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Journal of Chromatography B, 926 (2013) 21– 27

Contents lists available at SciVerse ScienceDirect

Journal of Chromatography B

j ourna l ho me page: www.elsev ier .com/ locate /chromb

eversed phase High Performance Liquid Chromatography used forhe physicochemical and thermodynamic characterization oficeatannol/�-cyclodextrin complex

anane Messiada,b, Habiba Amira-Guebailiaa,∗, Omar Houachec

Laboratory of Applied Chemistry, 8 Mai 1945 Guelma University, Guelma 24000, AlgeriaUnité de Recherche en Technologie Industrielle (URTI/CSC), BP1037, site de l’Université Badji Mokhtar, Chaiba, Annaba 23000, AlgeriaPetroleum & Chemical Engineering Department, P.O. Box 33, Al Khoud 123, Sultan Qaboos University, Muscat, Oman

r t i c l e i n f o

rticle history:eceived 27 September 2012ccepted 21 February 2013vailable online 27 February 2013

eywords:iceatannol-Cyclodextrin

a b s t r a c t

Piceatannol is one of resveratrol derivatives having health promoting potential. However, its low water-solubility and bioavailability could limit its use in both food and pharmaceutical fields. The aim ofthis work is the study of piceatannol complexation by �-cyclodextrin (�-CD) in aqueous media. Thecomplex formed could improve the bioavailability, the solubility and the stability of piceatannol. Themethod used was based on RP-HPLC in which, �-CD was added to methanol/water mixtures mobilephases. The apparent formation constant of piceatannol/�-cyclodextrin complex was determined. Withinthe concentration interval studied (0–4 mM), whenever the concentration of �-CD increased, retention

obile phaseolubilitypparent formation constanthermodynamic parameters

time of piceatannol decreased; indicating an enhancement of solubility due to the formation of thepiceatannol/�-CD complex. The formation constants (KF) of the piceatannol/�-CD complex varied sig-nificantly with both the methanol concentration in the water–methanol mixture and the temperature.Moreover, in all the physicochemical conditions tested, the stoichiometry of piceatannol/�-CD complexwas 1:1. Finally, the thermodynamic parameters were determined: �G◦ = -13.123 kJ mol−1, �H◦ = −33.265 kJ mol−1 and �S◦ = −67.559 J mol−1 K−1.

. Introduction

In the pharmaceutical field, cyclodextrins have been recog-ized as powerful candidates to overcome some drawbacks of drugolecules, such as low hydrosolubility, stability and bioavailabil-

ty through the formation of host–guest complexes in which, eachuest molecule is enclosed in the hydrophobic cavity of B-CD. Thisan result in the alteration of physical, chemical and biological fea-ures of guest molecules [1].

Cyclodextrins consist of glucose monomers arranged in a donuthape ring. The naturally occurring cyclodextrins are alpha, beta,nd gamma CDs [2]. All the hydroxyl groups in CDs are ori-nted to the outside of the ring while the glycosidic oxygen andwo rings of the non-exchangeable hydrogen atoms are directedowards the interior of the cavity. This combination gives cyclodex-

rins a hydrophobic inner cavity and a hydrophilic exterior. Theydrophobic internal cavity provides the capability to form inclu-ion complexes with a variety of guest hydrophobic molecules (e.g.

∗ Corresponding author. Tel.: +213 795164562.E-mail addresses: amira h g@yahoo.co.uk, guebailia habiba@yahoo.fr (H. Amira-

uebailia).

570-0232/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.jchromb.2013.02.024

© 2013 Elsevier B.V. All rights reserved.

aromatics, alcohols, halides, fatty acids, esters, etc.) [3–5]. The useof CDs in both food and pharmaceutical industries is increasingowing to their capacity to improve the bioavailability, stability,and hydrosolubility of a wide range of biological active compounds[6,7].

Many physico-chemical methods have been used for the studyof cyclodextrin–guest complexes among them; High PerformanceLiquid Chromatography. In this technique, the complex formation isconfirmed by the modifications of the retention properties of guestmolecules in presence of increasing CDs concentrations, differentmobile phases composition, and under different physico-chemicalconditions of PH and temperature [8,9].

Resveratrol, a compound with promising biological activities,has been the most studied stilbene in terms of its interaction withCDs. López-Nicolás et al. studied the complexation of resveratrolwith �-CD using HPLC with methanol–water mixtures [10], andpure water [11], as mobile phases. Besides resveratrol, results onthe retention behavior in RP-HPLC, in the presence and absenceof CDs in the mobile phase, have been recently reported for

other stilbenes such as: oxyresveratrol [12], pterostilbene [13] andpinosilvin [14].

Piceatannol (trans-3,5,3′,4′-tetrahydroxystilbene, A in Fig. 1) isa naturally occurring stilbene present in the skin of grapes, stems

22 H. Messiad et al. / J. Chromato

a[sofiaMarsoi

pc

rsm

p

pcpp

mtmatatpca�t

The elution of piceatannol was performed in triplicate and

Fig. 1. Molecular structures of piceatannol (A), and �-cyclodextrin (B).

nd stalks of the grapevine, rhubarb wine, berries and sugar cane15]. Piceatannol is structurally analogous to resveratrol; it pos-esses an additional hydroxyl group neighboring the active 4′-OHf resveratrol. It has been suggested that piceatannol is derivedrom resveratrol via cytochrome P450 1B1 to [16]. Other biolog-cal activities reported for piceatannol are its chemopreventive,nti-leukemic, anticardiovascular and anticancer activities [17,18].oreover, piceatannol shows a pronounced antioxidant and in vivo

nd in vitro anti-tumorigenic activities [19]. It has also beeneported as an inhibitor of protein-tyrosine kinase with immuno-uppressive action, which could contribute to the preventionf graft rejection [20]. In addition, piceatannol showed anti-nflammatory and anti-proliferative activities [21].

Roupe et al. previously reported on the poor absorption oficeatannol and the metabolism of the absorbed fraction to a glu-orinated derivative, detected in the plasma [22].

Hydrophobicity and low bioavailability of piceatannol, as well asesveratrol, could be a handicap for its use in pharmacology. Inclu-ion with cyclodextrins is a suitable choice to solve the problemset in the administration of poorly water-soluble drugs.To the best of our knowledge, there’s no report on the

iceatannol–CDs complexes.For this reason, we proceeded to the study of inclusion com-

lex of piceatannol with �-CD under different physico-chemicalonditions. This information is crucial if the complex betweeniceatannol and �-CD is to be used as a food ingredient and/or as aharmaceutical.

The purpose of this study is fourfold: first to determine theechanism of piceatannol complexation in a reversed-phase sys-

em involving the formation of �-CD inclusion complex in theobile phase; second the chromatographic determination of the

pparent association constants, the selection of organic solvent forhe mobile phase, the examination of the influence of mobile phasedditives and the methanol concentration on piceatannol reten-ion; third to study the effect of �-CD concentration and methanolercentage on piceatannol retention as well as the methanol per-entage and column temperature on apparent formation constants;nd fourth to obtain the thermodynamic parameters (�G◦, �H◦ and

S◦) in order to gain information about the mechanism aspect of

he piceatannol affinity for �-CD.

gr. B 926 (2013) 21– 27

2. Experimental

2.1. Materials

�-CD, copper sulfate and HPLC-grade methanol (MeOH) waspurchased from Sigma–Aldrich (Sigma, Germany) and used asreceived. Water was distilled and filtered. Binary mixtures ofwater–methanol, with methanol percentages from 30 to 70% (v/v),were used without further purification. Piceatannol was isolatedfrom stems of the grapevine by the GESVAB group (Université Vic-tor Segalen, Bordeaux 2, France).

HPLC analyses were performed on a Shimadzu apparatusequipped with two pumps and a UV-VIS detector-10AV (Shimadzu,Kyoto, Japan). A commercially available (CS chromatographieservice GMBH, Germany) reversed-phase column RP C18 (Nucle-osil100 -5 C18, 125 mm × 4.6 mm I.D, 5 �m particle size) was used.

2.2. Methods

Piceatannol solution was prepared at a concentration of0.05 mg mL−1 in methanol. Twenty microliters (20 �L) of this solu-tion were injected for HPLC analysis. The mobile phase flow-ratewas set up at 1.00 mL min−1 and detection was performed at306 nm.

2.3. Mobile phase preparation

The mobile phases were prepared by adding an accuratelyweighed amount of �-CD to the desired methanol–water mixture(250 mL) in a 500 mL volumetric flask. Sufficient time was allowedto obtain total dissolution at ambient temperature. Solvent amountwas added for a final mobile phase of 500 mL. The maximum quan-tity of �-CD that can be dissolved in such binary mixtures has beenreported by Taghvaei et al. and Chatjigakis et al. [23,24].

The working concentrations of �-CD were 0, 0.5, 2, 3, and 4 mM.Whenever the mobile phase solution was changed, we allowed atleast 1 h for the column to be equilibrated and conditioned with thenew solution mixture. The column void volume V0 was determinedusing reagent grade copper sulfate solution (0.01 mg mL−1) [25]. V0was thoroughly controlled all over the experimental procedure.

2.4. Temperature studies

The effect of temperature on the complexation process ofpiceatannol with �-CD was studied from 20 to 35.0 ± 0.1 ◦C. Eq.(1) was used for the determination of the standard enthalpy andentropy of piceatannol transfer from the mobile phase to �-CD [26]:

ln(KF) = −�H◦

RT+ �S◦

R(1)

where KF is the apparent formation constant of the inclusion com-plex, T is the temperature, R is the gas constant, �H◦ and �S◦ arestandard enthalpy and entropy changes of complex formation inthe mobile phase.

−�H◦/R and �S◦/R were the slope and intercept, respectively,of the linear plot of ln(KF) versus 1/T. To determine the Gibbs freeenergy change for the interactions taking place during the inclusionprocess, the following equation was used:

�G◦ = �H◦ − T�S◦ (2)

2.5. Statistical analysis

the resultant capacity factors were calculated and systemicallytested under different experimental conditions of linearity and

omatogr. B 926 (2013) 21– 27 23

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Table 1Correlation coefficients for 1:1 and 1:2 piceatannol/�-CD complexes, for differentMeOH–water mixtures.

MeOH:water (%, v/v) Correlation coefficients

1:1 from Eq. (4) 1:2 from Eq. (5)

30:70 0.999 0.90035:65 0.998 0.89940:60 0.994 0.89045:55 0.900 0.760

H. Messiad et al. / J. Chr

on-linearity. Data were expressed as means ± standard errors ofhree separate experiments performed in triplicate. Differencesetween groups were assessed by one-way analysis of varianceANOVA) from Microsoft Excel 2010.

. Results and discussion

.1. Mechanism of complexation of piceatannol with ˇ-CD

Many studies have reported on the competing equilibrian the HPLC column following the introduction of a solutento �-CD/solvent mixtures mobile-phases [12]. The presence oficeatannol in the column with �-CD added to the mobile phaseas studied. The equilibria presented in Scheme 1A and B were

btained for complexes with stoichiometry 1:1 and 1:2, respec-ively. As can be observed, when �-CD is added to the mobile phase,iceatannol retention is influenced by its partition between theobile and stationary phases, and the piceatannol complexationith �-CD.

CD]m = [CD]T

1 + Km[M](3)

[CD]m is the effective �-CD concentration in the mobile phase,CD]T is the total analytical �-CD concentration, Km describes theffinity of the modifier for the �-CD cavity determined as 0.32 M−1

or methanol [27], [M] is the methanol concentration of the mobilehase.

Eq. (4) was used to determine the KF values for theiceatannol/�-CD complex. In this equation, the capacity factor K iselated to the �-CD mobile-phase concentration [CD]m [10,12,15],

1:1 stoichiometry has been assumed, and interaction betweenhe piceatannol/�-CD complex with the stationary phase has beeneglected.

1 = 1 + KF (4)

K K0 K0 × [CD]m

In Eq. (4), K is the capacity factor of the solute, K0 the soluteapacity factor in the absence of �-CD, KF is the apparent forma-ion constant of the inclusion complex and [CD]m is the effective

Scheme 1. Equilibria proposed for a piceatannol/�-CD inclu

50:50 0.910 0.790

�-CD mobile-phase concentration. López-Nicolás et al. [10] demon-strated that trans resveratrol can be complexed by two moleculesof HP-�-CD. For this reason, we studied the possible formationof a 1:2 piceatannol/�-CD complex through a precursor 1:1 com-plex (Scheme 1A). Eq. (4) was extended to Eq. (5) containing asecond-order term that accounts for a possible 1:2 piceatannol/�-CD complex formation (Scheme 1B).

1K

= 1K0

+ KF1

K0 × [CD]m+ KF1KF2

K0 × [CD]2m

(5)

where K0 is the capacity factor of piceatannol in the absence of�-CD modifier, KF1 is the apparent formation constant for the 1:1piceatannol/�-CD complex and KF2 is the apparent formation con-stant for the 1:2 piceatannol/�-CD complex.

The plot of 1/K versus [CD]m, using Eq. (4) should be linear toindicate that a 1:1 piceatannol/�-CD complex was formed. How-ever, using Eq. (5), a plot of reciprocal of K versus [CD]2

m shouldgive a parabolic curve. The correlation coefficients correspondingto the 1:1 complex were always higher than those calculated forthe 1:2 complex, whatever the mobile phase used (Table 1). Theseresults are in good agreement with those previously obtained forthe 1:1 complex between �-CD and several compounds with struc-

tures similar to piceatannol such as resveratrol and oxyresveratrol[10,12].

sion complex with a stoichiometry (A) 1:1 and (B) 1:2.

2 omato

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ooscclp

3

ele

FCrt

4 H. Messiad et al. / J. Chr

.2. Chromatographic determination of the apparent associationonstants

When cyclodextrins are added to the mobile phase, solute reten-ion is governed by its partition between the mobile and stationaryhases and the solute complexation with cyclodextrins. Using theolute retention time and the void time, the capacity factors werealculated for the solute in the presence of increasing concentra-ions of �-CD.

As expected, the retention time decreased as the concentrationf �-CD in the mobile phase increased. This is due to the formationf piceatannol/cyclodextrin complex, which enhances the guestolubility in the mobile phase and reduces its residency time in theolumn; an assay is shown as an example in Fig. 2A. The variationoefficient in the retention times by replication has always beenower than 5%. Fig. 2B represents chromatograms of piceatannol inresence of increasing concentrations of �-CD in the mobile phase.

.3. Selection of organic solvent of mobile phase

The use of an aqueous-organic solvent as a mobile phase isssential, since the formation of CD inclusion complexes in theiquid phase proceeds more easily in an aqueous solution. Sev-ral authors have used mixtures of methanol and water to identify

ig. 2. (A) Decrease in the retention time of piceatannol in the presence of increasinghromatographic conditions – column: Nucleosil100-5 C18, m, 125 mm × 4.6 mm ID; moeplicates. (B) HPLC chromatograms of piceatannol in presence of increasing �-CD concentremperature, 25 ± 1 ◦C).

gr. B 926 (2013) 21– 27

trans-resveratrol by RP-HPLC [10,28,29]. In view of the similarityof piceatannol structure to resveratrol, a methanol water mixturewas used in our study.

3.4. Effect of mobile phase additives on piceatannol retention

Three amounts of d-glucose (3.5, 7 and 14 mM), correspondingto 0.5, 1 and 2 mM of �-CD, respectively, in the number of glucoseunits, were added to different binary methanol–water mixtures. Asshown in Table 2, the addition of glucose to the mobile phase hasno effect on the retention time and hence on K values of piceatan-nol, which means that there’s no interaction between glucose andpiceatannol. Whereas in the presence of �-CD at 0.5, 1 and 2 mM, Kvalues decreased, indicating that a complex �-CD/piceatannol hasbeen formed and that the modifications observed in the presence of�-CD are not due to modifications in solvent strength. These resultsreaffirm those reported by Fujimura et al. [8], López-Nicolás et al.[10], and Clarot et al. [25].

3.5. Effect of methanol concentration on piceatannol retention

The composition of the mobile phase has also a great effecton the capacity factor. The presence of �-CD caused a decrease inpiceatannol retention with increasing water percentage as shown

concentrations of �-CD (0, 0.5, 2, 3 and 4 mM) in the mobile phase at 25 ± 1 ◦C.bile phase: methanol–water (40/60, v/v). Data represent the means ± SD of threeations in a (30/70, v/v) MeOH–water mobile phase (flow-rate, 1.00 ± 0.01 mL min−1;

H. Messiad et al. / J. Chromatogr. B 926 (2013) 21– 27 25

Table 2Effect of additives in mobile phase on capacity factors of piceatannol (K) (flow-rate, 1.00 ± 0.01 mL min−1; temperature, 25 ± 1 ◦C). Data is presented as mean ± SD (n = 3).

K

Mobile phase (%MeOH) No addition 0.5 mM�CD 1 mM �CD 2 mM �CD 3.5 mM d-Glca 7 mM d-Glc 14 mM d-Glc

40 2.92 ± 0.02 2.65 ± 0.02 2.35 ± 0.02 2.16 ± 0.02 2.90 ± 0.02 2.91 ± 0.02 2.93 ± 0.0250 0.92 ± 0.02 0.80 ± 0.02 0.78 ± 0.02 0.74 ± 0.02 0.92 ± 0.02 0.93 ± 0.02 0.94 ± 0.02

a Glc, glucose.

Fig. 3. Correlation of Log K of piceatannol with volumetric fraction of waterin methanol–water mobile phases (flow-rate, 1.00 ± 0.01 mL min−1; temperature,25 ± 1 ◦C). (�) Without �-CD in the mobile phase; (�) with 2 mM �-CD in the mobilephase; (�) with 4 mM �-CD in the mobile phase. Data represent the means ± SD oft

iwo

c(

3

ttCntp

Cpm

(loeb�

mmdMc�m

Fig. 4. Apparent formation constant (KF) of piceatannol/�-CD complex as afunction of methanol percentage in methanol–water mobile phases (flow-rate,1.00 ± 0.01 mL min−1; temperature, 25 ± 1 ◦C). Each data point is the mean ± SD of 3replicates.

hree replicates.

n Fig. 3; representing the logarithm of K of piceatannol versusater percentage in the mobile phase in the presence and absence

f �-CD.A linear relationship with R2 > 0.99, between K and water per-

entage was observed in the solvent composition range studied30–70% (v/v) MeOH–water).

.6. Effect of ˇ-CD concentration on piceatannol retention

The addition of �-CD to the mobile phase resulted in a reduc-ion of piceatannol retention time. In this section, we will studyhe effect of �-CD concentration on the change of retention time.apacity factors presented in Table 3 were calculated for piceatan-ol, in the presence of increasing concentrations of �-CD, usinghe retention time and the void time, in different water–methanolroportions in the mobile phase.

Piceatannol retention time decreased with increasing �-D concentration in the mobile phase, because the complexiceatannol/�-CD formed improved the solubility of the guestolecule and decreased its residency time in the column.As shown in Table 3, when �-CD was added to the mobile phase

0.5–4 mM), the capacity factor of piceatannol decreased, regard-ess of the methanol–water percentage used. Moreover, it wasbserved that the lowest capacity factor was obtained for the low-st methanol concentration in mobile phase (30%, v/v). This maye due to the polarity of the mobile phase or interaction between-CD and the organic solvent.

As the methanol concentration increases from 30 to 50%, theobile phase becomes less polar, the non-polar solute becomesore soluble and its affinity for the hydrophobic cavity of �-CD

iminishes, therefore, the complexation process decreases [30].oreover, when the amount of methanol increases in the column,

ompetition between methanol and piceatannol for entrance to the

-CD hydrophobic cavity is possible; the association constant ofethanol with �-CD is 0.32 M−1 [27].

3.7. Effect of methanol percentage on apparent formationconstants

The evaluation of formation constants determines the amount ofcomplexed piceatannol in equilibrium with free piceatannol. More-over, these values indicate the stability of the complex under agiven set of conditions such as temperature, pH and presence ofmodifiers.

Using the data shown in Fig. 3 and linear regression slopes andintercepts, we calculated the apparent formation constants (KF)values for piceatannol complex with �-CD at different methanolconcentrations. As shown in Fig. 4, KF values depended strongly onmethanol concentration, in the mobile phase. This result is in fullagreement with those reported for other stilbenes such as resver-atrol [10] and oxyresveratrol [12].

3.8. Effect of temperature on apparent formation constants

One of the most important parameters that must be studiedconcerning the use of piceatannol/�-CD complex as an ingredientin food industry is the effect of temperature on the complex-ation mechanism. Indeed; several researchers have studied thechanges that occur in the equilibrium between CDs and differ-ent compounds when the temperature of the medium is changed.In general, stability of �-CD complexes decreases with increasingtemperature [10]. However, some authors found increased KF val-ues for increasing temperatures as is the case of the fatty acids/CDscomplexes [31].

In our study, the effect of temperature on capacity factors K wasstudied at 20, 25, 30 and 35 ◦C. As can be seen from Fig. 5, piceatan-nol retention decreases with decreasing temperature, because it isaccompanied by a higher degree of complexation. Therefore, the

amount of free piceatannol that can be adsorbed on the stationaryphase decreases.

26 H. Messiad et al. / J. Chromatogr. B 926 (2013) 21– 27

Table 3Capacity factors of piceatannol determined for five different methanol–water (v/v) mobile phases containing 0–4 mM of �-CD (flow-rate, 1.00 ± 0.01 mL min−1; temperature,25 ± 1 ◦C). Data is presented as mean ± SD (n = 3).

K

Mobile phase (%MeOH) No addition 0.5 Mm �-CD 2 mM �-CD 3 mM �-CD 4 mM �-CD

30 10.00 ± 0.02 9.98 ± 0.02

40 2.92 ± 0.02 2.65 ± 0.02

50 0.92 ± 0.02 0.80 ± 0.02

Fig. 5. Van’t Hoff plot (ln(KF) vs 1/T) for piceatannol/�-CD complex with amd

3c

2va

inmme

att

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pc

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[[

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[27] Y. Matsui, K. Mochida, Bull. Chem. Soc. Jpn. 52 (1979) 2808.

ethanol–water (30–70%, v/v) mobile phase (flow-rate, 1.00 ± 0.01 mL min−1). Eachata point is the mean ± SD of 3 replicates.

.9. Thermodynamic parameters for the piceatannol/ˇ-CDomplex

The thermodynamic parameters (�H◦, �S◦ and �G◦ at5 ± 0.2 ◦C) were obtained from Van’t Hoff plot (Eq. (1)). The ln(KF)ersus 1/T plot (Fig. 5) obtained for �-CD complex was linear with

correlation coefficient higher than 0.99.Enthalpy changes value was negative (−33.256 ± 1 kJ mol−1)

ndicating the exothermic nature of the complexation of piceatan-ol with �-CD. This could be due to hydrophobic interactions,ovement of water molecules from the cavity of �-CD, the aug-entation of Van der Waals interactions between molecules,

stablishment of hydrogen bonds and other interactions [12,19].A negative entropy changes value (−67.559 ± 1 kJ mol−1) was

lso obtained indicating a decrease in degrees of freedom of transla-ion and rotation of the piceatannol/�-CD complex compared withhe free piceatannol.

Finally, the negative value obtained for Gibbs free energy change−13.123 ± 1.0 kJ mol−1) shows that the process of inclusion ispontaneous.

. Conclusion

In this work, we investigated the complexation of piceatan-ol with �-CD as an attempt to improve the hydrosolubility ofhis biological active molecule, since its low hydrosolubility andioavailability could limit its use in the pharmaceutical field andood industry.

Our results indicated that the study of piceatannol complex with-CD, using RP-HPLC, requires a less polar mobile phase than water

e.g. mixtures of methanol–water) in order to achieve a reason-ble retention time. We also noticed that methanol becomes highlyompetitive with piceatannol for entrance to the �-CD cavity,specially at high concentrations, despite its very low associationonstant with �-CD.

Moreover, the apparent formation constants (KF) for theiceatannol/�-CD complex are strongly dependent on both the con-entration of methanol and the temperature.

[[[

8.00 ± 0.02 7.65 ± 0.02 5.98 ± 0.022.16 ± 0.02 1.88 ± 0.02 1.60 ± 0.020.74 ± 0.02 0.61 ± 0.02 0.58 ± 0.02

The stoichiometry of the complex piceatannol/�-CD was foundto be 1:1 for all the conditions used.

Potential applications of piceatannol/�-CD complex includeits use in the pharmaceutical or food ingredient industries asa nutraceutical due to its high solubility. Moreover, the use ofpiceatannol/�-CD complex could slow down the rapid metabolismand elimination of piceatannol, improving its bioavailability, as ithas been demonstrated for other guests/CDs complexes [32–34].

Another advantage is the decrease of analysis times in liquidchromatographic methods.

Acknowledgment

Authors wish to thank the GESVAB group, Université VictorSegalen Bordeaux2, France, for providing piceatannol used in thisstudy.

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