Physicochemical and structural properties of lidocaine-based ionic liquids with anti-inflammatory anions

Article abstract of DOI:10.1039/c9ra08815f

The purpose of this paper was to examine the density, viscosity and electrical conductivity at different temperatures, as well as the thermal stability and structural properties of previously reported ionic liquids based on active pharmaceutical ingredients. Lidocaine-based ionic liquids, with ibuprofen and salicylate as counterion, were prepared first. Their structures were confirmed by infrared, mass and ¹H and ¹³C nuclear magnetic resonance spectroscopy. The Newtonian behaviour of lidocaine ibuprofenate was confirmed from viscosity measurement results, while it was impossible to determine for lidocaine salicylate. The interactions and structures of the studied ionic liquids were analyzed based on the measured density values, viscosity, electrical conductivity, and calculated values of thermal expansion coefficients and activation energy of viscous flow. From a theoretical aspect, DFT and MD calculations were performed. The obtained descriptors and radial distribution, as well as structural functions, were used to understand the structural organization of the synthesized ionic liquids.

Full text of DOI:10.1039/c9ra08815f

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Physicochemical and structural properties of
lidocaine-based ionic liquids with anti-
Cite this: RSC Adv., 2020, 10, 14089
inflammatory anions†
a
a
b
c
Jovana Panic, Aleksandar Tot, * Nenad Jankovic,
Patrik Drid,
´
´
a
a
Slobodan Gadzuric
and Milan Vranes
ˇ
ˇ
´
The purpose of this paper was to examine the density, viscosity and electrical conductivity at different
temperatures, as well as the thermal stability and structural properties of previously reported ionic liquids
based on active pharmaceutical ingredients. Lidocaine-based ionic liquids, with ibuprofen and salicylate
1
13
as counterion, were prepared first. Their structures were confirmed by infrared, mass and H and
C
nuclear magnetic resonance spectroscopy. The Newtonian behaviour of lidocaine ibuprofenate was
confirmed from viscosity measurement results, while it was impossible to determine for lidocaine
salicylate. The interactions and structures of the studied ionic liquids were analyzed based on the
measured density values, viscosity, electrical conductivity, and calculated values of thermal expansion
coefficients and activation energy of viscous flow. From a theoretical aspect, DFT and MD calculations
were performed. The obtained descriptors and radial distribution, as well as structural functions, were
used to understand the structural organization of the synthesized ionic liquids.
Received 27th October 2019
Accepted 31st March 2020
DOI: 10.1039/c9ra08815f
rsc.li/rsc-advances
2
bond) and thus induce increased drug solubility. Further, there
Introduction
has been growing interest of using ILs in drug delivery, as
3
Over the last decade, ionic liquids (ILs), salts in the liquid form dispersing agents, copolymers or emulsiers. Nowadays, active
at or near room temperature, have captured much attention due pharmaceutical ingredients (APIs) are preparing in the form of
to their large number of striking properties, such as low bio- ionic liquids (API-ILs) to maximize solubility, bioavailability,
accumulation, high thermal stability, designable nature, negli- the concentration of the active ingredient(s), thermal stability,
2,4
gible vapour pressure, remarkable solvation abilities, good as well as to decrease the polymorphism of the drug. Through
1
recyclability, and low toxicity. Besides their unique properties, the API-ILs synthesis, numerous possibilities to obtain any
ILs can be considered as “tailored or designer solvents”, dual-function drug are opened, also. It also opens up the
because their physicochemical properties (viz. viscosity, density, possibility to synthesize the desired dual function. It has
conductivity, melting point, miscibility with other solvents) become evident that ILs may be benecial in the pharmaceu-
entirely depend on their structure, i.e. cation/anion selection. tical area as these salts may be included in aqueous, oily or
The ILs tunable nature expanded their use from the replace- hydroalcoholic solutions, inducing increased drug solubility
ment of solvents and catalysts for synthesis to promising and/or enhanced topical and transdermal administration.
1,2
application in the pharmaceutical industry. However, it is in
In this work, attention was dedicated to two API-ILs, lidocaine
the pharmaceutical and medical eld that ILs have attracted ibuprofenate ([Lid][Ibp]) and lidocaine salicylate ([Lid][Sal]). It is
particular attention since they can be used during the synthesis generally known that lidocaine has been using for local anaes-
of drugs (as catalysts or reaction media, solvents/antisolvents, thesia, while ibuprofen and salicylate are nonsteroidal anti-
cosolvents), due to the possibility of forming additional inter- inammatory drugs (NSAID). The combination of local anaes-
actions between the IL and the drug substance (like a hydrogen thetic and NSAID drugs has shown positive effects in the treat-
5
ment of analgesia in animals. In human practice, such
a
formulations would nd the most extensive use in the local
Faculty of Science, Department of Chemistry, Biochemistry and Environmental
Protection, University of Novi Sad, Trg Dositeja Obradovi ´c a 3, 21000 Novi Sad, treatment of acute pain and inammation, with the most
Serbia. E-mail: aleksandar.tot@dh.uns.ac.rs
effortless topical application. To achieve these dual drug func-
tion, necessary is to modify or improve some of the physico-
chemical properties that these drug substances have while in
solid form. By combining these drugs into the ionic liquid,
certain problems induced by their structure properties, like low
skin permeability for some NSAIDs, which limit their
b
Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja
Domanovi ´c a 12, 34000 Kragujevac, Serbia
c
Faculty of Sport and Physical Education, University of Novi Sad, Lov ´c enska 16, 21000
Novi Sad, Serbia
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c9ra08815f
1
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transdermal use, are overcome. Recently, studies about novel ILs lidocaine with the appropriate equimolar amount (1 : 1) of
with the potential anti-inammatory application reported that ibuprofen/salicylic acid, dissolved in methanol, and stirred for
transformation to an ionic liquid leads to the improved 2 h at room temperature (Scheme 1). The remaining solvent was
lipophilicity/hydrophilicity of drugs, and thus better permeability removed using a rotary evaporator on a temperature of 313.15 K.
through a cell membrane compared with solid salts, lidocaine The light yellow lidocaine ibuprofenate, and colourless, viscous
6–9
and ibuprofen. In the literature, is still arguing if lidocaine lidocaine salicylate, liquid at room temperatures with no
ibuprofenate is an ionic liquid or deep eutectic salt. Although tendency for crystallization during the work, were obtained. For
lidocaine ibuprofenate was rst labelled as an ionic liquid and the structure conrmations and the purities of the synthesized
8,9
7
that term further expanded, in the work of Berton et al. it has ILs, the IR, NMR, and MS spectra were recorded with appro-
been found as a deep eutectic liquid cocrystal with strong priate assignation (Fig. S2–S5 in the ESI†). The obtained purity,
hydrogen bonds or interactions between partially ionized species. calculated from NMR spectra, for lidocaine ibuprofenate
Lidocaine salicylate and acetylsalicylate have been prepared as amounts of 92.0% and lidocaine salicylate for 93.5%.
dual-functional ILs also, but lidocaine acetylsalicylate showed
limited stability due to conversion to salicylate.
The IR spectrum data of synthesized lidocaine ibuprofenate
and lidocaine salicylate, as well as spectra of lidocaine, salicylic
10
Altogether, both experimental and theoretical studies about acids and ibuprofen, was used to estimate the level of the
structure, physicochemical properties, as well as studies on conversion to ionic liquid (Fig. 1 in manuscript and Fig. S4–S6
contacts between ILs and lipid membranes, remain rather in ESI†). This approach was successfully applied in determi-
popular. Although the number of new ionic liquids based on active nation of starting compounds conversion to lidocaine etodolac
6
ꢀ1
pharmaceutical ingredients is rapidly rising, there is a lack of ionic liquid. The wave numbers, v (cm ) of the carbonyl
fundamental information about density, viscosity, electrical groups in the carboxylic group of salicylic acid and ibuprofen,
conductivity and thermal properties. Thus, this paper aims is to the carbonyl groups of amides in the lidocaine, the carbonyl
ꢀ
determine the physicochemical properties of earlier reported ionic groups of carboxylate anions (–COO ) and the amides in the
liquids based on APIs, lidocaine ibuprofenate and lidocaine lidocaine salicylate and lidocaine ibuprofenate were compared.
salicylate. Such study is signicant when combined with comple- Thereby, the presence of obtained products in form of ionic
mentary investigations, for developing and nding new active liquids was concluded. The measured spectra were presented in
ingredients with improved pharmacokinetic characteristics.
Fig. S4–S6 in ESI,† while characteristic bands were presented in
Table 1.
As can be seen from Table 1 and Fig. 1a, in lidocaine salic-
ylate, the absorption bands characteristic to C]O stretching of
Experimental
ꢀ
1
Apparatus and experimental procedures are described and the carboxyl group of salicylic acid were diminished (1658 cm
)
ꢀ
1
given in ESI,† as well as the provenance and purity of used and a new band appeared at about 1589 cm . This provided
compounds (Table S1†).
evidence that salicylic acid is completely deprotonated in lido-
caine salicylate, proving completely conversion to ionic liquid.
On the other hand, the C]O stretch in lidocaine ibu-
The general procedure of lidocaine-based ionic liquids
preparation
ꢀ
1
profenate is located at around 1688 cm , and present combi-
nation of three peaks (Fig. 1b). These peaks are located at
The preparation of lidocaine ibuprofenate and lidocaine salic-
ylate was accomplished by mixing the appropriate amount of
ꢀ1
ꢀ1
1
664 cm (C]O stretch of lidocaine amide group), 1720 cm
Scheme 1 Synthetic pathway of lidocaine ibuprofenate and lidocaine salicylate.
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ꢀ
1
(
C]O of ibuprofen) and a new broad peak at 1690 cm which temperature (T5% onset), glass transition (T ) and melting
g
indicate a dynamic equilibrium between ibuprofene, lidocaine temperatures (T ) are given in Table S2.† The obtained values of
m
7
and H-bonded lidocaine ibuprofenate. These observation 5% mass loss decomposition and glass transition temperatures
suggest that ibuprofene is not completely in deprotonated state, for lidocaine ibuprofenate and lidocaine salicylate are consis-
indicating that conversion of lidocaine ibuprofenate in form of tent with T5% onset, and T
g
previously reported (See Table
8
–11
ionic liquid is not complete.
S2†).
Small deviations from the literature values are due to
differently applied heating rates in the procedure of thermal
analysis. Observing the obtained DSC thermograms (Fig. S1c
ꢁ
and S1d†) the melting point above 100 C of lidocaine salicylate
Results and discussion
Thermal analysis
12
was noted. Z u¨ rner et al. explained this metastable liquid phase
at room temperature as a glassy state of ionic liquids induced by
the slow diffusion of the ions and insufficient crystal nucleation
during cooling of a system. In earlier work, the melting point for
lidocaine salicylate was not observed, as, during the DSC
The thermal stability of starting compounds and obtained ionic
liquids, as well as phase transition values of obtained ionic
liquids were determined by the thermogravimetric and DSC
measurements and compared with results noted in earlier
ꢁ
measurement, the sample was heated only up to 110 C.
8–11
works.
In Fig. S1,† TG decomposition curves of the starting
compounds and synthesized ionic liquids are presented. From
Fig. S1,† it can be seen that the decomposition of ionic liquids
Density
starts at higher temperatures, which indicate that the conver- The densities (d) of pure lidocaine ibuprofenate were measured
sion of starting components into ionic liquids increase the in the temperature range from T ¼ (293.15 to 323.15) K, while of
thermal stability of the compounds. Also, the number of pure lidocaine salicylate from T ¼ (318.15 to 353.15) K at
decomposition stage of salicylic acid is reduced to one by atmospheric pressure (p ¼ 0.1 MPa). The density of lidocaine
conversion into lidocaine salicylate. The established decompo- salicylate could not be measured below T ¼ 318.15 K by applied
sition onset temperatures (Tonset), 5% mass loss decomposition instrument due to the high viscosity of the pure ionic liquid.
p
The thermal expansion coefficients for the pure ILs, a , was
calculated from obtained experimental densities:
ꢀ
ꢁ
1
vd
a
p
¼ ꢀd
vT
p;m
The thermal expansion coefficient was determined in the
same temperature range as measured densities. The obtained
results are tabulated in Tables 2 and 3 and graphically shown as
p
a variation with temperature, in Fig. 2 for d and Fig. 3 for a .
By virtue of the fact that the density of ILs dependent upon
directly on cation–anion interaction, it can be concluded that
denser lidocaine salicylate has a better geometric t of planar
aromatic systems and stronger stabilization p–p interactions exis-
tence between lidocaine and salicylate than between lidocaine and
13
ibuprofenate. Additionally, a higher thermal expansion coefficient
of lidocaine ibuprofenate evidenced a faster movement of the
cation from the anion, due to weaker interactions between them.
Viscosity
The viscosity measurements were performed in temperature
range from T ¼ (293.15 to 323.15) K for lidocaine ibuprofenate
Table 1 IR absorption bands for characteristic vibrations
Wave number
ꢀ
1
Compound
Assignment
(cm )
Salicylic acid
–COOH
–COOH
1658
1720
1589
1688
ꢀ1
Fig. 1 The IR spectra in region of 1500–1800 cm for: (a) lidocaine Ibuprofene
salicylate (red) and salicylic acid (black); (b) lidocaine ibuprofenate (red) Lidocaine salicylate
and ibuprofene (black). The absorbance values of ionic liquids are Lidocaine ibuprofenate
multiplied with factor 5 for easier comparation.
ꢀ
–COO
ꢀ
–COO
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Table 2 Experimental densities (d), viscosities (h), electrical conductivities (k), calculated molar conductivities (l
m
), and thermal expansion
p
coefficients (a ) of lidocaine ibuprofenate at different temperatures
a
ꢀ3
b
b
4
ꢀ1
4
2
ꢀ1
4
ꢀ1
T/K
d /g cm
h /mPa s
k ꢂ 10 /mS cm
l
m
ꢂ 10 /S cm mol
a
p
ꢂ 10 /K
2
2
3
3
3
3
3
93.15
98.15
03.15
08.15
13.15
18.15
23.15
1.02546
1.02145
1.01715
1.01278
1.00860
1.00436
1.00006
20 712
5606.9
2806.0
1467.6
832.08
468.49
298.75
1.44
2.51
4.75
7.48
12.5
18.1
28.1
0.62
1.08
2.06
3.26
5.47
7.95
8.28
8.32
8.35
8.39
8.42
8.46
8.49
12.4
a
Standard uncertainty: u(d) ¼ 3.0 ꢂ 10ꢀ3g cmꢀ3, u(T) ¼ 0.015 K. b Relative standard uncertainty: u
r r
(h) ¼ 0.02, u (k) ¼ 0.01.
and from T ¼ (298.15 to 353.15) K for lidocaine salicylate. The
obtained results are given in Tables 2 and 3.
Variation of viscosity with temperature was tted using the
14–16
Vogel–Fulcher–Tammann (VFT) equation
(Fig. 4):
ꢀ
ꢁ
B
h ¼ A exp
T ꢀ T
g
A and B are adjustable parameters. T
g
represents glass tran-
sition temperature. The tting parameters are given in Table
S3.†
The determination of Newtonian or non-Newtonian behav-
iour was applied for lidocaine ibuprofenate, while for lidocaine
salicylate it was impossible. Namely, for determination of
Newtonian behaviour the measurements with a wide range of
RPM are necessary. Unfortunately, due to the high viscosity of
lidocaine salicylate and the limitation of equipment at higher
RPM measurements with LV-4 spindle were impossible. The
viscosity of uids with Newtonian behaviour at a given
temperature remains constant regardless of which Viscometer
model, spindle or speed was used for the measurements. A
linear dependency of shear stress from shear rate presented in
Fig. 5 (Table S4†), together with the constant viscosity with
shear rate values indicate Newtonian behaviour of lidocaine
ibuprofenate.
Fig. 2 Variation of: - lidocaine ibuprofenate, and B lidocaine salic-
ylate density with temperature.
Electrical conductivity
The electrical conductivity of lidocaine ibuprofenate was
measured in the temperature range from T ¼ (293.15 K to
m
Table 3 Experimental densities (d), viscosities (h), electrical conductivities (k), calculated molar conductivities (l ), and thermal expansion
p
coefficients (a ) of lidocaine salicylate at different temperatures
a
ꢀ3
b
ꢀ4
b
4
ꢀ1
4
2
ꢀ1
4
ꢀ1
T/K
d /g cm
h ꢂ 10 /mPa s
k ꢂ 10 /mS cm
l
m
ꢂ 10 /S cm mol
a
p
ꢂ 10 /K
298.15
303.15
308.15
313.15
318.15
323.15
328.15
333.15
338.15
343.15
348.15
353.15
—
—
—
—
1.12741
1.12311
1.11885
1.11468
1.11025
1.10558
1.10065
1.09597
5836.9
1483.1
290.52
89.149
29.004
10.226
5.0573
2.2890
0.9496
0.4308
0.1809
0.0970
—
—
—
—
—
—
—
0.57
1.84
4.16
9.57
20.5
38.6
70.0
118
—
—
—
—
8.10
8.13
8.17
8.20
8.23
8.26
8.30
8.34
0.40
1.75
5.62
12.6
29.0
61.8
116
209
349
a
Standard uncertainty: u(d) ¼ 3.0 ꢂ 10ꢀ3g cmꢀ3, u(T) ¼ 0.015 K. b Relative standard uncertainty: u
r r
(h) ¼ 0.02, u (k) ¼ 0.01.
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Fig. 6 Variation of electrical conductivity of pure ionic liquids with
temperature: - lidocaine ibuprofenate, and B lidocaine salicylate.
Fig.
3 Variation of thermal expansion coefficients of ILs with
temperature: - lidocaine ibuprofenate, and B lidocaine salicylate.
Fig. 7 Walden plot for lidocaine ibuprofenate, -, in temperature
range 293.15–323.15 K, and lidocaine salicylate, B, in temperature
range 318.15–353.15 K.
temperature is shown in Fig. 6, and tted using modied VFT
equation:
!
0
Fig. 4 Variation of viscosity with temperature for pure ionic liquids: -
lidocaine ibuprofenate, and B lidocaine salicylate.
0
ꢀB
k ¼ A exp
T ꢀ T
g
0
0
A is the pre-exponential coefficient, B is the pseudoactivation
3
(
23.15 K), while for lidocaine salicylate in the range from T ¼
313.15 K to 353.15 K). The measured values are presented in
Tables 2 and 3 The variation of electrical conductivity with
energy and T
g
is the ideal glass transition temperature. The

tting parameters are given in Table S5.† The values of molar
Fig. 5 (a) Flow curve, showing shear stress as a function of shear rate for pure lidocaine ibuprofenate; (b) changes of viscosity values at 298.15 K
with shear rate along with error bars.
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Fig. 8 Representation of MEP surfaces: (a) lidocaine ibuprofenate, (b) lidocaine salicylate.
m
conductivity (l ) were calculated from electrical conductivity that are distinguished based on vertical distance to the KCl line,
1
7
using relation:
denoting as DW. The rst group lies quite close to the KCl line
0.1 < DW < 0.5) suggesting that the ionic liquid is made up of
almost independently mobile ions and can be classied as good
(
k
l
m
¼ c
1
7–19
ionic liquids.
The second groups lies lower on the plot (0.5 <
and obtained results are presented in Tables 2 and 3.
To predict ionicity for lidocaine salicylate and lidocaine
ibuprofenate, Walden plot was applied.
The relation between molar conductivity and viscosity can be
demonstrated by the equation:
DW < 1.0) and is named “poor” ionic liquids. In this group
existence of H-bonds and other specic interaction between
ions in the pure state is more pronounced, leading to a signi-
cant reduction of ions mobility. The third group represents the
liquids that are at least an order of magnitude below the ideal
line, also described as liquid ion pairs or subionic liquids (DW >
log lm ¼ log C + a log hꢀ1
17–19
1.0).
In these liquids, ion conductivity is substantially less
ꢀ1
than would be expected based on their viscosity. The simplest
example is the ion pair, which is neutral and therefore, does not
contribute at all to the measured conductivity.
From Table 3 it can be seen that lidocaine salicylate,
although being more viscous (290 Pa s) than lidocaine ibu-
profenate (0.5 Pa s) nonetheless has similar conductivity,
presumably because the degree of ion association is lower for
lidocaine salicylate. This assumption is conrmed using Wal-
den plot, where lidocaine salicylate is closer to idel KCl line (DW
0.71) and can be classied as “poor” ionic liquid. On the other
side, lidocaine ibuprofenate lies in region of subionic liquids
DW ¼ 1.34) proving the predominance of ion pairs in its
structure. This result is in accordance with conclusions driven
m
where l is molar conductivity, h is uidity, a is the slope of
the line in the Walden plot which reects the decoupling of the
ions, C “is Walden product of fractional Walden rule”. The
Walden plot is presented in Fig. 7.
In the comparison of ideal KCl line, it can be seen that
lidocaine salicylate and lidocaine ibuprofenate lie below this
line. Further, the lidocaine salicylate is closer to KCl line,
indicating better ionicity compared to lidocaine ibuprofenate.
Typically, data for ionic liquids fall below this ideal line because
of the strong interaction between ions in the pure ionic
medium, which reduce the movement of most ions that are
partially correlated with their closest neighbours. The tradi-
tional Walden plot shows three distinct groups of ionic liquids
¼
(
Fig. 9 Representation of optimized structures along with visualization of non-covalent interactions: (a) lidocaine ibuprofenate, (b) lidocaine
salicylate.
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Fig. 10 Representation of LUMO orbitals: (a) lidocaine ibuprofenate, (b) lidocaine salicylate.
from FTIR measurements, proving that conversion of lidocaine Table 4 The Values of HOMO–LUMO energy gap (DEgap) for selected
ionic liquids
ibuprofenate in classical ionic liquid is not fully accomplished.
Ionic liquid
DEgap/eV
Computational simulations
Lidocaine ibuprofenate
Lidocaine salicylate
5.76
4.95
The cation–anion interactions in ionic liquids systems are
determined by electrostatic properties of constituting ions,
van der Waals interactions and the geometrical tting of
cation and anion. Thus, one of the useful descriptor for
potential interaction sites is molecular electrostatic potential
the structural rigidity of the molecule. In addition, in the case
of ibuprofenate it can be noted the existence of positive
potential around alkyl chain, which is absent for salicylate.
The presence of both positive and negative electrostatic
potential in the structure of cation, as well as in the case of
ibuprofenate anion, leads to possible lidocaine–lidocaine
and ibuprofenate–ibuprofenate interaction. With this
purpose, the non-covalent interactions (NCI) from optimized
monomer structure were presented in Fig. 9. As can be seen
from Fig. 9, lidocaine ibuprofenate have signicantly more
NCI, suggesting stronger interactions between cation and
anion, as it proved from Walden plot and FTIR
measurements.
(
MEP). In Fig. 8 the MEP surfaces for lidocaine ibuprofenate
and lidocaine salicylate are presented. The negative regions
of the molecular electrostatic potential are represented in red
colour and are connected with the region of a molecule with
the highest electrophilic reactivity. On the other hand, the
blue regions represent the positive regions with pronounced
nucleophilic reactivity. The negative electrostatic potential is
located around oxygen atoms from cation and both anions.
On the other hand, positive electrostatic potential is clearly
positioned around methyl and –NH groups of lidocainium
cation, and as well as around amid nitrogen of cation. The
negative electrostatic potential of C]O and positive on the
–
+
NH group of cation indicates a signicant contribution of
In addition, from Fig. 9 a potential intramolecular interac-
tion between the keto group of lidocaine and the methyl group
from the ortho position can be seen, which occurs as a result of
the resonant form of the peptide bond in which the nitrogen
is positive, and the oxygen is negatively charged, preventing
the free rotation around the C–N bond, and induces increase
Fig. 11 Representation of HOMO orbitals: (a) lidocaine ibuprofenate, (b) lidocaine salicylate.
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Fig. 12 Representation of hydrophilic (turquoise colour) and hydrophobic (orange colour) for investigated ionic liquids: (a) lidocaine ibu-
profenate, (b) lidocaine salicylate.
Table 5 The values of A log P along with the percentage of hydro-
philic surfaces obtained from DFT calculations of selected ionic liquids
As can be seen from Table 5, both descriptors indicate that
lidocaine salicylate is more hydrophilic than lidocaine
ibuprofenate.
Percentage of hydrophilic
The molecular dynamic simulations were applied in order to
obtain detailed information about global structure and inter-
actions of pure ionic liquids. The using of MD simulations
offers the opportunity to predict physical properties directly
from a molecular interaction model and also to visualize the
organization of molecules and their structure at a molecular
level. This method was rened to present the position of a given
ion corresponding to the position of the selected counterion,
describing the local structure around ions using the structural
analysis tools like radial distribution functions (RDFs) and
structural factor calculations (SDFs).
Ionic liquid
A log P
surfaces (%)
Lidocaine ibuprofenate
Lidocaine salicylate
3.97
1.55
36.96
46.83
an increase in the acidity of hydrogen atoms from the methyl
group due to the expressed positive inductive and hyper-
conjugation effect, indicating the potential cation–cation
interactions.
The next step was an analysis of frontier molecular orbitals
The information about the distance between cations and
anions were obtained from MD simulations using radial
distribution function (RDFs). RDFs for anion (oxygens from
(HOMO and LUMO) as a convenient tool for visualization of the
global stability and reactivity of investigated compounds. The
atomic contribution to HOMO–LUMO orbitals were generated
and presented in Fig. 10 and 11 (positive electron density
represents red colour and negative is in blue colour). From
mentioned gures, in both ionic liquids, the HOMO and LUMO
orbitals are mostly located above anions. The HOMO and LUMO
orbitals shows which part of molecule had potential to interact
with other structures, while the HOMO–LUMO difference
represents the descriptor of this molecule stability. The HOMO
and LUMO energy gap, DEgap (Table 4), quantify the possible
charge transfer interactions within the molecule. The smaller
value of band DEgap is connected to increased reactivity of the
molecule. As can be seen in Table 4, the DEgap is lower for
lidocaine salicylate. Based on this observation lidocaine ibu-
profenate is more stable IL implying lower chemical reactivity
because it hinders electrons to high-lying LUMO or extracting
electrons from a low-lying HOMO inhibiting the formation of an
activated complex for any further reaction.
ꢀ
COO ) and hydrogens from N1 and N2 in all ionic liquids are
presented in Fig. 13. From Fig. 13, it can be seen higher values
of g(r) at a smaller distance for lidocaine salicylate. This
behaviour indicates that salicylate, due to a smaller size, can
approach closer to lidocainium cation, than more bulk ibu-
profenate. This result, indicate better, denser packaging of
smaller salicylate between lidocainium cations, causing higher
values of density and viscosity of lidocaine salicylate comparing
to lidocaine ibuprofenate. The lidocaine ibuprofenate with
branched, more hydrophobic tail prevents packaging of the ions
and decrease the efficiency of p–p interactions more than
g
salicylate. These results are in accordance with lower T values
and higher conductivity of lidocaine ibuprofenate.
Further, comparing results for hydrogen attached to N1 and
N2 atoms, it can be seen that hydrogen connected to N2 is closer
to both anions. On the other hand, this makes N1 atom of
lidocaine more available for additional interaction. With this
purpose, the RDFs between N1 and O1 atom from lidocaine
cation were calculated and shown in Fig. 14, to present the
possibility of self-aggregation of lidocaine cation. From Fig. 14,
Further, hydrophobic/hydrophilic surfaces for both ionic
liquids were calculated and presented in Fig. 12. Moreover, the
percentage of hydrophilic surfaces, as well as lipophilic
descriptor A log P, were calculated and shown in Table 5.
ꢀ
the signicant peak at 2.8 A is noted, suggesting the self-
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Fig. 13 The RDFs of selected atoms from anion and cations (red line O2 and H2 from lidocaine ibuprofenate, blue line O2 and H1 from lidocaine
ibuprofenate, black line O2 and H2 from lidocaine salicylate, green line O2 and H1 from lidocaine salicylate).
is noted in lidocaine salicylate, which is in contrary to lidocaine
ibuprofenate. All obtained theoretical results indicate that
ibuprofenate have a tendency to interact with itself, creating
more cluster structures comparing to salicylates where this type
of interactions are absent. The existence of anion segregation in
lidocaine ibuprofenate originates from the partially deproto-
nated carboxylic group, which diminish electrostatic repulsion
between negative charged anions, allowing the formation of H-
ꢀ
bond between protonated and deprotonated –COO group of
ibuprofen. As the last evidence of stronger interactions between
Fig. 14 The RDF of O1 and H1 from lidocaine ibuprofenate.
cation and anion in lidocaine salicylate, the ion pair binding
energy (DGbin) was calculated. This is important parameter that
can be correlated with physico-chemical properties of ILs such
20
aggregation tendency of lidocaine due to possible formation of as melting point, thermal stability and transport properties.
H-bond between N1 and O1 atoms of lidocaine.
The signicantly more negative energy was obtained for lido-
ꢀ
1
To separate anionic and cationic contributions to RDFs, caine salicylate (Ebin ¼ ꢀ116.21 kJ mol ) than for lidocaine
ꢀ1
structure functions were calculated for the representative centre ibuprofenate (Ebin ¼ ꢀ71.44 kJ mol ). From work of Bernard
of cation's, and anion's center of mass and results are presented et al. and from obtained experimental results in this work, the
in Fig. 15. As can be seen from Fig. 15, the same contribution of dependence between low value of DGbin and higher values of
21
cation–cation and cation–anion to interaction in pure ionic viscosity and density were obtained. This conrms that ion
liquid were obtained. The only differences are in anion–anion pair binding energy is correlated with the strength of the
interactions, where the negative contribution to structure factor intermolecular interaction between ions. Lower value of
Fig. 15 Partitioning of S(q) to cation–cation (red line), cation–anion (black line) and anion–anion (blue line) correlations: (a) lidocaine ibu-
profenate, (b) lidocaine salicylate.
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binding energy points to stronger molecular packaging, sug-
gesting higher value of density and viscosity, as in the case of
investigated ionic liquids.
low toxicity ionic liquids, in Ionic Liquids – New Aspects for
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2
3
R. T. Ley and A. S. Paluch, J. Chem. Phys., 2016, 144(8),
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Conclusions
N. Adawiyah, M. Moniruzzaman, S. Hawatulailaa and
Given the growing interest in ionic liquids based on active
pharmaceutical ingredients, this study was conducted to obtain
a physicochemical and structural characterization of previously
reported lidocaine-based ionic liquids with anti-inammatory
anions. In that intent, lidocaine ibuprofenate and lidocaine
salicylate were synthesized, and their structures were veried by
IR, MS, and NMR spectra. Thermal, densimetric, viscosimetric,
and electrical conductivity measurements were performed,
supported by DFT calculations and molecular dynamics simu-
lation. Thermal analysis has shown that by the synthesis of
ionic liquids, more thermally stable compounds were obtained
relative to the starting components. From experimental and
theoretical results, the better, denser packaging of smaller
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1
1
Conflicts of interest
Authors have no any conict of interest to declare.
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17 D. R. Macfarlane, M. Forsyth, E. I. Izgorodina, A. P. Abbott,
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This work was nancially supported by the Ministry of Educa-
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Serbia under project contract ON172012.
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