Article pubs.acs.org/jced
Solubilities of Three Flavonoids in Different Natural Deep Eutectic Solvents at T = (288.15 to 328.15) K Ning Tang, Jialun Zhong, and Weidong Yan* Department of Chemistry, Zhejiang University, Hangzhou, 310027, China S Supporting Information *
ABSTRACT: The solubilities of phloretin, phlorizin, and naringin dihydrochacone (naringin DC) respectively were determined in a ternary system made of natural deep eutectic solvents (NADES) at the temperature range from 288.15 to 328.15 K with an analytical method. Compared with the solubility of phloretin in water, there was a dramatic improvement in the solubility of phloretin in the selected NADES, especially in CCiH and CSH. The density and viscosity of four kinds of NADES choline chloride + glucose + H2O, choline chloride + citric acid + H2O, citric acid + glucose + H2O, and choline chloride + sucrose + H2O were studied in this work. The solubility data were correlated with Apelblat equation and λh equation. The fitted results showed that the models are capable of representing the data with high accuracy.
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flavonoids is the scavenging of oxygen-derived free radicals. In vitro experimental systems also showed that flavonoids possess anti-inflammatory, antiallergic, antiviral, and anticarcinogenic properties.8 Reliable solubility data for complex molecules such as natural products and pharmaceutical drugs are essential in the selection of a suitable solvent or solvent mixture of a new active compound and design of the crystallization processes. To effectively separate the flavonoids from plant extracts with NADES instead of traditional solvents, it is necessary to determine the solubilities of flavonoids in these novel green solvents. The solubility of phloretin, phlorizin, and naringin dihydrochacone (naringin DC) (Figure 1) was measured in these selected NADES by an analytical method9 using highperformance liquid chromatography (HPLC). The solubility data of phloretin, phlorizin, and naringin DC in selected NADES were correlated with the Apelblat equation10,11and λh equation.12,13
INTRODUCTION Solvents occupy a strategic status in the area of green chemistry. As is known to all, common organic solvents have a negative influence on the environment because of their inherent toxicity and high volatility. Over the past two decades, with a high expectation to replace common organic solvents, room temperature ionic liquids (RTILs) have gained enormous attention particularly in the fields of catalysis, electrochemistry, drug delivery, and biocatalytic process.1 However, many reports have pointed out the potential toxicity and very poor biodegradability of most ILs.2 These drawbacks together with the high price of common ILs unfortunately hamper their application in the real chemistry industry. The natural deep eutectic solvents (NADES) were used as a new kind of solvents recently.3 NADES not only share the same advantages with ionic liquids (ILs), but also fully follow green chemistry principles such as low toxicity, sustainability, biodegradability, and low cost.4 In recent researches, deep eutectic solvents (DESs) showed comparable separation performance to those of ILs,5 and they were also expected to be good absorbents for CO2 capture in postcombustion or precombustion processes.6 In this study, different combinations of deep eutectic solvents from natural products were made through a heating method.7 We mainly focused on the NADES composed of choline chloride, glucose, citric acid, and sucrose, such as choline chloride + glucose + H2O (CGH), choline chloride + citric acid + H2O (CCiH), citric acid + glucose + H2O (CiGH), and choline chloride + sucrose + H2O (CSH). Flavonoids are widely distributed in fruit, vegetables, grains, bark, roots, stems, flowers, tea, and wine, which were known for their beneficial effects on health long before flavonoids were isolated as bioactive compounds. An important effect of © XXXX American Chemical Society
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EXPERIMENTAL SECTION Materials. The phloretin (pink powder, >0.95 mass fractions), phlorizin (yellow powder, >0.95 mass fractions), and naringin DC (white powder, >0.90 mass fractions) (Table 1) were supplied by Skyherb Ingredients Co., Ltd. All the materials were recrystallized to get a higher purity before measurement. For example, 10 g of naringin DC was dissolved in 200 mL of the distilled water at 80 °C, stirred for 2 h, filtered, and cooled naturally to room temperature. After three times recrystallization, Special Issue: Proceedings of PPEPPD 2016 Received: July 1, 2016 Accepted: November 8, 2016
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DOI: 10.1021/acs.jced.6b00552 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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Table 2. Selected Combinations of NADES from Natural Products Made through the Heating Method component
a
name
1
2
3
mole ratio
water (wt %)a
CiGH CCiH CGH CSH
citric acid choline chloride choline chloride choline chloride
glucose citric acid glucose sucrose
water water water water
1:1:12 1:1:11 1:1:11 1:1:10
36.71 37.37 38.24 27.19
Standard uncertainties u are u(wt) = 0.01; ur(ratio) = 0.01.
5000M, Anton Paar, Austria) at a range of temperatures T = (293.15 to 323.15 K) at atmospheric pressure p = 0.1 MPa. The standard uncertainty of the pressure was 1.0 KPa. The density meter was checked by itself, and it was calibrated with dried air and double-distilled water. The relative standard uncertainty of the density was estimated to be ur = 0.001. The viscosity test was performed using a rolling ball viscometer (AMVn viscometer, Anton Paar, Austria) at the temperature T = (293.15 to 323.15 K) and pressure p = 0.1 MPa. The standard uncertainty of the pressure was 1.0 KPa. The viscometer was calibrated with double-distilled water. The relative uncertainty of viscosity was 0.005. Sample Preparation. Glass centrifuge tubes (5 mL) with caps were used to prepare saturated solutions with excess solid solute in different NADES, and each sample repeated for three times. The tube was gastight, where the cap was screwed and tightened with a sizable rubber band. Then the tubes were directly placed in a constant temperature thermostatic bath (THD-2006, Ningbo Tianheng Instrument Works Co., Ltd., China) with an uncertainty of u(T) = 0.01 K. The tubes were allowed to settle about 36 to 48 h to ensure equilibrium after agitation. Samples were withdrawn from the clear saturated solution using preheated syringes with 0.45 μm filter membrane. The syringes with a saturated solution were weighed by a precision analytical balance (CP225D, Sartorius, Germany) with an uncertainty of u(m) = 0.01 mg. The needle was closed with silicon rubber to prevent evaporation of solvents during the weighing procedure. To prevent precipitation, the saturated solution should be injected into the 10 mL volumetric flask immediately. Later, the mass of the glass syringe with the remaining solution was weighed. Then the mass of saturated solution which was put into the 10 mL volumetric flask was calculated by the decrement method. The samples used for HPLC analysis were diluted with methanol to volume. Every sample was HPLCanalyzed twice. Chromatographic Conditions. The solubility was determined using a HPLC system (Shimadzu Corporation, Kyoto, Japan) consisting of a degasser (DGU-4A), a solvent delivery
Figure 1. Chemical structures of phloretin (a); phlorizin (b); naringin DC (c).
and dried in a vacuum oven at 110 °C for 24 h, about 8 g of white needle-like solid was obtained, and it was stored in a desiccator to avoid moisture absorption. The recrystallization process of phloretin and phlorizin were the same as that for naringin DC. The purity of phloretin, phlorizin, and naringin DC were more than 0.99 mass fractions, determined by HPLC (Shimadzu LC-10AT). NADES Preparation. All the chemical reagents used to obtain NADES were listed in Table 1. We used a heating method to prepare NADES. This method was employed to obtain NADES with a known amount of water. Components were weighed and mixed together at a certain molar ratio (Table 2), the synthesis was carried out in a bottle with a stirring bar and cap and heated in a water bath below 50 °C with agitation until a clear liquid was formed (about 30−90 min). Then, the obtained solvents were equilibrated for more than 2 h at room temperature in a capped flask to make the components mix completely. Choline chloride, glucose, citric acid and sucrose were selected to be mixed to make different combinations of NADES. Physicochemical Properties Tests of NADES. The density test was performed with a high accurate density meter (DMA
Table 1. Source and Mass Fraction Purity of the Chemicals Used in This Work at Temperature T = 298.15 K and pressure p = 0.1 MPaa
a
chemicals
CAS registry number
phloretin phlorizin naringin DC choline chloride citric acid glucose sucrose
60-82-2 60-81-1 18916-17-1 67-48-1 77-92-9 50-99-7 57-50-1
source Skyherb Skyherb Skyherb Sinopharm Sinopharm Sinopharm Sinopharm
Chemicals Chemicals Chemicals Chemicals
initial mass fraction purity
purification method
final mass fraction purity
analysis method
0.95 0.95 0.90 0.99 0.995 0.995 0.995
recrystallization recrystallization recrystallization
>0.99 >0.99 >0.99
HPLCa HPLC HPLC
High performance liquid chromatography. B
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module (LC-10AT), and UV detector (SPD-10A). Data were acquired using the N2000 Chromatographic Data System (Zheda information and Technologies Ltd., Hangzhou, China). The analysis was performed on a Diamonsil C18 column (250 mm × 4.6 mm, 5 μm) by an external standard method. The optimum separation of HPLC was carried out with a mobile phase composed of acetonitrile and water in a volume ratio of 30:70 (while phloretin was 40:60) at a flow rate of 1.0 mL/min. The injected volumes of sample and reference standard solutions were 20 μL. The detection wavelength was set at 280 nm. Differential Scanning Calorimetry. Thermal analysis was carried out for phloretin, phlorizin, and naringin DC using a differential scanning calorimeter calibrated with indium (Q100, TA Instruments, USA). A 15.6500 mg sample of indium was used as the inert reference to calibrate the heat flow and temperature at a heating rate of 10 K/min dependent upon purge gas. The cell constant is calculated as the ratio of the theoretical heat of fusion of indium to the measured heat of fusion. So the cell constant was equal to 28.71/28.51 = 1.007. The samples (3 to 4 mg) were sealed in aluminum crimp pans and heated at the rate of 10 K/min from onset point 303 K to maximum point 573 K in the atmosphere of nitrogen to get the melting point temperature.
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RESULTS AND DISCUSSION
Thermal Analysis of Phloretin, Phlorizin, and Naringin DC. The results of DSC measurements of phloretin, phlorizin, and naringin DC were shown in Figure 2. The melting point Figure 3. Density (a) and viscocity (b) of four kinds of NADES: □, CiGH; ▲, CCiH; ▽, CGH; ●, CSH.
Solubility Data of Phloretin, Phlorizin, and Naringin DC in NADES. The mole fraction solubility (x) of solute in a solvent can be calculated by eq 1: x=
mA /MA 3
mA /MA + ∑i = 1 mi /Mi
(1)
where mA and MA refer to the mass and molecule weight of the solute. mi and Mi represent the mass and molecule weight of solvent i. The mole fraction solubility data of phloretin, phlorizin, and naringin DC in different NADES from (288.15 to 328.15) K at atmospheric pressure are presented in Table 4 and plotted in Figure 4. From Table 4 and Figure 4, it can be seen that the solubility of three flavonoids in a given solvent improves with the increase of temperature, which is similar to the dissolution process of solid solute in common organic solvents. Compared with the solubility of phloretin in water,9 the solubility of phloretin was improved dramatically in the selected NADES, especially in CCiH and CSH. The comparison between the solubility of phloretin in NADES and water was shown in Figure 5. This phenomenon also happened on naringin DC. The solubility of naringin DC in NADES increased about 10−30 times at 25 °C, compared with its solubility in the water we previously tested. The results demonstrated that both phlorizin and naringin DC usually have good solubility in CiGH, CCiH, and CGH. According to Table 4, the solubility data of phlorizin and naringin DC in CCiH were approximately the same as CGH, and they were usually higher than CiGH. So the component choline chloride may contribute a lot to the solubility of flavonoids in NADES.
Figure 2. Experimental heat flow from DSC measurement: 1, phloretin; 2, phlorizin; 3, naringin DC.
(Tm) and enthalpy of fusion (ΔfusH) of phloretin, phlorizin, and naringin DC were found to be 269.81 °C and 56.44 kJ·mol−1, 103.17 °C and 50.93 kJ·mol−1, 159.07 °C and 29.63 kJ·mol−1, u(Tm) = 0.5K and ur (ΔfusH) = 0.03, respectively. Physical Properties of NADES. The density and viscosity data of selected NADES are listed in Table S1 of the Supporting Information and plotted in Figure 3 panels a and b. The semiempirical equations and fitted parameters for these data were listed in Table 3. The data in Figure 3a illustrated that the density of CiGH was the highest of these NADES, and from Figure 3b it can be seen that the viscosity of these NADES follow the order CSH > CiGH > CGH > CCiH. C
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Table 3. Equations and Parameters for Density and Viscosity from Temperature T = (288.15 to 328.15) K parameters properties
equation
unit
NADES
C1
C2
C3
CiGH CCiH CGH CSH CiGH CCiH CGH CSH
1.5098 1.3802 1.3328 1.4322 −37171.95 −7446.808 −8093.825 −152613.52
−0.0007 −0.0006 −0.0005 −0.0005 1787555.3 366525.95 397067.59 7299617.2
5478.058 1093.578 1189.153 22508.63
density
ρ = C1 + C2T
g·cm−3
viscosity
ln η = C1 + C2/T + C3 ln T
mPa·s
Table 4. Mole Fraction 103x of Phloretin, Phlorizin, and Naringin DC in Different NADES from Temperature T = (288.15 to 328.15) K at Pressure p = 0.1 MPaa T /K
103x
T /K
103x
T /K
103x
CCiH 288.15 298.15 308.15 318.15 328.15
0.17 0.18 0.19 0.22 0.38
288.15 298.15 308.15 318.15 328.15
CCiH 288.15 298.15 308.15 318.15 328.15
1.99 2.57 3.63 5.11 6.72
CGH 288.15 298.15 308.15 318.15 328.15
1.19 1.61 3.09 4.65 10.66
CCiH 288.15 298.15 308.15 318.15 328.15
0.65 1.53 1.88 2.25 2.91
CGH 288.15 298.15 308.15 318.15 328.15
1.39 1.62 1.89 2.09 2.25
phloretin 288.15 298.15 308.15 318.15 328.15 phlorizin
CiGH 2.08 5.13 1.29 2.51 3.32
CiGH 288.15 0.28 298.15 0.51 308.15 0.68 318.15 0.99 328.15 2.15 Naringin DC CiGH 288.15 0.29 298.15 0.38 308.15 0.61 318.15 0.89 328.15 1.47 a
× × × × ×
10−3 10−3 10−2 10−2 10−2
CSH 1.62 3.34 4.46 4.89 4.93
Standard uncertainties u are u(T) = 0.01 K, u(p) = 5 KPa, ur(x) = 0.3
To validate the HPLC method of measuring the solubility, the solubility of benzil in methyl acetate and acetonitrile were determined at 298.15 K, The experimental data are listed in Table S2. The solubility experiments were repeated three times. The relative standard deviation was less than 3%. The deviations from literature value were 2.55% and 3.26%, respectively. The validated results showed that this method can be applied to measuring solubility of flavonoids in different NADES as well. Calculation of the Solubility Parameter of phloretin, Phlorizin, And Naringin DC with Apelblat Equation Model. The relationship between mole fraction solubility and temperature is described by the Apelblat equation, which has been widely used in the correlation of solubility data and temperature of massive substances. According to the equation, the mole fraction solubility of three flavonoids can be calculated through eq 2: B ln x = A + + C ln T /K (2) T /K where x and T denote the calculated mole fraction solubility of the solute and absolute temperature (K), respectively. A, B, and C are the empirical model parameters and can be fitted to
Figure 4. Solubilities of phloretin (a), phlorizin (b), naringin DC (c) in four kinds of NADES: ●, CiGH; □, CCiH; ▼, CGH; ▲ CSH. D
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Table 6. Parameters and rmsd of the λh Equation solute
solvent
λ
h
104rmsd
phloretin
CiGH CCiH CSH CiGH CCiH CGH CiGH CCiH CGH
0.03 0.003 0.037 0.014 0.008 0.111 0.149 0.014 0.001
139959.32 580820.41 45952.35 375130.86 250598.75 56930.93 459997.06 171906.84 574706.69
0.37 0.39 5.88 1.18 1.09 4.74 0.04 1.89 0.57
phlorizin
Naringin DC
Buchowski et al.12 stated that, in an ideal solution, the value of λ equals 1. The values of λ in Table 6 showed that the solution of the three flavonoids in NADES were highly nonideal. And the values of h showed the solution of flavonoids in NADES usually got a high mixing enthalpy. As can be seen from Tables 5 and 6, the results correlated with Apelblat and λh model are both satisfactory. It means those parameters listed in Table 5 and Table 6 could be used to predict the solubilities of three flavonoids at different temperatures.
Figure 5. Comparison for solubilities of phloretin between aqua and NADES: ◆, water; ●, CiGH; □, CCiH; ▲ CSH.
the experimental data by a nonlinear least-squares method. The values of parameters A, B, and C and the root-mean-square deviations (rmsd’s) are listed in Table 5. The rmsd is defined as eq 3: ⎡ ∑N (x − x )2 ⎤1/2 i ,exp ⎥ i = 1 i ,cal rmsd = ⎢ ⎢⎣ ⎥⎦ N
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CONCLUSIONS The solubilities of phloretin, phlorizin, and naringin DC in four NADES were measured from T = (288.15 to 328.15) K with an analytical method. The density and viscosity of NADES have been measured experimentally. These experimental results were calculated with two empirical equations. It can be seen that the densities of CiGH and CSH are larger than those of CGH and CCiH, and CSH has a much greater viscosity than the others. The solubilities of phloretin, phlorizin, and naringin DC in the NADES increased with the rising temperature, and were correlated with the Apelblat model and λh model, respectively. The correlated result illustrated that the experimental data agreed well with the calculated results from the selected model. Considering several factors such as density, viscosity, and solubility data, CCiH and CiGH would be a better choice for application on extraction, separation, or purification of flavonoids using green solvents.
(3)
where N is the number of experimental points, and xi,cal and xi,exp represent the solubilities calculated from eq 2 and the experimental solubility values, respectively. From the data listed in Table 5, it can be seen that the calculated solubilities were in good agreement with the experimental values. Calculation of the Solubility Parameter of Phloretin, Phlorizin, and Naringin DC with λh Equation Model. The λheq 4 is another widely used model to describe the relationship between the mole fraction solubility (x) and temperature (T) for solid−liquid equilibrium. According to the solid− liquid equilibrium theory, the mole fraction solubility of three flavonoids can be expressed as eq 4: ⎛1 ⎛ 1 − x ⎞⎟ 1 ⎞ ln⎜1 + = λh⎜ − ⎟ ⎝ ⎠ x Tm ⎠ ⎝T
(4)
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where Tm is the melting point temperature of the solutes. The value of λ is identified as the approximate mean association number of solute molecules, which reflects the nonideality of the solution system, and h estimates the excess mixing enthalpy of solution. Both parameters λ and h were fitted to the experimental data by a nonlinear least-squares method. The interaction parameters obtained in this work are given in Table 6 together with the root-mean-square deviations (rmsd).
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.6b00552. Density and viscosity of NADES; mole fraction solubility and deviations from literature value of benzil (PDF).
Table 5. Parameters and rmsd of the Apelblat Equation solute
solvent
a
b/K
c
104rmsd
phloretin
CiGH CCiH CSH CiGH CCiH CGH CiGH CCiH CGH
−494.021 −1130.711 1395.145 −578.492 −164.852 −942.065 1061.2 1003.667 140.411
18936.413 49882.415 −66094.593 22299.309 4760.373 38379.76 −5474.489 −48864.206 −7684.082
74.191 167.565 −206.97 87.05 25.09 141.631 −156.15 −148.557 −21.246
0.14 0.14 1.67 0.99 0.09 0.28 0.01 1.80 0.11
phlorizin
naringin DC
E
DOI: 10.1021/acs.jced.6b00552 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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AUTHOR INFORMATION
Corresponding Author
*Tel: +86-571-87951430. Fax: +86-571-8795189. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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REFERENCES
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DOI: 10.1021/acs.jced.6b00552 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
