J. Chem.

Thermodynamics 107 (2017) 5157

Contents lists available at ScienceDirect

J. Chem. Thermodynamics
journal homepage: www.elsevier.com/locate/jct

A volumetric approach: Interactions of some local anesthetical drugs

with a-cyclodextrin in aqueous solutions at 298.15 K
Vasim R. Shaikh, D.G. Hundiwale, Kesharsingh J. Patil
School of Chemical Sciences, North Maharashtra University, Jalgaon 425001, India

a r t i c l e i n f o a b s t r a c t

Article history: The density measurements have been carried out for ternary aqueous solutions containing a fixed con-
Received 25 February 2016 centration (
0.1 molkg1) of a-cyclodextrin (a-CD) and varying concentrations (
0.003 to
Received in revised form 5 December 2016
0.21 molkg1) of some local anesthetical drugs, namely procaine hydrochloride (PCHCl), lidocaine
Accepted 24 December 2016
hydrochloride monohydrate (LCHCl) and tetracaine hydrochloride (TCHCl) at 298.15 K. The density data
Available online 26 December 2016
are used to determine apparent molar volumes of the drug molecules in ternary solutions at finite con-
centrations (/V ) as well at infinitely dilute solutions (/0V ). Following the methods developed by Hiland
Keywords:
et al. as well by Jolicoeur et al. and using the infinite dilution volume values for the drugs in ternary and
Density
Apparent molar volumes
binary solutions and incorporating the equilibrium constant values for the complexation between a-CD
Partial molar volumes of transfer and drugs, volume changes due to encapsulation or complexation have been estimated. It is observed that
Encapsulation and host-guest interactions all the studied hydrochlorides exhibit high positive volume change due to complexation. The results are
discussed in terms of host-guest interaction and structural specificity of guest molecules.
2016 Elsevier Ltd.

1. Introduction
Local anesthetical reagents belong to a large number of differ-
ent types of chemical compounds, such as cocaine, procaine and
other derivatives [1]. Generally local anesthetics are amphiphilic
molecules of tertiary amines, which form a suitable cation at the
membrane pH. These possess hydrophobic and hydrophilic
domains that are separated by an intermediate alkyl chain linkage
to the aromatic group is of either the ester type or amide type and
the nature of this bond determines several pharmacological prop-
erties of these agents.
The cyclodextrins are treated as a model compound due to its
symmetric structure, water solubility and ability to form
complexes with large number of guest molecules [26]. The
a-cyclodextrin (Schardinger0 s a-dextrin), b-cyclodextrin
(Schardinger s b-dextrin) and c-cyclodextrin (Schardinger0 s
0
c-dextrin) consists of six, seven and eight D-(+) glucopyranose
units, respectively, attached by a-1,4 glucosidic linkages. These
hosts are cycloamylases which have hydrophobic cavities that
can form inclusion complexes with various kinds of guest mole-
cules. In such host-guest complex formation, the process is con-
trolled by the structure of guest molecule (e.g. hydrophobicity,
functional group, charge effect etc.) and the cavity diameter of host
as well.
Corresponding author.
E-mail address: patilkesharsingh@hotmail.com (K.J. Patil).
L. Pauling [7] and Miller [8] have explained the anesthetic effect
of chloroform in terms of structural changes of water (especially in
Brain) in terms of clathrate formation resulting in lengthening of
relaxation time of comparatively rigid framework. In recent years,
many local anesthetics which cause a reversible loss of sensation
for a limited region of the body while maintaining consciousness
have been developed. However the mode of interaction of such
drugs especially in body fluid systems has not been known fully
or yet not probed in detail. We feel that by probing the interactions
through host-guest encapsulations, better understanding about the
mechanism of membrane (lipid)-anesthetical agents can be
achieved. We had carried-out the density measurements in ternary
aqueous solutions of fixed concentration (
0.1 molkg1) of a-CD
and varying concentration of local anesthetical compounds (pro-
caine hydrochloride PCHCl, lidocaine hydrochloride monohydrate
LCHCl and tetracaine hydrochloride TCHCl) at 298.15 K. The
results and analysis are presented in following pages.
2. Experimental
2.1. Materials
The name of chemicals, abbreviation, source and purity of stud-
ied drug molecules are given in Table 1. The molecular structure of
a-CD and drugs along with the dimensions of a-CD are shown in
Fig. 1. All chemicals were used without further purification. The
amount of water of hydration in the supplied sample was

http://dx.doi.org/10.1016/j.jct.2016.12.023
0021-9614/ 2016 Elsevier Ltd.
52 V.R. Shaikh et al. / J. Chem. Thermodynamics 107 (2017) 5157

Table 1 interesting and is exhibited in Fig. 2. The melting point of lidocaine

List of chemicals, abbreviation, source and mass fraction purity of studied drug hydrochloride monohydrate is in the vicinity of 79.84 0.5 C as
molecules.
observed from the onset of TGA thermogram. The peak at
Chemical Abbreviation Source Mass fraction 78.43 0.5 C in heat flow curve indicates an endothermic thermal
purity transition. In literature, it is reported that LCHCl monohydrate
a-Cyclodextrin a-CD Fluka P0.98a melts in the range of 7479 C [9]. It is to be noted from TGA curve
Procaine hydrochloride PCHCl Sigma-Aldrich P0.97 a that over the temperature range of 79140 C, there is a continu-
Lidocaine hydrochloride LCHCl Sigma-Aldrich P0.97b
(monohydrate)
ous mass loss. It is expected that after melting LCHCl hydrate,
Tetracaine hydrochloride TCHCl Sigma-Aldrich P0.99 a there will be loss in weight due to removal of water molecules, also
a
due to evaporation of volatile impurities and HCl. It is seen that
Mass fraction purity as mentioned by supplier.
b most of the decomposed product is getting evaporated at about
Mass fraction purity obtained experimentally by doing chloride estimation
potentiometrically as well as water analysis by TGA-DSC analysis. 222 C. The absence of a simple melting process and a value for
the heat of fusion, coupled with the presence of several peaks in
the DSC curve, makes it very difficult for us to speculate on the
estimated using the thermo-gravimetric analysis [Thermal Ana-
decomposition mechanism. On the basis of weight loss of 6.25%
lyzer (TG-DTA-DSC) TA Inc. SDT-2960]. The number of water mole-
observed at 140 C, we assume that the lidocaine hydrochloride
cules per molecule of cyclodextrin was found to be 5.72 from TGA-
contains one water molecule, which is in agreement with potentio-
DTA analysis. The amount of water determined was considered
metric data. All the solutions were freshly prepared on molality
during the preparation of solutions and the concentrations were
basis using quartz doubly distilled water. A Shimadzu AUW220D
corrected accordingly. The water of hydration for lidocaine
high precision analytical balance having readability of 0.01 mg
hydrochloride LCHCl (monohydrate) was also considered in calcu-
was used for weighing.
lations of molalities of LCHCl in ternary solution. The calculated
molality refers LCHCl for 1 kg of water. The purity of LCHCl was
determined by doing chloride estimation by potentiometric titra- 2.2. Density measurement
tion For this purpose, the electrochemical cell was set up as: Ag |
LCH+Cl||KNO3 salt bridge||Hg2Cl2(s)|Hg and the precipitation titra- The experimental densities of all ternary solutions were deter-
tion with
0.1 molkg1AgNO3 was carried out. The results from mined by using an Anton Paar Digital Densimeter (DMA-5000) at
potentiometric titration indicated that the LCHCl contains one 298.15 0.001 K. The densimeter was calibrated using quartz dou-
water molecule while the mass fraction purity is of the order of bly distilled water at 298.15 K and the density of water was found
P0.97. The TGA-DSC thermal profile of LCHCl monohydrate is to be 997.043 kgm3. The uncertainty in the density measurement

Fig. 1. (a) Molecular structure of aCD, (b) Dimensions of aCD and (c) Molecular structures of the studied drugs.
 V.R. Shaikh et al. / J. Chem. Thermodynamics 107 (2017) 5157 53

Fig. 2. TGA-DTA plot of lidocaine hydrochloride monohydrate.

and temperature was found to be 1 kgm3 and 0.01 K, respec- confirmation with the values of 607  106 and 607.5  106 m3-
tively. The details of density measurements and reliability of the mol1 reported by Origlia-Luster et al. [13] and Terdale et al.
measurement have been reported earlier [10]. [14], respectively.
The density (d) data for all ternary aqueous solutions containing
a fixed concentration (
0.1 molkg1) of a-CD and varying concen-
3. Results
trations of PCHCl (
0.0038 to
0.20 molkg1), LCHCl (
0.0057 to

0.15 molkg1) and TCHCl (
0.0028 to
0.21 molkg1) at
3.1. Density and apparent molar volume
298.15 K are collected in Table 3.The apparent molar volumes of
the drug molecules in solutions of finite concentrations (/V ) were
The density (d) data for binary aqueous a-CD solutions at
calculated from the measured density data using the equation:
298.15 K are reported in Table 2. There are reports on density val-
ues for a-CD in water at 298.15 K [11,12] which on comparison d0  d M
with our experimental density data of binary aqueous a-CD solu- /V 1
mdd0 d
tions at 298.15 K, show very good agreement The apparent molar
volumes (/V ) data for aqueous a-CD solutions at 298.15 K have where m is molality (in molkg1) of the solute (drug molecules) in
also been reported in literature [11,13,14] and in good agreement aqueous a-CD solution, d and do are the densities (in kgm3) of
with the present data collected in Table 2. The value of limiting ternary system and reference solvent (
0.1 molkg1 aqueous a-
apparent molar volume /0V (=607.38  106 m3mol1) is also in CD solution), respectively, and M is the molar mass of the solute
(in kgmol1). In all calculations of concentrations in terms of molal-
ity refers to the number of moles per 1 kg of water as a solvent.The
Table 2
Molality (m), density (d), apparent molar volumes (/V ) data of a-CD in aqueous binary
total error in estimated apparent molar volumes (/V ) values for
solutions at 298.15 K and at ambient pressure of 101.325 kPa.a solutes in binary and ternary solutions were calculated by consider-
ing error in density measurement (Dd) and error in molality (Dm).
mb/molkg1 db/kgm3 106/V /m3mol1
The combined error estimation for /V parameter is indicated in the
0.00000 997.0 607.38 0.41* form of D/V in Tables 2 and 3. These are calculated using the
0.00975 1000.6 607.30 0.41
0.01763 1003.4 607.34 0.23 expressions: D/V  1000 m
Dd and D/V  1000 1  d10 Dm, where Dd
m2 d
0.02931 1007.6 607.73 0.14 and Dm refers to uncertainty in density and molality parameters,
0.03389 1009.2 607.53 0.12 respectively.
0.04348 1012.5 607.77 0.09
0.05233 1015.6 607.34 0.08
The apparent molar volumes of the drug molecules at infinitely
0.06207 1018.9 607.77 0.06 dilute solutions /0V were obtained by least-squares fitting to the
0.07117 1022.0 607.93 0.06 following equation:
0.07830 1024.4 607.71 0.05
0.09004 1028.3 608.00 0.04 p
0.09764 1030.7 607.93 0.04
/V /0V SV m 2
0.10013 1031.6 607.52 0.04
where Sv is the experimental slope, considered as volumetric pair-
a
Standard uncertainties u are u (T) = 0.01 K; u (P) = 10 kPa. wise interaction coefficient [15] and which measures the solvent
b
Relative uncertainty in molality is ur (m) = u(m)/(m) = 0.03; Standard uncer-
tainty on density is u (q) = 1 kgm3.
induced strength of solutesolute interactions. It is assumed that
*
Extrapolated value at infinitely dilute solutions of a-CD in aqueous solutions at effects due to hydrolysis if any at the lowest concentration studied
298.15 K. can be neglected.
54 V.R. Shaikh et al. / J. Chem. Thermodynamics 107 (2017) 5157

Table 3
Molality (m), density (d), apparent molar volumes of the drug molecules (/V ), fraction of complexed ions (a) and fraction of uncomplexed ions (a) data for ternary system (H2O
+
0.1 molkg1 a-CD + PCHCl/LCHCl/TCHCl) at 298.15 K and at ambient pressure of 101.325 kPa.a

mb/molkg1 db/kgm3 106/V /m3mol1 106/V Drugwater */m3mol1 a a0 1  a

PCHCl + 0.09944 molkg 1
aCD ***
+ H2O
0.00000 1031.7 800 .00 1.05**
0.00377 1029.8 745.98 1.05 225.68 0.9995 0.0005
0.00496 1030.3 529.32 0.80 225.68 0.9995 0.0005
0.00887 1030.0 443.68 0.45 225.68 0.9994 0.0006
0.01150 1030.2 391.02 0.34 225.68 0.9994 0.0006
0.01263 1030.1 387.42 0.31 225.68 0.9994 0.0006
0.02741 1030.5 305.90 0.14 225.67 0.9993 0.0007
0.05496 1032.0 259.22 0.07 225.67 0.9989 0.0011
0.08209 1033.4 244.87 0.05 225.66 0.9972 0.0028
0.10884 1034.1 243.04 0.04 225.65 0.9091 0.0909
0.13439 1035.6 236.37 0.03 225.65 0.7389 0.2611
0.16827 1036.1 238.85 0.02 225.64 0.5905 0.4095
0.20747 1038.6 231.76 0.02 225.63 0.4791 0.5209
LCHCl + 0.09915 molkg1 aCD*** + H2O
0.00000 1031.6 750.00 0.69**
0.00571 1029.8 579.99 0.69 237.13 0.9947 0.0053
0.00803 1030.2 447.21.049 237.15 0.9945 0.0055
0.00885 1030.4 413.50 0.45 237.15 0.9945 0.0055
0.01246 1030.6 357.68 0.32 237.17 0.9943 0.0057
0.02730 1031.0 302.14 0.15 237.25 0.9931 0.0069
0.04356 1031.4 285.71 0.09 237.31 0.9911 0.0089
0.05409 1031.4 284.42 0.07 237.35 0.9891 0.0109
0.06464 1031.9 275.18 0.06 237.37 0.9860 0.0140
0.08151 1032.2 273.61 0.05 237.40 0.9751 0.0249
0.11041 1032.6 271.24 0.04 237.40 0.8681 0.1319
0.12984 1033.3 267.16 0.03 237.37 0.7519 0.2481
0.15278 1034.0 264.60 0.03 237.30 0.6431 0.3569
TCHCl + 0.09733 molkg1 aCD*** + H2O
0.00000 1031.0 700.00 1.41**
0.00281 1030.3 533.87 1.41 259.86 1.0000 0.0000
0.00520 1030.2 432.30 0.76 259.91 1.0000 0.0000
0.00891 1030.1 380.87 0.45 259.97 1.0000 0.0000
0.01154 1030.3 349.64 0.34 260.02 1.0000 0.0000
0.01237 1029.9 373.01 0.32 260.03 1.0000 0.0000
0.03012 1030.8 297.37 0.13 260.27 1.0000 0.0000
0.05715 1031.8 277.81 0.07 260.48 1.0000 0.0000
0.08546 1032.4 276.19 0.05 260.60 1.0000 0.0000
0.11592 1033.0 274.65 0.03 260.71 0.8396 0.1604
0.13935 1033.6 273.04 0.03 260.83 0.6985 0.3015
0.17722 1035.0 269.20 0.02 261.14 0.5492 0.4508
0.21768 1036.7 265.79 0.02 261.60 0.4471 0.5529
a
Standard uncertainties u are u(T) = 0.01 K; u(P) = 10 kPa.
b
The molality of drugs in aqueous aCD solutions is expressed as moles of drug per kg of solvent water. Relative uncertainty in molality is ur(m) = u(m) = (m) = 0.03;
Standard uncertainty in density is u (q) = 1 kgm3.
*
The /V Drugwater values are taken from Ref. [10]
**
Extrapolated value at infinitely dilute solutions of the drug molecules in aqueous a-CD solutions at 298.15 K.
***
The concentration of aCD in ternary solutions has been constant and specified as moles of a-CD in 1 kg of solvent water.

The variations of /V in ternary aqueous solutions as a function

of square root of molality of drugs are represented in Figs. 35
for PCHCl, PCHCl and TCHCl, respectively, at 298.15 K. The data
of /V and /0V are collected in Tables 3 and 4, respectively.
Using the data of apparent molar volumes of the drug molecules
at infinitely dilute solutions in ternary solutions containing a fixed
concentration (
0.1 molkg1) of a-CD and apparent molar vol-
umes of the drug molecules at infinitely dilute solutions in binary
solutions, the values of transfer volumes (D/0V tr ) were calculated.
The data of D/0V tr are collected in Table 4 along with the data of
/0V (for ternary system) and /0V (for binary system).

3.2. Volume change due to complexation

Following the methods developed by Jolicoeur [16] and our- Fig. 3. The variation of apparent molar volumes of the drug molecule (/V ) in
selves [17], we treat the apparent molar volumes of drug molecules ternary aqueous solutions as a function of square root of molality of drug PCHCl at
(PCHCl, LCHCl and TCHCl) in a dilute solution of a-CD as: 298.15 K.
 V.R. Shaikh et al. / J. Chem. Thermodynamics 107 (2017) 5157 55

obtained from the data reported by us at 298.15 K [10] and the val-
ues are incorporated in Table 3.
The complexation reaction between the host (H) and guest
(drug) cation (D+) is given as:

H D HD 4

HD  HD 
with equation K eq and a 5
HD  D 0
where [D+]0 is the total concentration of D+ in the solution. To sim-
plify, we assume [HD+] = x, [D+]0 = a and [H] = b, hence we can write
expression as:
x x
K eq and a 6
a  xb  x a
where
Fig. 4. The variation of apparent molar volumes of the drug molecule (/V ) in  h i1=2 
1 1 2
ternary aqueous solutions as a function of square root of molality of drug LCHCl at x a b K 1
eq  a b K eq  4ab 7
298.15 K. 2
We have used the complex equilibrium constant values
obtained by us using osmometry [18]. The equilibrium constant
values are 1.99  104, 1.99  103 and 6.31  107 for PCHCl, LCHCl
and TCHCl, respectively in aqueous a-CD solutions at 298.15 K.
The data of /v solution and a for ternary system (H2O
+
0.1 molkg1 a-CD + PCHCl/LCHCl/TCHCl) at 298.15 K are col-
/V /V H O
lected in Table 3. The calculations of the quantity solution a Drug 2
at various concentrations of drugs were made and variation of
/V /V H O
the quantity solution a Drug 2 with molality for PCHCl, LCHCl and
TCHCl are shown in Figs. 68, respectively. The extrapolation to
infinitely dilute solution yields the volume change due to
complexation for a-CD-drug complex at 298.15 K and the values
are collected in Table 4. Similar method was developed for
18-crown-6-alkali halides complexes as well for anion complexes
of a-CD and b-CD by Hiland and coworkers [19,20]. We analyzed
our data with this method also and found that the results are
Fig. 5. The variation of apparent molar volumes of the drug molecule (/V ) in consistent with the methodology developed by Jolicoeur [16].
ternary aqueous solutions as a function of square root of molality of drug TCHCl at
298.15 K.
4. Discussion

/V solution /V Drug H2 O aD/c B0 c
where /V Drug H2 O is apparent molar volumes of drug in water at same
molar concentration, D/c is the volume change due to complexa-
tion, c is the molar concentration of drug anda is the fraction of
complexed ions.Since the ionic strength is unchanged for the com-
plexation, long-range ion-ion Coulombic interactions should not
contribute to D/c , however, contributions from changes in other
solute-solute interactions may be expected and these are repre-
sented by B0 c term.
Hence, in the limit of low drug concentration, the quantity
/V /V
Drug H2 O
solution
should yield D/0c , the volume change due to com-
a available about volume changes due to complexation in case of
plexation. The /V Drug H2 O (binary solutions) values have been
3 It is well established that electrostatic, hydrophobic and hydro-
gen bonding interactions are the principle forces which determine
the stability of biological macromolecules and also in cyclodextrin
complexes [14,1925]. We note from our earlier studies that
PCHCl, LCHCl and TCHCl form very stable complexes in solutions
phase as the equilibrium constant (association constant) values are
very high [18]. The hydrocarbon portion (including benzene ring)
should just completely occupy the approximately 175 3
(105  106 m3mol1) a-CD cavity and exclude the estimated six
water molecules from the interior, while the charged polar residue
(N H) remaining in the bulk. It has been said that the complexa-
tion is driven by enthalpy changes while the stability is controlled
by entropy changes [26,27]. There is very little information
a-CD complexes, although volume changes associated with

Table 4
Limiting apparent molar volumes of the drug molecules (/0V ), partial molar volumes of transfer of drug molecules at infinite dilution (D/0V tr ), volume change due to complexation
at infinite dilution (D/0c ) data for ternary system (H2O +
0.1 molkg1 a-CD + PCHCl/LCHCl/TCHCl) at 298.15 K and at ambient pressure of 101.325 kPa.

106/0V (ternary system)/m3mol1 106/0V * (binary system)/m3mol1 106D/0V tr /m3mol1 106D/0c /m3mol1

PCHCl 800 225.0 575 560

LCHCl 750 237.1 513 500
TCHCl 700 259.8 440 395
*
The /0V (binary system) values are taken from Ref. [10].
56
Fig. 6. Variation of parameter
/V
solution
(m/molkg1) for drug PCHCl at 298.15 K.
/V
Fig. 7. Variation of parameter solution
(m/molkg1) for drug LCHCl at 298.15 K.
/V
Fig. 8. Variation of parameter solution
(m/molkg1) for drug TCHCl at 298.15 K.
protein-ligand binding have been well investigated [2831]. There
is only one study reported about anion complexes having small
association constants by Hiland et al. [20].
Hiland et al. [19] have studied the volume changes due to
complex formation between 18-crown-6 with electrolytes and
a  CD=D  5:72H2 O Cl
found that volume changes due to complex formation are positive
and of the order of 1015  106 m3mol1 depending upon the
V.R. Shaikh et al. / J. Chem. Thermodynamics 107 (2017) 5157
entrapped ions radii. We also noted a positive volume change on
complexation of K+ ions with 2,2,2-Cryptand which is of the order
of +25  106 m3mol1 [17]. Considering all these our present
results of calculation of volume changes due to complexation are
interesting.Our results depicted in Figs. 35 point-out that, the
apparent molar volumes (/V ) of the PCHCl, LCHCl, and TCHCl
for aqueous solutions containing
0.1 molkg1 a-CD decreases
with increase in concentration of drug molecules. After stoichio-
metric concentration, the /V values remain more or less constant.
The initial rapid decrease in /V values can be interpreted in terms
of hydrophobic hydration of the a-CD-drug complexed molecules,
that is, the complexed species exhibit solvent induced cation-
cation complex overlap interaction in the form of water structure
making effect [32,33]. The limiting apparent molar volumes /0V of
the PCHCl, LCHCl and TCHCl for aqueous solutions containing
/V
Drug H2 O
as a function of molality

0.1 molkg1 are obtained by extrapolation at infinite dilution
a
(Figs. 35) and the values found are 800, 750 and 700  106 m3-
mol1, respectively at 298.15 K (Table 4).
As such the /V values in dilute concentration region appears to
be high and extrapolation to limiting concentration becomes less
reliable. Since, the association constants of the drug-a-CD complex
species are high (the fraction of complexed ions a
1), we can
safely attribute these values to the complexed ions. The uncer-
tainty in the limiting values of /0V can be of the order of 5  106 -
m3mol1, since its magnitude depend upon the fraction of
complexed ions a, density errors and concentration errors. Also
there is a possibility of 2:1 a-CD-drug cations in the limiting con-
centration range as suggested by Wilson and Verrall [34], however,
we have neglected this possibility in the present approach since
the equilibrium constants for such complexes are not known. The
values of partial molar volumes of transfer of drug molecules at
infinite solutions (D/0V tr ) from to aqueous solutions containing a
fixed concentration (
0.1 molkg1) of a-CD for PCHCl, LCHCl
and TCHCl are found to be 575, 513 and 440.2  106 m3mol1,
/V
a
Drug H2 O
as a function of molality respectively at 298.15 K. It is known that when DV (volume
change) and DS (entropy change) are positive, the solubilizations
of organic molecules in water are controlled by hydrophobic inter-
action [35,36]. Seen in this light positive volume changes due to
complexation of drug molecules substantiates our interpretation
that complexed species get solubilized with cavity effect, van der
Waals and dipole interaction, while the portion outside the cavity
(or at periphery) in the form of polar charge centre (N H) also con-
tribute hydrophobically due to cation-cation interactions in solu-
tion phase, similar to that of aqueous tetraalkyl-ammonium salt
solutions [37,38].
/V /V H O
The concentration dependence of the quantity solution a Drug 2
for PCHCl, LCHCl, and TCHCl has been depicted in Figs. 68,
respectively. The linear extrapolation to infinitely dilute solution
yields the value for volume change due to complexation for drug
molecules PCHCl, LCHCl, and TCHCl in aqueous solutions contain-
ing a fixed concentration (
0.1 molkg1) of a-CD as 560, 500 and
395  106 m3mol1, respectively at 298.15 K. These values are in
fair agreement with the values of transfer volumes calculated
/V
directly. The examination of Figs. 68 indicates that, the quantity
Drug H2 O
a as a function of molality initially decreases and further remains almost constant with
increase in drug concentration. Following the scheme written for
solvation, desolvation and solvent reorganization processes associ-
ated with the formation of host-guest complexes in aqueous media
by Wilson and Verrall [34], we write the complexation equilibria
as:
K1:1
a  CD  5:72H2 O D  mH2 O Cl
where D+ is the drug molecule ion.
 V.R. Shaikh et al. / J. Chem. Thermodynamics 107 (2017) 5157
Considering this and examination of our data of volume
changes due to complexation and other one based on transfer vol-
umes for the drugs from aqueous solutions reveal that the volume
of water expelled from the cavity of a-CD (105  106 m3mol1) is
important. Also, the encapsulated drug molecule in a-CD cavities
can also form additional H-bonds with the surrounding water
molecules. Thus, high transfer volumes obtained show the hydra-
tion of encapsulated drug in a-CD cavities succinctly. In fact the
volumetric contribution for complexation reaction can be esti-
mated using Youngs rule (ideal mixing). Seen in this light the par-
tial molar volume of complexed species should be 832, 844.1 and
866.8  106 m3mol1 (that is, volume of a-CD in water:
607  106 m3mol1 [13,14] + /0V of drug in water) for PCHCl-,
LCHCl- and TCHCl-a-CD complexes, respectively. When these val-
ues are compared with the limiting values obtained, we find a loss
in volume for a complexation process which can be attributed to
electrostriction, H-bonding and hydrophobic interaction effects.
Procaine hydrochloride which contains additional polar NH2
group can interact through hydrogen bond formation or ionization
as well form ion pairs due to electrostatic forces. All these interac-
tions thus contribute to volume changes and hence we observe the
highest volume change in case of PCHCl-a-CD solutions. LCHCl
contains an amide linkage while TCHCl contains ester linkage.
We envisage that amide linkage is more favourable for ion-pair for-
mation and additional hydrophobic solute-solute interaction than
that of compound containing ester linkage. However, the volume
changes due to complexation are of similar magnitude (Table 4).
TCHCl drug is the most hydrophobic in the series studied and
exhibits the smallest volume change due to transfer as well as
due to complexation. Thus, TCHCl having highest equilibrium con-
stant value gets entrapped in a-CD cavity by expelling the inside
water. The high stability is imparted due to van der Waals interac-
tion since the cavity is hydrophobic.
 [20] H. Hiland, L.H. Hald, O.J. Kvammen, J. Solution Chem. 10 (1981) 775784.
The higher value of the complexed a  CD  PCH Cl ion pair
6 3 1
may (that is, 800  10 m mol ) may be due to formation of
 Press, New York, 1974.
hydrogen bonds with two water molecules as PCH Cl is having
NH2 group at the terminus of chain, which may have been must
be extruded from the cavity. The probable complexed species in
 [25] S.S. Terdale, D.H. Dagade, K.J. Patil, J. Chem. Eng. Data 54 (2009) 294300.
this case, can be represented as PCH Cl  xH2 O  a  CD in solu-
tion phase. This is a case of ion-dipole interaction, but the water
molecules along with NH2 group are outside the cavity and per-
pendicular to the plane of a-CD entity.
5. Conclusions
Using the equilibrium constant values and density measure-
ments, the complexation equilibria between anesthetical drug
compounds and a-CD (1:1) in aqueous solutions are studied. The
volume changes due to transfer and complexation were obtained.
The nature of amide and ester linkage along with the presence of
polar side groups contributes towards the observed volume
changes. The encapsulation of drug-ion in a-CD cavities occur with
57
water structure making effect and the stability is being determined
by hydrophobic interaction and van der Waals force stabilization
as well by the nature of ion-pairs and structural specificity in the
form of amide or ester binding. In conclusion all investigations
concerning volume changes in aqueous a-CD, drug ions solutions
support the idea that the drug cations occupy the channel forming
a-CD molecules singly exhibiting large positive volume change.
References
[1] H. Matsuki, S. Hashimoto, S. Kaneshina, M. Yamanaka, Langmuir 10 (1994)
18821887.
[2] Special section on supramolecular chemistry and self-assembly, Science 295
(2002) 23952421.
[3] L.C. Fetterly, in: L. Mandelcorn (Ed.), Non Stoichiometric Compounds, Wiley,
New York, 1964.
[4] W. Saenger, Angew. Chem. Int. Ed. 19 (1980) 344362.
[5] W. Saenger, J. Jacob, K. Gessler, T. Steiner, D. Hoffmann, H. Sanbe, K. Koizumi, S.
M. Smith, T. Takaha, Chem. Rev. 98 (1998) 17871802.
[6] J. Szejtli, Chem. Rev. 98 (1998) 17431753.
[7] L. Pauling, Science 134 (1961) 1521.
[8] S.L. Miller, Proc. Nat. Acad. Sci. 47 (1961) 15151524.
[9] Material Safety Data Sheet, Delta Synthetic Co., Ltd., New Taipei City, Taiwan
(from Internet).
[10] V.R. Shaikh, D.H. Dagade, D.G. Hundiwale, K.J. Patil, J. Mol. Liq. 164 (2011) 239
242.
[11] L. Paduano, R. Sartorio, V. Vitagliano, L. Costantino, J. Solution Chem. 19 (1990)
3139.
[12] A. Pal, N. Chauhan, J. Mol. Liq. 169 (2012) 163172.
[13] M.L. Origlia-Luster, T.G. Call, E.M. Woolley, J. Chem. Thermodyn. 33 (2001)
15871596.
[14] S.S. Terdale, D.H. Dagade, K.J. Patil, J. Phys. Chem. B 110 (2006) 1858318593.
[15] H.S. Harned, B.B. Owen, The Physical Chemistry of Electrolytic Solutions, 3rd
Ed., Reinhold Publishing Corporation, New York, 1958.
[16] C. Jolicoeur, L.L. Lemelin, R. Lapalme, J. Phys. Chem. 83 (1979) 28062808.
[17] V.R. Shaikh, S.S. Terdale, A. Abdul, G.R. Gupta, D.G. Hundiwale, K.J. Patil, J.
Solution Chem. 42 (2013) 20872103.
[18] V.R. Shaikh, S.S. Terdale, D.G. Hundiwale, K.J. Patil, J. Chem. Thermodyn. 68
(2014) 161168.
[19] H. Hiland, J.A. Ringseth, E. Vikingstad, J. Solution Chem. 7 (1978) 515523.
[21] C. Tanford, Physical Chemistry of Macromolecules, John Wiley and Sons, 1961.
[22] F. Franks, in: F. Franks (Ed.), Water-A Comprehensive Treatise, vol. IV, Plenum
[23] F. Franks, Water-A Matrix of Life, Second Edition., R. S. C. Cambridge University
Press, New York, 2000.
[24] S.S. Terdale, D.H. Dagade, K.J. Patil, J. Phys. Chem. B 111 (2007) 1364513652.
[26] P.D. Ross, M.V. Rekharsky, Biophys. J. 71 (1996) 21442155.
[27] M.V. Rekharsky, Y. Inoue, Chem. Rev. 98 (1998) 18751917.
[28] J.T. Edward, P.G. Farrell, Can. J. Chem. 53 (1975) 29652970.
[29] W. Kauzmann, Biochim. Biophys. Acta 28 (1958) 8791.
[30] S. Katz, J.E. Miller, J. Phys. Chem. 76 (1972) 27782780.
[31] J. Kerjanc, S. Lapanje, Eur. J. Biochem. 25 (1972) 4953.
[32] J.E. Desnoyers, M. Arel, G. Perron, C. Jolicoeur, J. Phys. Chem. 78 (1969) 3346
3351.
[33] H.L. Friedman, in: F. Franks (Ed.), Water-A Comprehensive Treatise, vol. III,
Plenum Press, New York, 1973.
[34] L.D. Wilson, R.E. Verrall, J. Phys. Chem. B 101 (1997) 92709279.
[35] C. Tanford, The Hydrophobic Effect, Wiley, New York, 1977.
[36] A. Ben-Naim, Hydrophobic Interactions, Plenumm Press, New York, 1980.
[37] W.Y. Wen, K. Miyajima, A. Otsuka, J. Phys. Chem. 75 (1971) 21482157.
[38] K. Patil, G. Mehta, J. C. S. Faraday Trans I (83) (1987) 24672474.
JCT 16-152