Design and synthesis of alverine-based ionic liquids to improve drug water solubility

Article abstract of DOI:10.1039/d0nj05216g

Alverine [3-phenyl-N-(3-phenylpropyl)-N-ethylpropan-1-amine] is a widely known smooth muscle relaxant used to relieve cramps or spasms of the stomach and intestines. As a free base, alverine is a liquid practically insoluble in water while its commercialized form, alverine citrate, is a white solid that can form different crystalline forms. With the aim of increasing alverine water solubility while avoiding polymorphs, in this work, the design, total synthesis, and characterization of a series of new ionic liquids incorporating alverine as the cation were carried out. The selection of the most suitable anions for the active pharmaceutical ingredient-based ionic liquids (API-ILs) was performed calculating the ionic liquid solubility in water by using a priori the COSMO-RS computational tool. The computational analysis of the intermolecular interactions between water and the API-ILs allowed understanding the water solubility of these systems. All the new salts were found to be ionic liquids and their water solubility was shown to be significantly increased compared with the free drug alverine. The highest value was obtained for alverinium tosylate, with a value of 38.10 mg mL-1, 39937-fold higher than that of alverine. Compared to the commercialized drug alverine citrate, a slight increase in water-solubility was observed in all cases. This journal is

Full text of DOI:10.1039/d0nj05216g

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Design and synthesis of alverine-based ionic
liquids to improve drug water solubility†
Cite this:DOI: 10.1039/d0nj05216g
b
V. Fernandez-Stefanuto,a P. Esteiro,a R. Santiago,
D. Moreno,b J. Palomarb and
´
a
E. Tojo
*
Alverine [3-phenyl-N-(3-phenylpropyl)-N-ethylpropan-1-amine] is
a widely known smooth muscle
relaxant used to relieve cramps or spasms of the stomach and intestines. As a free base, alverine is a
liquid practically insoluble in water while its commercialized form, alverine citrate, is a white solid that
can form different crystalline forms. With the aim of increasing alverine water solubility while avoiding
polymorphs, in this work, the design, total synthesis, and characterization of a series of new ionic liquids
incorporating alverine as the cation were carried out. The selection of the most suitable anions for the
active pharmaceutical ingredient-based ionic liquids (API-ILs) was performed calculating the ionic liquid
solubility in water by using a priori the COSMO-RS computational tool. The computational analysis of
the intermolecular interactions between water and the API-ILs allowed understanding the water
solubility of these systems. All the new salts were found to be ionic liquids and their water solubility was
shown to be significantly increased compared with the free drug alverine. The highest value was
obtained for alverinium tosylate, with a value of 38.10 mg mLÀ1, 39 937-fold higher than that of alverine.
Compared to the commercialized drug alverine citrate, a slight increase in water-solubility was observed
in all cases.
Received 23rd October 2020,
Accepted 9th November 2020
DOI: 10.1039/d0nj05216g
rsc.li/njc
influence the properties of an active pharmaceutical ingredient
(API), such as dissolution rate, solubility, stability and as a
1. Introduction
Some of the main challenges that the pharmaceutical industry consequence bioavailability. It has been estimated that more
has to face is overcoming the physicochemical problems that than 50% of APIs present more than one polymorphic form.3,4
many drugs present due to polymorphism, low solubility, and Since clinically unsuccessful attempts of polymorphic drugs
low bioavailability.1 Low water solubility and low dissolution have been common, the Food and Drug Administration (FDA)
rate result in lower absorption rate, and as a consequence, to requires a preliminary and exhaustive study of all the possible
higher doses of the drug to reach the therapeutic effect. It is polymorph crystal forms for each drug.5
estimated that poorly water-soluble drugs represent about 40%
Polymorphism has been shown to alter the efficacy of many
of available oral drugs and 40–70% of the innovative drug drugs; some examples are famotidine,6 barbital,7 axytetra-
candidates fail because they do not allow effective release into cycline, axitinib or ritonavir.8
the bloodstream.2
The development of ionic liquids based on active pharma-
Since most pharmaceutical compounds are obtained in a ceutical ingredients (API-ILs) has arisen as a possible solution
crystalline solid form, polymorphism often represents another to some of the problems that solid drugs present, such as low
important complication. Polymorphism can be defined as the solubility and polymorphism.1,9 Ionic liquids (ILs) present
ability of a solid material to exist in two or more crystalline unique physicochemical properties, such as low melting point
forms; although chemically the same, the polymorphs present (o100 1C), negligible vapour pressure, wide liquid range, non-
different lattice structures and as a consequence different physico- flammability, high thermal stability, etc.10 In addition, their
chemical properties. Thus, polymorphism can significantly physical properties can be tuned by the suitable selection of the
cation and the anion or by the incorporation of substituents or
functional groups in any of the ions. Between their possible
applications in pharmaceuticals and medicine, a search area
a Department of Organic Chemistry, Universidade de Vigo, Marcosende, As Lagoas,
Vigo-362180, Spain. E-mail: etojo@uvigo.es
relatively recent, their incorporation as components of drug
b
´
´
´
Departamento de Quımica Fısica aplicada, Universidad Autonoma de Madrid,
formulations to form API-ILs, is one of the most promising.11 It
has been shown that the combination of poorly water-soluble
APIs with suitable counter-ions to give liquid forms can resolve
´
Campus de Cantoblanco, C/Francisco Tomas y Valiente 7, Madrid 28049, Spain
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0nj05216g
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the limitations of low solubility and polymorphism.12 Among
others, some recent successful examples involve the prepara-
tion of API-ILs from sulfasalazine,13 paclitaxel,14 salicylic
acid,15 methotrexate,16 or selurampanel.17
Table 1 Predicted water mole fraction and solubility obtained using the
COSMO-RS method
Solubilityb
c
API-ILs
Mole fractiona
(mg mLÀ1
)
log KOW
5.16 Â 10À6
3.87 Â 10À7
1.67 Â 10À7
1.42 Â 10À7
1.94 Â 10À8
3.74 Â 10À10
1.42 Â 10À11
38.34
27.67
10.91
10.71
6.46
3.10
2.48
2.72
3.66
4.89
5.55
6.93
2.72
8.23
Alverine [3-phenyl-N-(3-phenylpropyl)-N-ethylpropan-1-amine]
(1) is a widely known smooth muscle relaxant used to relieve
cramps or spasms of the stomach and intestines. It is also
useful in treating irritable bowel syndrome, intestinal cramps,
abdominal cramps and pain caused by diverticular disease,
biliary spasm, urinary tract stones and dysmenorrhea. It selec-
tively acts on the gastrointestinal tract, uterus, urinary organs
and reproductive smooth muscles. It is commercialized as
crystalline salt alverine citrate under the names Audmonal,
Spasmaverine and Meteospasmyl among others18 for oral
administration. Alverine (1) as a free base is a liquid practically
insoluble in water (0.00096 mg mLÀ1),19 while alverine citrate,
[ALV][CIT], is a white solid that can form different crystalline
forms or polymorphs.20 Alverine is absorbed from the gastro-
intestinal tract and rapidly converted into its pharmacologically
active metabolite, which is then further converted to two
secondary metabolites. The plasma half-life averages 0.8 hours
for alverine and 5.7 hours for the active primary metabolite. Peak
plasma concentration is reached 1 hour – 1 hour 30 minutes
after oral administration. Renal excretion is the major route of
elimination of the metabolites of alverine. Within the cell, alverine
is primarily located in the membrane.19
The conductor-like-screening model for the real solvent
(COSMO-RS) method21 has been employed as an a priori tool
to select solvents for specific tasks.22 The COSMO-RS method
only needs the optimized geometry and its charge distribution
to predict solvent properties. In particular, it has been demon-
strated as a valid tool to design new unit operations and
processes based on ILs.23 Thus, it has been applied with
success to select ILs with optimal properties for liquid–liquid
extraction24–26 and gas absorption27–29 using ILs as absorbents.
The main aim of this work was to improve the pharmacolo-
gical properties of alverine (1), increasing its water solubility
while avoiding crystalline forms. For this purpose, the total
synthesis of alverine (1), the design by means of COSMO-RS
analysis, as well as the synthesis and characterization of a series of
new ILs incorporating alverine (1) as the cation were carried out.
[ALV][tosylate]
[ALV][salicylate]
[ALV][benzoate]
[ALV][cinnamate]
[ALV][octanoate]
[ALV][aminophen]
[ALV][flufenamicate]
a
Mole fraction of ILs on the aqueous phase obtained by LLE calcula-
b
tion. Solubility of ILs in water obtained by solubility calculation.
c
log KOW estimated by partition coefficient calculation at infinite
dilution.
order to predict the water solubility of the different possible
API-IL candidates prior to their synthesis. Table 1 shows the
API-IL candidates’ mole fraction in water reach-phase (liquid–
liquid equilibria) and solubility in water (solid–liquid equili-
bria) predicted by COSMO-R. As it can be seen, the salts derived
from [tosylate], [salicylate] and [benzoate] anions present the
highest predicted water solubility by means of COSMO-RS
calculations.
Moreover, log KOW is shown trying to anticipate the favour-
able bioavailability with respect to the neutral compound. As
can be seen, all the ILs present log KOW higher than 1, which
means that the solute would be mostly concentrated in the
organic phase. This value is higher when the water solubility is
decreasing, which means that selected ILs would potentially
present high lipophilicity.
In order to understand this behaviour, the COSMO-RS
method was applied to analyse the solute–solvent intermolecular
interactions. The COSMO-RS method calculates the molecular
surface polarity distributions (s-surface) of the compounds sepa-
rately. All this information is represented in a histogram called a
s-profile. Additionally, s-potential represents the affinity of a
solvent to interact with other compounds. Both representations
can be analysed simultaneously to anticipate the interactions that
take place in different compounds. s-Profile and s-potential
are quantitatively divided in three different regions (see Fig. 1).
Thus, the polarity of the compounds involved in this work can
be analysed. Fig. 1 shows the s-profiles (A) and s-potentials (B)
of water and selected API-ILs. First, the s-profile of water is
2. Results and discussion
2.1. Anion selection: COSMO-RS screening
COSMO-RS quantum chemical calculation allows calculating
the thermodynamic properties of mixtures only using the
molecular surface polarity distribution of each molecule. Thus,
it can be used to predict API-ILs solubility in water.
The initial selection of the anions that would form the new
ILs derived from alverine (1) was made looking for high
biocompatibility and low toxicity. For this purpose, seven
candidates, derived from aminoacids and salicylate, among
others, were considered (Table 1). Due to the high diversity
of possible anions, a COSMO-RS screening was performed in
Fig. 1 s-profile (A) and s-potential (B) of the compounds involved in
this work.
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characterized by a peak in the H-bond donor region and
another one in the H-bond acceptor region, giving to H2O its
well-known amphoteric behaviour. This is also checked by
s-potential, giving exothermic mixtures with both H-bond
donor and acceptor groups. The selected API-ILs are character-
ized by a series of peaks in the non-polar region. Moreover, they
present a peak in the H-bond acceptor zone, giving a basic
character to the compounds. [Tosylate] based ILs present the
peak of highest intensity in that region, which is in good
agreement with calculated solubility in water. The other two,
[salicylate] and [benzoate], follow the same trend of values of
Table 1, being ordered as a function of the peak intensity.
These results are endorsed by the s-potential figure, showing
an exothermic behaviour with H-bond donor groups and
endothermic behaviour with H-bond acceptor groups. This
analysis let us conclude that API-ILs will interact attractively
with H-bond donor groups of water.
Scheme 1 Synthetic procedure used to prepare alverine (1).
Fig. 2A shows the excess Gibbs energy, entropy, and excess
enthalpy of the binary API-IL + water mixtures under diluted
conditions (xIL o10À5). In addition, Fig. 2B presents the inter-
molecular interaction contributions to excess enthalpy of these
mixtures. First, it can be seen how more negative Gibbs
energies are found for these API-ILs that present higher solu-
bility in water. Therefore, Gibbs energy follows the same trend
obtained in Table 1. Then, it seems that both enthalpic
(favourable) and entropic (unfavourable) contributions play a
role in the thermodynamics of the mixing phenomena. Regard-
ing enthalpic contributions, the hydrogen bond is the one that
clearly controls the solute–solvent interactions, in good agree-
ment with the conclusion that the behaviour was anticipated by
the s-profile and s-potential of the compounds.
Scheme 2 Synthetic procedure used to prepare alverine API-ILs 5–7.
2.3. Synthesis
as a solid with a melting point of 65–66 1C. So, the three novel
salts obtained can be considered as API-ILs.
The synthesis of alverine (1) was carried out according to
the procedure previously described by Shakhmaev et al.
(Scheme 1).30 Details of the synthetic procedure and spectra
are provided in the ESI.†
Once alverine (1) was obtained and the most suitable anions
selected, the salts alverinium tosylate [ALV][TOS] (5), alveri-
nium salicylate [ALV][SAL] (6) and alverinium benzoate
[ALV][BNZ] (7) were prepared by treatment of alverine (1) with
the corresponding salicylic, p-toluenesulfonic and benzoic acid
(Scheme 2). [ALV][SAL] (6) and [ALV][BNZ] (7) were shown to be
liquid at room temperature while [ALV][TOS] (5) was obtained
The structure of all the API-ILs synthesized was confirmed
by 1H and 13C NMR spectra, as well as their HR-MS data, which
showed the absence of unreacted starting materials. From the
NMR spectra, a purity Z99% wt is estimated for all API-ILs
synthesized in this study, which was determined using the
following equation:
P
P
Purity% = [ Iproduct
/
Itotal] Â 100,
where I represents the relative area of each signal.
2.4. Solubility study of the synthesized API-ILs
In order to determine the aqueous solubility of the alverine-
based ionic liquids 5–7, samples were prepared by adding an
excess amount of the corresponding compound in 1 mL of
Milli-Q water. The mixtures were stirred thoroughly for 24 h at
20 1C, and then rested for another 24 h. Each liquid phase was
filtered using a 0.45 mm syringe filter. The filtrate was analyzed
via UV-vis spectroscopy using a Hewlett Packard model 8452A
diode array spectrophotometer, with quartz cells at a wave-
length of 235 nm, which is the wavelength of the maximum
Fig. 2 Excess enthalpy, entropy, and Gibbs energy (A) and excess
enthalpy contributions (B) of selected API-ILs.
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absorbance of alverine in water. A calibration curve was pre- were recorded on a BRUKER FTMS APEXIII spectrometer.
viously established to determine the amount of drug in the Melting points of the solids were recorded on a STUART
dissolution media, which was constructed using different SCIENTIFIC MELTING POINT APPARATUS SMP3.
solutions with known concentrations of the corresponding
ALV-ILs (for all curves R2 40.9952).
3.2. Computational details: COSMO-RS calculations
As it can be seen in Table 1, the water solubility of all the The geometries of the cations and anions involved in the work
ALV-ILs synthesized is significantly increased compared with were optimized using the ion paired molecular model (CA)
the free drug alverine (1). The highest value was obtained for at the BP86/TZVP computational level with solvent effect calcu-
[ALV][TOS] (5), with a value of 38.10 mg mLÀ1, 39 937-fold lations using the COSMO continuum solvation method with
higher than that of alverine (1) (0.00096 mg mLÀ1). Compared Turbomole 4.5.2. Then, vibrational frequency calculations were
to the commercialized drug alverine citrate, [ALV][CIT], a slight performed to optimize the structures to ensure that they are
increase in water-solubility was observed in all cases, the high- at their minimum energy. Last, a single point calculation
est value corresponding again to [ALV][TOS] (5) which showed a was done to obtain the polarized charge distribution of each
value 1.75-fold higher.
species, which is stored in *.cosmo files. The TmoleX v.19
It is very important to highlight the excellent predictive graphical interface was employed to carry out all these calcula-
capacity shown by the COSMO-RS method. The highest water tions. COSMOthermX (version 18) software was used for
solubility values were obtained by COSMO-RS analysis from the COSMO-RS computations with its implicit parametrization
seven initial candidates (Table 1), that is, the salts derived from BP_TZVPD_fine_18. The files included in the simulator were
[tosylate], [salicylate] and [benzoate] anions were quite similar those generated in this work (cation and anions) and water
to those experimentally obtained for the corresponding synthe- from COSMOthermX database. First, water solubility predic-
sized API-ILs (Table 2).
tions were accomplished for the different ILs based on alverine
cations by LLE calculation and solubility with the COSMO-RS
approach. Partition coefficient octanol–water (log KOW) was
estimated by distribution coefficient calculation at infinite dilu-
tion as implicit in COSMOthermX software. Then, s-profiles and
s-potentials of API-ILs and water were calculated. Last, excess
properties (Gibbs energy, enthalpy and entropy) of IL-H2O mix-
tures were computed using the 1Á10À5 molar fraction of ILs
(CA model), including the intermolecular interaction contribu-
tions to the excess enthalpy: hydrogen bond (HB), van der Waals
(VDW) and misfit-electrostatic (MF).
3. Experimental
3.1. Materials and methods
From the NMR spectra, a purity Z98% wt was estimated for
the synthesized alverine (1) and API-ILs alverinium tosylate
[ALV][TOS] (5), alverinium salicylate [ALV][SAL] (6) and alver-
inium benzoate [ALV][BNZ] (7). All other materials were of
reagent grade purchased from commercial suppliers: Acros
Organics and Sigma Aldrich, and employed without further
purification. The glass material employed in the synthetic
reactions was dried in an oven at 333 K for 24 h before use.
Tetrahydrofuran was distilled from sodium/benzophenone
prior to use. The evolution of the reactions was monitored by
thin layer chromatography (TLC) employing silica-gel sheets
(Merck, TLC Silica gel 60 F254).
Spectroscopic data were provided by the Center of Scientific-
Technological Support to Research (CACTI) of the University of
Vigo. 1H and 13C NMR spectra were recorded on a BRUKER ARX
4CO spectrometer at 400.1621 (1H) and 100.6314 (13C) MHz,
respectively. CDCl3 (ACROS Organics, 99.6 + atom% D) was
employed as a deuterated solvent. Chemical shifts are quoted
in parts per million (ppm) relative to the signals corresponding
to the residual non-deuterated solvents (CDCl3: dH = 7.26 ppm,
dC = 77.16 ppm). Low and high resolution ESI mass spectra
3.3. Synthetic procedures
General procedure. Alverine (1) and an equivalent amount of
the corresponding acid (p-toluenesulfonic acid, salicylic acid
and benzoic acid) were allowed to stir at 100 1C for 2 h.
Synthesis of alverinium tosylate [ALV][TOS] (5). The general
procedure using p-toluenesulfonic acid (0.072 g, 0.37 mmol)
was applied. The product was obtained as a solid (5) (0.168 g,
99%); mp 65–66 1C (from MeOH). RMN-1H (400 MHz, dH,
CDCl3): d = 7.80 (d, JH–H = 8.1 Hz, 2H, H-2 TOS, H-6 TOS),
7.32–7.16 (m, 12H, H–Ar), 5.03 (s, 1H, NH), 2.81 (m, 2H,
CH3CH2N), 2.71 (t, JH–H = 8.0 Hz, 4H, H-1 ALV), 2.65 (t, JH–H
7.5 Hz, 4H, H-3 ALV), 2.38 (s, 3H, CH3 TOS), 1.90 (m, 4H, H-2
ALV), 1.11 (t, JH–H = 7.2 Hz, 3H, CH3CH2N). RMN-13
=
C
(100.6 MHz, dc, CDCl3): 142.4 (C-1 TOS,C-4 TOS), 139.9 (C-4 ALV),
129.0 (C-3 TOS, C-5 TOS), 128.6 (C-6 ALV,C-8 ALV), 128.5 (C-5 ALV,
C-9 ALV, C-2 TOS,C-6 TOS), 125.9 (C-7 ALV), 53.0 (C-1 ALV), 47.6
(CH3CH2N), 33.9 (C-3 ALV), 28.7 (CH3 TOS), 21.5 (C-2 ALV), 11.7
(CH3CH2N). HRMS (ESI) m/z (%): calcd for [C20H28N]+ 282.2219
[M]+; found 282.2216 (100); calcd for [C14H15O6S2]: 343.0316 [M];
found: 343.0316 (100).
Table 2 Water-solubility of alverine (1), alverinium citrate and the synthe-
sized API-ILs 5–7
Physical
state (r.t.)
Solubility
(mg mLÀ1
)
API-IL
Alverine (1)
Liquid
Solid
Solid
Liquid
Liquid
0.00096
12.0
38.10 Æ 0.38
19.41 Æ 0.21
13.81 Æ 0.23
Synthesis of alverinium salicylate [ALV][SAL] (6). The general
procedure was applied using salicylic acid (0.050 g, 0.37 mmol) to
obtain a yellow liquid (6, 0.119 g, 99%). RMN-1H (400 MHz, dH,
CDCl3): d = 7.93 (d, JH–H =7.9 Hz, 1H, H-7 SAL), 7.29 (m, 5H, H-6 ALV,
Alverinium citrate, [ALV][CIT]
Alverinium tosylate, [ALV][TOS] (5)
Alverinium salicylate, [ALV][SAL] (6)
Alverinium benzoate, [ALV][BNZ] (7)
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H-8 ALV, H-5 SAL), 7.23 (t, JH–H = 7.1 Hz, 2H, H-7 ALV), 7.16 alverine (1) (0.00096 mg mLÀ1). However, better results were
(d, JH–H =7.3 Hz, 4H, H-5 ALV, H-9 ALV), 6.94 (d, JH–H = 8.1 Hz, found for [ALV][Sal] (6) and [ALV][Bnz] (7), which besides
1H, H-4 SAL), 6.84 (t, JH–H = 7.4 Hz, 1H, H-6 SAL), 3.12 (q, JH–H
=
significantly increasing alverine (1) water solubility (19.41 and
7.3 Hz, 2H, CH3CH2N), 2.99 (m, 4H, H-1 ALV), 2.69 (t, JH–H = 7.2 Hz, 13.81 mg mLÀ1 respectively), both are liquid at room tempera-
4H, H-3 ALV), 2.03 (m, 4H, H-2 ALV), 1.23 (t, JH–H = 7.2 Hz, 3H, ture, avoiding any limitation related to polymorphism.
CH3CH2N).
The COSMO-RS method showed an excellent predictive capa-
RMN-13C (100.6 MHz, dc, CDCl3): d = 174.9 (C-1 SAL), 162.1 city. The water solubility values obtained by COSMO-RS analysis
(C-3 SAL), 140.7 (C-4 ALV), 132.8 (C-5 SAL), 130.8 (C-7 SAL), for the selected salts were quite similar to those experimentally
128.6 (C-6 ALV, C-8 ALV), 128.4 (C-5 ALV, C-9 ALV), 126.3 (C-7 ALV), measured for the corresponding synthesized API-ILs. The three
119.1 (C-2 SAL), 117.8 (C-6 SAL), 116.5 (C-4 SAL), 51.3 (C-1 ALV), 46.9 novel synthesized API-ILs showed enhanced solubility in water
(CH3CH2N), 33.1 (C-3 ALV), 26.0 (C-2 ALV), 9.6 (CH3CH2N). HRMS due to their favourable anion-water hydrogen bond interactions.
(ESI) m/z (%): calcd for [C20H28N]+: 282.2218 [M]+; found 282.2216
(100); calcd for [C7H5O3]À: 137.0238 [M]À; found 137.0244 (100).
Conflicts of interest
Synthesis of alverinium benzoate [ALV][BNZ] (7). The general
procedure was applied using benzoic acid (0.043 g, 0.35 mmol)
There are no conflicts to declare.
to obtain an orange liquid (7, 0.106 g, 99%). RMN-1H (400 MHz,
dH, CDCl3): d = 8.10 (m, 1H, H-5 BNZ), 7.43 (m, 2H, H-3 BNZ,
H-7 BNZ), 7.30 (m, 6H, H–Ar), 7.22 (m, 6H, H–Ar), 2.90 Acknowledgements
(q, JH–H = 7.2 Hz, 2H, CH3CH2N), 2.81 (m, 4H, H-1 ALV),
The authors are grateful to Xunta de Galicia (project EDA431D
2017/06) and Comunidad de Madrid (project P2018/EMT4348) for
their financial support and also to the research support services of
2.67 (t, JH–H = 7.5 Hz, 4H, H-3 ALV), 1.96 (m, 4H, H-2 ALV),
1.16 (t, JH–H = 7.2 Hz, 3H, CH3CH2N). RMN-13C (100.6 MHz, dc,
CDCl3): d = 172.2 (C-1 BNZ), 140.5 (C-4 ALV), 135.7 (C-2 BNZ),
the Universidade de Vigo (CACTI) for the NMR and MS divisions
130.9 (C-3,5,7 BNZ), 129.6 (C-4 BNZ, C-6 BNZ), 128.6 (C-6 ALV,
´
´
and to Centro de Computacion Cientıfica de la Universidad
C-8 ALV), 128.3 (C-5 ALV, C-9 ALV), 126.3 (C-7 ALV), 50.6 (C-1 ALV),
46.4 (CH3CH2N), 33.1 (C-3 ALV), 25.2 (C-2 ALV), 9.0 (CH3CH2N).
HRMS (ESI) m/z (%): calcd for [C20H28N]+: 282.2215 [M]+; found
282.2216 (100); calcd for [C7H5O2]À: 121.0290 [M]À; found
121.0295 (100).
´
Autonoma de Madrid (CCC) for its computational resources.
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The water-solubility of the synthesized API-ILs was determined
using the ‘‘shake-flash’’ method and quantitatively measured
via UV-vis spectroscopy. A saturated solution of a known
amount of each synthesized API-IL was stirred for 24 h at room
temperature. The mixtures were then left to stand for 24 h and the
formation of two phases was observed. The supernatant phase
was collected and analyzed via UV-vis spectroscopy. Solubility tests
of the synthesized salts in water were performed in triplicate.
4. Conclusions
The design, total synthesis and characterization of a series of
new ionic liquids incorporating alverine (1) as the cation were
carried out. The most suitable anions were selected by the
application of a COSMO-RS computational analysis which led
to the selection of tosylate, salicylate and benzoate anions
as the most promising candidates. Alverine was obtained from
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New J. Chem.
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