Thermodynamics of inclusion complexes of natural and modified cyclodextrins with acetylsalicylic acid and ibuprofen in aqueous solution at 298 K

Article abstract of DOI:10.1016/j.tca.2013.01.037

Thermodynamic parameters for the association of natural and substituted α-, β-, and γ-cyclodextrins with acetylsalicylic acid, salicylic acid and ibuprofen have been determined by isothermal titration calorimetry. Analysis of the data shows that complexes

Full text of DOI:10.1016/j.tca.2013.01.037

Thermochimica Acta 557 (2013) 44–49
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Thermodynamics of inclusion complexes of natural and modified cyclodextrins
with acetylsalicylic acid and ibuprofen in aqueous solution at 298 K
Giuseppina Castronuovo∗, Marcella Niccoli
Department of Chemistry, University Federico II of Naples, Complesso Universitario a Monte S. Angelo, via Cintia, 80126 Naples, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Thermodynamic parameters for the association of natural and substituted ␣-, ␤-, and ␥-cyclodextrins
with acetylsalicylic acid, salicylic acid and ibuprofen have been determined by isothermal titration
calorimetry. Analysis of the data shows that complexes form, all having 1:1 stoichiometry. The shape-
matching between the host and guest is the factor determining the values of the thermodynamic
quantities. In the case of the smallest cyclodextrin interacting with acetylsalicylic acid and salicylic acid,
the parameters indicate that hydrophobic interactions play the major role. Association occurs through the
shallow inclusion of the benzene ring into the cavity. In the case of substituted ␤-cyclodextrins, instead,
inclusion of the benzene ring is deeper and the tight fitting of the guest molecule to the cavity makes
the enthalpy and entropy to be both negative. Ibuprofen interacts through its isobutyl group: the values
of the association constants are very high for ␤-cyclodextrins as determined by the large and positive
entropies due to the relaxation of water molecules from the cavity and the hydration spheres of the
interacting substances. For all systems, a compensatory enthalpy–entropy relationship exists unless for
those involving ␤-cyclodextrins and ibuprofen.
Received 15 November 2012
Received in revised form 21 January 2013
Accepted 25 January 2013
Available online xxx
Keywords:
Cyclodextrins
Acetysalicylic acid (aspirin)
Ibuprofen
Inclusion complexes
Calorimetry
© 2013 Elsevier B.V. All rights reserved.
1. Introduction
cyclodextrin and guest molecule [1,12–20]. The weight of every
one of these interactions depends on the substituent groups on
Natural cyclodextrins (CDs) are cyclic oligomers of ␣-d-glucose
characterized by a fairly polar exterior and by a relatively nonpolar
cavity. The most important property of CDs is their ability to form
complexes with a great variety of organic substances in solution
and in the solid state [1–5]. The host–guest chemistry of inclusion
complexes of cyclodextrins has been thoroughly studied, especially
in relation to their most common pharmaceutical applications. The
physicochemical properties of the included substances are altered
upon complexation and cyclodextrins are widely used to enhance
the aqueous solubility, stability and bioavailability of apolar drug
molecules [6–9]. Besides, toxicity tests have demonstrated that
orally administered CDs are essentially nontoxic, largely because
they are not absorbed in the gastrointestinal tract. In the attempt
to improve the properties of the natural macrocycles as drug car-
riers [10,11], many cyclodextrin derivatives have been prepared in
the last years to modify their inclusion ability
both the interacting molecules and on the dimensions of the
cyclodextrin cavity. Preceding studies on the complexes of various
cyclodextrins with different substances have allowed us to exam-
ine the factors which are necessary for a complex to form. The
aim of the present contribution is to have the complete thermo-
dynamic framework characterizing the inclusion process between
natural and modified cyclodextrins and substances of pharma-
cological interest in aqueous solution. To that, the interaction
of ␣-cyclodextrin (␣-CD), 2-hydroxypropyl-␣-cyclodextrin (HP-␣-
CD), methyl-␣-cyclodextrin (M-␣-CD), ␤-cyclodextrin (␤-CD), 2-
hydroxypropyl-␤-cyclodextrin (HP-␤-CD), methyl-␤-cyclodextrin
(M-␤-CD) and ␥-cyclodextrin with some drugs is investigated by
a calorimetric method at 298 K. The drugs used in this study
are: acetylsalicylic acid (aspirin, pKa = 3.5; Fig. 1), salicylic acid
(pKa = 2.97) and ibuprofen (pKa = 4.4, Fig. 1), which belong to a
group of medications called nonsteroidal, anti-inflammatory drugs
(NSAIDs), pH-dependent and practically insoluble in water. Aspirin
is one of the most widely used medications in the world. Its effects
as an analgesic, antipyretic, anti-inflammatory and antithrombotic
agent are widely known. Unfortunately, its use, especially in higher
doses, can cause severe side effects as gastrointestinal ulcers, stom-
ach bleeding, and tinnitus. Aspirin-CD inclusion complexes were
devised to increase the solubility and reduce the concentration of
free drug, with the consequent reduction of side effects. Ibuprofen
(BF, see Fig. 1b) is used primarily for fever, pain, dysmenorrhoea and
Complexation processes result from the contribution of a
series of noncovalent intermolecular forces: hydrophobic interac-
tions, hydrogen bonds, van der Waals interactions, conformational
energy, dipole–dipole and ion–dipole interactions and the
rearrangement of water molecules originally surrounding both
∗
Corresponding author. Tel.: +39 081674239; fax: +39 081674091.
E-mail address: giuseppina.castronuovo@unina.it (G. Castronuovo).
0040-6031/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.tca.2013.01.037

G. Castronuovo, M. Niccoli / Thermochimica Acta 557 (2013) 44–49
45
was considered to be negligible. The estimated uncertainties in the
molalities and the heat effects are 1% and 2%, respectively.
2.3. Treatment of the data
Assuming that a 1:1 complex is formed when mixing two
binary solutions, the association process can be represented as
follows:
CD + L = CD − L
(1)
where CD indicates a cyclodextrin and L a guest (drug) molecule.
The enthalpy of mixing two binary solutions, ꢀHmix, is related to
the enthalpy of formation of a complex, or in general to the enthalpy
of interaction between solutes, ꢀH*, and to the heats of dilution
experienced by the two solutes, ꢀHdil, [23–25]
Fig. 1. Scheme of the interaction between a modified ␤-cyclodextrin and (upper)
acetylsalicylic acid (aspirin) or (down) ibuprofen.
ꢀHmix[(mCi D)(miL) → mCf D, mfL] = ꢀH∗ + ꢀHdil(mi → mj
)
CD
CD
+ ꢀHdil(mi → mfL)
(2)
inflammatory diseases such as rheumatoid arthritis. Its pharmaceu-
tical applications, however, are limited because it is only slightly
soluble in water, has a bad taste and can have serious effects on the
gastro-intestinal apparatus. The formation of inclusion complexes
with cyclodextrins improves both its solubility and taste [21,22].
Microcalorimetry is the technique chosen to carry out this kind
of study: through the thermal effect detected, it is possible to eval-
uate the association constant, and from that the Gibbs energy and
entropy of the process. Knowing the values and signs of the thermo-
dynamic parameters makes possible proposing a hypothesis about
the forces involved in the interaction between CD and the exam-
ined guest molecules. That can be particularly useful for designing
new modified cyclodextrins having more suitable characteristics to
include specific drug.
L
where miCD, mLi , mCf D, and mfL are the initial and final molalities of
the cyclodextrin and drug. ꢀH*, normalized to the total molal-
ity of the guest, mL, can be related to the actual molality of the
cyclodextrin host molecule, mfCD, to the standard molar enthalpy of
association, ꢁHa◦ , and to the apparent association constant, Kaꢀ , as
follows [26]:
mL
ꢁH∗
1
1
=
+
(3)
ꢀHa◦
ꢀHa◦ Kaꢀ mfCD
For each value of ꢀH*, the actual concentration of the host molecule
is given by:
ꢀ
ꢁ
ꢀH∗
mfCD = mCD
−
mL
(4)
ꢀHs∗at
2. Experimental
where mL is the total stoichiometric molality of the host molecule.
The standard enthalpy and the constant are obtained from Eqs. (3)
and (4) by an iterative least-squares fitting. The iterations are con-
tinued until two successive values of ꢀHa◦ differ by less than 2%.
The values of the free energy and entropy are obtained through the
usual thermodynamic relations. The absence of any information
about the activity coefficients leads to the evaluation of associa-
tion parameters thermodynamically not exactly defined. Only an
apparent constant, Kaꢀ , can be determined, an◦d consequently the
2.1. Materials
Natural ␣-, ␤-, and ␥-cyclodextrin, as well as acetylsali-
cylic acid, salicylic acid and ibuprofen, were purchased from
Sigma. Methyl-␣-cyclodextrin, 2-hydroxypropyl-␣-cyclodextrin,
methyl-␤-cyclodextrin, 2-hydroxypropyl-␤-cyclodextrin and 2-
hydroxypropyl-␥-cyclodextrin were purchased from Cyclolab: it is
reported that the mean substitution degree has been determined
by NMR. All substances were used as received, without further
purification. The optical rotations of CDs were in agreement with
those reported in the literature. Solutions of natural and modified
cyclodextrins, of known molalities, were prepared by mass, using
0.05 mol kg−1 buffer phosphate, pH 7.4 or 9.3. Solutions of ibupro-
fen, acetylsalicylic acid and salicylic acid were, then, prepared using
the same phosphate buffer as solvent.
standard free energy and entropy, ꢀGa◦ꢀ and ꢀSa , suffer of the same
ꢀ
limitations
3. Results
The thermodynamic association parameters for the formation
of the drug/CD complexes were determined at 298 K. In Tables 1–3,
the association constant, standard Gibbs energy, enthalpy and
entropy are reported for the complexation of natural and modified
cyclodextrins with acetylsalicylic acid, salicylic acid and ibuprofen,
in aqueous phosphate buffer, pH 9.3 or 7.4.
2.2. Calorimetry
Measurements of the experimental heats of mixing, ꢀHmix
,
Table 1 shows the thermodynamic parameters, obtained in
phosphate buffer, pH 9.3, for the formation of inclusion complexes
between natural and modified cyclodextrins and acetylsalicylic
acid. The standard molar enthalpies of association, ꢁHa◦ , are
negative for all employed cyclodextrins: those relative to nat-
ural and modified ␤-cyclodextrins are larger, in absolute value,
than those for ␣-cyclodextrins, being intermediate that for ␥-
CD. The unsubstituted CDs are characterized by a less negative
standard molar enthalpy compared to the respective modified ones.
The enthalpies become more negative at increasing hydropho-
bicity of the modified ␤-CDs: in fact, enthalpy for the modified
hydroxypropyl-cyclodextrin having DS = 6,3 is larger than that for
of two binary solutions containing any one of the solutes, were
determined at 298 K using a thermal activity monitor (TAM) from
Thermometric, equipped with a titration vessel. A microcomputer
controlled the injections and collected the titration data. Approx-
imately 30 injections of the titrating solution were made in each
experiment, and at least two experiments were performed for each
substance. Enthalpies of dilution of the added substance in the
appropriate solvent were determined, using the same number of
injections and concentrations as in the titration experiments, and
were subtracted from the enthalpies of the mixing process. The
dilution of the component present in the cell (usually the drug)

46
G. Castronuovo, M. Niccoli / Thermochimica Acta 557 (2013) 44–49
Table 1
Thermodynamic parameters for the association of various cyclodextrins with acetyl salicylic acid in 0.05 mol kg−1buffer phosphate, pH 9.3, at 298.15 K.
ꢀHa◦
Kaꢀ
ꢀGa◦ꢀ
TꢀSa◦ꢀ
10
a,b
a,c
b,d
b,e
System
␣-CD
−2.2 0.9
−2.7 0.1
110 70
150 10
105 30
210 30
55 10
100 10
145 20
45 10
−12
2
3
Methyl-␣-CD (DSf = 11)
2-Hydroxypropyl-␣-CD (DSf = 4.5)
␤-CD
−12.4 0.2
−11.5 0.9
−13.2 0.4
−9.9 0.5
−11.4 0.3
−12.3 0.3
−9.4 0.6
9.7 0.3
−7
1
5
6
2
1
−7.5 0.8
−12
−15.8 0.9
−24
−4.9 0.6
2-Hydroxypropyl-␤-CD (DSf = 3)
2-Hydroxypropyl-␤-CD (DSf = 6.3)
Methyl-␤-CD (DSf = 12)
␥-CD
1
−2
1
1
2
−4
2
−12
5
1
2-Hydroxypropyl-␥-CD (DSf = 4.5)
N.A.g
a
Errors reported are the standard deviations as obtained by fitting the data to Eqs. (3) and (4).
b
c
d
e
f
kJ/mol.
kg/mol.
Errors are half the range of ꢀGa◦ꢀ calculated from the upper and lower error in Kaꢀ .
Errors are the sum of the errors on free energy and enthalpy.
Degree of substitution.
g
N.A. means that experiments have been performed, but no association was detected.
Table 2
For both cyclodextrins the inclusion processes are exothermic, and
entropies are positive. The values of inclusion enthalpies for natural
cyclodextrins are more negative than the corresponding modified
ones, those relative to ␤-CDs (except methyl-␤-CD) being much
larger as respect to the ␣-CDs. The standard molar entropies are
positive and very different for the various ␣-CDs, while they are
large and positive and approximately invariant for all the exam-
ined ␤-CDs. Gibbs energy distinguishes very well the two CDs: in
fact, for ␤-CDs it almost doubles that for ␣-CDs. For ␣-CDs, the
association constants increase at increasing hydrophobicity of the
cyclodextrin: they are very large for ␤-CDs, as determined by the
very high and positive entropic contribution. In particular, for the
natural ␤-CD, the large and negative value of enthalpy determines
that the complex is characterized by an association constant larger
than that involving modified ␤-CDs.
Thermodynamic parameters for the association of various cyclodextrins with sali-
cylic acid in 0.05 mol kg−1buffer phosphate, pH 9.3, at 298.15 K.
ꢁHa◦
Kaꢀ
90 30
ꢁGa◦ꢀ
−11
TꢀSa◦ꢀ
a,b
a,c
b,d
b,e
System
␣-CD
␤-CD
−2.4 0.6
1
9
0
2
1
1
−12
1
120 10 −11.9 0.3
Methyl-␤-CD (DSg = 12)
−16.3 0.8
110 10 −11.7 0.3 −5
a
Errors reported are the standard deviations as obtained by fitting the data to
Eqs. (3) and (4).
b
kJ/mol.
kg/mol.
c
Errors are half the range of ꢀGa◦ꢀ calculated from the upper and lower error in
d
Kaꢀ .
e
Errors are the sum of the errors on free energy and enthalpy.
DS = 3, while the largest value characterizes the interaction with
methyl-␤-CD. Entropies for ␣-CDs and ␥-CD are positive while neg-
ative for ␤-CDs. Despite the great variability in the values of the
Fig. 2 shows the complete thermodynamic framework for the
association of acetylsalycilic acid and ibuprofen with the natu-
ral and modified cyclodextrins. Enthalpies and Gibbs energies are
reported vs 3N-DS, where N is the number of glucopyranose rings
forming the cyclodextrin, and DS is the substitution degree. Repor-
ting the only DS as the independent variable would not allow to
distinguish between ␣-CDs and ␤-CDs having the same substitu-
tion degree, but different number of glucose units, hence different
residual hydrophilicity.
enthalpies and entropies of association, the values of ꢀGa◦ vary in
ꢀ
a limited range, showing a relationship between the enthalpy and
entropy change, i.e. the enthalpy–entropy compensation. That leads
to very similar and low values of the association constants, which
fall in the 50/200 kg/mol range. For the propyl substituted ␥-CD,
association was not detected.
Table 2 shows the thermodynamic parameters, obtained in
phosphate buffer at pH 9.3, for the formation of inclusion com-
plexes between natural and modified cyclodextrins and salicylic
acid., The values of the thermodynamic parameters for the unsub-
stituted ␣-CD and ␤-CD are similar to those obtained for the
complexes with acetylsalicylic acid.
4. Discussion
According to the commonly accepted view, complexation of a
hydrophobic guest molecule with a cyclodextrin occurs through
the inclusion of the alkyl portion into the prevailingly hydropho-
bic cavity. The functional group forms hydrogen bonds with the
The data for ibuprofen, reported in Table 3, indicate that the
complexation with ␣-CDs is very different from that with ␤-CDs.
Table 3
Thermodynamic parameters for the association of various cyclodextrins with ibuprofen in 0.05 mol kg−1buffer phosphate, pH 7.4, at 298.15 K.
ꢀHa◦
Kaꢀ
ꢀGa◦ꢀ
TꢀSa◦ꢀ
a,b
a,c
b,d
b,e
System
␣-CD
−8.5 0.4
−5.2 0.1
99
720 30
100 20
8
−11.4 0.2
−16.3 0.1
−11.6 0.4
−26.7 0.7
−25.5 0.1
−25.7 0.3
−22.2 0.2
2.9 0.6
11.1 0.2
Methyl-␣-CD (DSf = 11)
2-Hydroxypropyl-␣-CD (DSf = 4.5)
␤-CD
−5.3 0.7
6
1
−9.24 0.06
−8.16 0.09
−7.87 0.08
−4.92 0.05
(5.0 0.1)104
(2.9 0.1)104
(3.2 0.3)104
(7.6 0.7)103
17.5 0.8
17.3 0.2
17.8 0.3
17.2 0.3
2-Hydroxypropyl-␤-CD (DSf = 3)
2-Hydroxypropyl-␤-CD (DSf = 6.3)
Methyl-␤-CD (DSf = 12)
a
Errors reported are the standard deviations as obtained by fitting the data to Eqs. (3) and (4).
b
c
d
e
f
kJ/mol.
kg/mol.
Errors are half the range of ꢀGa◦ꢀ calculated from the upper and lower error in Kaꢀ .
Errors are the sum of the errors on free energy and enthalpy.
Degree of substitution.

G. Castronuovo, M. Niccoli / Thermochimica Acta 557 (2013) 44–49
47
-8
-9
-12
-16
-20
-24
-28
-32
-10
-11
-12
-13
-14
-15
α
-CD/aspirin
α
-CD/Ibuprofen
β
-CD/aspirin
β
-CD/Ibuprofen
-16
5
0
-4
-8
0
-5
-10
-15
-20
-25
-30
-12
α
β
-CD/Ibuprofen
-CD/Ibuprofen
α
β
-CD/Aspirin
-CD/Aspirin
6
8
10
12
14
16
18
20
22
24
26
6
8
10
12
14
16
18
20
22
3N-DS
Fig. 2. Enthalpies and Gibbs energies for aspirin and ibuprofen interacting with natural and modified ␣-CDs or ␤-CDs as a function of 3N-DS, where N is the number of
glucopyranose rings forming cyclodextrins and DS is the degree of substitution.
external hydroxyl groups on the rim of the macrocycle cavity, thus
preventing the further penetration of the alkyl chain [27,28]. The
present data relative to the interaction of natural or modified ␣-,
␤-, and ␥-cyclodextrins with some drugs as guest molecules show
that association occurs through the same mechanism. However,
the presence of external methyl or propyl groups in the substi-
tuted CDs causes the balance of the forces upon association to
be different from that acting when the natural cyclodextrins are
involved. In all cases, the association is characterized by negative
enthalpies. The value of enthalpy is the result of several factors,
among them the endothermic contribution due to the disrup-
tion of hydrogen bonds between water molecules in the cavity,
the endothermic dehydration of the including hydrophobic guest
molecule, and the exothermic contribution stemming from the van
der Waals interactions between the guest and the cyclodextrin cav-
ity. For the last interactions, the dimensions of the cyclodextrin
cavity play the major role. The ␣-CD cavity has the best dimen-
sions to include an alkyl chain, while ␤-CD can accommodate a
benzene ring at the best. In the case of a loose adaptation of the
guest molecule upon formation of a complex, contributions stem-
ming from the interactions with the cavity will be negative, but
smaller, as in the case of ␥-CD. Also entropy is a complex quantity
whose value is the result of several contributions. Upon inclu-
sion, water molecules relax from an ordered microenvironment,
namely the cavity, and from the ordered hydrophobic hydration
shells of the guests to a more disordered bulk. In the case of mod-
ified (alkylated) cyclodextrins, another additional effect must be
taken into account: the dehydration of the external alkyl groups,
an endothermic process. In those cases, the very large and posi-
tive values are determined by the relaxation to the bulk of water
molecules from the hydrophobic hydration shells of the external
alkyl groups and from the cavity. For natural and modified ␤-
CDs the last contribution can be assumed to be the predominant
one [12,29].
Acetylsalycilic acid has three possible points to include within
the cavity of a cyclodextrin: the carboxylic group, the acylic group
and the benzene ring (Table 1). At pH 9.3, the carboxyl group is ion-
ized in solution: hence, as reported in the literature, carboxylate ion
cannot enter into the hydrophobic cavity because of its extended
hydration [27]. Then, inclusion could occur or through the benzene
ring or through the acylic group. Calorimetric titrations of the two
natural cyclodextrins and of methyl-␤-cyclodextrin with salicylic
acid lead to inclusion parameters (Table 2) which describe the pen-
etration of benzene into the cavity of the CDs, since no other part of
the molecule can be included. The similarity of the binding param-
eters for the interaction of aspirin and salicylic acid with the same
cyclodextrins, makes to infer that, at the pH used, the interaction
of cyclodextrins with aspirin occurs through the inclusion of the
benzene ring into the cavity. For ␣-CDs, the values of the associ-
ation constants indicate the formation of rather weak complexes,
thus underlining that the fitting of the guest molecule to the cav-
ity is rather superficial. That is in agreement with literature data
which report that the benzene ring penetrates shallowly into the
˚
narrower ␣-CD cavity, whose diameter (about 5 A) is too small to
give a deep and tight inclusion of the guest molecule [13,30,31].
Instead, the fitting of benzene is deeper into the wider cavity of
˚
␤-CD, whose internal diameter is about 7 A, the best dimensions
for the association with a benzene ring. The values of enthalpies
for ␣-CDs are small and negative, while those for modified ␤-CDs
are negative and large, an indication that van der Waals interac-
tions between the guest molecule and the cavity are much more
significant. The last effect determines the entropy to be negative
for the reduced motion of the guest molecule. Consequently, the
Gibbs energy is rather small and the constants as low as those
for the smaller cyclodextrin. These conclusions are in agreement
with the findings from NMR studies on unionized aspirin, that has
been found to form stable inclusion complexes with various ␤-
cyclodextrins: the benzene ring is located inside the cavity while

48
G. Castronuovo, M. Niccoli / Thermochimica Acta 557 (2013) 44–49
20
10
there are structural [38–41] and thermodynamic [36] studies on
ibuprofen–cyclodextrin complexes. Our data are in good agreement
with calorimetric data, showing similar trend of the thermody-
namic parameters: any differences can be attributed to the different
solvent and pH of measurement.
Aspirin
Ibuprofen
0
5. Conclusion
-10
-20
-30
The formation of a complex between a cyclodextrin and a pre-
vailingly hydrophobic guest molecule is a process ruled by the
changes experienced by the solvent water upon association: dehy-
dration of the guest molecule, desolvation of the cavity, formation
of a hydration shell for the complex.
The complete thermodynamic framework reported in Fig. 2 is a
good synthesis of the association of acetylsalycilic acid and ibupro-
fen with natural and modified cyclodextrins. The 3N-DS abscissa
takes into account the number of hydroxyl groups substituted
by an alkyl group, hence it is bound to the residual hydrophilic
character of the examined cyclodextrins. For aspirin, it comes
out that the Gibbs energy varies in a small range because of the
enthalpy–entropy compensation. That leads to rather weak com-
plexes, described by small association constants. For ibuprofen,
enthalpies vary in a limited range for both ␣- and ␤-cyclodextrins.
Hence, the very different association constants characterizing the
formation of the complexes with the two types of differently sized
cyclodextrins are determined by entropy, which is positive in both
cases, but very large for the larger macrocycle. For most com-
plexes reported in the literature, a roughly linear trend is obtained
when reporting ꢀH◦ vs ꢀS◦’: this compensatory enthalpy–entropy
relationship exists [1,12,42–44] for all processes dominated by
equation phenomena and ascribed to the modifications experi-
enced by the solvent in the hydration cospheres of the interacting
substances. Fig. 3 is very descriptive of the processes examined. In
fact, the plot is roughly linear, whatever the cyclodextrin or the
guest molecule, with the exception of the last five points referring
to the systems involving ␤-CD interacting with ibuprofen. Then, for
those systems enthalpy–entropy compensation does not operate
and the large values of the association constants, among the high-
est found for cyclodextrin complexes, are determined prevailingly
by entropy.
-0,04
-0,02
0,00
0,02
0,04
0,06
Δ
S'°a / kJ mol-1 K-1
Fig. 3. Enthalpy–entropy compensation plot for the formation of the complexes of
natural and modified ␣-CDs or ␤-CDs with aspirin or ibuprofen.
the acetyl ester group protrudes from it. The same studies indicated
that the ionized aspirin does not form complexes with the exam-
ined ␤-cyclodextrins. Loftsson et al. carried out a structural analysis
of the inclusion complex between ␤-CD and aspirin by NMR [32].
They concluded that the phenyl ring of the guest is completely
included into the cavity and the ester group stands somewhat out
of it. In contrast, the ionized aspirin molecule is, to a certain degree,
pulled out from the ␤-CD cavity so that the included portion of the
aspirin molecule should be smaller than that under acidic condi-
tions [33]. IR studies, too, evidentiate the formation of inclusion
complexes stabilized by van der Waals interactions of aromatic
rings of salycilic acid molecules with the hydrophobic cavities of CD
molecules. The stabilization inside ␤-cyclodextrin is supported by
the formation of weak hydrogen bonds between phenyl hydroxyls
of salicylic acid and glycoside oxygens of cyclodextrin molecules
[34,35].
Ibuprofen includes into the cavity of cyclodextrins probably
through its isobutyl group. The ꢀHa◦ values for ␣-CDs are negative
and smaller than those for ␤-CDs. That is not unexpected probably
because, beyond the isobutyl group, also the benzene ring enters
partially into the cavity of CDs. This hypothesis is confirmed by NMR
literature data [36], which suggest that only the isobutyl group of
the BF molecule is included in the cavity of ␣-CD, while the ␤-CD
cavity accommodates, beyond the isobutyl, part of the aromatic
ring of the BF molecule, too [37]. The association constants and
then the values of the Gibbs energy depend on the cavity size of
cyclodextrins, being those for ␣-CDs much smaller than those for
␤-CDs. The values of entropies are positive for both cyclodextrins:
they originate from the dehydration of the isobutyl part of ibupro-
fen upon inclusion and from the relaxation of water molecules
from the cavity. However, for ␤-CDs, the entropic term is large,
positive and almost invariant. The complexes formed are charac-
terized by large association constants, for the favorable, concurrent
contribution of both enthalpy and entropy, being the former neg-
ative and the latter positive (see Fig. 3). Given the dimensions of
␤-cyclodextrins, the association occurs through the inclusion of
the isobutyl group together with the aromatic ring. The suitable
fit between host and guest determines the values of the thermody-
namic parameters. Hence, the values of the entropic contribution
are determined by the relaxation to the bulk of water molecules
from the hydrated interacting groups and from the cavity. The last
effect appears to be predominant, as detected by the invariance
of entropy whatever the cyclodextrin, natural, modified or hav-
ing different substitution degree (see Table 3). In the literature
References
[1] M.V. Rekharsky, Y. Inoue, Complexation thermodynamics of cyclodextrins,
Chem. Rev. 98 (1998) 1875–1918.
[2] M.V. Rekharsky, Y. Inoue, Chiral recognition thermodynamics of ␤-
cyclodextrin: the thermodynamic origin of enantioselectivity and the
enthalpy–entropy compensation effect, J. Am. Chem. Soc. 122 (2000)
4418–4435.
[3] R.J. Clarke, J.H. Coates, S.F. Lincoln, Inclusion complexes of the cyclomalto-
oligosaccharides (cyclodextrins), Adv. Carbohydr. Chem. Biochem. 46 (1988)
205–249.
[4] A. Connors, The stability of cyclodextrin complexes in solution, Chem. Rev. 97
(1997) 1325–1358.
[5] W. Saenger, Cyclodextrin inclusion compounds in research and industry,
Angew. Chem. Int. Ed. Engl. 19 (1980) 344–362.
[6] F. Bellia, D. La Mendola, C. Pedone, E. Rizzarelli, M. Saviano, G. Vecchio, Selec-
tively functionalized cyclodextrins and their metal complexes, Chem. Soc. Rev.
38 (2009) 2756–2781.
[7] E. Junquera, D. Ruiz, E. Aicart, Role of hydrophobic effect on the noncovalent
interactions between salicylic acid and a series of ␤-cyclodextrins, J. Colloid
Interface Sci. 216 (1999) 154–160.
[8] E. Junquera, V.G. Baonza, E. Aicart, Energetics of the encapsulation of o-, m-,
and p hydroxybenzoic acids by ␤-cyclodextrin and its methylated and hydrox-
ypropylated derivatives in aqueous solution, Can. J. Chem. 77 (1999) 348–355.
[9] E. Junquera, E. Aicart, Potentiometric study of the encapsulation of ketoprophen
by hydroxypropyl-␤-cyclodextrin. Temperature, solvent, and salt effects, J.
Phys. Chem. B 101 (1997) 7163–7171.
[10] K. Uekama, F. Hirayama, T. Irie, Cyclodextrin drug carrier systems, Chem. Rev.
98 (1998) 2045–2076.
[11] A.R. Hedges, Industrial applications of cyclodextrins, Chem. Rev. 98 (1998)
2035–2044.

G. Castronuovo, M. Niccoli / Thermochimica Acta 557 (2013) 44–49
49
[12] G. Castronuovo, M. Niccoli, L. Varriale, Complexation forces in aqueous
solution. Calorimetric studies of the association of 2-hydroxypropyl-␤-
cyclodextrin with monocarboxylic acids or cycloalkanols, Tetrahedron 63
(2007) 7047–7052.
[13] G. Castronuovo, M. Niccoli, Thermodynamics of inclusion complexes of natu-
ral and modified cyclodextrins with propranolol in aqueous solution at 298 K,
Bioorg. Med. Chem. 14 (2006) 3883–3887.
[29] G. Castronuovo, M. Niccoli, Solvent effects on the complexation of 1-alkanols
by parent and modified cyclodextrins. calorimetric studies at 298 K, J. Therm.
Anal. Calorim. 103 (2011) 641–646.
[30] Y. Inoue, Y. Miyata, Formation, Molecular dynamics of cycloamylose inclusion
complexes with phenylalanine, Bull. Chem. Soc. Jpn. 54 (1981) 809–816.
[31] M. Cervero, F. Mendicuti, Inclusion complexes of dimethyl
2
6-
Naphthalenedicarboxylate with ␣- and ␤-cyclodextrins in aqueous medium:
[14] L. Liu, Q.-X.J. Guo, The driving forces in the inclusion complexation of cyclodex-
trins, J. Inclusion Phenom. Macrocycl. Chem. 42 (2002) 1–14.
[15] M.V. Rekharsky, M.P. Mayhew, R.N. Goldberg, P.D. Ross, Y. Yamashoji, Y. Inoue,
Thermodynamic and nuclear magnetic resonance study of the reactions of ␣-
and ␤-cyclodextrin with acids, aliphatic amines, and cyclic alcohols, J. Phys.
Chem. 101 (1997) 87–100.
[16] M.F. Brewster, T. Loftsson, Cyclodextrins as pharmaceutical solubilizers, Adv.
Drug Deliv. Rev. 59 (2007) 645–666.
[17] P.D. Ross, M.V. Rekharsky, Thermodynamics of hydrogen bond and
hydrophobic interactions in cyclodextrins complexes, Biophys. J. 71 (1996)
2144–2154.
[18] G. Barone, G. Castronuovo, P. Del Vecchio, V. Elia, M. Muscetta, Thermodynamics
of formation of inclusion compounds in water. ˛-Cyclodextrin–alcohol adducts
at 298.15 K, J. Chem. Soc. Faraday Trans. I 82 (1986) 2089–2101.
[19] D. Hallén, A. Schön, I. Shehatta, I. Wadsö, Microcalorimetric titration of ␣-
cyclodextrin with some straight-chain alkan-1-ols at 288.15, 298.15, and
308.15 K, J. Chem. Soc. Faraday Trans. 88 (1992) 1859–2853.
[20] N.A. Todorova, F.P. Schwarz, The role of water in the thermodynam-
ics of drug binding to cyclodextrin, J. Chem. Thermodyn. 39 (2007)
1038–1048.
[21] M. di Cagno, P.C. Stein, N. Skalko-Basnet, M. Brandl, A. Bauer-Brandl, Solubi-
lization of ibuprofen with ␤-cyclodextrin derivatives: energetic and structural
studies, J. Pharm. Biomed. Anal. 55 (2011) 446–451.
[22] L.J. Waters, S. Bedford, G.M.B. Parkes, J.C. Mitchell, Influence of lipophilicity on
drug–cyclodextrin interactions: a calorimetric study, Thermochim. Acta 511
(2010) 102–106.
thermodynamics and molecular mechanics studies, J. Phys. Chem.
(2000) 1572–1580.
B
104
[32] T. Loftsson, E.M. Brewster, Pharmaceutical applications of cyclodextrins. 1. Drug
solubilization and stabilization, J. Pharm. Sci. 85 (1996) 1017–1025.
[33] T. Fukahori, M. Kondo, S. Nishikawa, Dynamic Study of interaction between ␤-
cyclodextrin and aspirin by the ultrasonic relaxation method, J. Phys. Chem. B
110 (2006) 4487–4491.
[34] L.A. Belyakova, A.M. Varvarin, D. Yu Lyashenko, O.V. Khora, E.I. Oranskaya,
Complexation in a ␤-cyclodextrin-salicylic acid system, Colloid J. 69 (2007)
546–551.
[35] L.A. Belyakova, D.Yu. Lyashenko, Complex formation between benzene car-
boxylic acids and ␤-cyclodextrin, J. Appl. Spectrosc. 75 (2008) 314–318.
[36] S. Xing, Q. Zhang, C. Zhang, Q. Zhao, H. Ai, D. Sun, Isothermal titration calorime-
try and theoretical studies on host–guest interaction of ibuprofen with ␣-, ␤-
and ␥-cyclodextrin, J. Solution Chem. 38 (2009) 531–543.
[37] I. Oh., M.Y. Lee, Y.B. Lee, S.C. Shin, I. Park, Spectroscopic characterization of
ibuprofen/2-hydroxypropyl-␤-cyclodextrin inclusion complex, Int. J. Pharm.
175 (1998) 215–223.
[38] B. Rossi, P. Verrocchio, G. Villani, I. Mancini, G. Guella, E. Rigo, G. Scarduelli,
G. Mariotto, Vibrational properties of ibuprofen–cyclodextrin inclusion com-
plexes investigated by Raman scattering and numerical simulation, J. Raman
Spectrosc. 40 (2009) 453–458.
[39] V. Crupi, D. Majolino, V. Venuti, G. Guella, I. Mancini, B. Rossi, P. Verrocchio,
G. Villani, R. Stancanelli, Temperature effect on the vibrational dynamics of
cyclodextrin inclusion complexes: investigation by FTIR-ATR spectroscopy and
numerical simulation, J. Phys. Chem. A 114 (2010) 6811–6817.
[40] J.L. Manzoori, M. Amjadi, Spectrofluorimetric study of host–guest complexation
of ibuprofen with ␤-cyclodextrin and its analytical application, Spectrochim.
Acta A 59 (2003) 909–916.
[23] W.G. Mc Millan, J.E. Mayer, The statistical thermodynamics of multicomponent
systems, J. Chem. Phys. 13 (1945) 276–306.
[24] J.J. Kozak, W.S. Knight, W. Kauzmann, Solute-solute interactions in aqueous
solutions, J. Chem. Phys. 48 (1968) 675–691.
[25] H.L. Friedman, C.V. Krishnan, Studies of hydrophobic bonding in aqueous alco-
hols: enthalpy measurements and model calculations, J. Solution Chem. 2
(1973) 119–140.
[41] V. Crupi, G. Guella, D. Majolino, I. Mancini, B. Rossi, R. Stancanelli, V. Venuti, P.
Verrocchio, G. Villani, T-dependence of the vibrational dynamics of IBP/diME-
␤-CD in solid state: a FT-IR spectral and quantum chemical study, J. Mol. Struct.
972 (2010) 75–80.
[26] M. Eftink, R. Biltonen, in: E. Beezer (Ed.), Biological Microcalorimetry, Academic
Press, London, 1980.
[27] G. Castronuovo, V. Elia, M. Niccoli, F. Velleca, G. Viscardi, Role of the functional
group in the formation of the complexes between ␣-cyclodextrin and alka-
nols or monocarboxylic acids in aqueous solutions. A calorimetric study at 25,
Carbohydr. Res. 306 (1998) 147–155.
[42] R. Lumry, S. Rajender, Enthalpy–entropy compensation phenomena in water
solutions of proteins and small molecules: a ubiquitous properly of water,
Biopolymers 9 (1970) 1125–1127.
[43] E. Grunwald, C. Steel, Solvent reorganization and thermodynamic
enthalpy–entropy compensation, J. Am. Chem. Soc. 117 (1995)
5687–5692.
[28] S. Andini, G. Castronuovo, V. Elia, E. Gallotta, Inclusion compounds in water:
calorimetric and spectroscopic studies of the interaction of cyclomalto-
hexaose (␣-cyclodextrin) with alkanols at 25◦, Carbohydr. Res. 217 (1991)
87–97.
[44] P. Lo Meo, F. D’Anna, M. Gruttadauria, S. Riela, R. Noto, Thermodynamics of
binding between ␣- and ␤-cyclodextrins and some p-nitro-aniline deriva-
tives: reconsidering the enthalpy–entropy compensation effect, Tetrahedron
60 (2004) 9099–9111.