Solubility of Bioactive Compound Hesperidin in Six Pure Solvents at

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Solubility of Bioactive Compound Hesperidin in Six Pure Solvents at (298.15 to 333.15) K Md Khalid Anwer,*,† Ramadan Al-Shdefat,† Shahid Jamil,† Prawez Alam,‡ Maged S. Abdel-Kader,‡ and Faiyaz Shakeel§ †

Department of Pharmaceutics, College of Pharmacy, Salman Bin Abdulaziz University, Al-Kharj, Saudi Arabia Department of Pharmacogonosy, College of Pharmacy, Salman Bin Abdulaziz University, Al-Kharj, Saudi Arabia § Center of Excellence in Biotechnology Research (CEBR), King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia ‡

ABSTRACT: Temperature-dependent solubility data of bioactive compound hesperidin has not been reported in any solvent in the literature so far. Therefore, the aim of the current study was to measure the solubility of bioactive compound hesperidin in six different pure solvents namely water, ethanol, isopropyl alcohol (IPA), propylene glycol (PG), poly(ethylene glycol)-400 (PEG-400), and 1-butanol from (298.15 to 333.15) K using the shake flask method. The experimental solubilities of hesperidin were regressed by Apelblat equation with root-mean-square deviations in the range of 6.32·10−7 to 0.184 in all solvents investigated. The correlation coefficients in pure solvents were observed in the range of 0.995 to 0.999. The mole fraction solubility of hesperidin was found to be higher in PEG-400 (6.33·10−3 at 298.15 K) and PG (5.35·10−4 at 298.15 K) as compared to water (1.47·10−7 at 298.15 K), ethanol (3.45·10−5 at 298.15 K), IPA (1.53·10−5 at 298.15 K), and 1-butanol (3.15·10−4 at 298.15 K). The data of the current study could be useful in crystallization/purification and formulation development of hesperidin in the chemical/ pharmaceutical industry. plant source.11,12 These organic solvents are not suitable for the formulation development due to their regulatory and toxicity concern. Safe/nontoxic solvents such as ethanol, isopropyl alcohol (IPA), propylene glycol (PG), and poly(ethylene glycol)-400 (PEG-400) have been used in formulation development and solubilization of various poorly soluble drugs.13−16 Hence, in the present study, we investigated the various safe/nontoxic solvents such as water, ethanol, IPA, 1butanol, PEG-400, and PG for the solubilization, which could be helpful in formulation development of hesperidin. Enhancement of solubility/bioavailability of hesperidin had been investigated by several approaches such as micrparticles, nanocrystals, and cyclodextrin complexation.2,17,18 A thorough literature search reveals that not a single data is available on temperature dependent solubility of hesperidin in water, ethanol, IPA, 1-butanol, PEG-400, and PG. Various temperature-based models/equations have been reported for correlation of experimental solubility data with calculated one but the Apelblat equation is simplest one and commonly used equation for this purpose.19−27 Therefore, the aim of this article was to measure and correlate the mole fraction solubility of bioactive compound hesperidin in water, ethanol, IPA, PG, PEG-400, and 1-butanol from (298.15 to 333.15) K at atmospheric pressure using the shake flask method. The experimental solubilities of hesperidin were correlated with Apelblat equation.

1. INTRODUCTION The IUPAC name of hesperidin is (s)-7-((6-o-(6-deoxy-alpha-lmannopyranosyl)-beta-D-glucopyranosyl)oxy)-2,3-dihydro-5hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4h-1-benzopyran-4one, and its molecular structure is presented in Figure 1

Figure 1. Molecular structure of hesperidin.

(molecular formula-C28H34O15 and molecular mass-610.56 g· mol−1).1,2 It is a flavonone glycoside which is predominantly found in lemon and orange.1 Hesperidin is white to yellow crystalline powder with poor aqueous solubility.2 It had a broad diversity of health associated properties such as antioxidant, anticancer, anti-inflammatory, antimicrobial, and antiviral role in nutrients.1,3−7 The poor aqueous solubility of hesperidin limits its dissolution rate in water, which finally results in poor in vivo bioavailability.8 Hesperidin has also been reported as insoluble in most of the physiologically safe organic solvents useful in pharmaceutical dosage form development. A major drawback in formulation development for natural bioactive compounds is their poor aqueous solubility and bioavailability.9,10 Unsafe or physiologically toxic solvents such as methanol, chloroform, and ether are frequently used for the extraction of natural bioactive compounds from their respective © 2014 American Chemical Society

Received: March 3, 2014 Accepted: April 23, 2014 Published: May 2, 2014 2065

dx.doi.org/10.1021/je500206w | J. Chem. Eng. Data 2014, 59, 2065−2069

Journal of Chemical & Engineering Data

Article

Table 1. General Property of Hesperidin and Chemicals Used in the Experiment material

molecular formula

molecular mass (g·mol−1)

purity (mass fraction)

analysis method

CAS no.

source

hesperidin ethanol propylene glycol isopropyl alcohol 1-butanol poly(ethylene glycol)-400 water

C28H34O15 C2H5OH C3H8O2 C3H8O CH3(CH2)3OH H(OCH2CH2)nOH H2O

610.56 46.06 76.09 60.10 74.12 400.00 18.01

0.992 0.999 0.995 0.996 0.996 0.999

HPLC GC GC GC GC GC

520-26-3 64-17-5 57-55-6 67-63-0 71-36-3 25322-68-3 7732-18-5

Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich BDH laboratory Sigma-Aldrich Sigma-Aldrich

Table 2. Experimental Mole Fraction Solubilities (xe) and Mass Fraction Solubilities (Sm) for Crystalline Hesperidin in Six Different Pure Solvents (S) at Temperatures T = (298.15 to 333.15) K and Pressure p = 0.1 MPaa Sm/kg.kg‑1

xe S

T = 298.15

T = 303.15

T = 313.15

T = 323.15

T = 333.15

T = 298.15

T = 303.15

T = 313.15

T = 323.15

T = 333.15

water ethanol PG PEG-400 1-butanol IPA

1.47·10−7 3.45·10−5 5.35·10−4 6.33·10−3 3.15·10−4 1.53·10−5

1.52·10−7 3.95·10−5 6.47·10−4 7.49·10−3 3.59·10−4 1.87·10−5

1.61·10−7 5.27·10−5 8.86·10−4 9.85·10−3 4.61·10−4 2.61·10−5

1.70·10−7 6.56·10−5 1.14·10−3 1.24·10−2 5.82·10−4 3.82·10−5

1.80·10−7 8.45·10−5 1.58·10−3 1.52·10−2 7.15·10−4 5.86·10−5

4.98·10−6 4.57·10−4 4.30·10−3 4.30·10−3 9.73·10−3 1.55·10−4

5.14·10−6 5.23·10−4 5.20·10−3 5.20·10−3 1.15·10−2 1.90·10−4

5.46·10−6 6.98·10−4 7.12·10−3 7.12·10−3 1.52·10−2 2.65·10−4

5.77·10−6 8.69·10−6 9.19·10−3 9.19·10−3 1.92·10−2 3.88·10−4

6.09·10−6 1.12·10−3 1.27·10−2 1.27·10−2 2.37·10−2 5.95·10−4

The standard uncertainty for the temperatures u(T) is ± 0.26 K, the relative standard uncertainty in solubility ur(xe) for crystalline hesperidin is 1.8 %.

a

2. EXPERIMENTAL SYSTEM AND METHODS 2.1. Materials. Hesperidin, ethyl alcohol (IUPAC nameethanol), PEG-400 [IUPAC name-poly(oxyethene)], PG (IUPAC name-propane-1,2-diol), and butyl alcohol (IUPAC name-1-butanol) were purchased from Sigma-Aldrich (St. Louis, MO). IPA (IUPAC name-2-propanol) was purchased from BDH Laboratory (Liverpool, UK). Distilled water was collected from a distillation unit in the laboratory. The general properties of these materials along with their purities are listed in Table 1. 2.2. Measurement of Hesperidin Solubility. The shake flask method was used to measure the solubility of hesperidin in six pure solvents useful in dosage form development namely water, ethanol, IPA, 1-butanol, PEG-400, and PG from (298.15 to 333.15) K at atmospheric pressure of 0.1 MPa.28 An excess amount of hesperidin was added in 5 g of each solvent in a conical flask in triplicates. The resulting dispersions were stirred using an isothermal biological shaker (Julabo, PA) at 100 rpm for 72 h to reach the equilibrium (preliminary studies were performed to validate equilibrium time).21 Samples of flasks were kept aside to settle the hesperidin (solute) particles for about 2 h at the bottom of the flask.14−16 All samples were centrifuged at 5000 rpm for 30 min and supernatants of the all samples were analyzed by reported high performance liquid chromatography (HPLC) at a detection wavelength of 346 nm after suitable dilution with mobile phase.29 The standard uncertainty in temperatures u(T) was found to be ± 0.26 K. However, the relative standard uncertainty in solubility ur(xe) was found to be 1.8 %. The experimental mole fraction solubility (xe) of hesperidin in each solvent was calculated according to eq 1:20−22 xe =

m1/M1 m1/M1 + m2 /M 2

solvent (water, ethanol, IPA, PG, PEG-400, and 1-butanol), respectively. 2.3. HPLC Analysis of Hesperidin. The contents of hesperidin in each solvent were analyzed by a modified method of El-Shafae and El-Domiatry (2001).29 Analysis of all samples were performed with a Waters Breeze HPLC system equipped with Waters 600 controller pump, autosampler (Waters 717 plus) fitted with a 20 Kl loop and Waters 486 tunable absorbance detector were used. The mobile phase (methanol and water, 45:55 v/v) was pumped at a flow rate of 0.6 mL· min−1 through a reversed-phase C18 (150 mm·4.6 mm, with particle size 5 μm) column at room temperature. The injected volume was 10 μL and the detection wavelength was 346 nm.

3. RESULTS AND DISCUSSION 3.1. Solubility data of hesperidin. The data of mole fraction as well as mass fraction solubility of hesperidin in six pure solvents (water, ethanol, IPA, 1-butanol, PEG-400, and PG) from temperatures (298.15 to 333.15) K at atmospheric pressure of 0.1 MPa are documented in Table 2. Majumdar and Srirangam (2009) measured the solubility of hesperidin in water as 4.93 μg.mL−1 at 298.15 K which was equal to the mole fraction solubility of 1.45·10−7.30 However, its solubility in other solvents such as ethanol, IPA, PG, PEG-400, and 1butanol has not been reported in the literature. In the present study, the mole fraction solubility of hesperidin in water was observed as 1.47·10−7 at 298.15 K which was very close to the reported value of hesperidin.30 The solubility of hesperidin in each pure solvent increased with temperature from (298.15 to 333.15) K. The mole fraction solubility of hesperidin was found to be highest in PEG-400 (6.33·10−3 at 298.15 K) followed by PG (5.35·10−4 at 298.15 K), 1-butanol (3.15·10−4 at 298.15 K), ethanol (3.45·10−5 at 298.15 K), and water (1.47·10−7 at 298.15 K) from (298.15 to 333.15) K as shown in Table 2. The mole fraction solubilities of hesperidin at all temperatures were significantly higher in PEG-400 and PG than its solubility in other solvents such as ethanol, IPA, 1-butanol, and water. The results demonstrated that PEG-400 and PG are more effective

(1)

where m1 and m2 are the masses of hesperidin (g) and respective pure solvent (water, ethanol, IPA, PG, PEG-400, and 1-butanol) (g), respectively. However, M1 and M2 are the molecular masses of hesperidin (g·mol−1) and respective pure 2066



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Figure 2. Correlation and curve fitting of logarithmic experimental mole fraction solubilities (ln xe) with Apelblat solubilities for crystalline hesperidin in (a) red square, PEG-400; blue diamond, 1-butanol; and green triangle, PG and (b) blue diamond, water; red square, IPA; and green diamond, ethanol from (298.15 to 333.15) K at atmospheric pressure of 0.1 MPa [solid lines represent the logarithmic Apelblat solubilities (calculated solubilities)].

correlations coefficients (R2) and RMSD in all solvents (water, ethanol, IPA, PG, PEG-400, and 1-butanol) are listed in Table 3. The RMSD values were observed in the range of

solvents for solubilization of hesperidin and these solvents could be used for the development of suitable dosage form of hesperidin. The mole fraction solubility of hesperidin was also found to be increased with increase in molecular mass of the pure solvents. As can be seen from results, highest mole fraction solubility was observed in PEG-400 that was probably due to its highest molecular mass (400 g·mol−1) as compared to PG (76.09 g·mol−1), ethanol (46.069 g·mol−1), IPA (60.1 g· mol−1), 1-butanol (74.12 g·mol−1), and water (18.015 g·mol−1). Based on these results, hesperidin has been considered as soluble in PEG-400 and PG; poorly soluble in ethanol, IPA, and 1-butanol; and practically insoluble in water. The solubility data of this study could be useful in crystallization/purification and formulation development of hesperidin. 3.2. Correlation of Hesperidin Solubility. The correlation of experimental solubilities of hesperidin were done with simple and wide range applicable Apelblat equation.19−21 According to this equation, the mole fraction solubility of hesperidin can be calculated by using eq 2: B ln x = A + + C ln(T ) T

Table 3. Apelblat Coefficients (A, B, and C) along with R2 and RMSD for Hesperidin in Six Different Pure Solventsa

1/2 ⎛ xAc − xe ⎞2 ⎤ ⎟⎥ ∑⎜ xe ⎠ ⎥⎦ i=1 ⎝

A

B

C

R2

103 RMSD

water ethanol PG PEG-400 1-butanol IPA

−14.77 17.11 −16.33 160.42 27.82 −336.50

−525.82 −3414.89 −2122.53 −9819.85 −3644.54 12014.31

0.14 −2.79 2.79 −23.26 −4.15 50.04

0.999 0.998 0.997 0.995 0.999 0.996

6.32·10−4 2.23 38.67 184.42 7.53 0.88

a

Pure solvents (S), propylene glycol (PG), poly(ethylene glycol)-400 (PEG-400), isopropyl alcohol (IPA), correlation coefficient (R2), and root-mean-square deviations (RMSD)

6.32·10−7 to 0.184 in all solvents investigated. The lowest values of RMSD were observed in water (6.32·10−7). However, the highest one was observed in PEG-400 (0.184). The R2 values for hesperidin in water, ethanol, IPA, PG, PEG-400, and 1-butanol were observed in the range of 0.995 to 0.999, indicating good fitting of experimental data in all solvents. 3.3. Thermodynamic Parameters for Hesperidin Dissolution. Thermodynamic parameters for hesperidin dissolution in pure solvents were determined in terms of molar enthalpy (ΔH0) and entropy (ΔS0). The modified forms of eq 2 were used to calculate ΔH0 and (ΔS0) for hesperidin dissolution (eqs 4 and 5).19,20,22,31

(2)

where x and T represents the calculated solubility of hesperidin and absolute temperature (K), respectively. Apelblat coefficients A, B, and C were determined by nonlinear multivariate regression analysis of solubilities listed in Table 2.20,21 The calculated/Apelblat solubilities (xAc) of hesperidin were then calculated using Apelblat coefficients. The correlation and curve fitting between xe and xAc in water, ethanol, IPA, PG, PEG-400, and 1-butanol at (298.15 to 333.15) K is presented Figure 2 (panels a and b). The deviations between xe and xAc were determined in terms of root-mean-square deviations (RMSD). RMSD were calculated using eq 3. ⎡ 1 RMSD = ⎢ ⎢⎣ N

S

N

⎛ B⎞ ΔH 0 = RT ⎜C − ⎟ ⎝ T⎠

(4)

⎛ B⎞ ΔS ° = R ⎜C − ⎟ ⎝ T⎠

(5)

where R is the universal gas constant and coefficients B and C are Apelblat coefficients presented in Table 3. The derivation and correlation of eqs 4 and 5 with eq 2 is presented in our recently published article.23 The values ΔH0 and ΔS0 at

(3)

where N are the number of data points in experiment. The values of Apelblat coefficients A, B, and C along with 2067



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(5) Chiba, H.; Uehara, M.; Wu, J.; Wang, X.; Masuyama, R.; Suzuki, K.; Kanazawa, K.; Ishimi, Y. Hesperidin, a citrus flavonoid, inhibits bone loss and decreases serum and hepatic lipids in ovariectomized mice. J. Nutr. 2003, 133, 1892−1897. (6) Kanno, S.; Shouji, A.; Asou, K.; Ishikawa, M. Effects of naringin on hydrogen peroxide-induced cytotoxicity and apoptosis in P388 cells. J. Pharmacol. Sci. 2003, 92, 166−170. (7) Benavente-Garcia, O.; Castillo, J. Update on uses and properties of citrus flavonoids: new Findings in anticancer, cardiovascular, and anti-inflammatory activity. J. Agric. Food Chem. 2008, 56, 6185−6205. (8) Manach, C.1.; Morand, C.; Gil-Izquierdo, A.; BouteloupDemange, C.; Rémésy, C. Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice. Eur. J. Clin. Nutr. 2003, 57, 235−42. (9) Freag, M. S.; Elnaggar, Y. S. R.; Abdallah, O. Y. Development of novel polymer-stabilized diosmin nanosuspensions: in vitro appraisal and ex vivo permeation. Int. J. Pharm. 2013, 454, 462−471. (10) Freag, M. S.; Elnaggar, Y. S. R.; Abdallah, O. Y. Lyophilized selfphytosomal nanocarriers (LSPNs) as platforms for enhanced diosmin delivery: optimization and ex-vivo permeation. Int. J. Nanomed. 2013, 8, 2385−2397. (11) Jassbi, A. R.; Miri, R.; Asadollahi, M.; Javanmardi, N.; Firuzi, O. Cytotoxic, antioxidant and antimicrobial effects of nine species of woundwort (Stachys) plants. Pharm. Biol. 2014, 52, 62−67. (12) Yadav, U. C. S.; Baquer, N. Z. Pharmacological effects of Trigonella foenumgraecum L. in health and disease. Pharm. Biol. 2014, 52, 243−54. (13) Jimenez, J. A.; Martinez, F. Thermodynamic study of the solubility of acetaminophen in propylene glycol+water cosolvent mixtures. J. Braz. Chem. Soc. 2006, 17, 125−134. (14) Shakeel, F.; Alanazi, F. K.; Alsarra, I. A.; Haq, N. Solubility prediction of indomethacin in PEG 400 + water mixtures at various temperatures. J. Mol. Liq. 2013, 188, 28−32. (15) Shakeel, F.; Alanazi, F. K.; Alsarra, I. A.; Haq, N. Thermodynamics-based mathematical model for solubility prediction of glibenclamide in ethanol-water mixtures. Pharm. Develop. Technol. 2014, 19, 702−707. (16) Shakeel, F.; Anwer, M. K.; Shazly, G. A.; Jamil, S. Measurement and correlation of solubility of bioactive compound silymarin in five different green solvents at 298.15 to 333.15 K. J. Mol. Liq. 2014, 195, 255−258. (17) Sansone, F.; Rossi, A.; Gaudio, P. D.; Simone, F. D.; Aquino, R. P.; Lauro, M. R. Hesperidin gastroresistant microparticles by spraydrying: preparation, characterization, and dissolution profiles. AAPS Pharm. Sci. Technol. 2009, 10, 391−401. (18) Ficarra, R.; Tommasini, S.; Raneri, D.; Calabrò, M. L.; Di Bella, M. R.; Rustichelli, C.; Gamberini, M. C.; Ficarra, P. Study of flavonoids/beta-cyclodextrins inclusion complexes by NMR, FT-IR, DSC, X-ray investigation. J. Pharm. Biomed. Anal. 2002, 29, 1005−14. (19) Apelblat, A.; Manzurola, E. Solubilities of L-aspartic, DLaspartic, DL-glutamic, p-hydroxybenzoic, o-anisic, p-anisic, and itaconic acids in water from T = 278 to 345 K. J. Chem. Thermodyn. 1997, 29, 1527−1533. (20) Apelblat, A.; Manzurola, E. Solubilities of o-acetylsalicylic, 4aminosalicylic, 3,5-dinitrosalicylic and p-toluic acid and magnesiumDL-aspartate in water from T = (278 to 348) K. J. Chem. Thermodyn. 1999, 31, 85−91. (21) Manzurola, E.; Apelblat, A. Solubilities of L-glutamic acid, 3nitrobenzoic acid, acetylsalicylic, p-toluic acid, calcium-L-lactate, calcium gluconate, magnesium-DL-aspartate, and magnesium-L-lactate in water. J. Chem. Thermodyn. 2002, 34, 1127−1136. (22) Shakeel, F.; Alanazi, F. K.; Alsarra, I. A.; Haq, N. Solubilization behavior of paracetamol in Transcutol-water mixtures at (298.15 to 333.15) K. J. Chem. Eng. Data 2013, 58, 3551−3556. (23) El-Badry, M.; Haq, N.; Fetih, G.; Shakeel, F. Measurement and correlation of tadalafil solubility in five pure solvents at (298.15 to 333.15) K. J. Chem. Eng. Data 2014, 59, 839−843.

saturation for hesperidin dissolution in water, ethanol, IPA, PG, PEG-400, and 1-butanol at (298.15 to 333.15) K were calculated using eqs 4 and 5, respectively. The ΔH0 values for hesperidin dissolution in water, ethanol, IPA, PG, PEG-400, and 1-butanol were observed in the range of (4.71 to 4.75) kJ· mol−1, (20.66 to 21.47) kJ·mol−1, (24.15 to 38.71) kJ·mol−1, (24.56 to 25.37) kJ·mol−1, (17.21 to 23.98) kJ·mol−1, and (18.80 to 20.01) kJ·mol−1 at (298.15 to 333.15) K, respectively. The positive values of ΔH0 in all solvents indicated the endothermic dissolution of hesperdin. These results indicated that the molecular interactions between the hesperidin and solvent molecules were much stronger than those between the solvent−solvent and hesperidin-hesperidin molecules. The ΔS0 values for hesperidin dissolution in water, ethanol, IPA, PG, PEG-400 and 1-butanol were observed in the range of (14.28 to 15.82) J·mol−1·K−1, (62.02 to 72.03) J·mol−1·K−1, (81.01 to 116.21) J·mol−1·K−1, (76.16 to 82.38) J·mol−1·K−1, (51.68 to 80.45) J·mol−1·K−1 and (56.45 to 67.12) J·mol−1·K−1 at (298.15 to 333.15) K, respectively. The positive values of ΔS0 in all solvents indicated the entropy-driven dissolution of hesperidin. These results indicated the favorable entropy for solubilization of hesperidin in all solvents investigated.

4. CONCLUSION In the present study, the solubility of bioactive compound hesperidin in six different pure solvents namely water, ethanol, IPA, PG, PEG-400, and 1-butanol were measured at (298.15 to 333.15) K. The solubility of bioactive compound hesperidin was found to be increased with temperature in all solvents investigated. The solubility of hesperidin was significantly higher in PEG-400 and PG as compared to water, ethanol, IPA, and 1-butanol. The experimental solubilities of hesperidin were correlated well with the Apelblat equation in all solvents from (298.15 to 333.15) K with the correlation coefficients of 0.995 to 0.999. Based on these results, hesperidin has been considered as practically insoluble in water; poorly soluble in ethanol, IPA, and 1-butanol; and soluble in PEG-400 and PG. The data of current study could be useful in crystallization/ purification and formulation development of bioactive compound hesperidin.

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AUTHOR INFORMATION

Corresponding Author

*Phone: +966-535541791. E-mail: [email protected]. Funding

This project was supported by the Deanship of Scientific Research, Salman Bin Abdulaziz University, Al-Kharj, Saudi Arabia (Project No. 47H/1433). Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Garg, A.; Garg, S.; Zaneveld, L. J. D.; Singla, A. K. Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytother. Res. 2001, 15, 655−669. (2) Mauludin, R.; Müller, R. H. Physicochemical properties of hesperidin nanocrystal. Int. J. Pharm. Pharm. Sci. 2013, 5, 954−960. (3) Selway, J. W. T. Antiviral activity of flavones and flavans. In Plant flavonoids in biology and medicine: Biochemical, pharmacological and structure activity relationships; Cody, V., Middleton, E., Harborne, J. B., Eds.; Alan R Liss, Inc.: New York, 1986; pp 521−536. (4) Shahid, F.; Yang, Z.; Saleemi, Z. O. Natural flavonoids as stabilizers. J. Food Lipids 1998, 1, 69−75. 2068



Article

(24) Shakeel, F.; Haq, N.; Alanazi, F. K. Alsarra. Measurement and correlation of solubility of olmesartan medoxomil in six green solvents at 295.15−330.15 K. Ind. Eng. Chem. Res. 2014, 53, 2846−2849. (25) Delgado, D. R.; Vargas, E. F.; Martinez, F. Thermodynamic study of the solubility of procaine HCl in some ethanol + water cosolvent mixtures. J. Chem. Eng. Data 2010, 55, 2900−2904. (26) Gantiva, M.; Yurquina, A.; Martinez, F. Solution thermodynamics of ketoprofen in ethanol + water cosolvent mixtures. J. Chem. Eng. Data 2010, 55, 113−118. (27) Jouyban, A.; Shokri, J.; Barzegar-Jalali, M.; Hassanzadeh, D.; Acree, W. E.; Ghafourian, T.; Nokhodchi, A. Solubility of benzodiazepines in polyethylene glycol 200 + water cosolvent mixtures at 303.2 K. J. Chem. Eng. Data 2010, 55, 519−522. (28) Higuchi, T.; Connors, K. A. Phase-solubility techniques. Adv. Anal. Chem. Instr. 1965, 4, 117−122. (29) El-Shafae, A. M.; El-Domiaty, M. M. Improved LC methods for the determination of diosmin and/or hesperidin in plant extracts and pharmaceutical formulations. J. Pharm. Biomed. Anal. 2001, 26, 539− 545. (30) Majumdar, S.; Srirangam, R. Solubility, stability, physicochemical characteristics and in vitro occular tissue permeability of hesperidin: a natural bioflavonoid. Pharm. Res. 2009, 26, 1217−1225. (31) Williamson, A. T. The exact calculations of heats of solutions from solubility data. Trans. Faraday Soc. 1944, 40, 421−436.

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Solubility of Bioactive Compound Hesperidin in Six Pure Solvents at

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