(x1 − x1calc) x1/100 0.0082 −0.0807 0.0044 0.0315 0.0676 −0.0145 −0.0353 −0.0250 0.0208
X2 = 0.8
(x1 − x1calc) x1/100
X2 = 1.0
(x1 − x1calc) x1/100
0.650 0.720 0.791 0.884 0.966 1.028 1.172 1.238 1.316
0.0085 0.0000 −0.0096 0.0038 −0.0002 −0.0248 0.0253 0.0034 −0.0074
0.863 0.881 0.920 1.018 1.140 1.231 1.366 1.471 1.584
0.0387 −0.0104 −0.0431 −0.0201 0.0120 0.0045 0.0210 0.0055 −0.0128
a The relative standard uncertainty ur for the mole fraction solubility ur(x1) is 0.05, for pressure ur(P) is 0.05, for solvent composition ur(x2) is 0.02, and the standard uncertainty u for temperature u(T) is 0.1 K.
Table 2. Parameters of Apelblat Equation for Naringenin in the Binary Solvent System of Ethanol and Water X2
0
0.2
0.4
0.6
0.8
1.0
A B C 105 rmsd
622.3364 −34138.7142 −91.5670 0.0125
−251.2400 7195.6753 38.3820 1.2951
−29.7641 −1172.6626 4.8610 11.0511
−103.8602 2710.6306 15.7355 14.9268
62.07083 −4407.5046 −9.1301 13.9194
−139.7943 4809.1640 20.9030 22.8815
3. RESULTS AND DISCUSSION 3.1. Experimental and Calculated Solubility. The experimental solubility of naringenin in mixtures of ethanol and water from (283.15 to 323.15) K are presented in Table 1. The solubility of naringenin in the mixtures of ethanol and water increases with the increasing mole fraction of ethanol and with increasing temperature. The empirical eq 310,11 was utilized to calculate the solubility (xcalc i ) of naringenin in the binary mixtures of ethanol and water as a function of temperature. ln(x1) = A +
B + C ln(T /K) T /K
N
rmsd =
∑i = 1 (xicalc − xi)2 N
(4)
Where N represents the number of experimental points, xcalc i represents the calculated mole fraction solubility, and x1 represents the experimental solubility. The experimental and calculated solubilities of naringenin at different temperatures are shown in Figures 1, 2, and 3.
4. CONCLUSIONS By using an UV spectrophotometric method, the solubility of naringenin in the binary solvent system of ethanol and water was measured at a temperature range from (283.15 to 323.15) K. The solubility of naringenin is a function of temperature in the binary solvent system. The solubility of naringenin gradually increases as the temperature increases. The solubility of naringenin also increases when the mole fraction of ethanol increases. The calculated solubilities of naringenin agree with experimental solubilities of naringenin. Therefore, the experimental data can be used in the extraction and purification process of naringenin.
(3)
Where x1 represents the mole fraction solubility of naringenin, T represents the absolute temperature, and A, B, and C are the parameters. The small discrepancy between the experimental data and the calculated values listed in Table 1 were obtained by (x1−xcalc i )/(x1/100). The values of the parameters A, B, and C are summarized in Table 2, the rootmean-square deviations (rmsd) were calculated by eq 4, and the rmsd values are also summarized in Table 2. 2403
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Figure 1. Solubility of naringenin in x2 = 0.
Figure 2. Solubility of naringenin in x2 = 0.2.
Figure 3. Solubility of naringenin in x2 = 0.4 (■), x2 = 0.6 (▲), x2 = 0.8 (⧫), x2 = 1.0 (●).
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AUTHOR INFORMATION
Corresponding Author
*Tel: +86-29-82657833. Fax: +86-29-82657833. E-mail:
[email protected]. Address: School of Pharmacy, Xi’an Jiaotong University, No. 76 Yanta Westroad, Xi’an, 710061, P. R. China. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Natural Science Foundation of Shaanxi Province (2012JQ4025) and the Fundamental Research Funds for the Central Universities (XJ08142011 and XJJ2011091). 2404
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