Study of interactions between L-alanine and 1-octyl-3-methylimidazolium salicylate or 1-octyl-3-methylimidazolium ibuprofenate using the thermophysical properties at T?=?298.15?K

Article abstract of DOI:10.1016/j.molliq.2019.01.030

The effect of 1?octyl?3?methylimidazolium salicylate, [OMIm][Sal] and 1?octyl?3?methylimidazolium ibuprofenate, [OMIm][Ibu] as active pharmaceutical ingredient ionic liquids (API-ILs) on the solvation properties of L-alanine in aqueous media have been inv

Full text of DOI:10.1016/j.molliq.2019.01.030

Accepted Manuscript
Study
of
interactions
between
salicylate
ibuprofenate
l-alanine
using
and
or
the
1-octyl-3-methylimidazolium
1-octyl-3-methylimidazolium
thermophysical properties at T=298.15K
Hemayat Shekaari, Mohammed Taghi Zafarani-Moattar,
Seyyedeh Narjes Mirheydari
PII:
S0167-7322(18)34648-8
DOI:
Reference:
https://doi.org/10.1016/j.molliq.2019.01.030
MOLLIQ 10261
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
9 September 2018
9 November 2018
6 January 2019
Please cite this article as: Hemayat Shekaari, Mohammed Taghi Zafarani-Moattar,
Seyyedeh Narjes Mirheydari , Study of interactions between l-alanine and
1-octyl-3-methylimidazolium salicylate or 1-octyl-3-methylimidazolium ibuprofenate
using the thermophysical properties at T=298.15K. Molliq (2019), https://doi.org/
10.1016/j.molliq.2019.01.030
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ACCEPTED MANUSCRIPT
Study of interactions between L-alanine and 1-octyl-3-methylimidazolium salicylate
or 1-octyl-3-methylimidazolium ibuprofenate using the thermophysical properties at
T= 298.15 K
Hemayat Shekaari, Mohammed Taghi Zafarani-Moattar, Seyyedeh Narjes Mirheydari*
Department of Physical Chemistry, University of Tabriz, Tabriz, Iran
Abstract
The effect of 1-octyl-3-methylimidazolium salicylate, [OMIm][Sal] and 1-octyl-3-
methylimidazolium ibuprofenate, [OMIm][Ibu] as an active pharmaceutical ingredient ionic
liquids (API-IL) on the solvation properties of aqueous L-alanine solutions have been
investigated by thermophysical properties determination. The partial molar volume of transfer (
traV0 ), partial molar isentropic compressibility of transfer ( tra0 ), viscosity B-coefficients of
transfer (∆traB), ion association constant (KA) and molar refraction (RD) quantities have been
determined using the measured density, viscosity, speed of sound, electrical conductance and
refractive index data. The results showed that the ion-polar and polar-polar interactions between
API-ILs and L-alanine are dominant.
Keywords: 1-Octyl-3-methylimidazolium salicylate; 1-Octyl-3-methylimidazolium ibuprofenate;
Partial molar volume of transfer; Viscosity B-coefficient; Molar conductivity.
* Corresponding author. Tel.: +98-41-33393094. Fax: +98-41-33340191.
E-mail address: mirheydari_n@yahoo.com (S.N. Mirheydari).
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1. Introduction
Salicylic acid and ibuprofen are the active pharmaceutical ingredients (API) with low water
solubility which limits their therapeutic applications [1]. In the new solubility improvement
approach, the active pharmaceutical ingredient (API) are combined with the second generation
of ionic liquid (ILs) and the third generation of ionic liquids namely API-IL have been created
[2, 3]. This form of API presents the improved solubility, drug delivery, and bioavailability due
to the hydrophophilicity and hydrophobicity nature [4-7]. In recent years, Viau and Pinto et al.
[8, 9] introduced the 1-butyl-3-methylimidazolium ibuprofenate and salicylate as a new gel for
drug delivery with excellent properties [8, 9].
To design and improve the biotechnological processes, the information about the
molecular mechanism interactions existing between pharmaceutically active ionic liquid form
and biomolecules is required [10-12]. Proteins as a complicated biomolecule are composed of
the amino acid units, therefore studying of the amino acids is easier than protein [13, 14]. In this
respect, the thermophysical properties (i.e., the volumetric and transport properties) of amino
acid in the presence of API-IL give us the useful information about the solute-solvent and
solute-solute interactions.
In recent years, some authors reported the thermodynamic properties of the mixtures
containing amino acid and the first generation of ionic liquid in the aqueous media at different
temperatures [15-20]. For the first time, shekaari et al. [20-22] have examined the effect of the
active pharmaceutical ingredient in the ionic liquids form (API-ILs), 1-butyl-3-
methylimidazolium salicylate and ibuprofenate on the thermodynamic properties of the amino
acid aqueous solutions, glycine and L-alanine. Results showed that dominant interactions
between these amino acids and API-IL are the ion-polar and polar-polar interactions.
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The present work is a continuation of our systematic thermodynamic studies of ternary
systems (amino acid + API-IL + water) [20-22]. In this study, the measured density, speed of
sound, viscosity, electrical conductance and refractive index data for L-alanine in the presence of
aqueous solutions of 1-octyl-3-methylimidazolium salicylate, [OMIm][Sal] and 1-octyl-3-
methylimidazolium ibuprofenate, [OMIm][Ibu] were reported at T= 298.15 K and atmospheric
pressure. The measured data were used to compute the partial molar volume of transfer traV0
,
partial molar isentropic compressibility of transfer tra0 , viscosity B-coefficients, ion
association constants (KA) and molar refraction RD.
2. Experimental
2.1 Materials
Table 1 gives the provenance, CAS number, purity in mass fraction and analysis method of the
used materials. The double distilled deionized water was used with a specific conductivity less
than 1 μS cm-1 at 298.15 K.
2.2 Synthesis of ionic liquid
The two new API-ILs, 1-octyl-3-methylimidazolium salicylate, [OMIm][Sal] and 1-
octyl-3-methylimidazolium ibuprofenate, [OMIm][Ibu] (see the structure of API-IL in Fig. 1)
were prepared from the 1-octyl-3-methylimidazolium chloride [OMIm][Cl] and sodium
salicylate and sodium ibuprofenate, respectively. 1-octyl-3-methylimidazolium chloride was
synthesized and purified according to the standard methods reported in the references [23-27].
The water content of prepared ionic liquid, [OMIm][Cl] by Karl Fischer method was less than
1
0.05% in mass fraction. Characterization of the ionic liquid by HNMR spectroscopy showed
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good agreement as compared with the literature and confirmed the absence of any significant
impurities [26]. The purity of prepared ionic liquid was 98% in mass fraction. To synthesize the
1-octyl-3-methylimidazolium salicylate ionic liquid [OMIm][Sal], (0.4 mol) sodium salicylate
was dissolved in dried acetonitrile and added slowly to (0.4 mol) [OMIm][Cl] dissolved in a
minimum amount of dried acetonitrile. The resulting mixture was stirred at room temperature
overnight then the rotary evaporator at 350 K and then reduced pressure was used to extract the
water in the mixture. The resulting mixture was subsequently dissolved in a large amount of
dichloromethane to observe white precipitate containing sodium chloride. The white precipitate
was then filtered and this process was continued until no white solid observed with the addition
of dichloromethane [23, 25]. The silver test confirmed the lack of sodium chloride. The obtained
product (a yellowish solid) was further evaporated at 343.15 K by rotary evaporator [26]. The
procedure for synthesis of 1-octyl-3-methylimidazolium ibuprofenate, [OMIm][Ibu] is similar to
[OMIm][Ibu] and the only difference is applying the ethanol as solvent and heating at 353.15 K
for 3 h at the beginning of the reaction. The water content of the [OMIm][Sal] and [OMIm][Ibu]
determined using coulometric Karl Fischer titrator (Metrohm 756 KF) was approximately 0.1%
1
in mass fraction. The H NMR (Brucker Av-400) spectroscopy was applied to characterize the
prepared API-ILs (see Fig. S1 and S2).
2.3 Apparatus and procedure
The density d and speed of sound u of the solutions were measured by vibrating tube
densimeter, Anton Paar, DSA 5000. Distilled deionized and degassed water as well as dried air at
atmospheric pressure were applied to calibrate the instrument [28]. The temperature was kept
constant within ±10−3 K using the Peltier technique embedded in densimeter. The experimental
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uncertainty of density and speed of sound measurements were less than 0.3 kg m-3 and 0.5 ms-1,
respectively.
Anton Paar Rolling-ball viscometer Lovis 2000 M/ME was also applied to measure the
viscosity of the solutions. The Peltier technique built in the thermostat was controlled the
temperature. The calibration of capillary was performed by the manufacturer using viscosity
standard fluids. Before each experiment, the calibration of the instrument was checked by
distillated water at specific temperature. The evaluated experimental uncertainty of the viscosity
measurements was less than 0.015 mPas.
Measurement of the electrical conductivities, κ were performed by a conductivity meter
(Metrohm model 712, Switzerland) with the accuracy of ± 0.5%. The instrument was calibrated
using the measurement specific electrical conductivities of the KCl solution with 0.01 molality.
For measuring the κ values, the weighed drop of pure API-IL was added into the cell container of
the conductivity meter with 60 mL capacity which was agitating using a magnetic stirrer. The
temperature was fixed by circulation of water from thermostatically adjusted bath around the cell
with an uncertainty ± 0.02 K. The molar conductivity (Λ) values of the solutions were computed
1000
using the relation,
, where κ and c are the specific electrical conductance and the
Λ 
c
molarity of the solutions, respectively.
Refractive indices nD of the solutions were measured by a digital refractometer (ATAGO-
DRA1, Japan) with an uncertainty of ±0.002. The temperature was kept constant using a
circulating bath thermostat (Cooling Bath 490, Iran) with the thermal stability of
 0.01 K.
3. Experimental results and discussion
3.1 Volumetric properties
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To study the hydration layer volume surrounding the amino acid and existing the
interactions in the studied systems, calculation of the apparent molar volume
using the
V
measured density is an appropriate approach. So, the density d of L-alanine in the aqueous
solutions of [OMIm][Sal] (0.0974, 0.2012 and 0.2988) molkg-1 and [OMIm][Ibu] (0.1101,
0.2001 and 0.2889) molkg-1 were measured and reported in Table 2. As can be seen in this table,
the densities increase with the solute (L-alanine) as well as with the cosolute ([OMIm][Sal],
[OMIm][Ibu]) concentrations. The measured densities were used to calculate the apparent molar
volumes:






M
d
1000(d  d0 )
(1)
V 

mdd0
where m and M is the molality and molar mass of the amino acid and d0, d are the densities of the
solvent ([OMIm][Sal], [OMIm][Ibu] + water) and ternary solutions. Table 2 reports the values of
for the studied solutions. Since the amino acid and (API-IL + water) were considered as
V
solute and solvent, respectively, the
related to the amino acid was correlated using the
V
following equation:
V V0  Svm
(2)
where  is the standard partial molar volume and Sv is an experimental parameter. Table 2
V

listed the evaluated values of
and Sv accompanied with their standard deviation
(V )
V
V
derived by least squares fitting of the
values by Eq. 2. (2).

The extent of the interaction between L-alanine and [OMIm][Sal] or [OMIm][Ibu] can be
evaluated from the hydration number nH using the following equation:
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
V (elect)
 

nH 
(3)
VE VB
3
-1



where the value of (VE VB )for electrolytes at T= 298.15 K is 3.0 cm mol and
is the
V (elect)
molar volume of electrostrictive water and can be obtained by the following relation [29,30]:



V (elect ) V V (int)
(4)

where
is the intrinsic partial molar volume which originates from the hydration of the
V (int)
amino acid zwitterions. Combining of the volume from Vander-Waals and packing effects can

obtain the
term from the following relation [31]:
V (int)
0.7


(5)
V (int) 
V (cryst)
0.634
M

where
is the molar volume of the crystal which was computed using the
V (cryst) 
d (cryst)
densities of the amino acid (crystal form) supposed by Berlin and Pallansch at 298.15 K [32].
Table 3 gives the calculated nH values for the studied solutions. The nH values for L-alanine in
the aqueous solutions of [OMIm][Ibu] are less than in [OMIm][Sal] which indicate the stronger
interactions between API-IL and zwitterion forms of L-alanine. At the high concentration of
API-IL, the water molecular structure around the amino acid are disrupted and the water
molecules release to the bulk and therefore the hydration number decrease.
Another suitable parameter to determine the extent of the interactions is the partial molar
volume of transfer calculated using the relation [33]:


0
=
traV V
(API-IL + water) –
(in water)
V
(6)
The data for the binary systems, L-alanine in water used in the calculations were taken

from the earlier published data [21]. The calculated values of
for the studied solutions
traV
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given in Table 3 are positive and increase with an increase in the APIL concentrations. The

observed positive values
indicate the strong ion–zwitterion interactions between API-IL
traV
and L-alanine. According to the co-sphere overlap model, the contribution of solute-solute
interactions is negligible and hence the information about the solute-solvent interactions is
obtained. The types of the interactions between L-alanine and API-ILs can be categorized as: (i)
ion–polar interactions (ii) polar-polar interactions (iii) ion–nonpolar interactions and (iv)
nonpolar-nonpolar interactions. Based on the co-sphere overlap model, the ion–nonpolar and

nonpolar–nonpolar interactions have a negative effect contribution on the
values while
traV
the effective contribution of the ion–polar and polar-polar interactions are positive. The

obtained
values presented in Table 4 and Fig. 2 for [OMIm][Ibu] are greater than
traV
[OMIm][Ibu] and increase with the API-IL concentration increment. This phenomenon suggests
the stronger interactions between the zwitterionic center of L-alanine and the ions of
[OMIm][Sal] and [OMIm][Ibu] which result in a decrease in the solvation layer volume [34].
3.2 Ultrasonic properties
Table 2 reports the measured speed of sound values for the studied solutions (L-alanine
s (Pa1)
+ [OMIm][Sal], [OMIm][Ibu] + water). The isentropic compressibility
was calculated
using the Laplace–Newton's equation as follows;
1
s 
(7)
du2
The following equation was used to calculate the apparent molar isentropic
compressibility
bulk;
for understanding the solvent structure around the amino acid as well as in

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(sd0 s0d)
M
d
 
s
(8)
mdd0
where κs0 and κs are the isentropic compressibility of the solvent (aqueous solutions of
[OMIm][Sal] and [OMIm][Ibu]) and ternary solutions (L-alanine in the aqueous solutions of
[OMIm][Sal] and [OMIm][Ibu]), respectively and definition of the other parameters are same as
V
for the  . The obtained
values for the studied solutions were presented in Table 3. The

apparent molar isentropic compressibility of L-alanine in the solutions of ([OMIm][Sal],
[OMIm][Ibu] + water) with 0.3 molality at T= 298.15 K was presented in Fig. 3. As can be seen
from Table 3 and Fig. 3, the
values increase with an increase in the [OMIm][Sal] and

[OMIm][Ibu] concentrations which means the increase in the API-IL-amino acid interactions and
release of the water molecules from the solvation layer to the bulk.
0
The partial apparent molar isentropic compressibility
value can be calculated from
the extrapolation of the apparent molar isentropic compressibility
the following linear equation:
to an infinite dilution using


   Skm
(9)
where Sk , m are the experimental slope and the molality of L-alanine in the solutions,
respectively. The obtained Sk values for the studied solutions accompanied with the
are given in Table 4. As shown in Table 4, the values increase
0
,
0
standard deviation
( )
with increase in API-IL concentrations. This phenomenon suggest the strong interactions
between API-ILs and L-alanine which result in the formation of more compressible solvation
layer [35, 36].
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The partial molar isentropic compressibility of transfer tra0 from water to the aqueous
solutions of [OMIm][Sal] and [OMIm][Ibu] was calculated using the following relation:



(10)
tra   (aqueous API IL)  (water)
Table 4 represents the obtained tra0 values for investigated solutions which increase
with the API-IL concentration. The positive values of the tra0 declare the dominance of the
+
ion-polar and polar-polar interactions between the head charged groups (NH3 and COO–) of L-
alanine and the ions of [OMIm][Sal] and [OMIm][Ibu] which they are more favorable at the high
concentration of API-IL [36].
3.3 Pair and triplet interaction coefficients
McMillan and Mayer [35] theory developed by Friedman and Krishnan, [37] offered a
simple method for calculation of the interaction coefficients between two or more solute
molecules. In this regard, the two following relations were applied to evaluate the partial molar
volume of transfer and partial molar isentropic compressibility of transfer:

traV  2VAB m  3VABB m2
(11)
(12)

tra  2ABm  3ABBm2
where A denotes amino acid, B denotes [OMIm][Sal] and [OMIm][Ibu] and mB is the molality of
L-alanine in the aqueous solutions of API-IL. The pair and triplet interaction coefficients express
the corresponding parameters VAB, VABB for volume and, κAB, κABB for compressibility. These
evaluated pair interaction coefficients VAB and κAB are positive, while triplet interaction
coefficients VABB and κABB are negative for the studied systems (see Table 3). The positive values
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of VAB and κAB predict that the frequent interactions between API-IL and L-alanine in the
solutions are mostly pairwise [38].
3.4 Viscometric properties
The measured viscosities η of (L-alanine + [OMIm][Sal] water) and (L-alanine +
[OMIm][Ibu] + water) with several modalities of ([OMIm][Sal] + water) and ([OMIm][Ibu] +
water) were presented in Table 2. Viscosity B-coefficients is one of the other parameters which
are used to study the solute-solvent interactions. Jones-Dole equation represents the variation of

the relative viscosity r 
of the amino acid in the aqueous solutions of API-IL [39]
0
r 1 Ac1/2  Bc
(13)
The A-coefficient (also called Falkenhagen coefficient, indicating the solute-solute
interactions) can be theoretically calculated but are usually small (negligible for nonelectrolytes).
The viscosity B-coefficients essentially illustrate the solute-solvent interactions. In fact, by
neglecting the A-coefficient in Eq. (14), it is simplified to the following equation:
(14)
where in Eq. (14) η and η0 are the viscosity of the solutions (L-alanine in the aqueous solution of
[OMIm][Sal] and [OMIm][Ibu]) and solvents ([OMIm][Sal] + water) and ([OMIm][Ibu] +
water), respectively, c is the molar concentration of L-alanine in the studied solutions. The slope
( -1)
of the linear plot of
vs. c using the least square method was used to calculate the viscosity
r
B-coefficients. Table 3 listed the calculated viscosity B-coefficients and () of the studied
solutions. The size, shape, structure and charge of solute molecules originated from the solute-
solvent interactions effect on the viscosity B-coefficient values [40]. The high positive values of
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the viscosity B-coefficients in the [OMIm][Ibu] solution compared to [OMIm][Sal] is illustrative
of the greater kosmotropic effect of [OMIm][Ibu] on the solution [40]
The following relation presents the variation of B-coefficients traB from water to the
aqueous [OMIm][Sal] and [OMIm][Ibu] solutions:
traB = B-coefficients in (API-IL + water) – B-coefficients (in water)
(15)
The viscosity B-coefficients of L-alanine in the API-IL solutions are higher than in water
and therefore the traB values are positive and increase with an increase in the API-IL
concentration. The presented traB values of L-alanine in the solutions of ([OMIm][Sal],
[OMIm][Ibu] + water) in Fig. 4. are higher for [OMIm][Ibu]. It can be interpreted as the stronger
interaction between [OMIm][Ibu] and zwitterions of L-alanine rather than [OMIm][Sal].
Feakins and co-worker analyze the viscosity data basis on the transition state treatment of
relative viscosity. The following relation gives the viscosity B-coefficient regarding this theory:
2  1



(16)
B  (V1 V 2 ) V1 (
)
RT
xiMi
0
0
(V 0 
)
where
is the mean volume of the solvent and
is the standard partial
(V2 V )

1

molar volume of the pure solute. The terms 0 , xi, Mi and d are the molar volume of the pure
V
1
solvent, mole fraction, molar masses and density of the solvent ([OMIm][Sal] + water) and
([OMIm][Ibu] + water), respectively. Eyring's simple model was used for calculation of the free
≠
energy of activation per mole of the solvent
and ≠as follow:
1
2

1V


1
1  G1  RT ln
(17)
(18)
hNA
RT


 
[B (V V2 )]
2  1 
1

V
1
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where h is the Planck’s constant, NA is the Avogadro number, is the viscosity of the solvent

and the other symbols have their usual meanings. Table 3 presents the calculated values of 1



and 2 . It is clear that the values of 2 are positive and more significant than 1 for
both API-IL solutions which indicate the stronger interactions between solute (L-alanine) and
solvents ([OMIm][Sal] + water) and ([OMIm][Ibu] + water) in the ground state compared to the

transition state. The values of 2 increase with an increase in the concentration of API-IL
solutions up to 0.3 molkg−1. The higher values of 2 for L-alanine in the [OMIm][Ibu]

solutions suggests that the transfer from ground state to the transition state requires more energy
than in [OMIm][Sal] [40, 41].
3.5 Conductometric properties
Another appropriate way to interpret the possible ions interactions is the molar
conductivity and ion association of API-IL. In this respect, the molar conductivity data for
[OMIm][Sal] and [OMIm][Ibu] in the aqueous solution of L-alanine were determined. The
values of molar conductivity,  for [OMIm][Sal] and [OMIm][Ibu] in water and in the aqueous
1000
solutions of the L-alanine were computed using
(see Table 4). The molar conductivity
 
C
of [OMIm][Sal] and [OMIm][Ibu] in the aqueous solutions of L-alanine with 0.5 molality was
plotted in Fig. 5. As can be seen from this table 4 and Fig. 5, the values of Λ decrease by the
API-IL concentration increment due to ionic atmosphere effects. In fact, in more concentrated
solutions, the ion pairing is responsible for the observed decrease in molar conductivities. The
Onsager model was used to estimate the initial guess of limiting molar conductivity
Λ0 and ion
KA
association constant
for the low concentration Chemical Model (lcCM) to calculate the real
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KA
Λ0 and
of the API-ILs in the studied solutions. The following set equations present the lcCM
model:
  [0  S(c)1/2  Ec ln(c)  J1c  J2 (c)3/2 ]
(19)
1
KA 
(20)
(21)
(22)
2c2
 q
ln  
1R
16000NAz2e2c
 2 
0 KBT
z ze2
q 
(23)
8 0 kT
in which, Λ0 is the molar conductivity at infinite dilution, (1-α) is the fraction of oppositely
charged ions acting as ion pairs, γ± is the corresponding mean activity coefficient of the free ions,
κ is the Debye parameter, e is the electronic charge, z is the ionic charge, 0 is the permittivity of

vacuum,
is the dielectric constant of the solvent, and the other symbols have their usual
meanings. The required coefficients E, J1, and J2 for calculations were taken from the literature
[42]. The parameter R represents the center-to-center distance between the ions in the formed ion
pairs in the solutions. The evaluated Λ0, KA and R for the studied API-ILs in water and the
aqueous L-alanine solutions were listed in Table 5. From this table, the values of Λ0 decrease
with an increase in the L-alanine concentration which indicates the low mobility of the solvated
+
ions by (COO− /NH3 ) zwitterionic centers with large radii and increase the viscosity of medium
with the addition of L-alanine. The lower values of Λ and Λ0 in the solutions of [OMIm][Ibu]
+
relative to [OMIm][Sal] indicate the more ion solvation of [OMIm][Ibu] by (COO− /NH3 )
zwitterions centers of L-alanine [22]. Moreover the KA values of the API-IL decrease with L-
14

ACCEPTED MANUSCRIPT
alanine concentration which relate to the strong interaction of ions with zwitterions and reduced
the ion-pair formation in the concentrated solutions. The lower values of KA in the solutions of
[OMIm][Ibu] compared to [OMIm][Sal] may be indicative of the stronger interactions between
+
(COO− /NH3 ) of zwitterions and ions of [OMIm][Ibu].
The parameter R represents the maximum center-to-center distance between the ions or
separated ion pairs in the solvent. The values of the distance parameter (R) have no meaningful
trend [43, 44].
To eliminate the effect of viscosity on the ionic mobility, the Walden product was
calculated. As the conductivity of the ions at infinite dilution only depends on their mobility, the
product of the viscosity of the solvent by the ion conductivity is independent of the solvent
nature [45]. The smaller Λ0η0 values in L-alanine solutions may be attributed to the large
effective radius of ions (due to the high association of API-IL). Table 5 represents the calculated
Walden product (Λ0η0) of the [BMIm][Sal] and [BMIm][Ibu] in the L-alanine solution.
The standard deviations of the experimental molar conductivities (Λ) and the calculated
ones (Λcal) were computed as follows:
1
2
(Λ Λ )2




cal
 (Λ) 
(24)
n  p




where n and p show the number of experimental data and parameters, respectively. Table 5 lists
the calculated standard deviations of electrical conductivity using lcCM model.
3.6 Diffusion Coefficients Walden products of ions
The diffusion coefficients of the API-ILs at infinite dilution were calculated using their
molar conductivities by the Nernst–Haskell equation [46] as follows:
15

ACCEPTED MANUSCRIPT
RT
0 0
F2 z z 0  0
z z

(25)
DAB

is the diffusion coefficient of API-IL (A) in water (B) at infinite dilution in m2 s-1, F is
DA0B
where
the Faraday’s constant, z+ and z- are the charge numbers of the cation and anion,
and λ0 is the
0
limiting molar conductivities of the cation and anion in S m2 mol-1, respectively. Table 5 presents
the calculated DA0B values of [OMIm][Sal] and [OMIm][Ibu] in water. The following relation
determines the ionic limiting molar conductivity values of the individual ions:
0  z 0  z 0
(26)
in water for [OMIm]+ was obtained from

The ionic limiting molar conductivity of the
0
literature [45]. Subsequently, Eq. (27) was used to calculate the limiting molar conductivity of

the (see in Table 5).
0
The diffusion coefficient [47,48] of the individual ions are calculated by the following
relation:
RT0
zion F 2

Dion 
(27)
Di0on
Table 6 lists the obtained values of the diffusion coefficient
and limiting molar
Di0on
and 0 of the cation in [OMIm][Sal] are lower than the
conductivity

0 of the ions. The
anion while this trend is vice versa for the [OMIm][Ibu] which is related to the low mobility o
ibuprofenate anion rather than salicylate.
D0
The
and η values of the pure water were used to evaluate the Stoke's radius (rs) or
ion
effective hydrodynamic radius of the ions which is closely related to solute mobility and affected
by not only size but also the solvent.
16

ACCEPTED MANUSCRIPT
kT
6Di0on
r 
(28)
s
The calculated values of rs for the ions are collected in Table 5. The Walden Product [49]
has been obtained from the following relation:
k zion F2
0 
(29)
6Rrs
Where rs is obtained by Eq. (28). As all other terms of Eq. (29) are constants, Walden
Product (0 ) vary if rs changes. This equation reveals that there is an inverse relationship
between the effective hydrodynamic radius of an ion and its Walden product ( 0 ).
The ion transport number called the transference number is the contribution of an ion to the
total molar conductivity of the solution. This parameter can be determined according to the
following relation:
λ0
t± =
(30)
Λ0
The symbols t+ and t- are usually used to express the transport numbers of cation and anion,
respectively. Table 6 gives the calculated values of t+ and t-.

The standard Gibbs free energy ( GA ) of the ion-association process was obtained using

the ion association constants. Tables 5 presents the calculated values of the GA value for the
ion association process of API-IL in water and L-alanine solutions which exhibit the negative


values of GA . The large negative values of the GA for the [OMIm][Sal] solutions indicates
the more spontaneously and feasibility of the ion association process in this API-IL compared to
[OMIm][Ibu].
17

ACCEPTED MANUSCRIPT
3.7 Refractometric properties
Experimental refractive index data
nD
for (L-alanine + [OMIm][Sal], [OMIm][Ibu] +
water) with several molality of ([OMIm][Sal] + water) and ([OMIm][Ibu] + water) are reported
in Table 2. The molar refraction RD is calculated using Lorentz-Lorentz equation [46]:
3






nD 1
nD2  2
xi M
d



i 
(31)
RD 

i1


where xi, Mi and d are the mole fraction and molar mass of components and density of the
solutions, respectively. Table 2 reports the calculated molar refractions of the investigated
solutions. Moreover, Fig.6 presents the molar refraction of ternary (L-alanine + [OMIm][Sal],
[OMIm][Ibu] + water). As observed in Table 2, the RD values increase with an increase in the
API-IL concentration. As the molecule structure is more complicated, the electron cloud
becomes more distributed, and the polarizability of the molecule is intensified.
5. Conclusion
The effect of two active pharmaceutical ingredient based ionic liquids (API-IL), 1-octyl-3-
methylimidazolium salicylate ([OMIM][Sal]) and 1-octyl-3-methylimidazolium ibuprofenate
([OMIm][Ibu]) on the volumetric, compressibility, viscometric, electrical conductivity and
refractometric properties of L-alanine have been studied at T= 298.15 K. The positive values of
partial molar volumes of transfer traV0 , partial molar isentropic compressibilities of transfer

and viscosity B-coefficients of transfer indicate that the ion–polar and polar-polar
tra
interactions between L-alanine and API-ILs are dominant and according to the VAB and κAB
≠
values the pairwise interactions are more preferred. The more significant values of
for
2
[OMIm][Ibu] than [OMIm][Sal] show the more effective structure making ability of L-alanine in
18

ACCEPTED MANUSCRIPT
this API-IL which strengthens with the addition of the API-IL. The low concentration Chemical
Model (lcCM) model was used to evaluate the ion association constant (KA), limiting molar
Λ
conductivity ( Λ0 ) and distance parameter (R). The lower values of  with the addition of L-
alanine to the aqueous [OMIm][Sal] and [OMIm][Ibu] solutions indicate the low mobility of the
+
solvated ions by (COO− /NH3 ) zwitterionic centers with large radii and increase in the viscosity
of the medium. From the thermodynamic data analysis, the more negative values of GA0 for
[OMIm][Sal] in the L-alanine solutions compared to the [OMIm][Ibu] solutions suggest the more
spontaneously of the ion association process of this API-IL.
Acknowledgment
The authors wish to thank financial support from the graduate council of the University of
Tabriz.
19

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Table 1
A sample description of the used chemicals.
Chemical name
L-Alanine
CAS No.
56-41-7
Supplier
Merck
Initial Mass
Fraction
Purity
Purification
Method
Final Mass
Fraction
Purity
-
Analysis
Method
>0.99
None
-
[OMIm][Sal]
[OMIm][Ibu]
This work Synthesized
This work Synthesized
-
-
Rotary/
evaporator
and vacuum
>0.97
>0.97
1HNMR
1HNMR
Rotary/
evaporator
and vacuum
N-methylimidazole
1-Chlorooctae
Sodium salicylate
Sodium ibuprofen
Ethyl acetate
7-47-616
111-85-3
54-21-7
Merck
Merck
Merck
>0.99
0.99
≥0.995
≥0.98
None
None
None
None
-
-
-
-
-
-
-
-
-
-
-
-
31121-93-4
Sigma Aldrich
Merck
6-78-14
75-09-2
>0.998
≥0.999
None
None
Dichloromethane
Fluka
25

ACCEPTED MANUSCRIPT
V
Table 2. The values of density (d), apparent molar volume ( φ ), speed of sound (u), apparent molar isentropic
κ
compressibility (
) viscosity (η), refractive index (n ) and molar refraction (R ) of L-alanine in the aqueous
D D
φ
solutions of [OMIm][Sal] and [OMIm][Ibu] at T = 298.15 K and 0.0868 MPa.a
b m/
10-3d/
kgm-3
η/
mPas
nD
106 RD /
m3mol-1
1014
/
106 V/

m3mol-1Pa-1
u /
molkg-1
m3mol-1
ms-1
L-alanine in mAPI-IL ([OMIm][Sal] + water)
mAPI-IL= 0.0974 molkg-1
0.0000
0.0993
0.1493
0.1974
0.2527
0.2960
0.3383
0.3978
0.4461
1.000224
1.003019
1.004415
1.005754
1.007286
1.008476
1.009632
1.011254
1.012565
1506.38
1512.76
1515.97
1519.02
1522.52
1525.25
1527.85
1531.53
1534.59
1.154
1.3386
1.3401
1.3408
1.3415
1.3423
1.3429
1.3435
1.3443
1.3450
3.876
3.912
3.927
3.942
3.960
3.973
3.986
4.004
4.020
60.77
60.75
60.73
60.71
60.71
60.70
60.69
60.67
-2.31
-2.31
-2.29
-2.27
-2.26
-2.24
-2.22
-2.21
1.187
1.204
1.219
1.237
1.249
1.264
1.282
1.298
mAPI-IL= 0.2012 molkg-1
0.0000
0.0993
0.1493
0.1974
0.2527
0.2960
0.3383
0.3978
0.4461
1.004246
1.006984
1.008349
1.009657
1.011154
1.012318
1.013448
1.015032
1.016309
1514.88
1.386
1.428
1.449
1.468
1.493
1.511
1.529
1.557
1.578
1.3440
1.3454
1.3462
1.3469
1.3477
1.3483
1.3489
1.3498
1.3504
4.034
4.082
4.099
4.115
4.133
4.147
4.161
4.181
4.195
61.21
61.21
61.20
61.19
61.19
61.18
61.17
61.17
1521.10
1524.22
1527.20
1530.64
1533.36
1535.95
1539.62
1542.63
-2.10
-2.09
-2.07
-2.06
-2.06
-2.05
-2.04
-2.03
mAPI-IL= 0.2980 molkg-1
0.0000
0.0985
0.1512
0.1970
0.2537
0.2857
0.3493
0.3852
0.4408
1.008029
1.010725
1.012157
1.013395
1.014917
1.015773
1.017464
1.018413
1.019877
1522.25
1.568
1.620
1.648
1.675
1.706
1.725
1.763
1.785
1.815
1.3488
1.3503
1.3512
1.3519
1.3529
1.3534
1.3545
1.3551
1.3560
4.189
4.262
4.281
4.297
4.318
4.329
4.353
4.366
4.385
61.27
61.26
61.25
61.24
61.24
61.23
61.22
61.21
1528.38
1531.66
1534.51
1538.02
1540.02
1543.96
1546.18
1549.58
-2.00
-1.99
-1.99
-1.98
-1.98
-1.97
-1.96
-1.95
L-alanine in mAPI-IL ([OMIm][Ibu] + water)
mAPI-IL= 0.1101 molkg-1
1505.96
1511.99
1515.18
1518.92
1523.56
1528.40
1531.73
1535.53
1.429
1.3408
1.3423
1.3432
1.3442
1.3453
1.3464
1.3472
1.3481
4.939
3.978
3.996
4.016
4.039
4.062
4.078
4.096
0.0000
0.0988
0.1493
0.2057
0.2728
0.3403
0.3854
0.4378
0.997665
1.000421
1.001808
1.003343
1.005147
1.006947
1.008131
1.009511
1.479
1.507
1.539
1.576
1.615
1.644
1.677
61.12
61.17
61.22
61.28
61.33
61.37
61.39
-2.12
-2.15
-2.21
-2.29
-2.35
-2.39
-2.42
mAPI-IL= 0.2001 molkg-1
1512.36
1.832
1.3465
4.132
0.0000
0.998173
26

ACCEPTED MANUSCRIPT
1517.81
1520.67
1523.94
1527.14
1529.87
1533.16
1536.51
1.911
1.951
1.999
2.041
2.079
2.117
2.157
2.202
61.35
61.34
61.33
61.33
61.33
61.32
61.31
61.33
-1.77
-1.83
-1.88
-1.93
-1.96
-2.01
-2.05
1.3487
1.3498
1.3510
1.3521
1.3530
1.3541
1.3552
4.197
4.217
4.240
4.261
4.278
4.299
4.320
0.0974
0.1458
0.1999
0.2509
0.2935
0.3434
0.3939
0.4472
1.000864
1.002192
1.003666
1.005048
1.006196
1.007532
1.008880
1.010342
mAPI-IL= 0.2889 molkg-1
1518.22
2.241
2.353
2.397
2.457
2.507
2.571
2.652
2.733
1.3517
1.3529
1.3534
1.3541
1.3548
1.3555
1.3565
1.3575
4.332
4.429
4.445
4.467
4.488
4.509
4.540
4.570
0.0000
0.1012
0.1406
0.1952
0.2476
0.3016
0.3779
0.4511
0.998651
1.001375
1.002434
1.003903
1.005305
1.006744
1.008759
1.010698
1523.74
1525.98
1529.15
1532.23
1535.52
1540.36
1545.08
62.06
62.00
61.91
61.85
61.81
61.77
61.69
-1.60
-1.64
-1.69
-1.72
-1.76
-1.83
-1.88
a Standard uncertainties u are, u (T) = 0.01 K, u (d) = 0.3 kg m-3, speed of sound u (u) = 0.5, u ( ) = 0.015
mPa.s, u (nD) = 0.002 and u(P) = 0.01 MPa. The estimated uncertainty are, uc (V ) = 0.05∙10-6 m3.mol-1, uc
(
) = 0.02∙10-14 m3mol-1.Pa-1 and uc (RD) = 0.003.
b Relative standard uncertainties ur for molalities of API-IL and amino acids are ur (mAPI-IL) = 0.02 and ur
(m) = 0.005, respectively, where mAPI-IL is the molal concentration of API-IL in water.
27

ACCEPTED MANUSCRIPT

Table 3. The values of standard apparent molar volume (V , experimental slope (Sv), standard deviation (σ (V)),

transfer volume (∆traV , hydration number (nH), pair (VAB) and triplet (VABB) interaction coefficients, partial

apparent molar isentropic compressibility (κ ) the experimental slope (Sκ), standard deviation (σ(κ)), partial molar

isentropic compressibility of transfer (∆traκ ), pair (κAB) and triplet (κABB) interaction coefficients, viscosity B-
coefficient (B), free energy of activation per mole of solvent (∆μ1#) and the solute (∆μ2#), viscosity B-coefficients of
transfer (∆traB), of L-alanine in the aqueous solutions of [OMIm][Sal] and [OMIm][Ibu] at T = 298.15 K and 0.0868
MPa.
L-Alanine in mAPI-IL ([OMIm][Sal] + water)
L-Alanine in mAPI-IL ([OMIm][Ibu] + water)
a mAPI-IL / molkg-1
106 V /m3mol-1
106 S v / m3mol-2kg
106 σ( V)
0.0974
60.79 ± 0.008
-0.27 ± 0.023
0.01
0.2012
61.23 ± 0.001
-0.14 ± 0.004
0.01
0.2980
61.29 ± 0.001
-0.18 ± 0.003
0.01
0.1101
61.05 ± 0.011
0.82 ± 0.039
0.01
0.2001
61.36 ± 0.003
-0.11 ± 0.009
0.01
0.2889
62.13 ± 0.023
-1.02 ± 0.082
0.03


106 ∆traV / m3mol-1
0.82
3.32
1.26
3.19
5.10
1.32
3.17
1.08
3.24
1.39
3.15
4.50
2.16
2.91
nH
106 VAB/ m3mol-2kg
106 VABB/ m3mol-3kg2
-6.48
-1.99

1014 κ /m3mol-1Pa-1
-2.35 ± 0.01
0.31 ± 0.02
-2.11 ± 0.00
-2.01 ± 0.00
0.14 ± 0.01
-2.02 ± 0.01
-0.95 ± 0.04
-1.70 ± 0.02
-1.53 ± 0.01
-0.79 ± 0.02
1014 Sκ /m3mol-2kgPa-1
1014 σ( κ)
0.19 ± 0.01
0.01
-0.85 ± 0.06
0.01
0.01
0.31
0.01
0.64
0.01
0.63
0.01
1.13
1014 ∆traκ / m3mol-1Pa-1

0.54
1.86
3.40
0.95
-1.75
-3.34
1014 κAB/m3mol-2kgPa-1
1014 κABB/ m3mol-3kg2Pa-1
B/ dm3mol-1
0.281 ± 0.002
0.306 ± 0.003
0.351 ± 0.003
0.386 ± 0.005
0.454 ± 0.003
0.483 ± 0.004
∆μ1#/ kJmol-1
∆μ2#/ kJmol-1
∆tra B/ dm3mol-1
9.88
52.99
0.024
10.40
49.95
0.049
10.77
60.67
0.094
10.43
67.26
0.129
11.14
74.53
0.197
11.69
77.25
0.226
28

ACCEPTED MANUSCRIPT
Table 4. The values of molar electrical conductivity (Λ) of the API-ILs, [OMIm][Sal] and [OMIm][Ibu]
in water and in the aqueous solutions of L-alanine as a function of API-IL concentration at T = 298.15 K
and 0.0868 MPaa.
b c /
104 Λ/
Sm2mol-1
104 Λ/
Sm2mol-1
104 Λ/
Sm2mol-1
104 Λ/
Sm2mol-1
/
/
/
c
c
c
molm-3
molm-3
molm-3
molm-3
[OMIm][Sal]
mAla = 0.1 molkg-1 mAla = 0.3 molkg-1
mAla = 0.0 molkg-1c
mAla = 0.5 molkg-1
0.0599
0.1239
0.1829
0.2435
0.3078
0.3746
0.4537
0.5388
0.6319
0.7107
0.7727
0.8601
0.9267
1.0003
1.0722
1.1517
67.46
0.0851
0.1474
0.2229
0.2993
0.3649
0.4443
0.5249
0.6088
0.6951
0.7762
0.8569
0.9547
1.0350
63.91
63.34
62.67
62.04
61.47
60.98
60.38
59.92
59.37
58.90
58.51
57.98
57.59
0.1015
0.1719
0.2541
0.3413
0.4464
0.5414
0.6465
0.7479
0.8262
0.9028
0.9943
1.0366
60.73
60.00
59.12
58.36
57.58
56.89
56.18
55.57
55.10
54.72
54.36
54.11
0.0913
0.1389
0.217
57.55
57.23
56.82
56.36
56.10
55.62
55.23
54.79
54.35
53.99
53.53
53.10
52.73
52.32
51.95
51.54
66.56
65.61
64.85
64.05
63.50
62.96
62.40
61.85
61.22
60.89
60.33
59.95
59.55
59.15
58.93
0.2848
0.3612
0.452
0.5459
0.6279
0.7177
0.7901
0.892
0.9935
1.0818
1.1890
1.2918
1.4116
[OMIm][Ibu]
mAla = 0.1 molkg-1 mAla = 0.3 molkg-1
mAla = 0.0 molkg-1c
mAla = 0.5 molkg-1
0.1194
0.1867
0.2455
0.3199
0.3832
0.4442
0.4996
0.5433
0.6031
0.6488
0.7089
0.7525
0.8156
0.8731
45.85
0.1176
0.1819
0.2358
0.2907
0.3475
0.4026
0.4608
0.5209
0.5697
0.6173
0.6669
0.7989
0.8471
0.9009
43.93
43.64
43.38
43.16
42.98
42.83
42.56
42.45
42.24
42.07
41.90
41.40
41.31
41.16
0.1044
0.1581
0.2171
0.2681
0.3640
0.4363
0.4983
0.5655
0.6360
0.7114
0.7618
0.8414
39.85
39.48
39.20
38.95
38.61
38.36
38.13
37.88
37.68
37.50
37.39
37.23
0.1285
36.78
36.32
36.10
35.85
35.61
35.36
35.15
35.01
34.78
34.60
34.40
33.93
45.31
44.98
44.45
44.01
43.70
43.47
43.16
42.80
42.45
42.16
41.89
41.55
41.36
0.2252
0.2772
0.3305
0.3886
0.4568
0.5032
0.5455
0.5975
0.6427
0.7024
0.8262
a Standard uncertainties u are, u (Λ) = 3×10 -6 S m2 mol-1 and u (T)= 0.01 K.
b Relative standard uncertainties ur for molarities of AP-IL is ur (c) = 0.004.
c mAla is the molal concentration of L-alanine in water.
29