H. Shekaari et al. / Journal of Molecular Liquids 209 (2015) 138–148
139
point of view but it also provides a better understanding of the mecha-
nisms involved when using these new media. For example, volumetric
and acoustic properties are powerful tools to study drugs behavior in
ionic liquid solutions and were used to provide information on solute–
solvent and solute–solvent interactions in the mixtures [22]. Viscometric
properties of drug molecules have also important implications for the
permeations of drug molecules through biological membrane [23]. The
thermodynamic properties of drug in solvent can also provide important
information in determining the appropriate solvent in the pharmaceuti-
cal industry; consequently many thermodynamic studies have been
done on the systems including drug and solvent by Iqbal et al. in some
organic solvents such as DMSO, THF, MeCN and alcohols [10,23–26].
Poor solubility of drugs in water can dramatically reduce their
bioavailability. For example, aspirin, discovered in 1853 [27], is one of
the most prominent and widely used pharmaceuticals with an incredible
spectrum of properties, but it is only sparingly soluble in water (0.33 g in
100 mL) or in the acidic environment of the stomach, leading to undis-
solved particles sticking to the gastrointestinal mucosa and resulting in
topical irritation and gastric distress [28,29]. Different strategies using
ILs have been studied to help overcome this problem. As previously men-
tioned, poorly water soluble drugs such as albendazole and danazol
groups could be readily dissolved in [Bmim][PF6] [30], and the solubility
could be enhanced by the inclusion of another IL, such as [Hmim]Br. This
showed that the usefulness of ILs as solvents can be improved by modu-
lating their aqueous miscibility through the addition of a second IL [31].
In another study, effect of alkyl chain length on the solubility of ibuprofen
and paracetamol has been investigated. Results show that the solubility
increases with increasing chain length, so the solubility of paracetamol
and ibuprofen in [HMIm]PF6 is higher than [BMIm]PF6 [32].
Merck. A sample description of the chemicals is provided in Table 1.
All purities are given in mass percentage. During the course of the ex-
periments, the purity of acetonitrile was checked by density, viscosity
and refractive index measurements. The physical properties of acetoni-
trile and 1-hexyl-3-methylimidazolum bromide are listed in Table 2.
The measured values were in agreement with those reported in the lit-
erature values at the experimental temperatures [33–46].
2.2. Synthesis of ionic liquid
1-Hexyl-3-methylimidazolium bromide ([HMIm]Br) in acetonitrile
was prepared and purified by using the procedure explained in liter-
ature [47,48]. Briefly, [HMIm]Br was synthesized by direct alkylation
of N-methylimidazole with an excess of 1-bromohexane in a round
bottom flask at T = 298.15 K for 36 h under a nitrogen atmosphere.
The crude product was filtered and then washed three times with
fresh 30 ml ethyl acetate each time. The removal of residual reagents
ethyl acetate compounds in the ionic liquid was performed at about
T = 333 K using a rotary evaporator for at least 4 h under reduced pres-
sure. The ionic liquid has no major impurity verified by 1H NMR spec-
trum. This ionic liquid was used after vacuum desiccation for at least
24 h to remove trace amount of moisture. Water content found in the
ionic liquid by Karl Fischer method using a Karl Fischer titrator (751
GPD Titrino-Metrohm, Herisau, Switzerland) was less than 0.12%.
Ionic liquid was analyzed by 1H NMR (Brucker Av-300) and FTIR
(PerkinElmer, Spectrum RXI) to confirm the absence of any major im-
purities which found to be in good agreement with those reported in lit-
erature [49,50].
Therefore, in the present work the density, speed of sound, viscosity
and refractive index data of aspirin as a drug model (solute) in the pres-
ence of ionic liquid (1-hexyl-3-methylimidazolium bromide) [HMIm]Br
(co-solute) in acetonitrile solutions (MeCN) at different temperatures
T=(288.15, 298.15, 308.15 and 318.15) K and at atmospheric pressure
have been measured. The apparent molar volume, standard partial
molar volume and transfer volume have been calculated using density
data. Also, the apparent molar isentropic compressibilities have been
computed from the experimental speed of sound data. The viscosity B-
coefficients were calculated using the Jones-Dole equation.The mea-
sured experimental refractive index data for the studied solutions
were used to calculate molar refraction. All these parameters were
used to interpret the solute–solute and solute–solvent interactions
and effect of temperature on the solvation properties of ASA in the pres-
ence of ionic liquid.
2.3. Apparatus and procedure
The solutions were prepared in glass vials and in molal base con-
centration by weighing using an analytical balance (AND, GR202, Japan)
with an uncertainty 1 · 10−8 kg and closed tightly with parafilm.
The uncertainty for molalities of the solutions is less than
2 · 10−4 mol·kg−1. The sample density d and speed of sound u were
measured with a vibrating tube densimeter (Anton Paar, DSA 5000
densimeter and speed of sound analyzer, Austria). The apparatus was cal-
ibrated with doubly distilled deionized and degassed water and dry air at
atmospheric pressure. Density and speed of sound is extremely sensitive
to temperature, so it was kept constant within 1.0 · 10−3 K using the
Peltier technique built in densimeter. In each measurement, the precision
of density and speed of sound were 0.3 · 10−3 kg.m−3 and 0.01 m.s−1
respectively.
The viscosities were measured using an Ubbelohde-type viscometer,
,
which has a flow time of about 200 s for water at 298.15 K. The visco-
meter was calibrated with doubly distilled deionized water. Viscosity
of solutions η is obtained by the following Eq. (1):
2. Experimental
2.1. Materials
η
ρ
K
t
¼ Lt−
ð1Þ
The chemicals used in this work were aspirin, 1-bromohexane,
acetonitrile, ethyl acetate, and N-methylimidazole were obtained from
where ρ is the density, t is the flow time of the solution, L and K are the
viscometer constants [51]. A digital stopwatch with a resolution of
0.01 s has been used for the measurement of flow time. The evaluated
uncertainty of the experimental viscosity was 0.005 mPa·s.
Refractive indices (nD) of the studied solutions were determined
using a digital refractometer (ATAGO-DRA1, Japan) with an uncertainty
of 1 · 10−4. The instrument was calibrated with doubly distilled
water before each series of measurements. A procedure called “zero
setting” was always performed before the actual measurements of the
sample's refractive index, to ensure that the refractometer is working
properly. Calibration was made with pure liquids of known refractive
index such as hexane. The temperature was controlled using a circulat-
ing bath thermostat (Julabo NP, Germany) with a thermal stability
of 0.01 K.
Table 1
A sample description of the used chemicals.
Chemical name
CAS number Mass percentage
purity
Purification
method
Analysis
method
Aspirin
Acetonitrile
[HMIm]Br
50-78-2
75-05-8
Synthetic
GR N 0.998
GR N 99.99
N99.88
–
–
–
–
Extraction
and
distillation
Karl
Fischer
titration
and 1H
NMR
–
N-methylimidazole 616-47-7
1-Bromohexane
Ethyl acetate
N0.99
N0.98
N0.998
–
–
–
111-25-1
141-78-6
–
–