Binding interactions of anesthetic drug with surface active ionic liquid

Article abstract of DOI:10.1016/j.molliq.2016.07.076

The application of aggregation behavior of a surface active ionic liquids (SAILs), 1-dodecyl-3-methylimidazolium chloride [C₁₂mim][Cl] and 1-tetradecyl-3-methylimidazolium chloride [C₁₄mim][Cl] in drug delivery of lidocaine hydrochloride has been investigated from surface tension and fluorescence measurements at 298.15?K and from conductance at 288.15, 298.15 and 308.15?K. Critical aggregation concentration (CAC), degree of ionization (α), and various thermodynamic parameters like Gibbs free energy of aggregation (??G_agg.^°) standard enthalpy of aggregation (??H_agg.^°)?and standard entropy of aggregation (??S_agg.^°) are calculated using conductivity measurements. The surface activity of the ILs in various mixed solvents are examined from surface tension measurements by calculating various surface parameters like maximum surface excess concentration (Г_max), minimum surface area per ionic liquid molecule (A_min), adsorption efficiency (pC₂₀), effectiveness of surface tension reduction (Π_cac) surface tension at CAC (γ_cac), p (packing parameter), and CAC at different compositions. Fluorescence measurements have been employed to get detailed insight of the local microenvironment of the aggregates, and critical aggregation concentration (CAC). Decrease in the CAC values was observed with the increase in the amount of drug which is attributed to the balancing between electrostatic and hydrophobic interactions. This shows that the spontaneity of aggregation process of IL increases with the increase in the concentration of drug.

Full text of DOI:10.1016/j.molliq.2016.07.076

Journal of Molecular Liquids 222 (2016) 471–479
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Binding interactions of anesthetic drug with surface active ionic liquid
⁎
Amalendu Pal , Alka Yadav
Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The application of aggregation behavior of a surface active ionic liquids (SAILs), 1-dodecyl-3-methylimidazolium
chloride [C12mim][Cl] and 1-tetradecyl-3-methylimidazolium chloride [C14mim][Cl] in drug delivery of lidocaine
hydrochloride has been investigated from surface tension and fluorescence measurements at 298.15 K and from
conductance at 288.15, 298.15 and 308.15 K. Critical aggregation concentration (CAC), degree of ionization (α),
and various thermodynamic parameters like Gibbs free energy of aggregation (ΔG°agg.) standard enthalpy of ag-
gregation (ΔHa°gg.) and standard entropy of aggregation (ΔSa°gg.) are calculated using conductivity measurements.
The surface activity of the ILs in various mixed solvents are examined from surface tension measurements by cal-
culating various surface parameters like maximum surface excess concentration (Гmax), minimum surface area
Received 27 February 2016
Received in revised form 6 June 2016
Accepted 18 July 2016
Available online 20 July 2016
Keywords:
Ionic liquids
Lidocaine hydrochloride
Conductance
per ionic liquid molecule (Amin), adsorption efficiency (pC20), effectiveness of surface tension reduction (Πcac
)
Surface tension
Fluorescence
surface tension at CAC (γcac), p (packing parameter), and CAC at different compositions. Fluorescence measure-
ments have been employed to get detailed insight of the local microenvironment of the aggregates, and critical
aggregation concentration (CAC). Decrease in the CAC values was observed with the increase in the amount of
drug which is attributed to the balancing between electrostatic and hydrophobic interactions. This shows that
the spontaneity of aggregation process of IL increases with the increase in the concentration of drug.
© 2016 Elsevier B.V. All rights reserved.
1. Introduction
imidazole side chain and plays a vital part in many biological activities.
The hydrophobicity of ILs can be changed by varying the alkyl chain
Ionic liquids (ILs) have a number of fascinating properties, such as
negligible vapor pressure, nonflammability, high thermal stability, re-
markable solvation abilities [1,2], exhibit low toxicity, antimicrobial ac-
tivity [3,4] and a wide range of applications covers their use in
extraction and separation, biocatalysts, organic synthesis, electrochem-
istry, polymer science, and lubricants [5–7]. The presence of long alkyl
chain in ILs make them somewhat more special as they start behaving
like surfactants and are referred to as surface-active ionic liquids
(SAILs) [8–10]. Hence, by considering the base of structure-activity rela-
tionships (SARs), it can be assumed that like cationic surfactants SAILs
also possess surface-active properties and tend to form micelles in aque-
ous solutions [11]. Thereby, these ILs can be used in place of convention-
al cationic surfactants due to their unique applications in many fields of
daily life [12]. These ILs are also found to have enormous biological ap-
plications by virtue of their antimicrobial activity [13–15]. The afore-
mentioned applications of these SAILs have generated our interest in
exploring the behavior of SAILs towards lidocaine hydrochloride drug.
The most widely studied SAILs are imidazolium cation based ILs [9,16–
18]. Additionally, the main thing about the imidazole ring is its presence
in many biomolecules like the amino acid histidine, which has an
length, the type of headgroup, and the nature and size of the counterion.
This allows a fine-tuning of both the structure and delicate dynamics of
their micellar aggregates [4]. SAILs have a good and important scope in
pharmaceutical sciences due to their ability to enhance the permeability
of drugs across the biological membranes. As the micelles have small
size and the stability of drug molecules in micelles is high, they can be
used as drug carriers, which is more advantageous as compared to
other drug carriers [19]. Moreover, to increase bioavailability, to mini-
mize the loss and degradation and to prevent harmful side effects of
drug micelles can be used as drug carriers, which is due to the reason
that the micelles minimize the drug's contact with inactivating species
like enzymes and others present in biological fluids as compared to
free drug molecules [20,21]. Although there are many reports in the lit-
erature on interactions of drugs with conventional surfactants, but lim-
ited study has been done on the interactions of SAILs with drugs [22–
24]. Rangel-Yagui et al. [25] have figured out the solubility of drug mol-
ecules with surfactants and concluded that micelles act as better drug
carriers. Mahajan et al. [26] have investigated the binding ability of
drug with surface-active ionic liquids. They found that SAILs act as bet-
ter drug carrier as compared to conventional cationic surfactants. Sanan
et al. [27] have studied the effect of composition and dilution on the mi-
cellar transition in cationic IL-Ibuprofen aqueous mixtures.
Since SAILs are known to exhibit low toxicity and have better surface
active properties than conventional surfactants, they can be used to
⁎
Corresponding author.
E-mail address: palchem21@gmail.com (A. Pal).
http://dx.doi.org/10.1016/j.molliq.2016.07.076
0167-7322/© 2016 Elsevier B.V. All rights reserved.

472
A. Pal, A. Yadav / Journal of Molecular Liquids 222 (2016) 471–479
study their interactions with drugs. Keeping these properties of SAILs in
view, an attempt has been made to study the applications of
[C12mim][Cl] and [C14mim][Cl] as drug carrier. The drug chosen for the
study is lidocaine hydrochloride, which is a local anesthetic drug. It is
used intravenously for the treatment of ventricular arrhythmias,
which occurred during the course of open-heart surgery. Lidocaine Hy-
drochloride is also used effectively for the treatment of liver diseases
and renal failure. This drug was found to be safe and highly effective
[28,29]. To make it more effective an attempt has been made to study
this drug with SAILs by studying the aggregation behavior using surface
tension, conductance, and fluorescence techniques. The aforemen-
tioned applications of SAILs have motivated us to explore the interac-
tions between them. This allows the evolution of number of SAILs in
curing numerous diseases and in the development of pharmaceuticals.
Literature survey revealed that until now no exhaustive work has
been done to study the interaction between SAILs and lidocaine hydro-
chloride. In this present study, the surface tension and conductivity
measurements have been done to study the influence of lidocaine hy-
drochloride on the degree of ionization (α), critical micelle concentra-
tion (cmc) and other solution properties. A number of thermodynamic
parameters like Gibbs free energy of aggregation (ΔG°agg.), standard en-
2. Experimental
2.1. Reagents
The ILs included in the study were [C12mim][Cl] and [C14mim][Cl]
which were synthesized in our lab. The different 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. The drug studied was acquired from Sigma Aldrich with puri-
ty (≥99%). Pyrene (≥99%) was also a Sigma Aldrich product. The com-
plete details of chemicals studied in the present work are tabulated in
Table 1. The solutions were prepared from triply distilled deionized
and degassed water having specific conductivity ≤3 × 10−6 S cm−1
.
2.2. Synthesis of SAILs [C12mim]Cl and [C14mim]Cl
The surface active ionic liquid 1-dodecyl-3-methylimidazolium
chloride [C12mim][Cl] and 1-tetradecyl-3-methylimidazolium chloride
[C14mim][Cl] were synthesized according to the procedure mentioned
elsewhere [31] by reacting n-chlorododecane and n-chlorotetradecane
respectively with n-methylimidazole in acetonitrile media and then
refluxing the solution at 90 °C for 72 h under the atmosphere of N2. In
order to remove the unreacted reactants, final product was washed
many times with ethyl acetate after cooling at room temperature. Ex-
cess ethyl acetate was decanted and the left ethyl acetate was eliminat-
ed by evaporating it under vacuum in order to get the required product
followed by drying it in vacuum oven for 72 h to receive the final prod-
uct. Karl-Fischer titration analysis was used to find the water content in
the ILs, which were b300 ppm and 290 ppm respectively and kept in a
dry place before using. The SAILs were then characterized by 1H NMR
technique for getting chemical shifts of different protons in CDCl3 oper-
ating at a frequency of 300 MHz whose δ values in ppm are given below
and agreed well with those reported in [32]:
thalpy of aggregation (ΔHa°gg.), standard entropy of aggregation (ΔS°agg.
)
and various interfacial parameters like maximum surface excess con-
centration (Гmax.), minimum surface area per ionic liquid molecule
(Amin), adsorption efficiency (pC20) effectiveness of surface tension re-
duction (Πcac), surface tension at CAC (γcac), and p (packing parameter)
of [C12mim][Cl] and [C14mim][Cl] were obtained from conductivity and
surface tension measurements. The probable location of drugs adsorp-
tion in the micelles of SAILs was identified by studying their micelliza-
tion behavior. For enhanced understanding of the surrounding
microenvironment of ILs aggregates, the fluorescence spectroscopy
has been used by using pyrene as a polarity probe. The obtained CAC
values are well agreed with each other and with literature value obtain-
ed by Sharma et al. [30]. The molecular structure and molecular formu-
lae of the compounds used in the study are presented in Scheme 1. A
pictorial presentation of the binding of the drug molecules with the ag-
gregates is shown in Scheme 2.
[C12mim][Cl]: 0.88 (3H, t), 1.25–1.32 (18H, m), 1.88–1.93 (2H, m),
4.32 (2H, t), 7.35 (1H, d), 7.61 (1H, d), 4.13 (3H, s), 10.47 (1H, s).
[C14mim][Cl]: 0.83 (3H, t), 1.23–1.32 (22H, m), 1.87–1.90 (2H, m),
4.24 (2H, t), 7.52 (1H, d), 7.55 (1H, d), 3.93 (3H, s), 10.20 (1H, s).
Cl
N
N
1-Dodecyl-3-methylimidazolium chloride
Cl
N
N
1-Tetradecyl-3-methylimidazolium chloride
and
H
N
N
O
H
Cl
Lidocaine hydrochloride
Scheme 1. Molecular structure and molecular formulae of SAILs and the drug.

A. Pal, A. Yadav / Journal of Molecular Liquids 222 (2016) 471–479
473
SAIL
SAIL
Scheme 2. Schematic diagram showing interactions between the molecules of lidocaine hydrochloride and the ionic liquid molecules.
2.3. Instruments and methods
measurements were prepared properly as mentioned in our earlier
study [33]. For obtaining emission spectra the excitation wavelength
was kept at 334 nm in the range of 350–600 nm using an excitation
and emission slit width of 3 nm. The interactions between the drug
and the surface active ionic liquids were investigated using fluorescence
technique into two ways. Firstly, the aggregation behavior of both the
ionic liquids has been studied by using an external hydrophobic
probe, pyrene and secondly, by studying the effect of addition of ionic
liquids on the maxima fluorescence intensity of the drug.
The samples were prepared using an A & D Co. limited electronic bal-
ance (Japan, model GR-202) with a precision of 0.01 mg by weighing the
required amount of chemicals. The SAILs were characterized by 1H NMR
spectra taken on a Brüker FT-NMR spectrometer using CDCl3 as an ex-
ternal solvent.
2.3.1. Surface tension measurements
Du Nuoy tensiometer (ring detachment method) was used for
obtaining surface tension measurements, which was purchased from
SD Hardsons Ltd. having a precision of 0.01 mN m−1. The ring used
in the study was platinum-iridium ring with a mean circumference of
6.00 cm and was calibrated before performing each experiment. The ex-
periments were performed at 298.15 K and water thermostat was used
to maintain the temperature in a double walled water-jacketed flow di-
lution cell having an uncertainty of 0.01 K. The values were measured in
triplicate, and the mean value was taken into consideration. The ring
was cleaned properly with triply distilled de-ionized degassed water
followed by subjecting the ring to a high temperature flame to remove
the residues of IL surfactant after each measurement.
(a) CAC measurements. The characterization of the aggregates has
been done by employing fluorescence method using pyrene as
an external probe. The concentration of the pyrene was kept
1 × 10−6 M and its spectra were recorded from 350 to 600 nm
keeping the excitation wavelength at 334 nm. The excitation
and emission slit width were kept 5 and 3 nm respectively.
After each addition the solutions were kept for 5 min in order
to attain the thermal equilibrium. At least three measurements
were taken and the mean value was considered. The CAC of
both ILs was obtained by taking the ratio of the first to the third
vibronic peaks i.e. I1/I3 which is very sensitive to the polarity of
the surrounding microenvironment, versus the concentration
of ionic liquids as shown in Fig. 4. The curves were fitted sigmoi-
dally and the mid-point of which gives the CAC of the system.
(b) Steady State Fluorescence measurements. In order to understand
the nature of the interactions between the drug and the ionic liq-
uids fluorescence-quenching method has been studied by titrat-
ing the drug with ionic liquids. The fluorescence emission spectra
of the lidocaine hydrochloride were recorded in the range of
250–400 nm at an excitation wavelength of 290 nm keeping
the excitation and emission slit width of 5 and 3 nm respectively.
The concentrations of the drug and the ionic liquids were kept
0.01 mM. The titrations were performed by adding the ionic liq-
uids successively into the quartz cuvette containing 2 ml of drug
solution and recorded the fluorescence intensities.
2.3.2. Conductance measurements
The conductance measurements of all the studied systems were ob-
tained using a digital conductivity meter at a temperature range of
288.15–308.15 K having an uncertainty of 0.01 K in a double walled
water-jacketed flow dilution cell. The conductivity meter used was
CM-183 microprocessor based EC-TDS analyser with ATC probe and
conductivity cell with platinized platinum electrodes were purchased
from Elico Ltd., India. The cell constant of the cell was found to be
1.0014 cm−1. The uncertainty of the measurements was b4%.
2.3.3. Fluorescence measurements
For getting fluorescence emission spectra, the samples were pre-
pared by dissolving aqueous solutions of SAILs with drug in pyrene at
room temperature. Model RF-5301PC with blazed holographic grating
excitation and emission monochromators fitted with a 150 W Xenon
lamp was used to obtain fluorescence emission spectra. The quartz
cuvette and the fluorometer used were purchased from Shimadzu.
The stock solution of pyrene and the solutions for fluorescence
3. Results and discussion
The interactions between SAILs, 1-dodecyl-3-methylimidazolium
chloride [C12mim][Cl] and 1-tetradecyl-3-methylimidazolium chloride
[C14mim][Cl] with lidocaine hydrochloride have been studied in differ-
ent compositions using tensiometry, conductometry, and fluorometry
at 298.15 K.
Table 1
Specification of chemicals.
Chemical name
Provenance
Mass fraction purity (%)
3.1. Surface tension measurements
1-Methylimidazole
1-Chlorododecane
1-Chlorotetradecane
Lidocaine Hydrochloride
Chloroform-d
Acros Organics
99.0
Sigma-Aldrich, USA
Sigma-Aldrich, USA
Sigma-Aldrich, USA
SD Fine Chemicals, India
Sigma-Aldrich, USA
Rankem, India
≥99.0
≥99.0
≥99.0
99.8
≥99.9
≥99.0
The surface tension method is an appropriate method that not only
helps in investigating the aggregation behavior of SAILs but also gives
important information about the adsorption process that is taking
place on the interface. Surface tension method has been used to investi-
gate the aggregation, interfacial behavior and interactions of the SAILs
Pyrene
Methanol

474
A. Pal, A. Yadav / Journal of Molecular Liquids 222 (2016) 471–479
Table 3
[C12mim][Cl] and [C14mim][Cl] with lidocaine hydrochloride at
298.15 K. The CAC values gained from various techniques are tabulated
in Table 2, which are well agreed with each other. By putting forth the
well known Gibbs equation, a series of various surface parameters like
CAC, pC20, Πcac (surface pressure at the interface), γcac, (surface tension
at CAC), and Amin.(minimum area occupied by a single molecule), Гmax
(maximum surface excess concentration), and p (packing parameter)
have been obtained which are provided in Table 3. Fig. 1 (a) and (b)
show the variation in the surface tension of [C12mim][Cl] and
[C14mim][Cl] with different concentration of lidocaine hydrochloride
at 298.15 K. Initially, the surface tension decreases constantly with the
increase in the concentration of SAILs but it becomes constant after a
certain point, which is due to the reason that in the bulk phase, the ag-
gregates start forming and at the surface layer, the concentration be-
comes almost constant. The breakpoint appeared in the plots
represent the CAC values and the value of surface tension at CAC gives
Various surface active parameters of aggregation of [C12mim]Cl and [C14mim]Cl at 298.15
K.
Solvent
Surface parameters
γcac
Πcac
Γ
max×106
Αmin
p
pC20
[C12mim][Cl]
0%
0.5%
1%
2.5%
5%
34.58
38.70
35.55
36.00
34.00
37.42
26.55
22.15
19.85
18.75
2.16
1.92
1.64
1.11
0.93
0.77
0.87
1.01
1.50
1.79
0.55
0.49
0.42
0.28
0.24
2.30
2.56
2.44
Nd
Nd
[C14mim][Cl]
0%
0.5%
1%
2.5%
5%
34.15
36.85
36.55
36.38
35.94
36.65
28.40
21.15
19.47
16.81
2.25
2.02
1.53
1.36
1.06
0.74
0.82
1.09
1.22
1.57
0.57
0.51
0.39
0.35
0.27
2.89
3.24
3.20
Nd
Nd
γ
cac. Πcac denotes the reduction in the surface tension to a minimum
γcac , Πcac, Гmax., and Amin. are expressed in mN m−1, mN m−1, mol cm−2, and Ǻ2
molecule−1 respectively.
Nd - not detected.
when the IL added to the solvents. Therefore, Πcac measures the effec-
tiveness of IL in reducing the surface tension of the solvent. Πcac can
be obtained by using Relation (1):
surface. The adsorption efficiency denoted by pC20 was achieved by
using the following relation [34–36]:
Πcac ¼ γo−γcac
ð1Þ
where γₒ is the surface tension of the pure solvent.
pC20 ¼ − logC20
ð4Þ
Gibbs adsorption isotherms explain the reduction in the surface ten-
sion when the ILs get adsorbed at the surface. Гmax is the maximum sur-
face excess concentration and the adsorbed amount of the IL which can
be calculated by using the following relation [34]:
75
70
65
60
55
50
45
40
35
0%
0.5%
1%
2.5%
5%
ꢀ
ꢁ
1
dγ
Γ max ¼ −
ð2Þ
nRT d lnC
where T is the absolute temperature, R is the gas constant, C is the con-
centration of IL in bulk solution, and n is the number of ionic species in
the solution upon dissociation in water. A decrease in the values of Гmax
was observed on increasing drug concentration indicating the lowering
of packing of IL molecules at the interface.
Further Amin was evaluated by using the following equation, which
represents the minimum surface area occupied by an IL molecule at
the surface of the solution [34,35]:
30
0.1
1
10
Amin ¼ 1020=NA Γ max
ð3Þ
log C / mmol kg-1
(a)
where NA is the Avogadro number. Also, Amin gives the information
about the packing density of the IL at the interface. A decrease in the
packing of IL molecules at the interface was observed on increasing
the concentration of drug as a result of which Amin increases at the
75
70
65
60
55
50
45
40
35
30
0%
0.5%
1%
2.5%
5%
Table 2
Experimentally determined CAC of IL in the presence of lidocaine hydrochloride in differ-
ent weight percentages from various techniques at 298.15 K.
Solvent
Critical aggregation concentration (mmol kg−1
)
Surface tension
Conductance
Fluorescence
[C12mim][Cl]
0%
0.5%
1%
2.5%
5%
15.22a
7.85
5.38
3.94
2.15
16.6a
12.4
6.5
4.6
2.2
8.97a
7.00
4.83
3.21
2.06
0.1
1
log C / mmol kg-1
(b)
[C14mim][Cl]
0%
0.5%
1%
2.5%
5%
3.63a
1.25
0.97
0.46
0.33
3.47a
1.41
0.63
0.45
0.36
3.20a
1.19
0.62
0.40
0.28
Fig. 1. Variation of surface tension as a function of SAILs concentration (a) [C12mim][Cl]
and (b) [C14mim][Cl] in aqueous and aqueous-drug mixtures at 298.15 K for varying
composition of mixed solvents: (■) 0% (w/w); (●) 0.5% (w/w); (▲) 1% (w/w); (▼)
2.5% (w/w) and (♦) 5% (w/w).
a
The CAC values obtained are cited in literature [30].

A. Pal, A. Yadav / Journal of Molecular Liquids 222 (2016) 471–479
475
Table 4
where C20 has its usual meaning. The greater value of pC20 depicts the
larger adsorption efficiency and better will be the surface activity of
the SAIL. The values of pC20 can only be achieved for pure water, 0.5%
and 1% of the drug for both ionic liquids as the surface tension could
not be reduced to C20 for the remaining mixtures. A perusal of the
data of pC20 reveals the better surface activity of [C14mim][Cl] as com-
pared to [C12mim][Cl].
Degree of counterion dissociation, α and thermodynamic parameters: standard free ener-
gy of aggregation (ΔG°agg.), standard enthalpy of aggregation (ΔH°agg.), standard entropy of
aggregation (ΔS°agg.), standard Gibbs free energy of adsorption (ΔG°ad.) and free energy of
the surface at equilibrium (Gms in.) of SAILs [C12mim][Cl] and [C14mim][Cl] at 298.15 K.
Solvent
Thermodynamic parameters
α
ΔG0agg.
ΔH0agg.
TΔS0agg.
ΔG0ad
Gsmin.
The packing parameter (p) has been evaluated by using the follow-
ing relation which helps in determining the shapes of the aggregates
[35]:
[C12mim][Cl]
0%
0.5%
1%
2.5%
5%
0.35
0.34
0.33
0.32
0.30
−33.14
−34.54
−37.41
−39.16
−42.64
−8.53
−7.15
−5.91
−5.00
−4.32
24.60
27.39
31.51
34.16
38.32
−50.46
−48.37
−50.92
−57.04
−62.80
16.01
20.16
21.68
32.43
36.56
P ¼ Vo=lcAmin:
ð5Þ
[C14mim][Cl]
0%
0.5%
1%
where Vo represents the volume occupied by the long alkyl chain groups
and lc gives the length of the long alkyl chain present in the mid of the
aggregate were determined using Tanford's formulae [37]:
0.36
0.35
0.34
0.33
0.32
−39.26
−43.26
−46.95
−48.55
−49.83
−14.84
−8.17
−7.87
−7.14
−4.37
24.42
35.09
39.08
41.41
45.46
−55.55
−57.32
−60.77
−62.87
−65.69
15.18
18.24
23.89
26.75
33.91
2.5%
5%
ꢂ
ꢃ
Vo ¼ ½27:4 þ 26:9 ðnc−1Þꢀ2 Å3
ð6Þ
ð7Þ
Standard uncertainties are ΔGa°gg.
=
=
0.02 (kJ mol−1), ΔHa°gg.
0.02 (kJ mol−1), Gms in.
=
=
0.01 (kJ mol−1),
0.02 (kJ mol−1), T
ΔS°agg.
=
0.02 (JK−1 mol−1), ΔGa°d.
ꢄ ꢅ
lc ¼ ½1:54 þ 1:26 ðnc−1Þꢀ
Å
=
1 × 10−2 K.
Generally, in both the above formulae the number of carbon atoms
taken is one less than the total number of carbon atoms in the hydrocar-
bon chain (nc) which is due to the reason that the first carbon atom at-
tached to the long alkyl chain is more solvated and is considered a
portion of it. Keeping concentration about 10 times of the CAC, the ob-
tained values of p for pure ILs is higher than 0.33, which indicates the
formation of vesicles. From Table 3, it can be observed that with the in-
crease in the concentration of drug, the shape of the aggregates changes
from vesicles to cylindrical to spherical [38]. This is due to the reason
that the drug molecules are residing primarily in the outer surface of ag-
gregates which consequently increases the Amin. Therefore, the value of
p decreases and the structure of the aggregates transforms accordingly.
By making use of surface active parameters, free energy of a surface
at equilibrium (Gmins) and standard Gibbs free energy change required
for adsorption (ΔG°ad.) were also evaluated in order to investigate the ef-
fect of addition of drug on the aggregation behavior of SAILs using fol-
lowing relations [36,39]:
weight percentages are provided in Table 2. The variation profiles
of conductance of [C12mim][Cl] in aqueous and aqueous solution of
lidocaine hydrochloride at different weight percentages at 298.15 K
are given in Fig. 2 (a), (b) and (c) and for [C14mim][Cl] the conductance
profiles are provided in Fig. 3 (a), (b) and (c). Fig. 4 (a) and (b) repre-
sent, the variation in CAC of SAILs with temperature as a function of dif-
ferent weight percentages of lidocaine hydrochloride. The CAC value of
both the SAILs in aqueous media obtained from conductivity measure-
ments agreed well with those reported by Sharma et al. [30]. From the
conductivity profiles, it can be seen that the electrical conductivity in-
creases with the increase in the concentration of ionic liquids. This var-
iation in the curve implies the onset of aggregation point and the
breakpoint indicates the CAC value. From Table 2 it can be observed
that the CAC of [C14mim][Cl] is lower than [C12mim][Cl] which is
due to the presence of long alkyl chain in [C14mim][Cl] as compared
to [C12mim][Cl] and therefore has better surface activity than
[C12mim][Cl].
A close look at Table 2 reveals that for a particular SAIL, the CAC
decreases with the increase in the concentration of lidocaine hydro-
chloride. This may be due to the fact that lidocaine hydrochloride
molecules being slightly polar in nature forms hydrogen bonding
with water which counter balances the lateral pressure that tend to
push the drug molecules into the core of the aggregates and also
with the protons present in the imidazolium ring of the SAILs as a re-
sult of which the drug molecules get adsorbed on the surface of the
aggregates [42]. This kind of adsorption of the drug molecules on
the surface of the aggregates decreases the electrostatic repulsions
among the head groups of the aggregates thereby decreasing the
work required for the aggregation. The aggregation process depends
on the two opposite interactions. First, the electrostatic forces of re-
pulsions between the charged head groups, which delay the aggre-
gation process and second, the attractive hydrophobic interactions
between the long alkyl chain of SAILs, which favors the aggregation
process. Here the electrostatic repulsions are being reduced by the
adsorption of the drug molecules on the surface of the aggregates
and hence the cac decreases.
ΔGꢁad: ¼ ΔGꢁagg:
−
ð8Þ
ð9Þ
Πcmc
Γ max
Gsmin ¼ Amin ꢂ Πcac ꢂ NA
where ΔG°agg. is standard Gibbs free energy of aggregation achieved
from conductivity measurements using Eq. (10). A perusal of the data
from Table 4 reveals that the values of ΔG°ad. are more negative than
their corresponding ΔG°agg. indicating the primary process which is tak-
ing place is the adsorption process as compared to aggregation. From
the table it is very clear that ΔG°ad. has negative values, which shows
that some work has to be done in transferring the SAIL monomers at
the interface to the aggregation stage [40]. Gsmin. represents the free en-
ergy of a surface at equilibrium, a thermodynamic quantity which is in-
troduced by Sugihara et al. [41]. Its lower values indicate the formation
of highly thermodynamically stable surface as a result of which it has
attained greater surface activity. From Table 4, it can be seen that the
values of Gsmin. are increasing with the increase in the concentration of
drug molecules, so it can be concluded that on increasing the concentra-
tion of drug the bulk phase is becoming more stable than the surface
phase [41].
3.2. Conductance measurements
3.2.2. Effect of temperature on CAC
The variation of the CAC with temperature are shown in Fig. 4 (a)
and (b). The curves obtained to be a U-shaped curve. This behavior of
the curve can be explained by considering two opposite factors. Firstly
with increasing temperature, the degree of hydration of head group
3.2.1. Determination of CAC
The CAC values of SAILs obtained from conductance at 298.15 K in
aqueous and aqueous solutions of lidocaine hydrochloride at different

476
A. Pal, A. Yadav / Journal of Molecular Liquids 222 (2016) 471–479
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
1.9
0%
0.5%
1.8
1.7
1.6
0%
0.5%
1.5
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
10
20
30
40
50
60
70
C/ mmol kg-1
0
2
4
6
8
C/ mmol kg-1
(a)
5.0
(a)
1%
4.8
4.6
4.4
4.2
4.0
3.8
3.6
3.4
3.2
3.22
3.20
3.18
3.16
3.14
3.12
1%
0
10
20
30
40
50
C/ mmol kg-1
(b)
12.7
12.6
12.5
12.4
12.3
12.2
12.1
12.0
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
C/ mmol kg-1
2.5%
5%
(b)
12.50
12.45
12.40
12.35
12.30
12.25
12.20
12.15
12.10
2.5%
5%
7
7.10
7.05
7.00
6.95
6.90
0
5
10
15
20
C/ mmol kg-1
(c)
Fig. 2. Specific conductance showing variation in cac of aqueous and aqueous-drug
mixtures of [C12mim][Cl] at 298.15 K for varying composition of mixed solvents: (a)
(■) 0% (w/w); (●) 0.5% (w/w); (b) (■) 1% (w/w); (c) (■) 2.5% (w/w) and (●) 5% (w/w).
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
C/ mmol kg-1
(c)
Fig. 3. Specific conductance showing variation in cac of aqueous and aqueous-drug
mixtures of [C14mim][Cl] at 298.15 K for varying composition of mixed solvents: (a)
(■) 0% (w/w); (●) 0.5% (w/w); (b) (■) 1% (w/w); (c) (■) 2.5% (w/w) and (●) 5% (w/w).
decreases as a result of which the hydrophobicity of solute increases
that supports aggregation. Secondly, with the increase in temperature
there will be disruption in the structure of water molecules surrounding
the hydrophobic part, which unfavors the aggregation process, and
consequently CAC increases. Thus, the first effect dominates at low tem-
perature while the second effect dominates after reaching CAC point
[43].
3.2.3. Thermodynamics parameters of aggregation
The various thermodynamic parameters were evaluated from con-
ductivity measurements. By using the concept of mass action model,

A. Pal, A. Yadav / Journal of Molecular Liquids 222 (2016) 471–479
477
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
And by using the values of ΔH°agg. and, ΔGa°gg. the standard entropy
of aggregation (ΔS°agg.) can be achieved from the equation [36]:
!
ΔΗꢁagg:−ΔGꢁagg:
ΔSꢁagg:
¼
ð12Þ
T
The above-mentioned thermodynamic parameters calculated from
these equations are presented in Table 4. A perusal of ΔH°agg. data
from Table 4 demonstrates the exothermic nature of the aggregation
process. According to Nusselder and Engberts, the main force that drives
this whole process towards the direction of formation of aggregates
having negative ΔH°agg. is the hydrophobic interactions [45]. Though
the aggregation process is exothermic but with the increase in the con-
centration of drug the process becomes less exothermic which shows
that there is less thermal agitation in the solution as a result of which
the molecules form aggregates more easily and hence CAC decreases.
The large and positive values of entropy indicate that the aggregation
process is entropy driven which states that the tendency of the hydro-
phobic group to shift from the solvent to the inside of the aggregate pro-
vides the driving force for the formation of aggregates and favors the
aggregation process. From Table 4, it is very clear that ΔG°agg. is mostly
0
285
290
295
300
305
310
T (K)
(a)
4.0
3.5
contributed by ΔSa°gg.
.
3.3. Fluorescence measurements
1.5
1.0
0.5
0.0
Fluorescence method has been performed for confirming the inter-
actions between the SAIL molecules and the drug molecule. It not only
helps in determining the CAC of the SAILs but also the aggregation num-
ber and the effect of concentration of SAILs on the quenching behavior
of the drug.
285
290
295
300
305
310
T (K)
(b)
3.3.1. Determination of CAC
Fluorescence method has been done in order to verify the results ob-
tained from surface tension and conductance at 298.15 K. Fig. 5 (a) and
(b) show the variation of I1/I3 with SAILs concentration in different com-
positions of the drug. I1/I3 ratio is very sensitive to the polarity of the
medium and as the polarity of the medium decreases this ratio also de-
creases. The polarity scale of pyrene is described by the ratio I1/I3 of the
fluorescence intensities bands at I1(Ca. 376 nm) and I3(Ca. 387 nm). As
pyrene is sensitive to the polarity of the medium, the ratio I1/ I3 of
pyrene increases on moving from non-polar to the polar medium [33].
This unique feature of pyrene makes it a suitable probe for determining
the CAC of SAILs in aqueous solutions of drug as the polarity of solution
generally differs from the microenvironment of the core of aggregates.
From the fluorescence profiles, it is very clear that the ratio I1/I3 remains
static up to a certain concentration and then decreases very speedily
and after then becomes stable on increasing SAIL's concentration. This
discontinuity in the curve implies the onset of aggregation. Pyrene
shows this unique type of behavior due to its hydrophobic nature be-
cause pyrene molecules get incorporated into the hydrophobic inner
core of the aggregates and pyrene sense non-polar environment in the
inner core as a result of which the value of I1/I3 ratio in the curve de-
creases [33]. The CAC values obtained from fluorescence validates our
result obtained from surface tension and conductance and are provided
in Table 2.
Fig. 4. Specific conductance showing variation in cac of aqueous and aqueous-drug
mixtures of (a) [C12mim][Cl] and (b) [C14mim][Cl] at 288.15 K; 298.15 K and 308.15 K
for varying composition of mixed solvent: (■) 0% (w/w); (●) 0.5% (w/w); (▲) 1% (w/
w); (▼) 2.5% (w/w) and (♦) 5% (w/w).
ΔG°aggof SAILs in aqueous solutions of drug were calculated by applying
the following equation [44].
ΔGꢁagg: ¼ ð2−αÞRT lnxcac
ð10Þ
where T is temperature, α is the degree of counterion ionization, and
R is gas constant. The values of α are tabulated in Table 4. The value
of α, counterion dissociation, decreases with the increase in the
amount of the drug which indicates an increase in the counterion
binding in the stern layer of the aggregates. Lower the α value, stron-
ger will be the binding of anions on the aggregate surface resulting in
the decrease in the electronic repulsions among the head groups on
the aggregate surface, which favors the aggregation process, and
thereby supporting the decreasing trend of CAC values [17]. The ob-
tained values of ΔG°agg are negative supporting the aggregation pro-
cess and becomes more negative with the increasing concentration
of drug which justifies the obtained trend for CAC values. This sug-
gests that these SAILs have good drug binding ability as compared
to conventional surfactants.
3.3.2. Effect of SAILs on the fluorescence intensity of the drug
Further evaluation of the interactions between lidocaine hydrochlo-
ride and the ionic liquids was done in terms of binding constant and free
energy change. The polarity of the medium highly affects the fluores-
cence emission spectra of the fluorophore because the fluorophore
stays in the excited state for more time which further exposed to the re-
laxed environment containing solvent molecules which are oriented
around the dipole moment of the excited state. Therefore, for getting
fluorescence emission spectra, the amount of ionic liquids was varied
The variation of the standard enthalpy (ΔG°agg.) can be obtained
using Gibbs-Helmholtz equation [36]:
ꢀ
ꢁ
ꢁ
d lnxcac
dT
dð1−αÞ
ΔHagg: ¼ −RT2 ð2−αÞ
þ lnxcac
ð11Þ
dT

478
A. Pal, A. Yadav / Journal of Molecular Liquids 222 (2016) 471–479
400
1.8
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1.0
0%
0.5%
1%
2.5%
5%
350
0.00µM
23.00µM
45.78µM
68.34µM
90.67µM
112.79µM
134.69µM
156.38µM
177.86µM
300
250
200
150
100
50
0
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
C / mmol kg-1
300
350
(a)
wavelength (nm)
1.9
(a)
1.8
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1.0
0.9
450
400
350
300
250
200
150
100
50
0%
0.5%
1%
2.5%
5%
0.00µM
10.6µM
21.1µM
31.5µM
41.8µM
52.1µM
62.2µM
72.2µM
82.1µM
91.9µM
-1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
C /mmol kg-1
0
(b)
280
300
320
340
360
380
400
wavelength (nm)
Fig. 5. Pyrene (1 μM) I1/I3 versus log of concentration of (a) [C12mim][Cl] and (b)
[C14mim][Cl] in presence of aqueous and aqueous-drug mixtures at 298.15 K for
varying composition of mixed solvents: (■) 0% (w/w); (●) 0.5% (w/w); (▲) 1% (w/w);
(▼) 2.5% (w/w) and (♦) 5% (w/w).
(b)
Fig. 6. Fluorescence spectra of lidocaine hydrochloride with the increasing concentration
of (a) [C12mim][Cl] and (b) [C14mim][Cl] at 298.15 K.
keeping the concentration of the drug constant [27]. This variation in
fluorescence intensity of the drug by [C12mim][Cl] is shown in Fig. 6
(a) and variation from [C14mim][Cl] is shown in Fig. 6 (b). From these
profiles, it can be seen that the fluorescence intensity increases with
the increase in the concentration of both the ionic liquids. The drug mol-
ecule is excited from ground state to the first singlet state due to the
transference of electron density from N atom to the benzene ring having
π character. On adding SAILs to the solution, there will be cation-π inter-
actions and hydrogen bonding between ionic liquid and drug molecules
which results in the perturbation of the environment around the drug
molecules and consequently there will be an increase in the fluores-
cence intensity. This increase in the fluorescence intensity of drug may
be due to the increase in the band gap between the excited and the
ground state [22].
relationship and give the stoichiometric ratio 1:1 for the drug-SAIL com-
plex (considering n as 1). The same results were obtained for
[C14mim][Cl] ionic liquid. Further, by using the value of K the free energy
0.024
C12mimCl
0.022
C14mimCl
0.020
0.018
0.016
0.014
0.012
0.010
0.008
0.006
0.004
The binding constant and the stoichiometric ratio of all the drug-
SAIL([C12mim][Cl] and [C14mim][Cl]) complex i.e. DS were evaluated
by using Benesi-Hildebrand (B-H) equation [22]:
ꢆ
ꢇ
ꢆ
ꢇ
1
I−I0
1
1
¼
n þ
ð13Þ
ðI1−I0Þ
kðI1−I0Þ½DSꢀ
0
2000
4000
6000
8000
10000
[DS]-1/M-1
The values of the binding constant for complexes of [C12mim][Cl]
and [C14mim][Cl] ionic liquids obtained were 1400 and 2430 M−2 re-
spectively. The double reciprocal B-H plots of (I-I0)−1 versus 1/[DS]n
for both the complexes are shown in Fig. 7 which show a linear
Fig. 7. Benesi-Hildebrand plot by using the changes in the Fluorescence spectra of
lidocaine hydrochloride with the increasing concentration of [C12mim][Cl] and
[C14mim][Cl] at 298.15 K.

A. Pal, A. Yadav / Journal of Molecular Liquids 222 (2016) 471–479
479
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CAC decreases with the increase in the concentration of the drug,
which is due to the presence of cation-π interactions between the SAIL
molecules and the drug molecules. The negative value of ΔG°agg.indicates
the spontaneity of the aggregation process. The surface tension tech-
nique was very helpful in obtaining the interfacial parameters, which
comes out to be very favorable in explaining the behavior at the inter-
face. The steady state fluorescence measurements have been used to ob-
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complexes and the stoichiometric ratios. This investigation shows the
pivotal role of lidocaine hydrochloride in modulating the aggregation
properties of surfactant like ILs. A comparative study has been done in
order to investigate the better surface activity among both the ionic liq-
uids. The main picture of the work is that the drug molecules get
adsorbed on the surface of the aggregates and thereby helping in the
drug delivery, which would serve for tremendous potential applications
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