Solubility of Hesperetin in Mixed Solvents - Journal of Chemical

Aug 14, 2013 - The study of the solubility of important biomolecules such as flavonoids is essential to support the design of several separation proce...
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Solubility of Hesperetin in Mixed Solvents Olga Ferreira,*,† Bernd Schröder,*,‡ and Simaõ P. Pinho† †

LSRE, Escola Superior de Tecnologia e Gestão, Instituto Politécnico de Bragança, 5301-857 Bragança, Portugal CICECO, Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal

S Supporting Information *

ABSTRACT: The study of the solubility of important biomolecules such as flavonoids is essential to support the design of several separation processes in the food and pharmaceutical industries. Following our previous studies, new solubility data of hesperetin in the mixed solvents water + acetone, water + ethanol, and water + methanol were measured, at 298.2 K, by the isothermal shake-flask method. The results obtained show three solid−liquid phase diagrams with distinct features. Additionally, the solid crystals obtained from the solubility studies were analyzed by powder X-ray diffraction, infrared spectroscopy, and thermogravimetric analysis indicating that, depending on the mixed solvents composition, two different crystal structures of hesperetin, already described in the literature, can be obtained, corresponding either to the anhydrous or the monohydrate forms.

1. INTRODUCTION Hesperetin (2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one) is one of the most studied flavanones, with great importance from the dietary point of view and with promising biological and pharmacological properties.1−8 An illustration of its structure is presented in Figure 1. The study of the solubility of this important biomolecule is relevant for supporting the design of separation processes such as extraction, precipitation, or crystallization, in the food and pharmaceutical areas. Naturally, developing those processes and guaranteeing the desired properties for each application is fundamental to collect information concerning the different crystal properties and structures that can be obtained from the solution. In the case of hesperetin, two different crystal structures were described in the literature; one corresponding to the anhydrous form, crystallized from an ethanol solution9 and another to the monohydrate form, crystallized from an aqueous ethanol solution at room temperature.10 This work follows our previous studies concerning the solubility of hesperetin in several pure organic solvents.11 Unlike for rutin,12 luteolin,13 or quercetin,14 for which solubility data were recently reported, to the best of our knowledge, no solubility studies are available for hesperetin in mixed solvents. These data are highly relevant for the selection of the best solvents for the separation of the mixture resulting from the hydrolysis of hesperidin, containing high-valued hesperetin, hesperetin-7-glucoside, and hesperidin.15 Here, new solubility data are presented for hesperetin in the mixed solvents (water + acetone), (water + ethanol), and (water + methanol) at 298.2 K, using the isothermal shake-flask method, followed by quantitative analysis by gravimetry. © 2013 American Chemical Society

As mentioned before, for these systems, the formation of the monohydrate form of hesperetin can be expected. A very instructive theoretical introduction on the topic of formation of hydrates in mixed solvent systems was presented by Li et al.,16 including an isothermal triangular representation of the phase diagram for this type of mixtures. Many other studies have described the transition from anhydrous to hydrated forms that may occur in mixed aqueous solvents for several solutes such as, for example, carbamazepine,16,17 theophylline,18 ampicillin,19 quinolones,20 sodium naproxen,21 L-phenylalanine,22 and risedronate monosodium,23 among others. Therefore, in this work, several techniques such as powder X-ray diffraction (PXRD), infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA) were also applied to characterize selected solid samples obtained from the solubility measurements.

2. MATERIALS AND METHODS 2.1. Chemicals. Table 1 presents the source and purity of the organic compounds used in this work. They were used as received. (S)-hesperetin ((S)-2,3-dihydro-5,7-dihydroxy-2-(3hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one) was kept in a dehydrator with silica gel to avoid water contamination. Distilled deionized water was used. 2.2. Solubility Measurements. The solubility experiments were carried out using the analytical isothermal shake-flask method, and the gravimetric method was chosen for the quantitative analysis. A detailed description of the experimental apparatus and procedure has been previously presented.11 Received: May 28, 2013 Accepted: July 27, 2013 Published: August 14, 2013 2616 | J. Chem. Eng. Data 2013, 58, 2616−2621

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six samples of 15 cm3 were withdrawn. (2) For the water + ethanol system, compositions x′ethanol = (0.494, 0.535, 0.564, and 0.600), the number of samples was increased to 8, 10, 10, and 7, respectively. 2.3. Solid-Phase Studies. 2.3.1. Sample Preparation. To study the solid crystals, for a set of selected compositions of the mixed solvents, the solid phase was removed by filtering the saturated solution, using membranes (NL16, Schleicher & Schuell) with 0.2 μm of pore size and allowed to dry at room temperature. The mass of solid was regularly weighted until a constant mass value was obtained. 2.3.2. Powder X-ray Diffraction (PXRD). Powder X-ray diffraction patterns were measured with a Philips X’Pert MPD diffractometer with a Cu anode (λ = 0.15406 nm; 45 kV; 40 mA) and a solid state D “X’Celerator” detector, at T = 298.2 K and a 2θ-angle range of 5° to 50°, with a step resolution of 0.020° and a step time of 40 s, active length 2.546°. 2.3.3. Infrared Spectroscopy (FTIR). Solid-state FTIR spectra were obtained, at room temperature, in the range of (4000 to 350) cm−1, using a FTIR Bruker Tensor 27 spectrometer, equipped with RT-DLaTGS (INTERNAL) detector, using pellets of KBr, 64 scans, and a resolution of 4 cm−1. 2.3.4. Thermal Analysis (TGA). Thermogravimetric analysis were performed with a thermal gravimetric analyzer SETSYS Evolution 1750 (Setaram). Samples, contained in open alumina pans and with sample masses between (20 and 40) mg, were scanned from (293 to 493) K, at a heating rate of 120 K·h−1. A flux of dry nitrogen of 0.012 m3·h−1 was applied. Figure 1. Hesperetin: illustration of the molecule and numbering scheme.

3. RESULTS AND DISCUSSION 3.1. Solubility in Mixed Solvents. Table 2 presents the solubility values obtained in the binary mixed solvents, measured at 298.2 K, where each is an average of, at least, three different measurements. The correspondent standard deviation (in brackets) was also calculated. As mentioned before, the gravimetric method was chosen for the quantitative analysis. The solid crystals were obtained by evaporating all of the solvent and, then, by completely drying them, in a drying stove at 343.15 K. The solid phase analysis of the crystals is described in detail in section 3.2, but in all the dried samples from the gravimetric analyses, only the anhydrous form was identified. Figures 2, 3 and 4 present the three phase diagrams obtained for the solubility of hesperetin in the binary mixed solvents (water + methanol), (water + ethanol), and (water + acetone), respectively. The solubility of hesperetin in the pure organic solvents was measured previously,11 and it is also presented graphically. Due to the very low value of the solubility in water, it was not possible to obtain it with enough precision, using the technique described in section 2.2. However, three recent values could be found in the literature, as given in Table 3. These values reflect the high difficulty to measure this solubility, as it changes more than 10 times, using analytical techniques like UV spectrophotometry24,25 or HPLC.26 As can be seen, a very different behavior can be observed for each mixed solvent system. Starting with the water + methanol system, the solubility of hesperetin in mole fraction increases almost 850-fold, from x′methanol = 0.10 to pure methanol, with a progressive increase in the slope of the curve. It should be mentioned that, to obtain greater precision in the solubility measurements, for

Table 1. Source and Mass Fraction Purity of the Chemicals Used in This Work


chemical name


acetone ethanol methanol (S)-hesperetin

Fischer Scientific Panreac Merck Cayman Chemical

mass fraction puritya ≥ ≥ ≥ ≥

0.995 0.995 0.999 0.98

Declared by the supplier.

To prepare a volume of 80 cm3 of the mixed solvents solutions, appropriate amounts of each solvent are weighed into a flask, using an electronic balance (Denver Instrument) with a precision of ± 0.1 mg. Hesperetin is weighted in a small excess relatively to the saturation value, and then, the equilibrium flasks are filled with the solid and solvent mixture. To reach equilibrium, the solution is stirred during 40 h, and after, the solution is allowed to settle for at least 12 h before sampling. The temperature is monitored with four-wire platinum resistance probes (Pt-104, Pico-Technology), with the ability to control the solution temperature within ± 0.1 K to the set temperature. The standard procedure includes, for each determination, the withdrawal of three samples of approximately 5 cm3. To increase the precision of the method, a few modifications were introduced in some specific cases, namely, the number of samples and/or the volume withdrawn for gravimetric analysis. The exceptions are the following: (1) For the water + methanol system, compositions x′methanol = (0.100 and 0.200), where x′ represents the mole fraction of the solvent in a solute-free basis, 2617 | J. Chem. Eng. Data 2013, 58, 2616−2621

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Table 2. Solubility of Hesperetin Shesperetin in Molality/mol· kg−1 in (Methanol + Water), (Ethanol + Water), and (Acetone + Water) Mixed Solvents with Composition x′organic solvent (Mole Fraction of the Organic Solvent on a Solute-Free Basis) at Temperature T = 298.2 K and Pressure p = 0.10 MPaa x′organic solvent 0.1000 0.2002 0.3000 0.4000 0.4901 0.5882 0.6827 0.7700 0.7717 0.8528 0.9251 0.1000 0.1852 0.2774 0.3399 0.3986 0.4500 0.4937 0.5347 0.5641 0.5999 0.6350 0.6990 0.7504 0.8202 0.9021 0.1002 0.2001 0.3001 0.3938 0.4001 0.4990 0.5956 0.6560 0.7000 0.7990 0.7997 0.8861 0.9000 0.9500

Shesperetin·102/mol·kg−1 Methanol + Water 0.023 0.063 0.262 0.640 1.770 3.066 4.474 6.211 6.105 7.825 9.534 Ethanol + Water 0.054 0.354 1.506 2.078 2.337 2.856 4.025 5.993 6.871 7.708 8.925 9.845 10.250 9.999 9.774 Acetone + Water 0.381 4.018 12.897 26.414 27.837 43.440 55.208 64.948 77.963 94.257 95.398 77.721 74.670 60.031

(0.004) (0.015) (0.010) (0.003) (0.032) (0.024) (0.040) (0.035) (0.014) (0.062) (0.034)

Figure 2. Solubility of hesperetin in mole fraction xhesperetin, in methanol + water solvent mixtures at 298.2 K versus the mole fraction of methanol in solute-free basis x′methanol: +, (this work); ×, ref 11.

(0.008) (0.013) (0.013) (0.014) (0.015) (0.098) (0.370) (0.204) (0.416) (0.246) (0.020) (0.026) (0.027) (0.022) (0.009)

Figure 3. Solubility of hesperetin in mole fraction xhesperetin, in ethanol + water solvent mixtures at 298.2 K versus the mole fraction of ethanol in solute-free basis x′ethanol: +, (this work); ×, ref 11.

(0.003) (0.021) (0.032) (0.021) (0.128) (0.033) (0.026) (0.051) (0.065) (0.095) (0.095) (0.141) (0.160) (0.058)


The correspondent standard deviation is presented between brackets. Standard uncertainties u are u(T) = 0.10 K, ur(p) = 0.05, and ur(x′) = 6·10−5. Figure 4. Solubility of hesperetin in mole fraction xhesperetin, in acetone + water solvent mixtures at 298.2 K versus the mole fraction of acetone in solute-free basis x′acetone: +, (this work); ×, ref 11.

compositions x′methanol = (0.100 and 0.200), six samples of 15 cm3 were collected, as described earlier in section 2.2. Similarly, in the case of the water + ethanol system, a significant increase (around 390-fold) is obtained from x′ethanol = 0.10 to pure ethanol. However, in this case, the sharpest increase in the solubility curve is obtained between x′ethanol = 0.50 and x′ethanol = 0.60. This is also the region in which the solubility measurements present the highest standard deviation

and the reason why a higher number of samples was withdrawn, as described in section 2.2. Finally, in the case of water + acetone system, a maximum in the solubility is found around x′acetone = 0.80. That maximum in 2618 | J. Chem. Eng. Data 2013, 58, 2616−2621

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Table 3. Solubility of Hesperetin in Water at 298 K, Published in the Literature original value and units


4.5·10−6 M 15.72 μg·mL−1 (5.2·10−5 M) 3.3·10−6 M

ref 24 ref 26 ref 25

the solubility was already described,15 where some scattered solubility tests were performed for hesperetin, at room temperature. This is the mixed solvent system for which higher solubilities of hesperetin are obtained, for a given organic solvent mole fraction in a solute-free basis. To clarify some of aspects of this behavior, the crystals in equilibrium with the saturated solution were analyzed, as mentioned in section 2.3.1. This was done for the six selected liquid phase compositions presented in Table 4. The solid

Figure 5. Typical X-ray powder diffraction patterns obtained from the isolated crystalline bulk phases (line below, anhydrous; line above, monohydrated).

Table 4. Hesperetin Solid-Phase Characterization for Samples with Mixed Solvents Composition x′organic solvent (Mole Fraction of the Organic Solvent in a Solute-Free Basis) mixed solvents

x′organic solvent

crystal form

methanol + water

0.2990 0.7680 0.3391 0.9013 0.3002 0.9497

monohydrate anhydrous monohydrate anhydrous monohydrate anhydrous

ethanol + water acetone + water

examination of the solid state (see Figure 6). For the monohydrated form, an absorption band has been found in

phase analysis, described thoroughly in section 3.2, resulted in very interesting results. The selected samples obtained from mixed solvent solutions, with higher compositions in water, showed the presence of the monohydrate form of hesperetin, while the others were anhydrous. Thermodynamic modeling of these mixtures turned out very difficult using predictive models such as conductor-like screening model for real solvents (COSMO-RS)27,28 and nonrandom two-liquid segment activity coefficient (NRTLSAC).29 This last method was successfully implemented for pure solvent systems,11 but for the mixed solvents studied in this work the three different shapes of the solubility curves could not be predicted. Of course, semiempirical models such as the modified Apelblat equation could be applied, but that was not the objective of this work. 3.2. Solid-Phase Studies. 3.2.1. Powder X-ray Diffraction (PXRD). In the powder diffraction X-ray experiments, only two different sets of spectra have been obtained for all analyzed samples (see Figure 5; for reproducibility of powder patterns from different aqueous solvent mixtures, see Supporting Information S1−S2). A comparison of the spectra with the ones obtained from previously reported single crystal X-ray structural data of monoclinic anhydrous (R,S)-hesperetin9 and triclinic (R,S)-hesperetin monohydrate10 via powder pattern calculations with Mercury v. (see Supporting Information S3) permitted an unambiguous spectral assignment of the powder diffraction X-ray data, corresponding either to the pure form of anhydrous or monohydrated (R,S)-hesperetin in the bulk phase. 3.2.2. Infrared Spectroscopy (FTIR). The bisection of the bulk crystalline moieties into either anhydrous or monohydrated species is consistently supported by FTIR spectroscopic

Figure 6. Typical infrared spectrum of the analyzed crystalline bulk phases (line below, anhydrous; line above, monohydrated).

the range of 3100 cm−1 < ν < 3400 cm−1, corresponding to the O−H stretch band due to interactions of water with the molecules through intermolecular hydrogen bonding, while the water of crystallization causes a broadening of the chromone carbonyl absorption peak at 1635 cm−1. The carbonyl peak in the anhydrous form appears at 1636 cm−1. The shift toward lower frequencies in both forms is attributable to chelation between (O(7)H(25)) and O(5). In the monohydrate, a distinct O−H stretching frequency band appears at 3567 cm−1, absent in the anhydrous form. The location of the peak points toward constrained water in the crystal lattice. The O−H stretching vibration related to intermolecular hydrogen bonding in anhydrous hesperetin results in a sharp band at 3500 cm−1. In anhydrous hesperetin, the keto oxygen O(5) has been reported to be involved in the intermolecular hydrogen bond network, while in the monohydrate form, it does not make part of it.9 Benzopyrone subunits in anhydrous hesperetin are connected through strong O(5)···H···O(10) hydrogen bonds, while cyclic tetrameric formation of additional hydrogen bonds (O(17)...H...O(5)) is another packing feature. The O−H 2619 | J. Chem. Eng. Data 2013, 58, 2616−2621

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stretch peak related to the strong intramolecular hydrogen bond (O(7)H(25)···O(5)) appearing at 3119 cm−1 in the anhydrous form is slightly obscured by the broad polymeric band in the monohydrate (3149 cm−1). 3.2.3. Thermal Analysis (TGA). From the two distinct bulk lots, randomly chosen samples, one each, have been subjected to thermal analysis. Comparison of thermograms from thermogravimetric experiments as given in Figure 7 clearly



Corresponding Author

*Telephone: +351 273 303 087 and +351 234 370 957. Fax: +351 273 313 051 and +351 234 370 084. E-mail: [email protected] and [email protected] Funding

The authors acknowledge FCTFundaçaõ para a Ciência e a Tecnologia and the European Social Fund (ESF) under the 3rd Community Support Framework (CSF) for the projects PestC/CTM/LA0011/2011 and PTDC/AAC-AMB/121161/2010 and for the postdoctoral grant (SFRH/BPD/38637/2007) of Bernd Schröder. This work is also supported by project PEstC/EQB/LA0020/2011, financed by FEDER through COMPETEPrograma Operacional Factores de Competitividade and by FCT. Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS The authors are very grateful to Professor João A. P. Coutinho for many helpful discussions, to Maria Soares (PXRD), Maria Azevedo (FTIR), Sandra Magina (TGA), and Paula Brandão (preliminary single-crystal X-ray diffractometry) with respect to the supporting analytical work.

Figure 7. TGA curves, showing the elimination of water of crystallization from hesperetin monohydrate, relative to nearly unchanged anhydrous hesperetin (line below, anhydrous; line above, monohydrated).

illustrates the loss of 1 mol of bound water in the monohydrated form; the corresponding DTG plot is given as Supporting Information S4. The mass loss obtained at the chosen experimental conditions is in agreement with an assumed value of 1 mol of water in hesperetin monohydrate (−1.7%). An onset temperature of dehydration of approximately 330 K indicates a relatively loose involvement of the bound water molecules in the overall structure of the monohydrate. This is supported by the previously published crystal packing of hesperetin monohydrate.10 Here, the tworing systems are nearly parallel to each other, in contrast to the twisted arrangement in the anhydrous form. The molecules are connected through strong O(17)···H···O(7) intermolecular hydrogen bonds, forming chains. These chains are interconnected via hydrogen bonds involving water molecules, to form molecular double layers. The minimum separation between the layers is 0.365 nm; it is assumed that there are only van der Waals interactions between the molecular double layers.

4. CONCLUSIONS In this work, new solubility data of hesperetin in several binary mixed solvents (water + acetone), (water + ethanol), and (water + methanol) are presented, at 298.2 K. A set of selected solid samples were analyzed showing the presence of either the monohydrate or the anhydrous forms of hesperetin, depending on the mixed solvent composition. Evidence from complex molecular interactions involving hesperetin and/or water, including intramolecular and intermolecular hydrogen bonding was shown by the PXRD, FTIR, and TGA analysis.


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S Supporting Information *

Supporting figures: PXRD data and TGA curves. This material is available free of charge via the Internet at 2620 | J. Chem. Eng. Data 2013, 58, 2616−2621

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