Ionic Liquids and Salts from Ibuprofen as Promising Innovative Formulations of an Old Drug

Article abstract of DOI:10.1002/cmdc.201900040

Herein we report the synthesis of novel ionic liquids (ILs) and organic salts by combining ibuprofen as anion with ammonium, imidazolium, or pyridinium cations. The methodology consists of an acid–base reaction of neutral ibuprofen with cation hydroxides, which were previously prepared by anion exchange from the corresponding halide salts with Amberlyst A-26(OH). In comparison with the parent drug, these organic salts display higher solubility in water and biological fluids and a smaller degree of polymorphism, which in some cases was completely eliminated. With the exception of [C₁₆Pyr][Ibu] and [N_1,1,2,2OH1][Ibu], the prepared salts did not affect the viability of normal human dermal fibroblasts or ovarian carcinoma (A2780) cells. Therefore, these ibuprofen-based ionic liquids may be very promising lead candidates for the development of effective formulations of this drug.

Full text of DOI:10.1002/cmdc.201900040

Accepted Article
Title: Ionic Liquids and salts from Ibuprofen as promising innovative
formulations of an old drug
Authors: Miguel M. Santos, Luís R. Raposo, Alexandra Costa,
Madalena Dionísio, Pedro V. Baptista, Alexandra R.
Fernandes, and Luis C. Branco
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10.1002/cmdc.201900040
ChemMedChem
COMMUNICATION
Ionic Liquids and salts from Ibuprofen as promising innovative
formulations of an old drug
Miguel M. Santos,[a] Luís R. Raposo,[b] Gonçalo V. S. M. Carrera,[a] Alexandra Costa,[a] Madalena
Dionísio,[a] Pedro V. Baptista,[b] Alexandra R. Fernandes,[b]* Luís C. Branco,*[a]
[a]
[b]
Dr. M. M., Santos, Dr. G. V. S. M. Carrera, Dr. A. Costa, Dr. L. C. Branco
LAQV-REQUIMTE, Chemistry Department, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Campus de Caparica, Portugal
E-mail: l.branco@fct.unl.pt
Dr. L. R. Raposo, Prof. P. V. Baptista, Prof A. R. Fernandes
UCIBIO, Life Sciences Department, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Campus de Caparica, Portugal
E-mail: ma.fernandes@fct.unl.pt
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein we report the synthesis of novel ionic liquids (ILs)
and salts by combination of Ibuprofen as anion with ammonium,
imidazolium and pyridinium cations. The methodology consisted in the
acid-base reaction of neutral Ibuprofen with cation hydroxides, which
were previously prepared by anion exchange from the corresponding
halide salts with Amberlyst A-26(OH). In comparison with the parent
drug, these organic salts display higher solubility in water and
biological fluids and a smaller degree of polymorphism, which in some
cases was completely eliminated. With the exception of [C16Pyr][Ibu]
and [N1,1,2,2OH1][Ibu], the prepared salts did not affect the viability of
normal human dermal fibroblasts or ovarian carcinoma (A2780) cell
line. Thus, in the future these Ibuprofen-based ionic liquids may be
very promising lead candidates for the development of effective
formulations of this drug.
In the field of pharmaceutical sciences, we and others have
reported that the cation-anion interactions in the prepared API-ILs
induce improved physicochemical properties over the original
drugs, reduce toxicity to healthy cells and thus render a potentially
enhanced pharmaceutical activity to the API[17-22]. In more detail,
such combinations boost the stability and solubility of the API in
physiological media, changing its pharmacokinetics and delivery
mode[23-27]. Hence, the biopharmaceutics drug classification
system for the API-ILs can be significantly modified in comparison
with the parent drugs, meaning that this new organic salt of the
old API can be treated as a new chemical entity, and thus be
independently patented. Furthermore, the polymorphism of a
given API can be reduced to a certain extent, or even eliminated
(e.g. by becoming liquid at room temperature), tackling one of the
most important issues in the pharmaceutical industry which is
responsible for limitations in drug’s solubility and dosages[28-30]
.
Ibuprofen is used in treatment of pain and inflammation in
rheumatoid arthritis and other musculoskeletal disorders in both
humans and animals[1]. It is considered one of the Essential
Medicines by the WHO. Ibuprofen is a non-steroidal anti-
inflammatory drug (NSAID), which non-selectively inhibits
cyclooxygenase isozymes 1 and 2 (COX-1 and COX-2), resulting
in inhibition of prostaglandins[2]. Although it has a stronger
analgesic effect than other NSAIDs in some types of pain[3], the
mean onset of action per 400 mg dose is 45 minutes, which can
be critical in an acute pain situation where a fast relief is critical[4].
The low solubility in the acidic aqueous media of the stomach is
responsible for the slow pharmaceutical effect[5], despite its ease
of permeability through the gastrointestinal membranes rendering
close to 100% bioavailability[6]. In order to increase absorption
rate and provide faster pain relief, new formulations of ibuprofen
have been developed over the years, in particular salts (sodium[7],
lysine[8] and arginine[9]) and extrudate[10]. These forms, however,
do not tackle the degree of Ibuprofen’s polymorphism[11], whose
different crystal shapes display distinct pharmaceutical effects.
For the last 10 years, Ionic Liquids (ILs) from active
pharmaceutical ingredients (APIs), or simply API-ILs, have been
studied at the academic level, as the 3rd generation of Ionic
Liquids[12-15]. ILs are salts with melting temperatures below 100 ºC,
with some of them being liquid at room temperature (RTILS), that
result from the combination of organic cations with organic and
inorganic anions. The scope of their physical and chemical
properties has prompted the study and application of these
Hence, in this paper we report the synthesis of eight new Ionic
Liquids and organic salts from ibuprofen, plus one already
reported[30]
, in quantitative yields by deprotonation of the
carboxylic acid from Ibuprofen by the hydroxide salt of the cations.
Scheme 1 depicts the methodology and the structure of the
imidazolium, ammonium and pyridinium cations employed.
Scheme 1. Synthetic methodology and set of cations combined with Ibuprofen.
compounds in several topics of science and technology[16]
.
1
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COMMUNICATION
The selected cations were 1-ethyl-3-methylimidazolium [EMIM], 1-
hydroxy-ethyl-3-methylimidazolium
hydroxyethyl)-2,3-dimethylimidazolium
Table 1. Physical state and DSC data (vitreous transition (Tg), melting (Tm),
crystallization (Tc) and cold crystallization (Tcc) temperatures) of the synthesized
Ibuprofen ionic liquids and organic salts.
[C2OHMIM][30],1-(2-
[C2OHDMIM], 1-(2-
methoxyethyl)-3-methylimidazolium [C3OMIM], tetraethylammonium
[TEA], choline [cholin], 2-hydroxy-N-(2-hydroxyethyl)-N,N-
dimethylethanaminium [N1,1,2OH,2OH], N-ethyl-2-hydroxy-N,N-
Cation
Appearance
Yellow paste
Tg /oC
Tm /oC
-
Tc /oC
-
Tcc /oC
[EMIM]
-29.1
-
-
-
dimethylpropan-1-aminium [N1,1,2,2OH1] and cetylpyridinium [C16Pyr].
The most straightforward methodology for the preparation of ILs
consists on the metathesis reaction of an organic cation halide
with an alkaline salt, in which the desired product must be
separated from the halide salt by-product by precipitation and
filtration of the later[31,32]. Depending on the solubility of the
compounds in hands this task can be quite laborious with possible
detrimental effects on the reaction yield. In fact, the need to obtain
halide-free ILs has been one of the major concerns within the IL
community, leading to the development of other methodologies.
More precisely, inorganic acids have been employed instead of
[C2OHMIM][30]
Pale yellow
solid
70.8
73.8
125.3
[C2OHDMIM]
[C3OMIM]
[TEA]
White solid
-
-27.0
-
169.1
-
97.3
-
-
-
-
paste
Yellow
Yellow solid
Yellow solid
94.3
50.5
[cholin]
42.0
46.6
-
-
104.0
-
[N1,1,2OH,2OH
]
19.3
90.7
118.6
salts[33]
, however anion exchange by weaker acids than
-22.8
100.3
White solid
29.0
hydrohalic acids also cannot be efficiently performed with many
substrates[34]. In addition, carbenes from imidazolium cations
were found to be very efficient[35] yet this approach is limited to
these substrates due to the high reactivity and low stability of the
radical species.
[N1,1,2,2OH1
[C16Pyr]
]
Yellow paste
-24.8
-27.2
-
-
-
-
-
-
paste
Brown
In our experience[17], the most comprehensive methodology
consists on the reaction between organic anions and hydroxide
cations which are prepared from the corresponding halide salts
using hydroxide exchange resins, as depicted in Scheme 1. In
more detail, we eluted a methanolic solution of chloride and
bromide salts of the cations through an Amberlyst A-26(OH)
packed column immediately before dropwise addition to a
methanolic solution of Ibuprofen. Upon neutralization the
corresponding products are isolated quantitatively and halide-free
upon evaporation of the solvent.
Five of them are solids while the other four are liquids at room
temperature (RTILs). No single crystals suitable for X-ray
diffraction were obtained. However, we may postulate on the
differences in the physical state according to the different cation-
anion interactions. As a general trend the salts whose cation has
hydrogen-bonding groups such as hydroxyl groups may form
more stable products than the ones without, thus yielding solid
compounds;
this
is
observed
for
[C2OHMIM][Ibu],
[C2OHDMIM][Ibu], [N1,1,2OH,2OH][Ibu] and [cholin][Ibu]. As an
exception, [N1,1,2,2OH1][Ibu] is a paste at room temperature
probably due to steric hindrance issues. Despite the fact that
[TEA] cannot establish any predictable intermolecular interaction,
the corresponding ionic liquid is also solid at room temperature.
This can be probably accounted to its very small size. Finally, as
the [EMIM], [C3OMIM] and [C16Pyr] cations can only establish
very weak π-π interactions, the corresponding ibuprofen ionic
liquids are pastes at room temperature.
Once the melting point of [C2OHDMIM][Ibu], [C2OHMIM][Ibu] and
[cholin][Ibu] is higher than 100 ºC, these compounds are formally
considered organic salts salts. While the first salt does not
possess polymorphs, given by the seldom melting and
crystallization peaks, the second and third salts display two
distinct crystallization peaks in the cooling step, which is
consistent with the presence of polymorphic structures. On the
other hand, [TEA][Ibu] is a solid ionic liquid without polymorphs.
[N1,1,2OH,2OH][Ibu] falls in between categories as it presents three
different melting temperatures, 19.3 ºC (followed by a cold
crystallization step at 29 ºC), 90.7 ºC and 118.6 ºC. To each
melting step there is a crystallization phenomenon in the
consequent cooling step, which is consistent with the existence of
different polymorphs.
All prepared [Ibu]-ILs were characterized by spectroscopic
techniques and their solubility in water and biological fluids was
determined. An evaluation of the cytotoxicity towards human
healthy and tumour cells was also performed.
The FTIR spectra of the nine [Ibu]-ILs prepared showed that the
ionization of Ibuprofen occurred in every case, in particular by
disappearance of the C=O(OH) stretching band at 1721 cm-1 from
Ibuprofen and appearance of the C=O(O-) stretching band at 1572
± 10 cm-1 in the products. The remaining signals in the FTIR
spectra are in agreement with the cation and anion structures.
The 1H and 13C NMR spectra from all products contained the
expected signals from the anion and the corresponding cation,
and showed only one set of signals, meaning that the reactions
were complete and only one highly pure product was formed in
each reaction. In agreement with the intended stoichiometry, a
strict 1.0:1.0 proportion was always observed in the 1H NMR
spectra. On one hand, the formation of the carboxylate group is
supported by the variation towards higher field of the signal from
the proton (Hf) at the chiral centre in ca. 0.13 ppm in the 1H NMR
spectra. On the other hand, the signal from the quaternary carbon
atom from the carboxylate group of the products is shifted 4.15 ±
0.65 ppm towards lower field in comparison with the analogous
signal in the 13C NMR spectrum of ibuprofen free acid.
All RTILs display glass-transition temperatures (Tg) between -29.1
and -24.8 ºC, while no crystallization peaks were observed during
the heating/cooling cycles. This data suggests that these ionic
liquids don’t possess polymorphic structures, as opposing to the
The elemental analysis obtained for the products agree with the
theoretical values for the expected products as hydrates (see ESI),
which correlates with the high hygroscopic character of ILs.
Table 1 resumes the physical appearance and Differential
Scanning Calorimetry (DSC) data from of the prepared salts.
free acid Ibuprofen[11]
.
Thus, by transforming Ibuprofen into an ionic liquid through
combination of its anionic form with imidazolium, ammonium and
2
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10.1002/cmdc.201900040
ChemMedChem
COMMUNICATION
pyridinium cations, the inherent polymorphism of the drug is
reduced or even completely eliminated.
Due to the anion-cation interactions, the solubility of the ionic
liquids and salts in water and 0.1 M phosphate buffer saline
solution at 37 ºC are much higher than the ones found for
Ibuprofen in the neutral and sodium salt forms (Figure 1).
Figure 1. Solubility of Ibuprofen, Na[Ibu] and [Ibu]-ILs/salts in water (white) and
0.1M PBS (light grey) at 37 ºC. The detection limit was 5000 mg/mL.
The least water soluble ionic liquid is [C16Pyr][Ibu] (504 mg/mL),
however it is 24000- and 1.5-fold more soluble than Ibuprofen and
its sodium salt, respectively. Furthermore, the water solubility of
[EMIM][Ibu], [TEA][Ibu] and [N1,1,2OH,2OH][Ibu] ionic liquids were the
highest recorded, and fell beyond the limits of the experimental
conditions. The registered solubility of the synthesized ionic
liquids in phosphate buffer saline (PBS) solution is similar in most
cases to the ones found for water, despite the 280-fold increase
observed for Ibuprofen. [C16Pyr] was the one that recorded the
highest increase, more precisely 50%.
Figure 2. Cytotoxicity of Ibuprofen-Ionic Liquids (light grey) and precursor halide
salts (white) in (A) Human Dermal Fibroblasts and in (B) A2780 ovarian
carcinoma cells, in comparison with Na[Ibu] (in dark grey). Fibroblasts were
incubated with 1 mM and A2780 cells were incubated with 100 µM of each [Ibu]-
IL, precursor salt or Na[Ibu] for 48 h. Cell viability was determined by the MTS
assay, using cells incubated with DMEM or RPMI as control. The results shown
are expressed as the mean ± SD). * p < 0.0001 and ** p<0.0002 (as compared
to the values of Na[Ibu] for each cell line).
Table 2. IC50 values of [C16Pyr]Cl salt and [Ibu]-ILs [C16Pyr][Ibu] and
[N1,1,2,2OH1][Ibu] in Human Dermal Fibroblasts and in A2780 ovarian carcinoma
cells exposed to different concentrations of the compounds for 48 h. Results are
the mean ± SEM of three independent biological replicates.
Cytotoxicity of [Ibu]-ILs and corresponding precursor halide salts
was evaluated in human normal dermal fibroblasts and in A2780
ovarian carcinoma cell line. In human dermal fibroblasts, a
concentration of 1 mM was chosen to evaluate the cytotoxic effect
of [Ibu]-ILs and precursor halide salts based on the previously
reported IC50 value for Ibuprofen (1.12 mM)[36]. In human ovarian
carcinoma cell line A2780, 100 µM concentration of the [Ibu]-ILs
and precursor salts was chosen due to the effect of Ibuprofen on
the WNT/β-catenin pathway that affects the proliferation of these
Salt
Cell type
IC50 (µM)
Fibroblasts
A2780
< 100
2.2 ± 0.1
[C16Pyr]Cl
Fibroblasts
A2780
< 100
< 1
[C16Pyr][Ibu]
cells[37-40]
.
With the exception of [C16Pyr][Ibu] for both cell lines and
[N1,1,2,2OH1][Ibu] for A2780 tumour cell line, no cytotoxic effect was
observed for both cell lines when exposed for 48 h to each
compound (in comparison with Na[Ibu]) (Figure 2). Interestingly,
for both cell lines, the cytotoxic activity of [C16Pyr][Ibu] might be
attributed to its cation, once [C16Pyr]Cl displayed IC50 values <
100 and 2.2 ± 0.1 µM for fibroblasts and A2780 cells, respectively
(Figure 2.A and Table 2). In the case of [N1,1,2,2OH1][Ibu] the same
effect might not be considered since no cytotoxic activity was
observed for its cation in the form of bromide salt in A2780 tumour
cell line (Figure 2.B and Table 2).
From the data displayed in Figure 2 we can also see that
[Cholin]Cl has an IC50 around 100 µM for A2780 cell lines,
however this effect was not observed in the corresponding
[Cholin][Ibu] salt.
In this work we successfully and quantitatively combined
Ibuprofen with nine different imidazolium, ammonium and
pyridinium cations. While two of the resulting compounds are
organic salts, seven of them are ionic liquids, four being liquid at
Fibroblasts
A2780
> 1000
75.6 ± 0.5
[N1,1,2,2OH1][Ibu]
room temperature (RTILs). Studies by Differential Scanning
Calorimetry techniques revealed that the characteristic
polymorphic behavior of Ibuprofen was mitigated in three of the
compounds, while six out of the nine ILs/salts did not display any
polymorphic behavior. Furthermore, the entire set of ionic
compounds showed improved solubility in water and buffered
saline solution in comparison with both free acid and sodium salt
of ibuprofen. The majority of the Ibuprofen ILs/salts prepared and
corresponding precursor halide salts did not affected the cell
viability of Human dermal fibroblasts and A2780 ovarian cancer
cells at the concentrations tested, with the exception of
[C16Pyr][Ibu] and its precursor [C16Pyr]Cl which significantly
reduced the viability of both normal fibroblasts and A2780 cells.
In the latter cell lines, [Cholin]Cl salt and [N1,1,2,2OH1][Ibu] ionic
liquid also affected significantly the cellular viability at 100 µM. In
3
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ChemMedChem
COMMUNICATION
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Experimental Section
General procedure for the synthesis of [Ibu]-ILs
The halide salt was dissolved in methanol and passed through an ion-
exchange column Amberlyst A26(OH) (3 eq., 0.5-1 mL/min flux rate). The
corresponding hydroxide salt methanolic solution was added dropwise to
ibuprofen (1 eq.) dissolved in methanol. After stirring the mixture for 1 h,
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This work was supported by Fundação para a Ciência e
Tecnologia
through
projects
(PEst-C/LA0006/2013,
PTDC/CTM/103664/2008), and one contract under Investigador
FCT (L. C. Branco). This work was also supported by the
Associate Laboratory for Green Chemistry LAQV and by the
Unidade de Ciências Biomoleculares Aplicadas-UCIBIO which
are
financed
by
national
funds
from
FCT/MEC
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2010, 27, 521-526.
(UID/QUI/50006/2013 and UID/Multi/04378/2013, respectively)
and co-financed by the ERDF under the PT2020 Partnership
Agreement (POCI-01-0145-FEDER-007265 and POCI-01-0145-
FEDER-007728, respectively). Authors also thank Solchemar
company.
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Keywords: API-IL • cytotoxicity • ibuprofen • ionic liquids •
polymorphism
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10.1002/cmdc.201900040
ChemMedChem
COMMUNICATION
Entry for the Table of Contents
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Ibuprofen-based Ionic Liquids and organic salts have been prepared with ammonium, imidazolium and pyridinium cations. Depending
on the cation-anion combination, RTILs or solid organic salts were obtained with reduced polymorphism or in complete amorphous
state. An enhancement of the solubility of such salts in water and phosphate buffer saline in comparison with the neutral or sodium salt
was observed, alongside low toxicity to human healthy cells and ovarian cancer cell lines.
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