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J. Chem. Thermodynamics
journal homepage: www.elsevier.com/locate/jct
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 L. Pauling [7] and Miller [8] have explained the anesthetic effect
of chloroform in terms of structural changes of water (especially in
Local anesthetical reagents belong to a large number of differ- Brain) in terms of clathrate formation resulting in lengthening of
ent types of chemical compounds, such as cocaine, procaine and relaxation time of comparatively rigid framework. In recent years,
other derivatives [1]. Generally local anesthetics are amphiphilic many local anesthetics which cause a reversible loss of sensation
molecules of tertiary amines, which form a suitable cation at the for a limited region of the body while maintaining consciousness
membrane pH. These possess hydrophobic and hydrophilic have been developed. However the mode of interaction of such
domains that are separated by an intermediate alkyl chain linkage drugs especially in body fluid systems has not been known fully
to the aromatic group is of either the ester type or amide type and or yet not probed in detail. We feel that by probing the interactions
the nature of this bond determines several pharmacological prop- through host-guest encapsulations, better understanding about the
erties of these agents. mechanism of membrane (lipid)-anesthetical agents can be
The cyclodextrins are treated as a model compound due to its achieved. We had carried-out the density measurements in ternary
symmetric structure, water solubility and ability to form aqueous solutions of fixed concentration (0.1 molkg1) of a-CD
complexes with large number of guest molecules [26]. The and varying concentration of local anesthetical compounds (pro-
a-cyclodextrin (Schardinger0 s a-dextrin), b-cyclodextrin caine hydrochloride PCHCl, lidocaine hydrochloride monohydrate
(Schardinger s b-dextrin) and c-cyclodextrin (Schardinger0 s
0
LCHCl and tetracaine hydrochloride TCHCl) at 298.15 K. The
c-dextrin) consists of six, seven and eight D-(+) glucopyranose results and analysis are presented in following pages.
units, respectively, attached by a-1,4 glucosidic linkages. These
hosts are cycloamylases which have hydrophobic cavities that 2. Experimental
can form inclusion complexes with various kinds of guest mole-
cules. In such host-guest complex formation, the process is con- 2.1. Materials
trolled by the structure of guest molecule (e.g. hydrophobicity,
functional group, charge effect etc.) and the cavity diameter of host The name of chemicals, abbreviation, source and purity of stud-
as well. 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
Corresponding author. Fig. 1. All chemicals were used without further purification. The
E-mail address: patilkesharsingh@hotmail.com (K.J. Patil). 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
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
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
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 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
where /V Drug H2 O is apparent molar volumes of drug in water at same
PCHCl, LCHCl and TCHCl form very stable complexes in solutions
molar concentration, D/c is the volume change due to complexa- phase as the equilibrium constant (association constant) values are
tion, c is the molar concentration of drug anda is the fraction of very high [18]. The hydrocarbon portion (including benzene ring)
complexed ions.Since the ionic strength is unchanged for the com- should just completely occupy the approximately 175 3
plexation, long-range ion-ion Coulombic interactions should not (105 106 m3mol1) a-CD cavity and exclude the estimated six
contribute to D/c , however, contributions from changes in other water molecules from the interior, while the charged polar residue
solute-solute interactions may be expected and these are repre-
(N H) remaining in the bulk. It has been said that the complexa-
sented by B0 c term.
tion is driven by enthalpy changes while the stability is controlled
Hence, in the limit of low drug concentration, the quantity
/V /V
by entropy changes [26,27]. There is very little information
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 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
Considering this and examination of our data of volume water structure making effect and the stability is being determined
changes due to complexation and other one based on transfer vol- by hydrophobic interaction and van der Waals force stabilization
umes for the drugs from aqueous solutions reveal that the volume as well by the nature of ion-pairs and structural specificity in the
of water expelled from the cavity of a-CD (105 106 m3mol1) is form of amide or ester binding. In conclusion all investigations
important. Also, the encapsulated drug molecule in a-CD cavities concerning volume changes in aqueous a-CD, drug ions solutions
can also form additional H-bonds with the surrounding water support the idea that the drug cations occupy the channel forming
molecules. Thus, high transfer volumes obtained show the hydra- a-CD molecules singly exhibiting large positive volume change.
tion of encapsulated drug in a-CD cavities succinctly. In fact the
volumetric contribution for complexation reaction can be esti- References
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polar side groups contributes towards the observed volume
changes. The encapsulation of drug-ion in a-CD cavities occur with JCT 16-152