DOI: 10.1002/cmdc.201100082
Ionic Liquids as Active Pharmaceutical Ingredients
Ricardo Ferraz,*
[a, b]
Lus C. Branco,
[b]
Cristina PrudÞncio,
[a, c]
Jo¼o Paulo Noronha,
[b]
and
Z
ˇ
eljko Petrovski*
[b]
Introduction
Ionic liquids (ILs) have been a topic of great interest since the
mid-1990s.
[1]
They have attracted particularly high attention in
recent years; approximately 1800 papers were published in the
area of ILs in 2008 alone,
[2]
documenting a variety of new IL
applications. The range of IL uses had been broadened , and
there was a significant increase in the scope of both physical
and chemical IL properties.
[3,4]
ILs are generally defined as organic salts with melting points
below 1008C (some of them are liquid at room temperature)
and composed entirely of ions.
[2,4–6]
Despite the fact that ILs
were first reported in the mid-1800s, widespread interest in
this compound class has occurred only recently. ILs have come
under worldwide scrutiny mainly through their use as sol-
vents.
[2,4,7,8]
In particular, the room temperature ionic liquids
(RTILs), also known as “designer solvents” (because it is possi-
ble to create an IL with a given required property), have
served as greener alternatives to conventional toxic organic
solvents.
[2,7,9]
RTILs have been used for several other applica-
tions, and their development continues at a considerable rate
owing to their peculiar physical and chemical properties such
as high thermal and chemical stability, lack of inflammability,
low volatility, and tunable solubility with several organic com-
pounds. By taking advantage of their unique properties,
[2,10]
several IL applications have been described, includi ng reaction
media for many organic transformations,
[2,11]
in separations and
extractions,
[2,12]
as electrolytes for electrochemistry,
[2,13]
in nano-
technology,
[2,14]
in biotechnology,
[2,15]
and in engin eering pro-
cesses,
[2,16]
among others.
ILs can be grouped into three generations according to their
properties and characteristics.
[17]
The first generation includes
ILs for which the accessible physical properties such as de-
creased vapor pressure and high thermal stability
[18]
are often
unique (Figure 1, 1st Generation). Second-generation ILs have
potential use as functional materials such as energetic materi-
als, lubricants, and metal ion complexing agents, (Figure 1, 2nd
Generation). By taking advantage of their tunable physical and
chemical properties, ILs can produce a remarkable platform on
which—at least potentially—the properties of both cation and
anion can be independently modified and designed to enabl e
the production of new useful materials while maintaining the
main properties of an IL. Some RTILs have been used as reac-
tion media to produce or improve the preparation of various
pharmaceuticals.
[7,19,20]
Recently, the third generation of ILs
[17]
(Figure 1, 3rd Generation) has been described using active
pharmaceutical ingredients (APIs) to produce ILs with biologi-
cal activity.
While a tremendous amount of research has focused on the
physical and chemical prope rties of ILs, more recently the tox-
icity and biological behavior of ILs have been included as two
Ionic liquids (ILs) are ionic compounds that possess a melting
temperature below 1008C. Their physical and chemical proper-
ties are attractive for various applications. Several organic ma-
terials that are now classified as ionic liquids were described as
far back as the mid-19th century. The search for new and dif-
ferent ILs has led to the progressive development and applica-
tion of three generations of ILs: 1) The focus of the first gener-
ation was mainly on their unique intrinsic physical and chemi-
cal properties, such as density, viscosity, conductivity, solubility,
and high thermal and chemical stability. 2) The second genera-
tion of ILs offered the potential to tune some of these physical
and chemical properties, allowing the formation of “task-spe-
cific ionic liquids” which can have application as lubricants, en-
ergetic materials (in the case of selective separation and ex-
traction processes), and as more environmentally friendly
(greener) reaction solvents, among others. 3) The third and
most recent generation of ILs involve active pharmaceutical in-
gredients (API), which are being used to produce ILs with bio-
logical activity. Herein we summarize recent developments in
the area of third-generation ionic liquids that are being used
as APIs, with a particular focus on efforts to overcome current
hurdles encountered by APIs. We also offer some innovative
solutions in new medical treatment and delivery options.
[a] R. Ferraz, Prof. C. PrudÞncio
CiÞncias Qumicas e das Biomolculas
Escola Superior de Tecnologia da Safflde do Porto do Instituto Politcnico
do Porto
Rua Valente Perfeito 322, 4400-330, Vila Nova de Gaia (Portugal)
Fax: (+ 351)22-206-1001
E-mail: ricardoferraz@eu.ipp.pt
[b] R. Ferraz, Dr. L. C. Branco, Prof. J. P. Noronha, Dr. Z
ˇ
. Petrovski
Departamento de Qumica, REQUIMTE-CQFB
Faculdade de CiÞncias e Tecnologia da Universidade Nova de Lisboa
2829-516 Caparica (Portugal)
Fax: (+ 351)-21-294-8550
E-mail: zeljko.petrovski@dq.fct.unl.pt
[c] Prof. C. PrudÞncio
Centro de Farmacologia e Biopatologia Qumica (U38-FCT)
Faculdade de Medicina da Universidade do Porto
Alameda Prof. Hernni Monteiro, 4200-319 Po rto (Portugal)
ChemMedChem 2011, 6, 975 – 985 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 975
of the most highly debated topics in this field. Biologically
active ions have been used to develop novel ILs; however, the
primary drive behind the research into these materials has
been focused on the use of well-known low-toxicity ions to
obtain ILs with the desired set of properties.
[17,21,22]
Historical perspective
The first ionic liquid was described as “red oil” and was pro-
duced in the course of Friedel–Crafts reactions carried out in
the mid-19th century. However, the composition of this red oil
was only lately identified as a salt. For AlCl
3
-catalyzed reactions,
the structure proposed for this liquid was the heptachlorodia-
luminate salt shown in Figure 2. This IL as red oil, along with
more complicated structures, were patented as useful materi-
als, but no industrial application has been reported.
[7,23]
Modern ILs are quite different from those of the beginning
of the 20th century, such as the alkylammonium nitrates 2,
shown in Figure 2.
[23]
The most common ILs containing quater-
nary heterocyclic cations (such as alkylpyridinium or dialkylimi-
dazolium) and inorganic anions have an ancestry traceable to
traditional high-temperature molten salts.
[23]
The inorganic
chloroaluminates are considered examples of salts between
the truly high-temperature molten salts (such as cryolite or
LiCl–KCl) and the current ionic liquids.
The history behind the alkali chloroaluminate molten salts is
a good example of fundamental research emerging rather
quickly into practical application. In an example case, research-
ers at the United States Air Force Acad-
emy (Colorado Springs, CO, USA)
picked up on work carried out by Frank
Hurley and Thomas Wier
[24]
on electro-
deposition of aluminum using AlCl
3
-
based molten salts. This led to the de-
velopment of electrolytes for thermal
batteries based on mixtures of AlCl
3
and 1-ethylpyridinium halides, mainly
the bromide (Figure 3).
One of most important break-
throughs in the history of ILs is related
to the discovery of the 1-butylpyridini-
um chloride–aluminum chloride mix-
ture (BPC–AlCl
3
, Figure 4).
[25]
This all-
chloride system represented a substan-
tial improvement over the mixed bro-
mide–chloride ionic liquids,
[25]
but had
some disadvantages; this lead to new
research and developments that
brought forth the water-stable ionic liq-
uids.
[23,26]
The research for novel water-soluble ILs was described by
Fuller et al.
[27]
using a series of ILs from the traditional dialkyli-
midazolium cations combined with different anions (tetrafluor-
oborate, hexafluorophosphate, nitrate, acetate, and sulfate)
along with the additional series of mostly larger anions
(Figure 5). Over the years, new classes of cations and anions
have been reported.
[2]
Because ILs are intrinsically safer than
highly volatile and flammable organic solvents, their use as sol-
vents improves the safety margins and environmental perfor-
mance in solution chemistry.
[4]
Nowadays, the interest from dis-
ciplines outside chemistry and engineering is growing. Recent
IL applications include use in sensors, solar cells, and solid-
state photocel ls and batteries, as well as thermal fluids, lubri-
cants, hydraulic fluids, and ionogels. ILs are indeed tunable,
multipurpose materials for a variety of applications.
[6]
Figure 1. The scientific evolution of ILs, from unique physical properties
(Generation 1) through the combination of chemical and physical properties
(Generation 2), to the more recent studies of their biological and pharma-
ceutical activities (Generation 3) [adapted from Hough et al].
[17]
Figure 2. The structure proposed for the heptachlorodialuminate salt inter-
mediate 1 in the Friedel–Crafts reactions. An example of alkylammonium ni-
trates: ethylammonium nitrate (2).
Figure 3. Mixture of
AlCl
3
and 1-ethylpyridi-
nium bromide (5).
Figure 4. 1-Butylpyridi-
nium chloride (6) and
aluminum chloride mix-
ture (BPC–AlCl
3
).
Figure 5. Tetrafluoroborate (7), hexafluorophosphate (8), nitrate (9), acetate
salts (10), and sulfate (11) as anions combined with 1-ethyl-2-methylimidazo-
lium cation ILs.
976 www.chemmedchem.org 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemMedChem 2011, 6, 975 – 985
MED
R. Ferraz, Z
ˇ
. Petrovski, et al.
Finally, the particular interest in ILs from the biological and
pharmaceutical sciences is not only for use as reaction media,
but as pharmaceutical solvents or co-solvents for the delivery
of drugs with poor water solubility.
[28]
They are also applied in
micro-emulsion systems, which can facilitate the dissolution of
drugs that are insolub le or poorly soluble in water. Some IL
micro-emulsions can be used as modern colloidal carriers for
topical and transdermal delivery, while other IL systems have
been used as entrapped/solubilized drug reservoirs for con-
trolled release.
[29]
ILs as Active Pharmaceutical Ingredients (APIs)
Ionic pharmaceuticals and the polymorphism problem
The pharmaceutical industry is unquestionably facing a series
of challen ges. While many of these challenges are related to
the features of this industry and present business models,
there is also an urgent need for new scientific advances that
yield innovative and effective drugs and therapies. The classical
strategies currently being followed are reaching the point at
which it is difficult to come up with effective and acceptable
new chemical entities. Very few drugs (< 10 %) that are evalu-
ated in clinical tests make it to the market, decreasing the ac-
cessibility of efficient therapies for the people who need
them.
[30]
Roughly 50 % of available drugs are administrated as salts.
The physicochemical and biopharmaceutical properties of a
given drug can be finely tuned by pairing with various coun-
terions. From a pharmaceutical point of view, the melting tem-
perature and solubility are relevant parameters because of
their routine measureme nt and due to their potential influence
on drug processing and bioavailability.
[31]
This is an easy way
to adjust the properties of a drug with ionizable functional
groups to overcome undesirable features present in the parent
drug.
[32]
The quality, safety, and performance of a drug are re-
lated to the salt structure. The selected ion pair can significant-
ly influence the pharmacokinetics of a drug candidate. This is
one of the reasons why regulatory authorities have begun to
classify novel salts of a registered drug as a new chemical
entity.
The development of salts of the targeted active compounds
is a suitable and well-known approach to overcome the limita-
tions faced by the pharmaceutical industry. In spite of this, co-
crystals, amorphous forms, and polymer-embedded pharma-
ceuticals have been tested in order to solve such classical
problems as spontaneous polymorphic transformation of crys-
talline drug forms; this can pose significant problems for drug
designers, and can convert an effective dose into a lethal dose
by altering the solubility of the active ingredient.
[30]
Pure com-
pounds, salts, and all kinds of pharmaceuticals and drug candi-
dates can suffer polymorphism (Figure 6), and there are no
means to predict the emergence of polymorphism in any
given compound despite recent efforts toward a better under-
standing of crystal polymorphism in pharmaceutical com-
pounds.
[33–35]
The cost of a pharmaceutical product is depends directly on
crystal polymorphism and solvation state. This situation has
been illustrated by costly product failures and protracted
patent litigation. For example, the case of the Norvir capsule
product failure in 1998 was recounted and rationalized by solv-
ing the crystal structures of the Ritonavir polymorphs.
[36]
In
theory, all solid drugs are susceptible to unpredictable poly-
morph formation. An unexpected metastable form of 5-fluo-
rouracil (a well-known drug) was described as a new poly-
morphic structure.
[33,37]
The use of initial generic versions of
some relevant drugs has been permitted based on patently
different yet pharmaceutically equivalent polymorphs (or hy-
drates), which in some cases have led to legal disputes.
[33]
Aca-
demic researchers are currently working with both experimen-
tal (engineering) and theoretical (prediction) insight into crystal
forms.
[35]
The pharmaceutical industry should be open to the poten-
tial benefits that crystal engineering can offer, but it also has
to be aware of other forms. Drug companies mainly rely on
solid, primarily crystalline forms for the delivery of APIs for rea-
sons of purity, thermal stability, manufacturability, and ease of
handling. In contrast, liquid drug formulations are much less
common, and are usually based on eutectic mixtures.
[38,39]
However, problems associated with the solid form of many
drugs have been consistently reported; issues include poly-
morphic conversion, low solubility, low bioavailability for crys-
talline solids, and the tendency of amorphous forms to sponta-
neously crystallize. For these reasons, and also due to consider-
able financial interests brought about by legal ramifications,
screening for new drug forms, including salts, solvates, and co-
crystals is a continuous pursuit.
[33,39]
Therefore, the use of an
active drug in liquid form can avoid some of polymorphism
problems associated with solids. Other similar approaches
Figure 6. Examples of the types of crystal forms of pharmaceutical com-
pounds that can have problems with polymorphism.
ChemMedChem 2011, 6, 975 – 985 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemmedchem.org 977
Ionic Liquids
have been developed with liquid drug formulations prepared
as eutectic mixtures,
[39,40]
but these can dilute the APIs owing
to large quantities of inactive ballast in the formulation. In this
light, pure liquid-phase APIs would provide new perspectives
for drug delivery and treatment approaches.
From the point of view of the pharmaceutical industry, the
use of liquid salts is relevant, preferably those with melting
points below room temperature. Some synthetic strategies
that have been employed to decrease the melting point of the
salts include selection of cations with a low tendency to crys-
tallize, or ions with a more diffuse charge. For example, 3-
ethyl-1-methylimidazolium chloride is an organic salt with a
melting point of 77–79 8C that can be lowered to 218Cby
simple replacement of the chloride with a dicyanamide
anion.
[39,41]
Pharmaceutical activity
The question of IL toxicity has
delayed the entry of ILs into the
biosciences. The toxicities ob-
served toward mi croorganisms
and cell cultures cover a wide
range of biocidal potencies,
from those of rather inactive
molecular solvents such as etha-
nol or dimethyl sulfoxide, which
are biocompatible to very high
aqueous concentrations, to
highly active biocides. The latter
have even led to the proposal
for the use of some ionic liquids
as wood preservatives and in a
variety of other pharmaceutical
applications
[39,42]
(Figure 7). The
number of publications report-
ing antimicrobial activity for ILs is growing, and this could be
very interesting for the development of new bioactive materi-
als as antiseptics,
[39,43–45]
for example (Figure 8). Table 1 and
Table 2 list some examples of antimicrobial activity (minimum
inhibitory concentration and minimum bactericidal or fungici-
dal concentration, respectively) observed for ILs based on am-
monium and benzalkonium cations comb ined with sacchari-
nate and acesulfamate anions. These results demonstrate the
potential use of ILs, in particular, against Streptococcus mutans.
ILs could even be used as potential anticancer agents
[22,39,46,47]
(Figure 9 and Table 3). Recently the anti-biofilm activity of
some ILs and their reported potent, broad-spectrum activity
against a variety of clinically significant microbial pathogens,
including methicillin-resistant Staphylococcus aureus (MRSA),
[39]
have been investigated
[45]
(Figure 10 and Table 4).
Microbial biofilms are everywhere in nature and represent
the dominant mode of microorganism growth. Various types
of bacteria, such as MRSA, are observed in colonies adherent
to material surfaces. These colonies often form coatings,
known as biofilms. A common feature of biofilm communities
is their tendency to exhibit significant tolerance and resistance
to antibiotics and antimicrobial or biocidal challenge, relative
to planktonic bacteria of the same species.
[45]
One of the at-
tractions of ionic liquids in this regard is the possibility to tailor
their physical, chemical, and biologi cal properties by building
specific features into the chemical structures of the cation
Figure 7. Some examples of ILs and their application.
Figure 8. Examples of antibacterial agents.
Table 1. Minimum inhibitory concentrations for various ILs and starting salts.
MIC [ppm]
[a]
Strain [BA][Sac] (23)
[b]
[DDA][Sac] (19)
[c]
[BA][Ace](24)
[d]
[DDA][Ace] (25)
[e]
[BA][Cl]
[f]
[DDA][Cl]
[f]
S. aureus 44 4 8 22
S. aureus (MRSA) 4 4 4 4 2 2
E. faecium 88 8 8 44
E. coli 16 16 31 16 8 8
M. luteus 84 8 8 42
S. epidermidis 44 4 4 22
K. pneumoniae 44 8 4 44
C. albicans 16 16 16 16 8 8
R. rubra 16 16 16 16 8 4
S. mutans 0.1 31 1 16 2 2
[a] Lowest compound concentration that inhibits visible growth of a microorganism after overnight incubation.
[b] Benzalkonium saccharinate. [c] Didecyldimethylammonium saccharinate. [d] Benzalkonium acesulfamate.
[e] Didecyldimethylammonium acesulfamate. [f] Starting salts: benzalkonium chloride ([BA][Cl]) and didecyldi-
methylammonium chloride ([DDA][Cl]); data from Hough-Troutman et al.,
[43]
listed for comparison.
978 www.chemmedchem.org 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemMedChem 2011, 6, 975 – 985
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R. Ferraz, Z
ˇ
. Petrovski, et al.
and/or anion components that could
facilitate antibiotic entry into the
biofilm.
The pharmaceutical industry is
currently paying more attention to
ILs because they are customizable
materials that can be specially tail-
ored with selected characteristics by
varying the combination of their cat-
ions and anions. This combination
results in various ILs that can offer a
wide range of hydrophobicity/hydro-
philicity, acidity/basicity, viscosities,
among other attributes.
[39,48]
The arrangement of cations and
anions with few possibilities for
strong attractive intermolecular hydrogen bonding interactions
decreases the potential for crystal lization and provides facile
access to pharmaceutically active ILs.
[39,49]
This will naturally
lead to ILs or salts that otherwise would not be explored if
crystallization is the primary goal. One such example is the
combination of a didecyldimethylammonium cation and sac-
charinate: the former is a cation with antimicrobial activity, and
the latter is an anion with a
sweet taste (compound 19 ,
Figure 7). Indeed, the frequent
designation of “designer sol-
vents” for ILs might be easily
adapted for IL “designer drugs,”
as physical, chemical, and bio-
logical properties of a drug can
be tuned by choice of counter-
ion rather than by covalent
modification.
Some compounds have diffi-
culty penetrating biological
membranes because they are
very hydrophilic. The correct ar-
rangement between an active
ion with another more lipophilic
character could offer a solution
for this problem. An elucidative example is the case of lido-
caine docusate, which combines the local surface anesthetic li-
docaine cation with the hydrophobic anion, docusate (an
emollient) to create a novel hydrophobic IL salt. This IL demon-
strates decreased or controlled water solubility, and thus
should exhibit extended residence time on the skin
[17,39]
(Figure 11). The counterions are chosen by their inactive nature
in order to give the desired physicochemical properties of a
neutral drug. Recently, a small number of so-called “combina-
tion salts” have been prepared, including two active units
(APIs) (compound 36, Figure 11) in the same singular com-
pound coupled as a cation and an an ion.
[39,50]
In general this
approach tends to be influenced by the need to obtain a crys-
talline material, or the fixed stoichiometry of active units found
in such a crystalline salt. So called “dual functionality” has been
explored as an important aspect of the IL field (for example, in
dual acidic or double chiral ILs).
[39,51]
In the context of APIs,
Table 2. The minimum bactericidal or fungicidal concentrations for vari ous ILs and starting salts.
MIC [ppm]
[a]
Strain [BA][Sac] (23)
[b]
[DDA][Sac] (19)
[c]
[BA][Ace](24)
[d]
[DDA][Ace] (25)
[e]
[BA][Cl]
[f]
[DDA][Cl]
[f]
S. aureus 31.2 62.5 31.2 16 62.5 31.2
S. aureus (MRSA) 31.2 31.2 31.2 31.2 31.2 31.2
E. faecium 16 16 31.2 31.2 31.2 31.2
E. coli 62.5 16 125 62.5 62.5 31.2
M. luteus 62.5 31.2 62.5 62.5 31.2 31.2
S. epidermidis 31.2 16 62.5 31.2 16 31.2
K. pneumoniae 62.5 16 31.2 31.2 31.2 16
C. albicans 31.2 16 31.2 31.2 16 16
R. rubra 62.5 31.2 62.5 62.5 31.2 31.2
S. mutans 0.5 62.5 16 125 16 16
[a] Lowest compound concentration requir ed to kill a microorganism. [b] Benzalkonium saccharinate. [c] Dide-
cyldimethylammonium saccharinate. [d] Benzalkonium acesulfamate. [e] Didecyldimethylammonium acesulfa-
mate. [f] Starting salts: benzalkonium chloride ([BA][Cl]) and didecyldimethylammonium chloride ([DDA][Cl]);
data from Hough-Troutman et al.,
[43]
listed for comparison.
Figure 9. Examples of potential anticancer agents.
[46]
Figure 10. Som e examples
of anti-biofilm agents.
[45]
Figure 11. Examples of ILs with targeted biological properties combined
with adequate selected physical and chemical properties.
[17]
ChemMedChem 2011, 6, 975 – 985 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemmedchem.org 979
Ionic Liquids
![Table 6. Examples of drugs (or their APIs) that could be used in ILs that are listed in the 2009 Top-200 generic drugs by retail dollars.[58]](/figures/table-6-examples-of-drugs-or-their-apis-that-could-be-used-5k30ossy.webp)
![Figure 1. The scientific evolution of ILs, from unique physical properties (Generation 1) through the combination of chemical and physical properties (Generation 2), to the more recent studies of their biological and pharmaceutical activities (Generation 3) [adapted from Hough et al] .[17]](/figures/figure-1-the-scientific-evolution-of-ils-from-unique-dlr6zny1.webp)
![Table 4. MIC and minimum biofilm eradication concentration (MBEC)[a] values (in mm) of 1-alkyl-3-methylimidazolium chlorides ([Cnmim]Cl) (33) from Carson et al.[45]](/figures/table-4-mic-and-minimum-biofilm-eradication-concentration-siko0psg.webp)