Ultrasonic relaxation associated with inclusion complex of drugs and β-cyclodextrin

Article abstract of DOI:10.1246/bcsj.80.694

The dynamic interactions between β-cyclodextrin (β-CD) (host) and salicylic acid (guest) at pH ≈6 and ≈3 and between β-CD and benzoic acid (guest) at pH ≈6 were investigated in aqueous solutions in terms of ultrasonic absorption in the frequency range fro

Full text of DOI:10.1246/bcsj.80.694

694 Bull. Chem. Soc. Jpn. Vol. 80, No. 4, 694–698 (2007)
Ó 2007 The Chemical Society of Japan
Ultrasonic Relaxation Associated with Inclusion Complex
of Drugs and ꢀ-Cyclodextrin
ꢀ1
Sadakatsu Nishikawa, Minako Kondo,2 Eri Kamimura,2 and Shaoyong Xing2
1Saga University, Saga 840-8502
2Department of Chemistry and Applied Chemistry, Faculty of Science and Engineering, Saga University, Saga 840-8502
Received August 28, 2006; E-mail: nishikas@cc.saga-u.ac.jp
The dynamic interactions between ꢀ-cyclodextrin (ꢀ-CD) (host) and salicylic acid (guest) at pH ꢁ6 and ꢁ3 and
between ꢀ-CD and benzoic acid (guest) at pH ꢁ6 were investigated in aqueous solutions in terms of ultrasonic absorp-
tion in the frequency range from 0.8 to 95 MHz. A single relaxational absorption was found when the host and the guest
were coexisting in water. Ultrasonic relaxation parameters were determined as a function of the guest concentration.
From the concentration dependence of the parameters, the cause of the relaxation was attributed to a perturbation of
an equilibrium associated with an inclusion complex formed by the host and the guest. The forward and backward rate
constants, the equilibrium constants and the standard volume changes for the host–guest complexation reaction were
determined from the acid concentration dependences of the relaxation frequency and the maximum absorption per wave-
length. The results were compared with those in solution containing aspirin and ꢀ-CD. It was found that the substituent
effect on the rate and thermodynamic parameters was not remarkable in the dissociated forms of the ortho-substituted
benzoic acid. However, the charge effect on a carboxylic group on the parameters was determined to contribute signifi-
cantly to stability of the complexes formed by the acids and ꢀ-CD and to the rate constants for the departure of the acids
from ꢀ-CD cavity.
Cyclodextrins (CDs) with specific cavities are target com-
pounds which can be used for drug-delivery systems. There
are many publications associated with the complexation of
drugs with CDs.1–3 A lot of reports have also been publish-
ed on the applications of CDs in foods, cosmetics, etc.4–6
Junquera et al.7 have reported that undissociated form (carbox-
ylic form) of carboxylic acids binds CDs with higher affinities
than the dissociated partners (carboxylate form) from the sta-
bility constants obtained by pH potentiometric measurements.
Liu and Guo8 have shown correlations between the experimen-
tal stability constant and the calculated one for the inclusion
complexes formed by CDs and benzene derivatives. However,
most of these studies are associated with the static properties
of the interaction between CDs and organic or inorganic mole-
cules. Murphy and Bohne9 have stressed the importance of
the dynamics of entry and exist of guest molecules into or
out of CD cavity for the applications of CDs to drug-delivery
systems.
In our dynamic studies on the inclusion complexes by CDs
(host) and several organic molecules (guest) in terms of an ul-
trasonic relaxation, we have extended the examinations to the
complexation reaction between host and drug (guest). That is,
we have reported in a previous paper10 the results of the ultra-
sonic relaxation in aqueous system containing aspirin and ꢀ-
cyclodextrin (ꢀ-CD). It has been found that benzene moiety
is included in the cavity of ꢀ-CD and the effect of charge on
a carboxylic group is important for the release rate of the guest
molecule into a bulk phase. In order to obtain a more precise
understanding of the complexation reaction between ꢀ-CD
and related drugs with a benzene ring, we have chosen two
guest compounds, i.e., salicylic acid and benzoic acid, in this
study. By comparing the kinetic and thermodynamic results
obtained with those for solution with both ꢀ-CD and aspirin,
it is desired to clarify the dynamics of how the complex is sta-
bilized and how the rate constants of the formation and disrup-
tion of the complex are affected when the structures of the
guest molecules are different. This type information is also de-
sirable for understanding more complex biological reactions
and the interaction reactions between host and guest, because
the inclusion complex reactions are models for enzyme sub-
strate binding.
Experimental
Chemicals. ꢀ-CD was purchased from Wako Pure Chemical
Co., Ltd. and recrystallized once from distilled water. Salicylic
acid (2-hydroxybenzoic acid) and benzoic acid were also obtained
from the same company as their purest reagent grades, and they
were used without further purification. Water distilled and filtered
by using a Milli-Q SP-TOC filter system from Japan Millipore
Ltd. was used as solvent, and it was degassed under a reduced
pressure. Aqueous solutions of salicylic acid and benzoic acid
as the ionized form (pH ꢁ6) were obtained by adding a concen-
trated aqueous solution of sodium hydroxide. The nonionized
form of salicylic acid and benzoic acid in aqueous solution was
prepared by an addition of concentrated hydrochloric acid. All
sample solutions were freshly prepared by weighing just before
the experimental measurements.
Apparatus. Ultrasonic absorption coefficients, ꢁ, were mea-
sured by using a resonance method in the frequency range from
about 0.8 to 7.5 MHz using x-cut crystals with 3 and 5 MHz x-
cut fundamental frequencies. The temperature for the resonator
Published on the web April 13, 2007; doi:10.1246/bcsj.80.694

S. Nishikawa et al.
Bull. Chem. Soc. Jpn. Vol. 80, No. 4 (2007)
695
Fig. 2. Ultrasonic absorption spectra in aqueous solution of
benzoic acid in the presence and absence of ꢀ-cyclodex-
trin at 25.0 ꢃC. ( ): 0.010 mol dmꢄ3 benzoic acid only,
Fig. 1. Ultrasonic absorption spectra in aqueous solution of
salicylic acid in the presence and absence of ꢀ-cyclodex-
trin at 25.0 ꢃC and at pH ꢁ6. ( ): 0.012 mol dmꢄ3 sali-
cylic acid only, ( ): 0.0030 mol dmꢄ3 salicylic acid +
0.0087 mol dmꢄ3 ꢀ-CD, ( ): 0.0070 mol dmꢄ3 salicylic
acid + 0.0087 mol dmꢄ3 ꢀ-CD, ( ): 0.010 mol dmꢄ3 sali-
cylic acid + 0.0087 mol dmꢄ3 ꢀ-CD. The arrows are the
positions of the relaxation frequency.
(
): 0.0020 mol dmꢄ3 benzoic acid + 0.0087 mol dmꢄ3
ꢀ-CD at pH 6.01, ( ): 0.0040 mol dmꢄ3 benzoic acid +
0.0087 mol dmꢄ3 ꢀ-CD at pH 6.04, ( ): 0.0060 mol dmꢄ3
benzoic acid + 0.0087 mol dmꢄ3 ꢀ-CD at pH 6.07 and
( ): 0.010 mol dmꢄ3 benzoic acid + 0.0087 mol dmꢄ3 ꢀ-
CD at pH 1.9.
cells was precisely maintained within ꢂ0:01 ꢃC (Lauda RM20).
A pulse method equipped with 5 MHz fundamental x-cut crystals
was applied at the odd overtone harmonic frequencies in the
range from 25 to 95 MHz, and the temperature for the pulse cell
was maintained within ꢂ0:1 ꢃC (EYEYA UNI ACE BATH
NCB-2200). More details for the absorption apparatus have been
described elsewhere.11,12 Sound velocity values were obtained by
the resonance method at around 3 MHz using the same absorp-
tion apparatus with 5 MHz crystals. From the two different
resonance frequencies, the sound velocity was calculated, the
details of which have been reported elsewhere.13 Solution densi-
ties were measured on a vibrating density meter (Anton Paar
NMA 60/602). Solution pHs were received through a glass elec-
trode (HM-60S Toa Denpa pH meter) in the same thermostatic
bath for the pulse method. All experiments were carried out at
25.0 ꢃC.
are shown in Figs. 1 and 2. A Debye-type single relaxational
2
equation, ꢁ=f2 ¼ A=f1 þ ð f=frÞ g þ B, was applied to ana-
lyze the frequency dependence of the absorption coefficients,
where fr is the relaxation frequency, A and B are the con-
stants. The ultrasonic relaxation parameters, fr, A, and B,
were determined by using a nonlinear least-mean square com-
puter program so as to receive the best fit of the experimental
data to the above equation. The parameters thus determined are
listed in Table 1 along with the experimental values of the
sound velocity (v), the density (ꢂ), and the pH. The solid
curves in Figs. 1 and 2 are the calculated values by using
the determined parameters. The experimental data could be fit-
ted to the calculated lines, the results of which support the ob-
servation of the single relaxational absorption. The ultrasonic
absorption measurements were also carried out in solution with
both ꢀ-CD and benzoic acid at pH ꢁ1:9, and the results are
shown in Fig. 2 and Table 1. The position of the relaxation
frequency shifted to a considerably lower frequency. At this
condition, the most of the acid molecules exist as the nonion-
ized forms.
Results and Discussion
Ultrasonic absorption measurements were carried out in
aqueous solution of salicylic acid at 0.012 mol dmꢄ3 and of
benzoic acid at 0.010 mol dmꢄ3. The absorption coefficients
divided by the square of the measurement frequency, ꢁ=f2,
were independent of the frequency as can be see in Figs. 1
and 2. These results indicated that no relaxation occurred
in these acid solutions. Ultrasonic relaxation in the MHz fre-
The fact that the relaxation was only found when the host
and the guest were both in solution suggested that the observed
relaxation is related to an interaction between the host and the
guest. Thus, the perturbation of the following equilibrium by
the applied sound wave is thought to be a cause of the ob-
served relaxation.
quency range did not exist in aqueous solution of ꢀ-CD,
14,15
when the concentration was less than 0.013 mol dmꢄ3
.
In order to make the experimental condition simple, the con-
centration of ꢀ-CD was fixed at 0.0087 mol dmꢄ3 in the pres-
ent study, where any relaxation was not observed in solution
of ꢀ-CD in our frequency range. When ꢀ-CD (host) was add-
ed to aqueous solutions of salicylic acid (at pH ꢁ6 and pH
ꢁ3) or to solution of benzoic acid (at pH ꢁ6), the ultrasonic
relaxation was clearly observed, and the representative results
kf
CD þ GT ꢀ CDGT;
ð1Þ
kb
where CD is the host molecule, GT is the guest one and CDGT
is the inclusion complex formed by the host and guest mole-
cules. The relationship between the relaxation frequency and
the concentrations is as

696 Bull. Chem. Soc. Jpn. Vol. 80, No. 4 (2007)
Dynamics of Inclusion Complex with Cyclodextrin
Table 1. Ultrasonic and Thermodynamic Parameters for Aqueous Solutions of Salicylic Acid and
Benzoic Acid with 0.0087 mol dmꢄ3 ꢀ-CD at 25.0 ꢃC
vaÞ
/m sꢄ1
ꢂbÞ
/kg dmꢄ3
A
B
pH
CGT
/mol dmꢄ3
fr
/10ꢄ15 s2 mꢄ1
/MHz
Salicylic acid
0.0007
0.0010
0.0025
0.0050
0.0075
0.0100
0.0120
0.0010
0.0030
0.0050
0.0070
0.0080
0.010
1:91 ꢂ 0:13
1:84 ꢂ 0:10
1:89 ꢂ 0:06
1:49 ꢂ 0:06
1:31 ꢂ 0:05
1:25 ꢂ 0:05
1:30 ꢂ 0:04
2:41 ꢂ 0:11
2:72 ꢂ 0:15
2:43 ꢂ 0:11
2:40 ꢂ 0:05
2:19 ꢂ 0:06
1:95 ꢂ 0:08
60:4 ꢂ 5:2
87:8 ꢂ 6:1
168 ꢂ 7
22:1 ꢂ 0:1
22:7 ꢂ 0:1
21:9 ꢂ 0:1
23:0 ꢂ 0:1
22:4 ꢂ 0:2
23:6 ꢂ 0:2
23:0 ꢂ 0:1
22:1 ꢂ 1:3
21:9 ꢂ 0:1
21:9 ꢂ 0:1
22:2 ꢂ 0:1
21:9 ꢂ 0:1
23:1 ꢂ 0:1
1505
1505
1505
1506
1506
1506
1505
1505
1505
1506
1506
1505
1505
1000.91
1000.94
1001.01
1001.04
1001.08
1001.23
1001.24
1001.13
1001.45
1001.49
1001.78
1001.49
1001.62
3.74
3.67
3.38
3.18
3.02
2.86
2.90
6.33
6.47
6.13
6.26
6.40
6.87
353 ꢂ 18
568 ꢂ 31
626 ꢂ 32
601 ꢂ 25
22:1 ꢂ 1:3
34:7 ꢂ 2:4
53:4 ꢂ 3:1
66:1 ꢂ 1:7
76:4 ꢂ 2:7
99:0 ꢂ 5:3
Benzoic acid
0.0015
0.0020
0.0030
0.0040
0.0050
0.0060
0.0070
0.0080
0.0090
0.0100
0.0100
3:51 ꢂ 0:31
3:12 ꢂ 0:17
3:15 ꢂ 0:20
3:05 ꢂ 0:12
2:74 ꢂ 0:11
2:62 ꢂ 0:09
2:93 ꢂ 0:15
2:99 ꢂ 0:07
3:39 ꢂ 0:14
3:35 ꢂ 0:10
0:87 ꢂ 0:02
19:6 ꢂ 1:9
24:5 ꢂ 1:5
34:8 ꢂ 2:5
45:5 ꢂ 2:0
62:7 ꢂ 3:1
72:9 ꢂ 3:0
72:4 ꢂ 4:3
77:1 ꢂ 2:1
78:2 ꢂ 3:4
87:8 ꢂ 2:1
1030 ꢂ 30
22:0 ꢂ 0:1
22:6 ꢂ 0:1
22:5 ꢂ 0:0
21:9 ꢂ 0:4
22:1 ꢂ 0:1
22:8 ꢂ 0:1
22:2 ꢂ 0:1
22:7 ꢂ 0:0
21:2 ꢂ 0:9
21:5 ꢂ 0:1
22:5 ꢂ 0:1
1494
1493
1493
1495
1494
1494
1495
1494
1494
1494
—
1001.04
1001.05
1001.16
1001.20
1001.20
1001.23
1001.35
1001.46
1001.53
1001.56
—
6.01
6.06
6.06
6.04
6.02
6.07
6.02
6.08
5.96
6.10
1.90
a) Error of the sound velocity is ꢂ1 m sꢄ1. b) Error of the density is ꢂ0:01 kg dmꢄ3
.
was used iteratively to acquire the best straight line that goes
through a zero intercept in the plots of 2RTꢄmax=ꢃꢂv2 vs
2ꢃfr ¼ kff½CDꢅ þ ½GTꢅg þ kb
ð2Þ
2
1=2
ꢅ
ꢄ1. When the best linear fit was obtained for the plots, a lin-
¼ kbfðKCCD þ KCGT þ 1Þ ꢄ 4K2CCDCGT
g
;
ð20Þ
ear least-mean square method was applied to obtain the stan-
dard volume change of the reaction. The above plots are shown
in Fig. 4, and the best adjusted K values are listed in Table 2.
The value of kb was calculated by rearranging Eq. 2 as
kb ¼ 2ꢃfr=½Kf½CDꢅ þ ½GSTꢅg þ 1ꢅ. The mean values of kbs
are listed in Table 2 along with the error which is defined as
where kf and kb are the forward and backward rate constants,
CCD and CGT are the analytical concentration of the host and
that of the guest, respectively, and K is defined as K ¼
kf=kb. As can be seen in Table 1 and in Fig. 3 (the lines are
explained later), the change in the relaxation frequency with
the guest concentration was very small for both systems with
salicylic acid and benzoic acid. In the case of the system for
aspirin at pH ꢁ1:7, Eq. 20 was directly applied to obtain the
most probable values of K and kb along with the most probable
errors for them. However, it was crucial at this stage to use
Eq. 20 in order to determine the rate and equilibrium constants.
In this case, another analytical procedure should be applied to
receive the constants, K and kb. The maximum absorption per
wavelength (ꢄmax), is defined as ꢄmax ¼ 0:5Afrv. This quanti-
ty is related to the equilibrium concentrations of the reac-
0:674fꢁðkb exp ꢄ kbÞ =ðn ꢄ 1Þg1=2, where n is the number of
2
experimental data. Then, the value of kf was obtained from
the definition of the equilibrium constant, and the error was al-
so calculated in a similar procedure as that for kb. They are
tabulated in Table 2. As the errors for kf and kb were estimat-
ed, the region of the probable relaxation frequency could be
calculated by Eq. 20, and they are indicated by the lines in
Fig. 3. The experimental relaxation frequencies were located
in the calculated regions for the three systems. It is seen that
the relaxation frequency increases with the analytical concen-
tration of the acid or goes through a minimum with a decrease
in the concentration, depending on the values of the equilibri-
um constant.
2
tants as ꢄmax ¼ ꢃꢂv2ꢅꢄ1ðꢀVÞ =2RT, where ꢅ ¼ 1=½CDꢅ þ
1=½GSTꢅ þ 1=½CDGSTꢅ, ꢀV is the standard volume change
of reaction, R is the gas constant, and T is the absolute temper-
ature.16 If the equilibrium constant has been determined, the
equilibrium reactant concentrations in ꢅ term can be calculat-
ed. Assuming various values of K, a trial and error procedure
The results of the dynamic interaction between the acids and
ꢀ-CD at the condition of pH ꢁ6 are considered firstly. The
acids in these solutions with salicylic acid, with benzoic acid

S. Nishikawa et al.
Bull. Chem. Soc. Jpn. Vol. 80, No. 4 (2007)
697
or with aspirin exist as the dissociated forms (carboxylate)
which was estimated from their acid dissociation constants.
For salicylic acid, there are only a few reported values of the
equilibrium constant of complexation, and one17 of which is
90 ꢂ 20 molꢄ1 dm3. The value obtained in this study is close
to it. For benzoic acid, the equilibrium constant ranges from
10 to 36 molꢄ1 dm3,5,18 and our result in this system was sim-
ilar. It is seen from Table 2 that the values of kf and kb are sim-
ilar to one another for each guest molecule. These results are
interpreted as follows. (1) The forward process for the forma-
tion of the inclusion complex is diffusion controlled based on
Smoluchowski’s equation.19 Thus, the values of kf are similar,
which have also been obtained in solutions of alcohols,20
amines,21 amino acids,22 and carboxylic acids23 (3{8 ꢆ 108
molꢄ1 dm3 sꢄ1). This is because the diffusion coefficients for
these guest molecules are not so different. (2) The values of
kb are, on the other hand, strongly dependent on hydrophobic-
ity of the guest molecules. With an increase in the hydropho-
bicity, the constant decreases steeply. The guest compounds in
the present study are considered to have a similar hydropho-
bicity due to the benzene ring. As a result, similar values of
kb were obtained from the experiments. Since K is the ratio
of the forward rate constant to the backward rate constant,
the resultant equilibrium constants are almost the same values.
This explanation supports that the benzene ring of the guest
molecule was captured.24 In addition, K and rate constants
are scarcely dependent on the ortho-substituents in the dissoci-
ated forms of benzoic acid and its related compounds.
The experimental values of the standard volume changes of
the reaction are listed in Table 2, and they are almost same for
each guest compound. These results also indicate that the same
group of the guest molecules is included into the ꢀ-CD cavity.
The smaller volume changes, which are more than the molar
volume of benzene, occurred to compensate for the water
molecules expelled from the cavity of ꢀ-CD upon inclusion
of the guest molecules. The sign of the volume change is
thought to be positive on the basis of a precise experimental
study for the partial molar volume.25 Thus, the volume change
can be expressed simply as ꢀV ¼ mVH2O ꢄ Vincl where m is
the number of ejected water molecules from the cavity, VH2O
is the molar volume of water and Vincl is a part of the guest vol-
ume inserted into the cavity. If Vincl is the molar volume of the
benzene (83 ꢆ 10ꢄ6 m3 molꢄ1),26 the number of water mole-
cules expelled from the cavity is about 5.1, which is close to
the number of water molecules that are originally in the cavity
when no guest is incorporated.25,27
Fig. 3. The guest-concentration dependences of the relaxa-
tion frequency. ( ): benzoic acid solution with 0.0087
mol dmꢄ3 ꢀ-CD at pH ꢁ6, ( ): salicylic acid solution
with 0.0087 mol dmꢄ3 ꢀ-CD at pH ꢁ6, ( ): salicylic acid
solution with 0.0087 mol dmꢄ3 ꢀ-CD at pH ꢁ3. The re-
gion indicated by dotted lines (ꢇ ꢇ ꢇ) is the relaxation fre-
quency range calculated by Eq. 2 for the benzoic acid so-
lution, the region by solid lines (—) is the range for sali-
cylic acid solution at pH ꢁ6 and the region by dashed
lines (– – –) is that for salicylic acid solution at pH ꢁ3.
Fig. 4. Plots of 2RTꢄmax=ꢃꢂv2 vs ꢅꢄ1
( ): the results for
solution of salicylic acid at pH ꢁ3, ( ): those for solution
of benzoic acid at pH ꢁ6, ( ): those for salicylic acid so-
lution at pH ꢁ6.
Table 2. The Rate and Thermodynamic Parameters Associated with Dynamic Interaction between ꢀ-CD and the
Acids at 25.0 ꢃC
Guest
pH
kf
kb
K
ꢀV
/10ꢄ6 m3 molꢄ1
/108 molꢄ1 dm3 sꢄ1
/106 sꢄ1
/molꢄ1 dm3
Salicylic acid
Benzoic acid
Aspirin
Aspirin
Salicylic acid
ꢁ6
ꢁ6
4:4 ꢂ 0:5
5:8 ꢂ 0:4
7:8 ꢂ 0:5
7:21 ꢂ 0:05
8:0 ꢂ 1:1
9:7 ꢂ 1:0
12:7 ꢂ 0:9
15 ꢂ 1
45
46
51
549 ꢂ 2
253
9:4 ꢂ 0:9
8:9 ꢂ 2:6
8:5 ꢂ 1:1
15:5 ꢂ 0:1
17:7 ꢂ 1:1
This work
This work
Ref. 10
Ref. 10
This work
ꢁ6
ꢁ1:7
ꢁ3
1:31 ꢂ 0:03
3:2 ꢂ 0:5

698 Bull. Chem. Soc. Jpn. Vol. 80, No. 4 (2007)
Dynamics of Inclusion Complex with Cyclodextrin
3
W. Tong, J. L. Lach, T. Chin, K. J. Guillory, J. Pharm.
Next, we consider solutions pH <4 containing benzoic acid
or salicylic acid. Most of the acid molecules exist in their the
undissociated forms in these solutions. In the salicylic acid so-
lution, the relaxation frequency was lower at pH <4 than that
at neutral pH as can be seen in Table 1. This trend was also
reflected in the value of kb which was smaller than that in
the neutral solutions Similar results were also obtained for so-
lutions containing aspirin as the guest. This is because the in-
clusion process is associated with the diffusion controlled reac-
tion. Therefore, the forward rate constants were similar as can
be seen in Table 2. The benzene derivatives with carboxylate
group appear to exit more quickly from the cavity than those
with carboxylic group, which is a clear charge effect on the
stability of the inclusion complex between host and guest.
The slightly greater value of the standard volume change of
the reaction than that in the neutral condition suggests that
the number of the expelled water molecules was slightly high-
er at lower pH. If the same group or the same part of the hydro-
phobic group of salicylic group at the condition of pH ꢁ6 is
included in the cavity, then the number of the expelled water
molecules from the ꢀ-CD cavity should be m ꢁ 5:5.
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In solution of benzoic acid at pH 1.9 and 0.01 mol dmꢄ3, the
ultrasonic parameters were obtained experimentally. The ultra-
sonic spectrum is shown in Fig. 2, and the results are tabulated
in Table 1. It should be noticed that the relaxation frequency
was 0.87 MHz. If the value kf is the same as that at pH ꢁ6, be-
cause the process is diffusion controlled reaction and the diffu-
sion coefficient of the carboxylic form is not so different from
that of carboxylate form, kb ¼ 0:96 ꢆ 106 sꢄ1 for K ¼ 604
molꢄ1 dm3,28 kb ¼ 1:6 ꢆ 106 sꢄ1 for K ¼ 358 molꢄ1 dm3,8
and kb ¼ 4:5 ꢆ 106 sꢄ1 for K ¼ 127 molꢄ1 dm3.4 These values
indicate that the relaxation frequency is in the rage from 0.75
to 1.7 MHz, which is the same range as the experimental value
observed as can be seen in Table 1. In other words, the ob-
served relaxation is associated with the dynamics of the inter-
action between the host and the guest.
22 T. Fukahori, K. Yamaguchi, S. Nishikawa, J. Acoust. Soc.
Am. 2004, 115, 2325.
In conclusion, the ultrasonic relaxation process could only
be observed in aqueous solution when ꢀ-CD and drug mole-
cule were both present. The cause of the relaxation is due to
the complexation reaction between the host and the guest.
The ortho-substitution effect on the rate and thermodynamic
constants was not remarkable, although the charge effect was
important for the departure of the drug from the CDs cavity.
The included portion of benzoic acid and the related drugs
appeared to be the benzene ring.
23 S. Nishikawa, M. Kondo, J. Phys. Chem. B 2006, 110,
26143.
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24 T. Loftsson, B. J. Olafsdottir, H. FriDriksdottir, S.
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25 G. Gonzalez-Gaitano, A. Crspo, A. Compostizo, G.
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28 H. Shimizu, A. Kaito, M. Hatano, Bull. Chem. Soc. Jpn.
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