Isothermal titration calorimetry and theoretical studies on host-guest interaction of ibuprofen with α-, β- And γ-cyclodextrin

Article abstract of DOI:10.1007/s10953-009-9394-3

Thermodynamic parameters for formation of the inclusion complexes of α-, β- and γ-cyclodextrin (α-, β- and γ-CD) with ibuprofen (BF) in Tris-HCl buffer solutions (pH=7.0) have been determined by isothermal titration calorimetry (ITC) with nanowatt sensiti

Full text of DOI:10.1007/s10953-009-9394-3

J Solution Chem (2009) 38: 531–543
DOI 10.1007/s10953-009-9394-3
Isothermal Titration Calorimetry and Theoretical
Studies on Host-guest Interaction of Ibuprofen
with α-, β- and γ -Cyclodextrin
Shengkai Xing · Qian Zhang · Chong Zhang ·
Qiang Zhao · Hongqi Ai · Dezhi Sun
Received: 12 September 2008 / Accepted: 31 December 2008 / Published online: 5 March 2009
© Springer Science+Business Media, LLC 2009
Abstract Thermodynamic parameters for formation of the inclusion complexes of α-, β-
and γ -cyclodextrin (α-, β- and γ -CD) with ibuprofen (BF) in Tris-HCl buffer solutions
(pH = 7.0) have been determined by isothermal titration calorimetry (ITC) with nanowatt
sensitivity, and the inclusion structures have been investigated by using 1H-NMR spectra at
298.15 K. A theoretical study on the inclusion processes between BF and CDs has been per-
formed with the B3LYP/6-31G*//PM3 method in order to investigate the formation mech-
anism of the inclusion complexes. An analysis of the thermodynamic data indicates that
the stoichiometries of α-, β- and γ -CD with BF are all 1:1 and formation of the inclusion
complexes α-CD·BF and β-CD·BF are driven by enthalpy and entropy, whereas formation
of γ -CD·BF is an entropy driven process. The 1H-NMR spectra provide clear evidence for
the inclusion phenomenon, and show that the isobutyl group and aromatic ring of the guest
molecule are trapped inside the cavity of the CDs. Theoretical calculations suggest that the
complex formed by the BF molecule entering into the cavity of the CD molecule from the
wide side is more stable than that from the narrow side.
Keywords Cyclodextrin · Ibuprofen · Inclusion complex · Isothermal titration
1
calorimetry · H-NMR · DFT · PM3
1 Introduction
Cyclodextrins (CDs), the most prominent host molecules used in supramolecular chemistry
up to now [1, 2], are cyclic oligosaccharides composed of glucopyranose units and can
S. Xing · Q. Zhang · C. Zhang · Q. Zhao · D. Sun (
)
ꢀ
School of Chemistry and Chemical Engineering of Liaocheng University, Liaocheng,
Shandong 252059, China
e-mail: sundezhi@lcu.edu.cn
C. Zhang
e-mail: zhangchong@lcu.edu.cn
H. Ai
School of Chemistry and Chemical Engineering University of Jinan, Jinan, Shandong 250022, China

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J Solution Chem (2009) 38: 531–543
Fig. 1 Molecular structure of cyclodextrin
Fig. 2 Molecular structure of
ibuprofen. Letters a, b, c, d, e
and f are used to label the
different H atoms of ibuprofen
and the *C is used to express the
relative position between BF and
the CDs in the theoretical
calculations
be characterized by a truncated cone structure with a hydrophobic interior and hydrophilic
exterior [3] as shown in Fig. 1. The most common CDs are α-, β-, and γ -CD, which consist
of six, seven, and eight D-glucose units, respectively. They possess the remarkable property
of forming inclusion complexes with many organic, inorganic and biological compounds
without covalent bonds, and the resultant inclusion complexes can induce modification of
the physicochemical properties of guest molecules (such as increasing water solubility and
solution stability) [4, 5]. In addition, CDs can mediate many organic reactions in which the
CDs represent good models for mimicking enzymes [6, 7]. Consequently, CDs are widely
used in analytical chemistry, organic synthesis and the pharmaceutical industry [8–13].
Ibuprofen (BF, see Fig. 2) is a typical example of a molecule whose physicochemical
properties can be modified by CDs. BF is a member of a group of drugs called nonsteroidal
anti-inflammatory drugs. It is widely used to reduce fever and treat pain or inflammation
caused by many conditions such as headache, back pain, arthritis, chronic laryngitis and
bronchiolitis. However, its application in the pharmaceutical field is limited by its low aque-
ous solubility, bad taste as well as increasing risk of serious effects on the stomach and
intestines [14–16]. Fortunately, CDs can improve its solubility and taste by reacting with BF
to form inclusion complexes.
Isothermal titration calorimetry (ITC) is an extremely powerful and highly sensitive tech-
nique that is very helpful for investigating weak interactions between molecules, yielding
both thermodynamic and kinetic information [17]. It has been applied to determine stability
constants, stoichiometry, interaction enthalpies, entropies, Gibbs energies and heat capacity
changes. Thus, ITC has been applied in many areas such as cyclodextrin chemistry, poly-
mer chemistry, cellular biology and biochemistry [18–22]. To our knowledge, there have
been no reports of the direct investigation of the complexes of CDs with BF in Tris-HCl
buffer solutions (pH = 7.0) using nanowatt sensitivity ITC. Thus, the purpose of this report
is to investigate the thermodynamic properties from reaction of CDs with BF by utilizing
isothermal titration calorimetry. In addition, a quantum-chemical study has also been done

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533
on the structures of the inclusion complexes as well as the inclusion processes between CDs
and BF.
2 Materials and Methods
2.1 Materials
The α- and γ -CDs were bought from Aldrich and β-CD was purchased from the Shang-
hai Chemical Reagent Company (Shanghai China). They were purified twice by recrystal-
lization in redistilled water and then dried under reduced pressure at 353 K for 48 h prior
to use. The reagents were stored over P2O5 in a vacuum desiccator at room temperature.
BF was obtained from Fluka Chemical Company and was ≥99% pure. NaOH (GR) and
tris(hydroxymethyl)aminomethane (Tris, BR) were purchased from the Sinopharm Chemi-
cal Reagent Co. Ltd. (China).
2.2 Isothermal Titration Calorimetry
The nanowatt isothermal titration microcalorimeter is supported by a Thermometric Activity
Monitor (TAM) Thermometric 2277 (Thermometric, Sweden) and controlled by Digitam 4.1
software [23]. This instrument has a precision of electrical calibration better than 1%,
and its accuracy was checked by measuring the dilution enthalpy of a concentrated sucrose
solution [24]. A BFNa solution (titrant, 1.5×10−2 mol·dm−3), which was prepared from the
same quantities of BF and NaOH in Tris-HCl buffer solutions (pH = 7.0), is injected into
the 1.0 cm3 stainless steel ampoule containing 0.5 cm3 of CDs solution (titrand, 5.00×10−3
mol·dm−3), in 40 aliquots of 12 µL each, using a 500 µL Hamilton syringe controlled by
a 612 µL Lund Syringe Pump. The interval between two injections varied from 35 to 45
min, which is sufficiently long for the signal to return back to the baseline. The stirrer in the
ampoule was operated at a constant speed of 30 rpm. All the experiments were performed at
298.15 0.01 K. The enthalpies of dilution of BFNa and the CDs solutions were determined
in separate experiments. No significant heat effect was found so that the dilution heats are
negligible.
2.3 1H-NMR Measurements
1H-NMR spectra were recorded on a FT-NMR 1500A model 400M superconductive Nu-
clear Magnetic Resonance Instrument (USA, Varian Company). The spectra were acquired
at 298.15 K and the center of the solvent signal (D2O, at 4.640 ppm) was used as the refer-
ence point.
2.4 Computational Methods
Besides the experimental measurements, molecular modeling is very popular for investigat-
ing CD chemistry in order to calculate the binding energy (ꢀE) as well as the geometrical
structure of the inclusion complex and it has proved to be a very useful tool [25, 26]. In this
paper the inclusion models used have been successfully employed by Liu and co-workers
[25], as shown in Fig. 3. In the models, the glycosidic oxygen atoms of CDs are placed in the
XY plane and their center is defined as the center of the whole system. BF approaches and
passes through the cavity of CDs in the +Z to −Z direction, and the distance between the

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J Solution Chem (2009) 38: 531–543
Fig. 3 Coordinate systems used to define the inclusion processes: (a) head-up and (b) head-down
labeled carbon atom (C*) of BF and the Z-coordinate origin was varied in 1 Å steps from
+8 to −8 Å. For convenience, the BF passing through the cavity of CDs from the narrow
side (Fig. 3a) and the wide side (Fig. 3b) are defined as “Head-up” and “Head-down” con-
figurations, respectively. For each step, the geometry of the complex was fully optimized by
the PM3 method [26] without imposing any symmetrical restrictions. Harmonic frequency
analysis was used to ensure that the located stationary point is the true minimum. The single
point energies of the inclusion complexes were calculated at the B3LYP/6-31G* level. All
of the calculations were performed with the Gaussian 98 software package [27].

J Solution Chem (2009) 38: 531–543
535
3 Results and Discussion
3.1 Thermodynamic Data Analysis
In order to analyze the standard enthalpies ꢀHio of the inclusion complexes of BF with α-,
β- and γ -CD, the apparent equilibrium constant (βi) for overall reaction has been defined
as follow:
[MLi]
M + iL→←MLi;
βi =
;
ꢀHio
(1)
[M][L]
where i = 1, 2 or 3, and M or L, respectively, represent the host (CDs) and guest (BF)
molecules. Therefore, there are five possible reaction models.
The total concentration of M and L can be obtained by the formulas Eq. 2 and Eq. 3:
ꢀ
ꢂ
ꢁ
[M]t = [M] 1 +
βi[L]
(2)
(3)
i
ꢃ
ꢄ
ꢁ
i−1
[L]t = 1 + [M]
iβi[L]
The relationship between the overall equilibrium constants (βi) and the stepwise equilibrium
constants (Ki) is given by the formula
βi = ꢁKi
(4)
The thermodynamic parameters, ꢀHio and βi(or Ki), can be derived by the regression
method [28], which was performed with the Ligand Binding Analysis routine of the Digi-
tam 4.1 software [23]. By comparing the simulation curves for the five possible reaction
models with the experimental titration curve, we confirmed that the most reasonable stoi-
chiometries of α-, β- and γ -CD with BF are all 1:1 (see Fig. 4) in these systems. Then,
the standard Gibbs energy changes (ꢀG◦) and standard entropy changes (T ꢀS◦) of the
interaction processes were calculated and are listed in Table 1.
3.2 Thermodynamics Parameters
From Table 1, one can see that: (i) the overall equilibrium constants (βi) are 0.65 × 103,
1.27 × 104 and 0.14 × 103 dm3·mol−1 for the inclusion complexes, α-CD·BF, β-CD·BF
and γ -CD·BF, respectively. These data indicate that the inclusion complex β-CD·BF is more
stable than the others, which can be explained by β-CD having the optimal size for its inter-
nal cavity (8 Å) to encase the BF molecule. (ii) The standard formation enthalpies (ꢀH◦)
of the complexes α-CD·BF and β-CD·BF are −3.20 and −14.11 kJ·mol−1, respectively,
which indicate that the formation reactions for these two complexes are weak exothermic
processes. However, the ꢀH◦ value for γ -CD·BF is 3.49 kJ·mol−1 which indicates that
formation of this complex is an endothermic process. (iii) Negative values for the standard
Gibbs energy changes (ꢀG◦) indicate that the formation of all of the complexes are sponta-
neous processes. (iv) The entropy effects (T ꢀS◦) for formation of the inclusion complexes
are positive and make a smaller contribution to the negative value of the standard Gibbs
energy than the heat effect. The positive entropy effect may be due to the combined results
of the host-guest reaction (negative contribution to entropy) and releasing of water mole-
cules from the cavity (positive contribution to entropy). Finally, formation of the inclusion
complexes α-CD·BF and β-CD·BF are enthalpy-entropy synergistically driven processes,
whereas that of γ -CD·BF is an entropy-driven process.

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J Solution Chem (2009) 38: 531–543
Fig. 4 Curves (a, c and d), variation of the heat-flow/electrical power P as a function of time t (titrant:
−2
−3
−3
−3
BFNa, 1.5 × 10 mol·dm ; titrand: α-, β-, γ -CDs, 5.00 × 10 mol·dm ); (b, d and f) rate of reaction
heat changes with the amount of M versus the ratio of concentrations [BFNa]/[CDs] (the line is the result of
simulation and the points are experimental values)
3.3 1H-NMR Spectroscopy
1H-NMR spectroscopy has been used to obtain information about the microscopic struc-
tures of inclusion complexes [29, 30]. The induced shift, ꢀδ, is defined as the differ-
ence between the chemical shifts in the presence and absence of the other reactants

J Solution Chem (2009) 38: 531–543
537
◦
◦
Table 1 Stability constants (β ), standard changes of enthalpy (ꢀH ), Gibbs energy change (ꢀG ) and
of the temperature-entropy products (T ꢀS ) for the complexes formed by the host (α-, β-, γ -CD) with the
guest (BF) in aqueous solution at 298.15 K
i
◦
3
3
−1
◦
−1
◦
−1
◦
−1
)
10 β /(dm ·mol
)
ꢀH /(kJ·mol
)
ꢀG /(kJ·mol
)
T ꢀS /(kJ·mol
i
α-CD·BF
β-CD·BF
γ -CD·BF
0.65
12.71
0.14
−3.20
−14.11
3.49
−16.00
−23.35
−12.21
12.80
9.24
15.70
1
Table 2 H chemical shifts of ibuprofen protons in the inclusion complexes (ꢀδ = δ
− δ
)
complex
free
Different H atoms of ibuprofen
Number of H protons
ꢀδ (ppm)
α-CD·BF
β-CD·BF
γ -CD·BF
H(a)
H(b)
H(c)
H(d)
H(e)
H(f)
6
3
1
2
2
2
+0.046
−0.006
+0.049
+0.040
+0.013
+0.009
+0.023
+0.001
−0.012
−0.013
−0.179
−0.022
−0.055
−0.007
−0.078
−0.041
−0.086
−0.016
1
Table 3 H chemical shifts of glucopyranose-unit protons of the CD molecule in the inclusion complexes
(ꢀδ = δ
− δ
)
complex
free
ꢀδ (ppm)
1-H
2-H
0.001
3-H
0.013
4-H
0.004
5-H
0.002
6-H
α-CD
β-CD
γ -CD
0.002
−0.032
−0.034
−0.002
−0.085
−0.025
−0.036
−0.032
−0.113
−0.050
−0.015
−0.027
−0.086
−0.026
1
(ꢀδ = ꢀδ(complex) − ꢀδ(free)). The H chemical shifts of the ibuprofen protons and glu-
copyranose unit protons of the CD molecule in the studied host-guest\systems are shown in
Tables 2 and 3, respectively.
1
From Table 2 one can see that the H chemical shifts of H(a) (0.046 ppm), H(c) (0.049
ppm) and H(d) (0.040 ppm) of the BF molecule in the α-CD·BF system are much larger
than those of H(b) (−0.006 ppm), H(e) (0.013 ppm) and H(f) (0.009 ppm). The chemical
shifts of protons in the D-glucose-unit of the α-CD molecule are very small, except for 3-H
(which is in the cavity of α-CD) as given for the α-CD·BF system in Table 3. These data
suggest that perhaps only the isobutyl group of the BF molecule is included in the cavity of
α-CD. In the β-CD·BF system, the chemical shifts of H(a), H(e), H(f) are very large (the
shift of H(e) is especially large, extending to −0.179 ppm). The data in Table 3 clearly show
that the 1H chemical shifts of 3-H, 5-H and 6-H in β-CD are much larger than those of 1-H,
2-H and 4-H. Therefore, it can be generalized that the cavity of β-CD accommodates the
isobutyl group and part of the aromatic ring of the BF molecule. In the γ -CD·BF system,
the chemical shifts of all H atoms of the BF molecule are very large except for H(b) in the
γ -CD·BF system, and the chemical shifts of 3-H and 5-H (in the cavity of γ -CD) obviously

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J Solution Chem (2009) 38: 531–543
Fig. 5 Energy curves obtained by BF passing through the cavity of α-, β- and γ -CD: head-up (a) and
head-down (b)
change from the values given in Tables 2 and 3. This indicates that the isobutyl group and
aromatic ring of the BF molecule are trapped in the cavity of γ -CD. The chemical shifts of
specific protons in the CDs systems provide direct evidence for the formation of inclusion
complexes, which indicates that NMR is a very useful tool for investigating the host-guest
interaction in CD chemistry.
3.4 Theoretical Investigation
As described above, interactions between CDs and BF have been studied experimentally
with isothermal titration calorimetry (ITC) and 1H-NMR spectroscopy, which provide evi-
dence for the formation of inclusion complexes. However, the geometries and stabilities of
the complexes, as well as the inclusion energetics for formation of the complexes, are still
unclear. Therefore, a theoretical study of the energies and inclusion processes for formation
of the inclusion complexes has also been done.
By using the simulation models as shown in Fig. 3, the binding energy change curves
for BF passing through the cavity of α-, β- and γ -CD are shown in Figs. 5a (for Head-up)
and 5b (for Head-down), respectively. As shown in Fig. 5a, taking the α-CD·BF system as an
example, the energy decreases sharply from the starting point A (ZA = 8 Å; ZA being the Z-
coordinate of point A) until it reaches point B (ZB = 1 Å), which is a local minimum. Then,
the energy increases rapidly and achieves a local maximum at point C (ZC = −1 Å). After
that, the energy decreases again until it reaches point D (ZD = −2 Å), the global minimum
for the whole curve. This indicates that BF and α-CD could form the most stable inclusion
complex in the Head-up pattern. Lastly, the energy increases until point E (ZE = −8 Å).
Similarly, we give a simple presentation of the energy changes obtained from BF passing
through the cavity of α-CD from the wide side (Head-down). In Fig. 5b, the energy decreases
sharply from the starting point a until reaching point b (Zb = 2 Å), which is the global
minimum of the whole curve and indicates that BF and α-CD could form another stable
inclusion complex in the Head-down pattern. Subsequently, the energy increases rapidly
until reaching point c (Zc = −8 Å). The energy change curves of BF passing through the
cavity of β-CD and γ -CD are also shown in Figs. 5a and 5b. It can be seen that BF and
β- and γ -CD can also form stable inclusion complexes both for Head-up and Head-down
interactions.

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539
Table 4 Thermodynamic parameters of the inclusion complexes of α-CD·BF, β-CD·BF and γ -CD·BF cal-
a
culated by the PM3 method
Species
BF
α-CD
β-CD
γ -CD
α-CD·BF β-CD·BF γ -CD·BF
PP
head-up
E
(kJ·mol
)
−418.15 −5238.65 −6117.05 −6981.27 −5747.48 −6611.87 −7493.23
−90.68 −76.67 −93.81
367.49 −2405.04 −2813.73 −3201.82 −2115.18 −2511.68 −2914.88
−77.63 −65.44 −80.55
HF
ꢀE (kJ·mol
H (kJ·mol
ꢀH (kJ·mol
G (kJ·mol
201.54 −2821.93 −3341.40
−776.41 −2616.57 −3114.02 −3576.50
ꢀG (k·mol
3.82
25.84
−1.63
)
−273.18
−304.95
−264.70
PP
head-down
−1
E (kJ·mol
)
−418.15 −5238.65 −6117.05 −6981.27 −5756.75 −6623.89 −7504.01
−99.95 −88.69 −104.59
367.49 −2405.04 −2813.73 −3201.82 −2124.02 −2518.78 −2924.54
−86.47 −72.54 −90.21
−1
−1
ꢀE (kJ·mol
)
H (kJ·mol
)
−1
−1
ꢀH (kJ·mol
)
G (kJ·mol
)
201.54 −2821.93 −3341.40 −3776.41 −2638.95 −3122.76 −3572.46
−1
ꢀG (kJ·mol
)
−18.56
17.10
2.41
−
−1
)
ꢀS (J·mol 1·K
−227.77
−300.65
−310.65
a
ꢀE is the binding energy; ꢀE = E
− E − E ;ꢀH = H
− H − H ; ꢀG =
BF
BF
complex
CD
complex
CD
G
− G − G ;ꢀS = (ꢀH − ꢀG)/T
BF
complex
CD
Table 5 Single point energies of the inclusion complexes α-CD·BF, β-CD·BF and γ -CD·BF calculated by
the B3LYP/6-31G* method
Species
BF
α-CD
β-CD
γ -CD
α-CD·BF
β-CD·BF γ -CD·BF
E (a.u.)
−656.4185 −3664.3385 −4275.0622 −4885.8013
Head-up
−4321.0066 −4931.7167 −5542.4727
−655.18 −619.54 −664.08
−4321.0474 −4931.7315 −5542.4909
−762.22 −658.59 −712.02
−1
−1
ꢀE (kJ·mol
Head-down
ꢀE (kJ·mol
)
)
To investigate the thermodynamics of the inclusion process, the binding energies (ꢀE),
enthalpy changes (ꢀH), Gibbs energy changes (ꢀG) and entropy changes (ꢀS) for the
most stable complexes α-CD·BF, β-CD·BF and γ -CD·BF (both Head-up and Head-down
configurations) are summarized in Table 4. From Table 4 it can be seen that: (i) the binding
energies (ꢀE) of the complexes formed by BF passing through the cavity of α-, β- and
γ -CD from its wide side are about 10.0 kJ·mol−1 lower than those from approach at the
narrow side. The single point energies (in Table 5), calculated by B3LYP/6-31G*, also are
much lower for the complexes obtained from Head-down approaches than those from Head-
up. Thus, it is predicted that the BF is favored to enter the cavity of CD from its wide side
compared to approaching from the narrow side. (ii) The negative ꢀH and ꢀS values suggest
that formation of all these inclusion complexes is an enthalpy-driven processes. However,
the experimental data indicate that formation of the inclusion complexes α-CD·BF and β-
CD·BF are enthalpy-entropy synergistically driving processes, whereas that of γ -CD·BF is

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J Solution Chem (2009) 38: 531–543
Fig. 6 Structures of the inclusion complexes (α-CD·BF, β-CD·BF and γ -CD·BF) obtained by the PM3
method: the inclusion complexes seen from the narrow side of the CD cavity (a, c and e); complexes seen
from the wide side of the CD cavity (b, d and f)

J Solution Chem (2009) 38: 531–543
541
an entropy-driven process. This can be explained by the solvent effect. Unfortunately, be-
cause of limitations in the calculation ability of our computer and the large molecular size
of cyclodextrins (CDs), calculations for these systems can hardly be performed for aqueous
solutions. However, it is observed that the solvent effect on the host-guest interactions easily
changes the inclusion reaction from a non-spontaneous process in the gas phase to a spon-
taneous one in the aqueous phase. The host-guest interaction causes an enthalpy-entropy
compensating process in the gas phase whereas the same interaction causes an enthalpy-
entropy co-driven process in aqueous solution, because inclusion complexation releases a
number of water molecules from the cavity of CDs.
Further studies on the geometrical structures of the inclusion complexes were also made,
in order to explore the stability of these complexes and their PM3-optimized structures as
shown in Figs. 6(a–f). In Fig. 6 it can be observed that the BF molecule is almost encapsu-
lated in the cavity of a CD molecule. In addition, there are several intermolecular H-bonds
in the structures. Here, the H-bond is defined as C–H···O or O–H···O with the distance
between O and H being less than 3.0 Å [31]. The H-bond lengths range from 1.79 to 3.00 Å
in the structures, which fall just within the reported length range for H-bonds. These data
indicate that intermolecular H-bonds play an important role in the stability of these inclusion
complexes.
4 Conclusions
The inclusion interactions between α-, β-, γ -CD and BF have been investigated by isother-
1
mal titration calorimetry and H-NMR spectra measurements at 298.15 K. Analysis of the
thermodynamic data indicates that the stoichiometries of all of the CD complexes with BF
are 1:1, and that formation of the inclusion complexes α-CD·BF and β-CD·BF is driven
by both enthalpy and entropy whereas that for γ -CD·BF is an entropy-driven process. The
1H-NMR spectra data provide clear evidence for the inclusion phenomena indicating that
the BF molecule inserts its isobutyl group and aromatic ring into the molecular cavity of the
CDs. Theoretical studies suggest that H-bond interaction plays an important role in deter-
mining the stability of the inclusion complexes and that the BF is favored to enter into the
cavity of the CDs from the wide side rather than the narrow side.
Acknowledgements This work was supported financially by the National Natural Science Foundation of
China (No. 20573047).
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