Interactions Between Surface Active Ionic Liquid and Procaine Hydrochloride Drug in Aqueous Solution

Article abstract of DOI:10.1007/s10953-018-0778-0

Complex formation between the anesthetic drug, procaine hydrochloride and a surface active ionic liquid (SAIL), 1-tetradecyl-3-methylimidazolium chloride, [C₁₄mim][Cl], in aqueous medium has been investigated using surface tension, fluorescence and DLS measurements at 298.15?K and conductance at 288.15, 298.15 and 308.15?K. Critical aggregation concentration (CAC), degree of ionization (α), and various thermodynamic parameters were determined using the conductivity measurements. The interfacial behavior of SAIL at different concentrations of the drug was evaluated from surface tension measurements by calculating a series of surface parameters and CAC values. Fluorescence spectroscopy was used to evaluate the binding constant (K) and the standard state Gibbs energy change (ΔG°) for the formation of drug–SAIL complexes, which confirms the existence of cation–π interactions between the drug molecules and imidazolium ring of the SAIL molecules. The CAC values were found to decrease with increase in the concentration of the drug, which is due to the balancing between hydrophobic and electrostatic interactions. Dynamic light scattering provides sufficient information about the size of the aggregates and the variation in the hydrodynamic diameters pertaining to the changes in the drug concentration. The results from above methods show that the aggregation process of SAIL is favored by increases in the concentration of the drug. It is demonstrated that with the better understanding of the interactions, [C₁₄mim][Cl] can be judiciously utilized in making use of procaine hydrochloride.

Full text of DOI:10.1007/s10953-018-0778-0

Journal of Solution Chemistry
https://doi.org/10.1007/s10953-018-0778-0
Interactions Between Surface Active Ionic Liquid
and Procaine Hydrochloride Drug in Aqueous Solution
1
1
Amalendu Pal · Alka Yadav
Received: 19 July 2017 / Accepted: 24 April 2018
Springer Science+Business Media, LLC, part of Springer Nature 2018
©
Abstract
Complex formation between the anesthetic drug, procaine hydrochloride and a surface
active ionic liquid (SAIL), 1-tetradecyl-3-methylimidazolium chloride, [C mim][Cl], in
1
4
aqueous medium has been investigated using surface tension, ꢀuorescence and DLS meas-
urements at 298.15 K and conductance at 288.15, 298.15 and 308.15 K. Critical aggrega-
tion concentration (CAC), degree of ionization (α), and various thermodynamic parameters
were determined using the conductivity measurements. The interfacial behavior of SAIL
at diꢁerent concentrations of the drug was evaluated from surface tension measurements
by calculating a series of surface parameters and CAC values. Fluorescence spectros-
copy was used to evaluate the binding constant (K) and the standard state Gibbs energy
change (ΔG°) for the formation of drug–SAIL complexes, which conꢂrms the existence
of cation–π interactions between the drug molecules and imidazolium ring of the SAIL
molecules. The CAC values were found to decrease with increase in the concentration of
the drug, which is due to the balancing between hydrophobic and electrostatic interactions.
Dynamic light scattering provides suꢃcient information about the size of the aggregates
and the variation in the hydrodynamic diameters pertaining to the changes in the drug con-
centration. The results from above methods show that the aggregation process of SAIL is
favored by increases in the concentration of the drug. It is demonstrated that with the better
understanding of the interactions, [C mim][Cl] can be judiciously utilized in making use
14
of procaine hydrochloride.
Keywords Ionic liquid · Procaine hydrochloride · Conductance · Surface tension ·
Fluorescence · Dynamic light scattering
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1095
3
-018-0778-0) contains supplementary material, which is available to authorized users.
*
Amalendu Pal
palchem21@gmail.com
1
Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India
Vol.:(0123
1
456789)
3

Journal of Solution Chemistry
1
Introduction
Ionic liquids (ILs) have been studied very intensely due to their unusual and interesting
physicochemical and biological properties [1–5]. Further, a number of experiments have
been performed for the better understanding of properties and behavior of ILs at the molec-
ular level, including X-ray photoelectron spectroscopy (XPS) [6], molecular dynamic (MD)
simulations [7], etc. In this regard, Umebayashi et al. [8] have studied the structural het-
erogeneity and distortion of hydrogen-bonding in the ammonium-based ionic liquid using
MD simulations and XRD experiments. ILs having long chain cations are amphiphilic and
this class of ILs has been named surface active ionic liquids (SAILs). The self-association
behavior of long alkyl chain IL molecules has remarkable biological applications [9–11].
The micelles of SAIL help in enhancing the penetrability of drugs across biological ꢂlms
and minimizing the contact of drug molecules with inactivating species present in the bio-
logical ꢀuids [12, 13]. Albeit, the literature survey on the interactions of surfactants with
drugs reveals that not much work has been done to elucidate the interactions of SAILs with
drugs [14–16]. In the literature [17] numerous drug delivery and drug targeting systems
have been studied in an attempt to minimize drug degradation and loss, to prevent harmful
side eꢁects, and to increase drug bioavailability. The SAIL, 1-tetradecyl-3-methylimida-
zolium chloride, [C mim][Cl] (cationic) has also been studied with the anionic polyelec-
14
trolyte poly sodium 4-styrene sulphonate (NaPSS) to investigate the interactions between
them by Sharma et al. [18]. Further, it is reported that the use of micelles as drug carriers
presents some advantages. Micellar systems can solubilize poorly soluble drugs and thus
increase their bioavailability in the targeted area [13]. Mahajan et al. [19] have determined
the binding ability of a drug with SAILs. In similar studies, Sanan et al. [20] have investi-
gated the eꢁect of composition and dilution on the micellar transition in cationic IL–Ibu-
profen aqueous mixtures. Very recently, Mahajan et al. [21] studied the solubilization of
the hydrophobic drug Quercetin in pluronic F108 and its mixed micelles with SAILs hav-
ing the same alkyl chain length but a diꢁerent hydrophobic head. They concluded that
F108-SAILs mixed micellar systems act as better drug delivery vehicles.
Our research group has reported the binding interactions of an anesthetic drug with
SAILs in aqueous solutions by employing conductivity, surface tension, and ꢀuorescence
measurements [22]. In continuation of our interest in anesthetic drugs, we have now stud-
ied the interactions of SAIL [C mim][Cl] with procaine hydrochloride. Since SAILs have
14
better surface active properties and exhibit low toxicity than conventional surfactants, they
can also be used to study their interactions with drugs. Keeping these properties of SAILs
in mind, an attempt has been made to study the aggregation behavior of 1-tetradecyl-
3
-methylimidazolium chloride [C mim][Cl] with a drug molecule. This work shows the
14
signiꢂcant role of this SAIL in drug delivery, which could provide better applications in
medicinal chemistry. The main motive of this work is to provide basic information of the
complex formed between the SAIL and the drug, and also to determine the eꢁect of the
drug on the growth of the aggregates and the structure of the aggregates. Procaine and
its derivatives constitute an important family of local anesthetic drugs, which participate
actively in nerve impulse transmission due to their resemblance to the structure with natu-
ral compounds. It is believed that the cationic form of the drug, which is the active princi-
+
ple, combines with the Na channels present on the nerve membrane resulting in blocking
the initiation and transmission of nerve impulses [23–25].
Summarizing, this work delineates the detailed examination of the interactional
phenomenon of drug–SAIL complex formation in solution through an assessment of
1
3

Journal of Solution Chemistry
aggregation parameters by using conductance, surface tension, ꢀuorescence, and DLS
measurements. The interactions between the drug and the SAIL molecules at the interface
were studied through an appraisal of surface active parameters like minimum surface area
per ionic liquid molecule (A ), eꢁectiveness of surface tension reduction (ꢀ ), surface
min
cac
tension at the CAC (ꢀ ), maximum surface excess concentration (Г ), adsorption eꢃ-
cac
max.
ciency (pC ) and p (packing parameter) of [C mim][Cl] using surface tension measure-
20
14
ments which decode the eꢁect of procaine hydrochloride on the aggregation and interfa-
cial behavior of this SAIL in detail. The thermodynamic parameters, for instance standard
°
°
Gibbs energy of aggregation (ΔG ), standard enthalpy of aggregation (ΔH ) and stand-
agg.
agg.
°
ard entropy of aggregation (ΔS ), were determined from conductivity measurements.
agg.
The study of the aggregation behavior of SAIL provides suꢃcient information about the
possible location of drug molecules in the aggregates. For an enhanced understanding of
the surrounding microenvironment of SAIL aggregates and the SAIL-drug complex forma-
tion, ꢀuorescence spectroscopy has been used, which deciphers completely the interactions
in these complexes. DLS is very beneꢂcial in obtaining the size of the aggregates. The
obtained CAC values agree well with each other and with literature values obtained by
Sharma et al. [18]. The molecular structure and molecular formulae of the compounds used
in the study are presented in Scheme 1.
2
Experimental
2
.1 Reagents
The SAIL involved in the study is 1-tetradecyl-3-methylimidazolium chloride [C mim]
1
4
[
Cl], which was synthesized in our lab. The diꢁerent compositions of drug, i.e. 0% (w/w),
0
.5% (w/w), 1% (w/w), 2.5% (w/w), and 5% (w/w) were prepared in triply distilled deion-
−6
−1
ized and degassed water with speciꢂc conductivity≤3×10 S·cm . The drug studied
Cl
N
N
1
-Tetradecyl-3-methylimidazolium chloride
and
O
CH CH
2
3
N
H N
O
2
(
HCl)
CH CH
2
3
Procaine hydrochloride
Scheme 1 Molecular structure and molecular formulae of SAIL and procaine hydrochloride
1
3

Journal of Solution Chemistry
was a product of Sigma–Aldrich having purity (≥97%). The complete details of chemicals
used in the present work are given in Table S1 in the Supporting Information.
2
.2 Synthesis of [C mim]Cl
14
The SAIL 1-tetradecyl-3-methylimidazolium chloride, [C mim][Cl], was synthesized
1
4
according to the procedure described in the literature [26]. The reaction was performed
between N-methylimidazole and n-chlorotetradecane in acetonitrile, followed by reꢀux-
ing the solution at 363.15 K for 3 days under N . After completion of the reaction, the
2
ꢂnal product was washed with ethyl acetate to remove the unreacted reactants. Followed by
decanting oꢁ the excess ethyl acetate, the residual ethyl acetate was removed by drying the
ꢂnal product in vacuum oven for at least 3 days. The synthesized ionic liquid was analyzed
1
by H NMR (Bruker 300 MHz) using CDCl as an external solvent to conꢂrm the absence
3
of any major impurities and the ꢂnal purity of ionic liquid was found to be better than 99%.
The details are provided in the Supplementary Information. Karl Fischer titration was used
1
to ꢂnd the water content, which was less than 290 ppm. H NMR spectral data (δ values in
ppm) are given below:
ꢀ
ꢁ
C mim [Cl] ∶ 0.88(3H, t), 1.25 − 1.32(22H, m), 1.87 − 1.90(2H, m),
1
4
4.13(3H, s), 4.30(2H, t), 7.29(1H, d), 7.47(1H, d), 10.58(1H, s).
2.2.1 Instruments and Methods
The samples were prepared by weighing the required amount of the chemicals using an
A&D Co. limited electronic balance (Japan, model GR-202) with a precision of 0.01 mg.
2
.3 Conductance Measurements
The conductance measurements of all the studied systems were obtained using a digital
conductivity meter over the temperature range 288.15–308.15 K with an uncertainty of
0
.01 K in a double walled water-jacketed ꢀow dilution cell. The conductivity meter used
was a CM-183 microprocessor-based EC-TDS analyzer with an ATC probe and conductiv-
ity cell with platinized platinum electrodes, purchased from Elico Ltd., India. The instru-
ment works on an alternating current power supply. The cell was calibrated with aqueous
−1
KCl solutions in the concentration range of 0.01–0.1 mol·kg . At least ꢂve measurements
were made for each concentration and only the mean values are considered. The cell con-
−
1
stant obtained is 1.0021 cm which was calculated by taking the ratio of known speciꢂc
conductance to the measured speciꢂc conductance of a standard KCl solution. The small
conductivity value of water has been subtracted from the obtained conductance data. The
uncertainty of the measurements was less than 4%.
2
.4 Surface Tension Measurements
Surface tension measurements were obtained using a Du Nuoy tensiometer (ring-detach-
−1
ment method) purchased from SD Hardsons Ltd. with a precision of ± 0.01 mN·m . A
platinum-iridium ring with a mean circumference of 6.00 cm was used. The tensiometer
was calibrated and the maximum error in the surface tension value of water (71.99 mN·m−
1
1
3

Journal of Solution Chemistry
−
1
at 298.15 K [27]) was found to be ± 0.2 mN·m . The experiments were performed at
2
98.15 K and the temperature was maintained in a double walled water-jacketed ꢀow dilu-
tion cell using a water thermostat with an uncertainty of 0.01 K. The values were measured
in triplicate, and the mean value was taken. After each measurement, the ring was cleaned
thoroughly with degassed triply distilled de-ionized water and then heated in a high-tem-
perature ꢀame to eliminate the SAIL’s residues.
2
.5 Fluorescence Measurements
The ꢀuorescence measurements were obtained using a Model RF-5301PC ꢀuorescence
spectrometer with blazed holographic grating excitation and emission monochromators,
ꢂtted with a 150 W xenon lamp purchased from Shimadzu. The interactions between the
drug and the SAIL were investigated by studying the eꢁect of the addition of ionic liq-
uids on the maximum ꢀuorescence intensity of the drug using ꢀuorescence quenching. The
ꢀ
uorescence emission spectra of the procaine hydrochloride were recorded in the range
of 220–600 nm at an excitation wavelength of 290 nm, keeping both the excitation and
emission slit width at 5 nm, at 298.15 K. The concentrations of both the drug and the ionic
−
5
−1
liquid were kept at 2×10 mol·kg . The titrations were performed by adding the ionic
liquid successively into the quartz cuvette containing 2 mL of drug solution and recording
the ꢀuorescence intensities.
2
.6 DLS Measurements
The size of the aggregates of SAIL with diꢁerent concentrations of the drug was obtained
using DLS. DLS measurements were performed using a Malvern Nano Zetasizer instru-
ment equipped with a He–Ne laser power of 4 mW. All the measurements were carried
out at a scattering angle of 90° and the data were evaluated with the inbuilt CONTIN
algorithm. The samples of the micellar solutions were ꢂltered through syringe ꢂlters of
0
.2 µm. To obtain the size of the aggregates, solutions of diꢁerent concentration were pre-
pared. Prior to each measurement, the quartz cell was cleaned properly with deionized and
degassed water several times. The measurements were carried out at room temperature,
which was controlled to an accuracy of± 0.1 K.
3
Results and Discussion
The interactions between SAIL, 1-tetradecyl-3-methylimidazolium chloride, [C mim][Cl],
1
4
with procaine hydrochloride have been studied in diꢁerent compositions using conductom-
etry, tensiometry, ꢀuorometry, and DLS at 298.15 K.
3
.1 Conductance Measurements
3.1.1 Determination of CAC
The CAC values of SAIL obtained from conductance at 298.15 K in water and aqueous
solutions of procaine hydrochloride at diꢁerent weight percentages are provided in Table 1.
Figure 1 shows the variation proꢂles of the conductance of [C mim][Cl] in the water and
1
4
1
3

Journal of Solution Chemistry
Table 1 Experimentally
Solvent (%)
0
Critical aggregation concentration
−1
determined CAC of SAIL
in the presence of procaine
hydrochloride with diꢁerent
weight percentages, from surface
tension and conductance at
(
mmol·kg )
Surface tension
Conductance
3.63
3.47
2
98.15 K
a
2.80a
3
.10
0
1
2
5
.5
.5
1.29
0.81
0.69
0.51
1.49
0.86
0.59
0.49
aThe CAC values obtained are cited in literature [18]
aqueous solutions of procaine hydrochloride at diꢁerent weight percentages at 298.15 K.
Figure 2 presents the variation in CAC of SAILs with temperature as a function of the
weight percentages of procaine hydrochloride. The CAC value of the SAIL in aqueous
media obtained from conductivity measurements is in good agreement with those reported
by Sharma et al. [18]. From the conductivity proꢂles, it is very clear that the electrical
conductivity increases with increasing concentration of SAIL. This variation in the curve
implies the onset of aggregation point and the breakpoint obtained in the curves indicates
the CAC point. Due to the presence of long alkyl chain, the CAC of [C mim][Cl] is low
1
4
−
1
−1
(
3.63 mmol·kg ) as compared to [C mim][Cl] (15.22 mmol·kg ) [18] and has better sur-
12
face activity. The behavior and properties of [C mim][Cl] have motivated us to explore it
14
for the applications with the drug.
From Table 1, it is evident that the CAC decreases with the increasing concentration of
procaine hydrochloride. This is due to the polar nature of procaine hydrochloride mole-
cules, which form hydrogen bonds with water (and also with the protons present in the imi-
dazolium ring of the SAIL) which further counter balance the lateral pressure (which tends
to push the drug molecules into the core of the aggregates). This results in the adsorption
of the drug molecules on the surface of the aggregates [28]. This type of adsorption of
drug molecules, on the surface of the aggregates, leads to a decrease in the electrostatic
repulsion among the head groups of the aggregates, thereby decreasing the work required
for aggregation. The whole process of aggregation depends on two opposite interactions.
First, the attractive hydrophobic interactions between the long alkyl chain of SAILs, which
favor the aggregation process, and second the electrostatic forces of repulsion between
the charged head groups, which oppose the aggregation process [18]. Here the adsorption
of the drug molecules on the surface of the aggregates reduces the electrostatic repulsion
between the head groups, hence the CAC decreases. In comparison with our previous work
[
22], it can be seen that the decrease in CAC is greater in the case of lidocaine hydrochlo-
ride as compared to procaine hydrochloride but the diꢁerence in the CAC is not so much
pronounced. So, it can be concluded that the aggregate formation of amphiphilic ILs and
the utilization of colloidal suspension involving procaine hydrochloride is also signiꢂcant
as it is for lidocaine hydrochloride.
1
3

Journal of Solution Chemistry
Fig. 1 Speciꢂc conductance
showing variation in CAC of
aqueous and aqueous procaine
hydrochloride mixtures with
(
a)1.9
1.8
[
C mim][Cl] at 298.15 K for
14
0
0
%
.5%
1
1
1
.7
.6
.5
varying composition of mixed
solvents: a (ꢂlled square) 0%
(
w/w); (ꢂlled circle) 0.5% (w/w);
b (ꢂlled square) 1% (w/w); c
(
(
ꢂlled square) 2.5% (w/w) and
ꢂlled circle) 5% (w/w)
0.6
0.5
0
0
0
0
0
.4
.3
.2
.1
.0
0
2
4
6
8
-
1
C/ mmol kg
(
b)
3
3
3
3
3
3
.22
.20
.18
.16
.14
.12
1
%
-0.2 0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
-
1
C/ mmol kg
(
c)
1
1
1
1
1
1
1
1
1
2.50
2.45
2.5%
5%
2.40
2.35
2.30
2.25
2.20
2.15
2.10
7
.10
.05
.00
.95
.90
7
7
6
6
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
-1
C/ mmol kg
1
3

Journal of Solution Chemistry
Fig. 2 Speciꢂc conductance
showing the variation in CAC of
aqueous and aqueous procaine
hydrochloride mixtures with
4.0
3.5
[
C mim][Cl] at 288.15; 298.15
14
and 308.15 K for varying com-
position of mixed solvent: (ꢂlled
square) 0% (w/w); (ꢂlled circle)
0
.5% (w/w); (ꢂlled triangle) 1%
(
w/w); (ꢂlled inverted triangle)
1
.5
2
5
.5% (w/w) and (ꢂlled diamond)
% (w/w)
1.0
0
0
.5
.0
2
85
290
295
300
305
310
T (K)
3.1.2 Eꢀect of Temperature on CAC
When the variation of the CAC with temperature is studied, it turns out to be a U-shaped
curve, which can be explained by taking two opposite factors into consideration. First, with
the increase in temperature, the structure of water surrounding the hydrophobic part is dis-
rupted, which disfavors the aggregation process, and consequently, the CAC increases. Sec-
ond, the degree of hydration of head group decreases with increasing temperature as a conse-
quence of which the net hydrophobicity of the solute increases, which favors the aggregation
process. Thus, the ꢂrst eꢁect dominates after reaching CAC point, but at low temperature the
second eꢁect dominates [29].
3.1.3 Thermodynamics Parameters of Aggregation
The various thermodynamic parameters were obtained from conductivity measurements. By
°
using the concept of mass action, ΔG of SAIL in aqueous solutions of drug were calculated
agg.
by applying the following equation [30]
◦
ΔGagg. = (2 − ꢀ)RT ln xcac
(1)
where T, R and α are temperature, universal gas constant and degree of counterion dis-
sociation, respectively. The values of α are provided in Table 2. The decrease in the value
of α, the counterion dissociation, with the increase in the amount of the drug indicates an
increase in the counterion binding in the Stern layer of the aggregates. These low values
of α support the decreasing trend of CAC values. This decrease in the α values indicates
the stronger binding of anions on the aggregate surface, as a result the electronic repulsion
among the head groups decreases, which favors the aggregation process [31]. The obtained
°
values of ΔG are negative, which indicates that the aggregation process is feasible and
agg.
becomes more negative with increasing concentration of the drug which fully reꢀects the
trend of the CAC values.
The variation of the standard enthalpy ΔH° can be obtained using Gibbs–Helmholtz
agg.
equation [32]:
ꢀ
ꢁ
◦
dlnxcac
d(1 − ꢀ)
dT
2
ΔHagg. = −RT (2 − ꢀ)
+ lnxcac
(2)
dT
1
3

Journal of Solution Chemistry
Table 2 Degree of counterion dissociation, α and thermodynamic parameters: standard Gibbs energy of
°
°
°
aggregation (ΔG ), standard enthalpy of aggregation (ΔH ), standard entropy of aggregation (ΔS ),
agg.
agg.
agg.
°
s
standard Gibbs energy of adsorption (ΔG ) and Gibbs energy of the surface at equilibrium (G ) of SAIL
ad.
min.
[
C mim]Cl in the presence of procaine hydrochloride in diꢁerent weight percentages at 298.15 K
14
Solvent (%)
Thermodynamic parameters
ΔG°
ΔH°
TΔS°
ΔG°
G
s
α
agg.
agg.
agg.
ad.
min.
0
0.36
0.35
0.34
0.32
0.30
− 39.26
− 42.97
− 45.68
− 47.64
− 48.93
− 14.84
− 12.91
− 11.83
− 9.95
24.42
30.07
33.85
37.69
40.61
− 55.55
− 60.52
− 71.41
− 71.37
− 70.15
15.18
17.35
27.23
28.61
28.91
0
1
2
5
.5
.5
− 8.32
Standard uncertainties are ΔG =± 0.02 (kJ·mol ), ΔH° =± 0.01 (kJ·mol−1), ΔS =± 0.02
°
−1
°
agg.
agg.
agg.
−
1
−1
o
−1
s
−1
−2
(
J·K ·mol ), ΔG =± 0.02 (kJ·mol ), G =± 0.02 (kJ·mol ), T=± 1×10
K
ad.
min.
In addition, by using the values of ΔH and ΔG° the standard entropy of aggregation
°
agg.
agg.
°
ΔS can be calculated using the equation [32]:
agg.
ꢀ
ꢁ
◦
◦
ΔHagg. − ΔGagg.
◦
ΔSagg.
=
(3)
T
The above-mentioned thermodynamic parameters calculated from these relations are pre-
°
sented in Table 2. A close look at ΔH
data in Table 2 demonstrates the exothermic
agg.
nature of the aggregation process. According to Nusselder and Engberts, these negative
°
ΔH
values reꢀect the hydrophobic interactions that drive the whole process of aggre-
agg.
°
gation [33]. A perusal of ΔH
data shows that the aggregation process is exothermic
agg.
but it becomes less exothermic with increasing concentration of the drug, as a result of
which there is less thermal agitation in the solution. Consequently, the molecules of SAIL
form aggregates very easily and hence the CAC decreases. The large positive values of
the standard state entropy change indicate that the aggregation process is entropy driven,
which indicates that the tendency of the hydrophobic group to shift from the solvent to
the inside of the aggregate provides the driving force for the formation of aggregates and
favors the aggregation process. The thermodynamic study clearly explains that SAILs are
good in drug binding.
3
.2 Surface Tension Measurements
Surface tension measurements were performed to investigate the aggregation, interfa-
cial behavior and interactions of the SAIL [C mim][Cl] with procaine hydrochloride at
1
4
2
98.15 K. By taking the well-known Gibbs equation into account, a number of various sur-
face parameters, including the CAC, pC , Π (surface pressure at the interface), γ (sur-
20
cac
cac
face tension at CAC), and A
(minimum area occupied by a single molecule), Г (maxi-
min.
max
mum surface excess concentration), and p (packing parameter) have been obtained and are
tabulated in Table 3. Figure 3 shows the variation in the surface tension of [C mim][Cl]
1
4
with procaine hydrochloride at diꢁerent concentrations, at 298.15 K. From the plot, it is
very clear that in the beginning there is a constant decrease in the surface tension with the
1
3

Journal of Solution Chemistry
Table 3 Various surface active
parameters of aggregation of
SAIL [C mim]Cl with diꢁerent
Solvent (%)
0
Surface parameters
Γmax ×106
Amin
p
pC20
1
4
γcac
Πcac
compositions of procaine
hydrochloride at 298.15 K
34.15
35.05
34.86
35.48
34.98
36.65
35.45
32.94
29.42
25.67
2.25
2.02
1.28
1.24
1.21
0.74
0.82
1.30
1.34
1.37
0.57
0.51
0.33
0.31
0.25
2.89
3.24
3.20
Nd
0
1
2
5
.5
.5
Nd
γ
, Π , Γ , and A are expressed in mN·m−1, mN·m−1, mol·m−2
,
cac
cac
max
min
2
−1
and nm ·molecule respectively
Nd not detected
Fig. 3 Variation of surface ten-
75
sion as a function of [C mim]
1
4
0
0
1
2
5
%
7
6
0
5
[
Cl] concentration in aqueous
.5%
%
and aqueous procaine hydrochlo-
ride mixtures at 298.15 K for
varying composition of mixed
solvents: (ꢂlled square) 0%
.5%
%
60
5
5
5
0
(
(
w/w); (ꢂlled circle) 0.5% (w/w);
ꢂlled triangle) 1% (w/w); (ꢂlled
inverted triangle) 2.5% (w/w) and
(
ꢂlled diamond) 5% (w/w
45
4
3
3
0
5
0
0
.1
1
1
-
log C / mmol kg
10
increase in the concentration of SAIL and then this becomes constant, which is attributed
to the two processes that are taking place in the system. Firstly, surface solvation will take
place followed by the formation of aggregates in the bulk phase [7, 34] and secondly, after
the CAC the concentration becomes constant at the surface. The breakpoint observed in the
plots indicates the CAC values and the value of surface tension at the CAC gives ꢀ . ꢁ
cac
cac
expresses the reduction in the surface tension to a minimum when the SAIL is added to the
solvent. Therefore, ꢀ measures the eꢁectiveness of IL in reducing the surface tension of
cac
the solvent. The relations for obtaining ꢀ and Γ are provided in Supplementary Infor-
cac
max
mation. A decrease in the values of Γ was observed, which shows that, with increasing
max
concentration of drug, the packing of SAIL molecules at the interface decreases.
Further, A represents the minimum surface area occupied by an IL molecule at the
min
surface of the solution and can be obtained by using the following relation [35, 36]:
2
0
Amin = 10 ∕N ꢀ
(4)
A
max
where N is the Avogadro number. Also, A provides information about the packing den-
A
min
sity of the IL at the interface. The packing of SAIL molecules at the interface decreases
with the increase in the concentration of drug as a consequence of which Amin increases at
1
3

Journal of Solution Chemistry
the surface. pC the adsorption eꢃciency, was calculated by using the following relation
20,
[
32, 35, 36]:
pC20 = − log10 C20
(5)
where C20 is the concentration required to reduce the surface tension of pure solvent or
−
1
solution by 20 mN·m . A greater value of pC of SAIL with the drug is a measure of
20
large adsorption eꢃciency and hence better will be the surface activity of the SAIL. The
pC values can only be obtained for pure water, 0.5 and 1% compositions of the drug as
2
0
the surface tension for the other remaining mixtures could not be reduced to C . Thus the
2
0
adsorption eꢃciency ꢂrst increases (at 0.5% of drug) and then decreases with further addi-
tion of drug (at 1% of drug).
The packing parameter (p) helps in determining the shapes of the aggregates and
can be calculated by using the below relation [36]:
p = V ∕l A
c min.
(6)
o
where V represents the volume occupied by the long alkyl chain groups and l gives the
o
c
length of the long alkyl chain present in the middle of the aggregate, which was estimated
using Tanford’s formulae [37]:
3
V = [27.4 + 26.9(n − 1)]2 (Å )
(7)
(8)
o
c
l = [1.54 + 1.26(n − 1)] (Å)
c
c
In the above formulae, n represents the total number of carbon atoms present in the hydro-
c
carbon chain of the tail and generally its value taken is one less than n . This is because the
c
ꢂrst carbon attached to the hydrocarbon chain is more solvated and is considered a part of
it. The concentration of the samples was about 10 times the CAC; the value obtained for
p for the pure IL is higher than 0.33 indicating the formation of vesicles [16, 19]. From
Table 3, it can be seen that, as the concentration of drug increases, the shape of the aggre-
gates transforms accordingly from vesicles to cylindrical to spherical [38, 39]. This is
mainly due to the presence of drug molecules on the outer surface of the aggregates which
increases A . Therefore, this results in the decrease in the value of p and the structure of
min.
the aggregates transform accordingly.
Further, to investigate the eꢁect of the addition of drug on the aggregation behavior
of SAIL, surface active parameters are very helpful in calculating the Gibbs energy of
s
a surface at equilibrium (G ) and standard Gibbs energy change required for adsorp-
min
◦
tion (ΔGad.) using the following relations [32, 40]:
◦
◦
ꢀcmc
ΔGad. = ΔGagg. − ꢁmax
(
9)
s
min
G
= Amin.ꢀcac.NA
(10)
°
where ΔG is the standard Gibbs energy of aggregation, calculated from Eq. 1. A glance
agg.
◦
°
at Table 2 reveals that the values of ΔG are more negative than the corresponding ΔG
ad.
agg.
showing that the primary process taking place is adsorption rather than aggregation. The
°
negative values of ΔG show that some work is required to be done in order to transfer
ad.
s
the IL monomers at the interface to the aggregation stage [41]. G
is a very important
min.
thermodynamic quantity, which represents the Gibbs energy of a surface at equilibrium;
s
this was introduced by Sugihara et al. [42]. The lower is the value of G
the more ther-
min.
modynamically stable is the surface formed, which indicates the greater surface activity of
1
3

Journal of Solution Chemistry
the IL and its higher value indicates the formation of a stable bulk phase. From Table 2, it
s
is clear that the values of G
increase with increasing concentration of drug molecules,
min.
the bulk phase is therefore becoming more stable as compared to the surface phase after
the CAC [42].
3
.3 Fluorescence Measurements
Fluorescence has been used to conꢂrm the interactions between the SAIL and drug mol-
ecules, by observing the eꢁect of concentration of SAIL on the quenching behavior of the
drug. The binding constant and Gibbs energy change are very helpful in evaluating the inter-
actions between procaine hydrochloride and the ionic liquid. The ꢀuorescence emission spec-
tra depend on the polarity of the medium as the ꢀuorophore resides in the excited state for
a longer time and thereafter is exposed to the more relaxed environment containing solvent
molecules, which are oriented around the dipole moment of the excited state. Therefore, to
obtain the ꢀuorescence emission spectra, the concentration of the drug was kept constant and
the amount of ionic liquid was varied [22]. The variation in ꢀuorescence intensity of the drug
by [C mim][Cl] is shown in Fig. 4. From Fig. 4, it is clear that the ꢀuorescence intensity
14
increases with increases in the concentration of the SAIL. The electron density of the N atom
transfers to the benzene ring, as a result of which the drug molecule is excited from the ground
state to the ꢂrst singlet state. The cation–π interactions and hydrogen bonding between the
ionic liquid and drug molecules are responsible for the perturbation in the aqueous environ-
ment around the drug molecules, which increases the band gap between the excited state and
the ground state resulting in the increase in the ꢀuorescence intensity [15]. Also, the solvent
has played a crucial role around the drug molecules.
Using the Benesi–Hildebrand (B–H) equation, the binding constant (K) and the stoichio-
metric ratio of the drug–SAIL complexes, i.e. DS, were evaluated [15]:
ꢄ
ꢅ
ꢀ
ꢁ
1
1
1
=
ꢂ
ꢃ
+
ꢂ
ꢃ
(11)
n
I − I0
K I − I [DS]
I1 − I0
1
0
The binding constant for the complex of [C mim][Cl] ionic liquid achieved was
1
4
−1
−1
n
1
500 kg mol . The B–H plot of (I − I ) versus 1/[DS] for the complex is shown in Fig. 5.
0
Fig. 4 Fluorescence spectra of
procaine hydrochloride with
increasing concentration of
250
0
.00µM
2
1
1
00
50
00
[
C mim][Cl] at 298.15 K, where
14
10.6µM
21.1µM
31.7µM
42.0µM
μm denotes the concentration in
μmol·L−
1
5
6
7
8
9
2.3µM
2.4µM
2.5µM
2.4µM
2.3µM
50
0
280
300
wavelength (nm)
1
3

Journal of Solution Chemistry
Fig. 5 Benesi–Hildebrand plot
0.040
0.035
0.030
by using the changes in the
ꢀ
uorescence spectra of procaine
C mimCl
14
hydrochloride with the increasing
concentration of [C mim][Cl] at
1
4
2
98.15 K
0
0
0
0
0
.025
.020
.015
.010
.005
0
2000
4000
6000
8000
10000
-1
-1
[
DS] /kg mol
Figure 5 shows a linear relationship and gives the stoichiometric ratio 1:1 for the drug–SAIL
◦
complex (considering n as 1). Further, the standard state Gibbs energy change (ΔG ) can be
calculated from K for the complex formation of the drug and the ionic liquid by using the
below equation [15].
◦
ΔG = −RT ln K
(12)
◦
The value of ΔG for complex [C mim][Cl] ionic liquid obtained is − 18.132 kJ·mol .
−1
14
◦
The negative values of ΔG indicate the feasibility of the formation of the drug–SAIL com-
plex at room temperature.
3
.4 DLS Measurements
DLS was used to investigate the variation in the hydrodynamic diameters (D ) of the SAIL
h
aggregates with addition of the drug. The peak diameters of the SAIL aggregates with
diꢁerent weight percentage compositions of the drug have been tabulated in Table 4. An
appraisal of D data clearly shows an increase in the D values with the increase in the
h
h
concentration of drug, that is, from 110.5 to 237.2 nm up to 2.5%, but at 5% the value of
D decreases to 103.2 nm. Figure S1 in the Supporting Information shows the variation
h
of hydrodynamic diameters of aggregates of SAIL with diꢁerent weight percentage com-
positions of the drug in aqueous solution at 298.15 K. This trend of the D values can be
h
Table 4 The micellar size
Solvent (%)
0
Hydrodynamic
(
diameter) of aqueous solutions
diameter (D in
h
of SAIL with diꢁerent weight
percentages of the drug at
nm)
2
98.15 K
110.5
138.6
144.5
237.2
103.2
0
1
2
5
.5
.5
1
3

Journal of Solution Chemistry
explained on the basis that the aggregates grow up to a maximum size due to the decrease
in the electrostatic repulsion among the head group, which permits the SAIL molecules to
come closer, as a result aggregates of bigger size are formed. But with further increase in
the concentration of the drug (i.e. 5%), more drug molecules generate steric hindrance and
electrostatic repulsion on the surface of the aggregates leading to the interruption of the
large aggregates and giving smaller aggregates. The increased concentration of drug (up to
2
.5%) allows more SAIL molecules to aggregate and above that 5% fewer SAIL molecules
are aggregating due to steric hindrance; as a result the size of aggregates ꢂrst increases and
then decreases after the CAC. Further, it seems that ꢂrst saturation of aggregation happens
at the surface and then in the bulk. This behavior is totally in accordance with the obtained
D values.
h
4
Conclusion
The present study deals with the eꢁects of the addition of a local anesthetic drug pro-
caine hydrochloride on the aggregation and interfacial behavior of [C mim][Cl] by sur-
1
4
face tension, conductivity, ꢀuorescence and DLS measurements. The CAC values show a
decrease with increases in the concentration of the drug, which is attributed to the presence
of cation–π interactions between the SAIL molecules and the drug molecules. The sur-
face tension technique was very helpful in determining the interfacial parameters, which
explains the interfacial behavior. The steady-state ꢀuorescence measurements were used
to obtain the binding constant, Gibbs energy change for the formation of drug–SAIL com-
plexes and the stoichiometric ratio. The DLS technique provides very valuable information
regarding the size of the aggregates pertaining to the noticeable changes in the D values.
h
This investigation indicates how procaine hydrochloride modulates the aggregation proper-
ties of the surfactant-like IL. The main frame of the study is that the aggregates of SAILs
are helpful in drug delivery, which could execute many surpassing applications of SAILs.
This work can help to other researchers to follow such studies, considering the amphiphilic
nature of ILs and the use of aggregation involving procaine hydrochloride in medicinal and
pharmaceutical ꢂelds.
Acknowledgements One of the authors Alka Yadav gratefully acknowledges the ꢂnancial support
for the work by Government of India through University Grants Commission, New Delhi (Letter No. F.
4
1-328/2012 (SR)).
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