PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY

2020, VOL. 25, NO. 7, 779–796

https://doi.org/10.1080/10837450.2020.1735414

REVIEW ARTICLE

Deep eutectic solvents for pharmaceutical formulation and drug delivery

applications
Shahram Emamia and Ali Shayanfarb
a
Department of Pharmaceutics, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran; bPharmaceutical Analysis Research
Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

ABSTRACT ARTICLE HISTORY

Solvents play key roles in designing drug delivery systems (DDSs). They are used as the reaction Received 15 July 2019
media in the preparation of DDSs and as vehicles for delivery of problematic drugs. The number of Revised 22 February 2020
pharmaceutically acceptable solvents is limited and developing new green ones is of a great of inter- Accepted 24 February 2020
est. A deep eutectic solvent (DES) is a room temperature liquid composed of a mixture of hydrogen
KEYWORDS
bond acceptor and hydrogen bond donor. DESs exhibit interesting physical and chemical characteris- Deep eutectic solvents;
tics such as low vapor pressure, non-inflammability, chemically tailorable, solvency power for a wide active pharmaceutical
range of solutes, and water non-reactivity. Furthermore, they can be easily prepared from low tox- ingredient; drug delivery;
icity, readily available, and inexpensive constituents. Due to these properties, DESs have attracted solubility; nanomaterials;
growing attention as green solvents in different areas of science from chemistry to material engineer- self-assembly; toxicity
ing and biology. In this review, after a brief introduction about DESs, we provide an overview about
current advances made over the last decade in utilizing of DESs for solubilization of water insoluble
drugs, transdermal drug delivery, inorganic nanoparticle synthesis, and designing polymeric and self-
assembled drug carriers. This paper also discusses main challenges and limitations of DESs that
should be considered before using of them.

1. Introduction -biocompatibility, and -sustainability (Egorova and Ananikov 2014;

Pharmaceutical production processes require solvents and
pharmaceutical industry is one the biggest consumers of organic
solvents (Grodowska and Parczewski 2010). Organic solvents are
involved in synthesis, purification, crystallization, and formulation
processes of active pharmaceutical ingredients (APIs).
Furthermore, solvents play the role of vehicles in designing drug
delivery systems (DDSs), for example for parenteral and transder-
mal delivery of water-insoluble drugs (Mottu et al. 2000).
However, organic solvents are volatile, toxic, flammable, and have
limited solvency (Alonso et al. 2016). Thus, researchers attempt to
find more benign alternatives to problematic organic solvents.
The attempts to discover green and designer solvents brought
ionic liquids (Wilkes and Zaworotko 1992). Ionic liquids (ILs) are
organic salts with melting points less than 100
C and some of
them are in liquid state at room temperature (Marrucho et al.
2014). Ionic liquids exhibit unique characteristics such as low
vapor pressure, non-inflammability, wide liquid-range, chemically
tailorable, solvency power for a wide range of solutes, and chem-
ical and thermal stability (Mizuuchi et al. 2008). Due to these fea-
tures, ILs have been employed extensively as solvents, cosolvents,
and/or materials in different disciplines of chemistry (Plechkova
and Seddon 2008) and biology (Egorova et al. 2017). In the field
of drug delivery, they have been studied for enhancing transder-
mal permeability (Moniruzzaman et al. 2010), improving solubility
(Williams et al. 2014), and developing liquid APIs (Keramatnia
et al. 2016; Shayanfar and Shayanfar 2018). Nevertheless, toxicity
studies on ILs have reported high toxicity, poor-biodegradability,
Amde et al. 2015; Kudłak et al. 2015).
In 2003, Abbott et al. (2003) dissolved a variety of solutes in
the room temperature liquids resulted from mixing two solid
organic materials; urea and a quaternary ammonium salt at a 2:1
molar ratio. The authors employed the term of ‘deep eutectic sol-
vents (DESs)’ to name the formed liquids and suggested DESs as
sustainable, biodegradable, and chemically tailorable solvents.
Since this pioneer work, a rapidly growing interest has been
devoted to DESs because of their unique physical and chem-
ical properties.
Due to the similarities between physical characteristics of DESs
and ILs, DESs are often erroneously categorized as a subclass of
ILs. However, in contrast to ILs that are composed of a pair of
large asymmetric organic cation and inorganic or organic anion,
DESs are mixtures of natural molecules. These two different types
of solvents share common properties including low vapor pres-
sure, high viscosity, non-inflammability, wide liquid-range, chem-
ically tailorable, solvency power for a wide range of solutes, and
chemical and thermal stability. Despite these similar features,
advantages of DESs over ILs such as water nonreactivity, low- or
nontoxicity, biodegradability, ease of preparation, and inexpensive
and readily available constituents suggest DESs as versatile alter-
natives to ILs (Smith et al. 2014).
In this review, first, we give a brief introduction about DESs.
Then we discuss the prominent advances that have been made
over the recent years in the applications of DESs in the different
areas of drug formulation. The paper covers designing polymeric
drug delivery systems, delivery of water insoluble APIs, dermal

CONTACT Shahram Emami emami.sh@umsu.ac.ir; shahramemami67@gmail.com Department of Pharmaceutics, School of Pharmacy, Urmia University of
Medical Science, Urmia 571478334, Iran
ß 2020 Informa UK Limited, trading as Taylor & Francis Group
780 S. EMAMI AND A. SHAYANFAR

Figure 1. Formation of a deep eutectic solvent (DES) between choline chloride and urea. HBA: hydrogen bond acceptor, HBD: hydrogen bond donor, Tm:
melting point.

Table 1. Different types of DESs.
Type Composition
I Organic salt þ metal salt
II Organic salt þ hydrated metal salt
III Organic salt þ hydrogen-bond donor
IV Metal chloride þ hydrogen-bond donor
V Nonionic hydrogen-bond acceptor
þ hydrogen-bond donor
Example
Choline chloride–ZnCl2(1:2)
Choline chloride–CaCl2.6H2O (2:1)
Choline chloride–urea (1:2)
ZnCl2–urea (2:7)
Citric acid–glucose (1:1)
industrial scale production feasible without need to complex
facilities. Most researchers have prepared DESs by direct mixing
with gentle heating (Tang and Row 2013). This method does not
need solvents and produces no waste and by-products. For
thermo-sensitive materials, one can dissolve the components in a
suitable solvent then remove the solvent by evaporation (Dai
et al. 2013) or freeze drying (Gutierrez et al. 2009).

1.1.2. Natural deep eutectic solvents

and transdermal delivery, self-assembly of amphiphilic molecules
in DESs, and synthesis of inorganic nanomaterials. Finally, we dis-
cuss some of the main challenges and limitations of DESs that
should be considered before using of DESs.
1.1. Deep eutectic solvents
A DES is a room temperature liquid composed of a mixture of hydro-
gen bond acceptor (HBA) and hydrogen bond donor (HBD) compo-
nents at a specific molar ratio (Smith et al. 2014). The pure
components are typically solid at ambient condition but formation
of strong intermolecular interactions mainly as hydrogen bonds leads
to significant melting point depression of the mixture (Figure 1).
Based on the compositions, Smith et al. (2014) classified DESs into
four types (types I–IV of Table 1). However, some recently developed
DESs could not belong to the types I–IV. Therefore, we added Type V
to Table 1 to cover all DESs discussed in the literature. It is worth not-
ing that in addition to binary mixtures, DESs can also originate from
three components (Liu et al. 2014; Zhang et al. 2016). Types III and V
include most of the studied DESs in the field of pharmaceutics
because of their advantages such as power to dissolve chemically
diverse compounds, low-toxicity, large number of possible combina-
tions, nonreactivity with water, and biodegradability.
Figure 2 presents examples of common HBAs and HBDs to
prepare DESs. The structure of HBA and HBD and their molar ratio
determine the physicochemical characteristics of a DES (Rado
sevic
et al. 2016). Therefore, a tailor made DES can be customized for a
certain purpose by choosing appropriate ratios of HBAs and
HBDs. Theoretically around 106 DESs can form by combining com-
ponents that show eutectic behavior and many have been devel-
oped in last few years (Francisco et al. 2013). This huge number
of combinations makes DESs as designer solvents. Furthermore, a
third component such as water can be added to optimize the
properties of the DES.
1.1.1. Preparation of DESs
In contrast to ILs, DESs have an easy way of synthesis because
their synthesis involves no chemical reaction (salt formation)
between HBA and HBD constituents. This simplicity makes
In 2011, Choi et al. (2011) hypothesized that primary plant metab-
olites may form a liquid medium other than two immiscible liquid
phases of plant cells (water and lipids). This third liquid phase
may be involved in certain biosynthetic steps or storage of water
insoluble products. The authors prepared a 30 set of novel DESs
containing natural cellular constituents including sugars, carbox-
ylic acids, aminoacids, choline, and water and named the resulted
DESs as natural deep eutectic solvents (NADES). Since then, more
than 150 NADES composed of sugars, sugar alcohols, polyalco-
hols, organic acids and bases, and amino acids and also ternary
NADES have been reported (Liu et al. 2018). Due to their natural
origin, NADESs are considered as non-toxic and biodegrable and
environmentally benign alternatives for ILs and DESs.
1.1.3. Active pharmaceutical ingredient based DESs
Many APIs have hydrogen-bond donors or acceptor groups in their
structures; therefore, eutectic systems can be developed composed
of one or more API. If the formed eutectic systems melt at temper-
atures lower than room temperature they are named as API based
DESs or Simply API-DESs (Abbott et al. 2017). API-DESs can be
formed between an API and excipient or between two APIs.
Examples of reported API-DESs are ibuprofen–menthol (Aroso et al.
2015), lidocaine–1,8 octanediol (Serrano et al. 2012), lidocaine–prilo-
caine (Brodin et al. 1984), ranitidine hydrochloride–urea, and aspir-
in–choline chloride (Abbott et al. 2017). API-DESs, also called
therapeutic deep eutectic systems, have been used to design poly-
meric drug delivery system (Serrano et al. 2012), overcome poly-
morphism (Abbott et al. 2017), enhance dissolution rate (Aroso
et al. 2016), increase membrane permeability (Santos et al. 2018),
and improve transdermal delivery (Stott et al. 1998). Until now,
most of the research conducted on API-DESs has focused on trans-
dermal delivery of APIs using API-DESs, therefore we will discuss
this topic in a separate sub-section (Section 2.5.1).
2. Applications of DESs in drug delivery fields
To achieve the desired therapeutic effects, APIs must efficiently
and specifically reach to their sites of action. However, transport-
ing APIs from the administration point to the site of action is

Figure 2. Structures of some hydrogen bond acceptors and hydrogen bond donors utilized in the preparation of DESs.
often hampered by poor biopharmaceutical properties such as
low solubility in body fluids, low permeability through biological
membranes, chemical instability, and rapid metabolism and elim-
ination from the body (Emami et al. 2018). To address the men-
tioned problems, APIs are formulated as various types of drug
delivery systems such as solid dispersions (Serajuddin 1999), coc-
rystals (Emami et al. 2019), and polymeric delivery systems
(Kumari et al. 2010). In the following section, we attempt to
briefly overview potentials of DESs to improve drug delivery.
2.1. Designing polymeric drug delivery systems by DESs
Polymeric carriers improve efficacy of drug delivery by controlling
release, providing cell- and tissue-specific targeted delivery, and
protecting from degradations (Tibbitt et al. 2016). Natural (Yang
et al. 2015), semi-synthetic (Qi et al. 2015), and synthetic (Englert
et al. 2018; Selselehjonban et al. 2019) polymers are used to
design DDSs. However, there are remaining challenges in green
synthesis, processing, and efficient loading of drugs in poly-
meric carriers.
In the last decade, DESs have emerged as alternative reaction
media for synthesis of functional materials such as nanomaterials
(Chen et al. 2013), metal-organic frameworks (Zhang et al. 2009),
and biocompatible polymers (Sanchez-Leija et al. 2014;
Pradeepkumar et al. 2018), as well as enzymatic reactions (Durand
et al. 2012). DESs can provide green media for polymerization
reactions to occur where DESs may act as solvent, monomer, or
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 781
functional additive. By using DESs, synthesis can occur in mild
conditions (lower temperature, biocompatible media). In addition,
availability of numerous nontoxic combinations makes it possible
to modulate DES properties and provide optimized condition for
each reaction. Therefore, biocompatible and environmentally
friendly synthesis methods can be designed (del Monte et al.
2014). Some excellent reviews have been published on applica-
tions of DESs as reaction media for synthesis of different types of
materials (Carriazo et al. 2012; del Monte et al. 2014; Alonso et al.
2016; Mota-Morales et al. 2018).
2.1.1. DESs as media for synthesis of polymers
Probably the first attempt to design polymeric carrier by DESs
was polycondensation of citric acid with 1,8-octanediol to synthe-
size poly(diol-co-citrate) (Serrano et al. 2012). Poly(diol-co-citrate),
a biodegradable and biocompatible elastomer, can function as a
tissue-engineering scaffold (Prabhakaran et al. 2012) and shape-
memory polymer for temperature-controlled drug delivery
(Serrano et al. 2011). The routine synthesis of this elastomer needs
a very high temperature (several minutes at 160–165
C followed
by 60 min at 140
C) which can lead to thermal instability of APIs
intended to be loaded in it. Difficulty in homogeneous loading of
high amounts of APIs in the prepared elastomer can pose more
challenge to conventional methods. To overcome these obstacles,
Serrano et al. (2012) introduced a DES-assisted synthesis method
to prepare poly(octanediol-co-citrate) elastomers containing high
loading of lidocaine (Figure 3). First, they prepared lidocaine–1,8-
782 S. EMAMI AND A. SHAYANFAR
Figure 3. Schematic representation of the preparation of lidocaine loaded poly(diol-co-citrate) elastomer by using DES assisted synthesis method. Tm represents melt-
ing point.
octanediol (1:1) API-DES with a melting point of 40
C. Then citric
acid was dissolved in the liquid API-DES. By increasing the tem-
perature of the resulted solution to about 90
C, polycondensation
reaction was started and lidocaine loaded elastomer was formed.
In the mentioned example, DES-assisted synthesis resulted in a
homogenous and high drug loading and protected the thermoli-
able lidocaine from degradation.
With the aim of preparing antimicrobial wound dressings,
Garcıa-Arg€uelles et al. (2013) attempted to incorporate high con-
centrations of antibacterial compounds into networks of poly(diol-
co-citrate) polyester by using DES-assisted polymerization. To this
means, first, they prepared API-DESs of antimicrobial agents
including tetraethylammonium bromide, hexadecyltrimethylam-
monium bromide, and methyl triphenyl phosphonium bromide
with 1,8-octanediol. Then citric acid was dissolved in the resulted
liquids. Finally, polymerization was performed by thermal cross
linking at 80
C. Resulting biodegradable polysters were cytocom-
patible with murine L929 fibroblasts and inhibited Escherichia coli
bacteria growth on solid agar.
In another study, 2-hydroxyethylmethacrylate (HEMA), a com-
monly used monomer to produce biocompatible polymers, self-
polymerized in choline chloride–fructose (2:1) in the presence of
indomethacin, a model anti-inflammatory drug (Mukesh et al.
2016). The API was immobilized in the formed poly(2-hydroxye-
thylmethacrylate) ion gel and the immobilized API was stable up
to 6 months at room temperature. Drug release studies showed
that the formed ion gel was stable in gastrointestinal fluid pH
and showed pH dependent and sustained drug release. In add-
ition, in vitro cell viability and hemolysis assays showed noncyto-
toxic and hemocompatible nature of the ion gel.
2.1.2. DESs as media to process biopolymers
Naturally occurring polymers, or simply biopolymers, are derived
from living organisms and include proteins, polysaccharides, and
nucleic acids. Biodegradability, biocompatibility, and low immuno-
genicity of biopolymers make them promising carriers for drug
delivery applications (Talebian et al. 2018). However, low solubility
of most biopolymers in conventional solvents significantly limits
the development of functional materials based on these versatile
carriers (Mondal et al. 2013). The ability of DESs to dissolve vari-
ous types of biopolymers ranging from DNA to proteins and poly-
saccharides have suggested them as processing media for these
valuable materials and some biopolymer-based functional materi-
als have been developed in DESs (Mondal et al. 2013; Sharma
et al. 2013).
In recent decade, DNA, owing to its unique physicochemical
properties, have been introduced as a useful tool for designing
materials with desired properties (Han et al. 2017). Mukesh and
Prasad (2015) used a choline chloride–ethylene glycol (1:2) to pre-
pare different structural formats of DNA including pH reversible
ion gel having aggregated DNA structures, pH responsive DNA
micro-hydrogels, and spheroid-shaped DNA micro-structured
assemblies. The formed structures would find applications in drug
and gen delivery purposes.
DNA-hybrid nanomaterials can be used for gene- and drug-
delivery and also as antimicrobial agents (Bhatt et al. 2015; Zhang
et al. 2015). Hybrid materials of DNA with metal nanoparticles
based on iron, gold, and silver have been prepared using DESs as
reaction media. As an example, a DNA based material exhibiting
magnetic and antibacterial properties was prepared in a DES com-
posed of choline chloride–ethylene glycol (1:2) (Mondal et al.
2014). For this mean, iron oxide nanoparticles and protonated lay-
ered dititanate sheets were added to the solution of DNA in the
DES. Then the dual functionalized DNA based material was pre-
cipitated by isopropyl alcohol (Figure 4). In the same context,
Bhatt et al. (2016) used choline chloride–ethylene glycol (1:2) DES
for functionalizing of DNA with iron oxide nanoparticles and N-
doped graphene. These hybrid martials of DNA can be used for
drug and gen delivery applications.
In addition to DNA, polysaccharides can also be processed in
DESs. Chitin is an amino-polysaccharide and is obtained from the
exoskeletons of shellfish and insects (Rinaudo 2006). This abun-
dant natural polymer is a promising carrier for wound care and
drug delivery due to its advantages such as, being mucoadhesive
and low toxicity (Mi et al. 2003; Madhumathi et al. 2010).
However, the application of chitin is limited mainly because of its
insolubility in water and conventional organic solvents (Sharma
et al. 2013). In a study, DES of choline chloride–thiourea (1:2) was
 PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 783

Figure 4. Schematic representation of the preparation of the DNA based hybrid material in choline chloride–ethylene glycol (1:2).

Figure 5. Scanning electron microscopy images of star-, snowflake-, and thorn-shaped gold nanoparticles synthesized in choline chloride–urea (1:2) by varying the
water content in the DES. Pure choline chloride–urea (1:2): snowflake-shaped, 5000 ppm of water in the DES: star-shaped, and more than 10 000 ppm of water in the
DES: thorn-shaped. The figure was adapted with permission from (Liao et al. 2008). Copyright (2008) Wiley-VCH.

successfully used to prepare chitin nanofibers with diameter of
20–30 nm (Mukesh et al. 2014). By using these nanofibers, the
authors were able to prepare bionanocomposite gel beads of cal-
cium alginate containing 5-flurouracil, an antitumor drug.
Addition of chitin nanofibers to calcium alginate beads improved
the elasticity of beads and provided a higher released drug in a
sustained manner in comparison to calcium alginate beads.
2.2. DESs in the synthesis of inorganic nanomaterials
Inorganic nano-sized materials can be used in imaging or targeted
drug delivery and have found undeniable position in detection
and treatment of diseases (Liang et al. 2014). An emerging area of
application of DESs is as media for designing/synthesis of desired
nanomaterials. Some review articles have been published on
applications of DESs in nanotechnology (Wagle et al. 2014; Abo-
Hamad et al. 2015; Tome et al. 2018). In this section, we briefly
discuss the potential applications of DESs for designing tailor
made nanomaterials with pharmaceutical interests.
The first report on application of DESs in this area was by Liao
et al. (2008) in 2008. The authors synthesized various shapes of
gold nanoparticles in choline chloride–urea (1:2) by simply varying
the water content in the DES without seeds or stabilizer at
ambient condition (Figure 5). Since then, DESs have been used
for decorating various shape and size controlled nanomaterials
with pharmaceutical interests including, calcium phosphate nano-
particles (Karimi et al. 2016), iron oxide magnetic nanoparticles
(Chen et al. 2013), Prussian blue nanoparticles (Sheng et al. 2012),
silver nanoparticles (Bhatt et al. 2015), and carbon nanomaterials
(Abo-Hamad et al. 2017).
In addition to synthesis, DESs can also be utilized for function-
alizing nanomaterials to give them particular properties.
Functionalization is the process of modifying the surface of nano-
materials by adding desired functional groups through physical or
chemical bonding (Emadi et al. 2017). DESs have been studied as
functionalizing agents for carbon nanotube (Abo-Hamad et al.
2017) and graphene (Zainal-Abidin et al. 2019). Graphene is a
promising drug nanocarrier but its drug delivery applications have
been hampered due to the cellular toxicity (Guo and Mei 2014).
Surface modification with DES has been successfully utilized to
improve biocompatibility, reduce cellular toxicity, and enhance
drug loading of graphene (Zainal-Abidin et al. 2020). For instance,
Zainal-Abidin et al. (2019) utilized choline chloride–urea (1:2), cho-
line chloride–glucose (2:1), choline chloride–fructose (2:1), and
choline chloride–malonic acid (1:1) to modify the surface of gra-
phene by sonication of the suspension of oxidized graphene in
784 S. EMAMI AND A. SHAYANFAR
DESs for 3 h at 60
C. The functionalization was confirmed by
Fourier transform infrared spectroscopy and Raman spectroscopy.
Results indicated that not all of the studied DESs could improve
the biocompatibility of oxidized graphene. Indeed, oxidized gra-
phene modified with choline chloride–urea (1:2), choline chlori-
de–glucose (2:1), and choline chloride–fructose (2:1) were more
toxic to some studied cell lines than untreated oxidized graphene.
The best result obtained for choline chloride–malonic acid (1:1).
Graphene oxide modified with this DES showed lower toxicity in
human cell lines and higher loading of tamoxifen compared to
untreated graphene oxide. The authors attributed the observed
results to differences in added functional groups by investi-
gated DESs.
2.3. Applications of DESs in delivery of poorly water
soluble APIs
Aqueous solubility/dissolution rate plays an important role
through all stages of drug discovery and development process;
from early pharmacological and toxicological evaluations of drug
candidates to development of effective pharmaceutical product
(Williams et al. 2013; Emami et al. 2015). It is important because
only solubilized form of a compound can transport through bio-
logical membranes and exhibit pharmacological effect. The num-
ber of drug candidates with poor aqueous solubility is increasing
and it is estimated that about 90% of drug candidates in develop-
ment pipelines exhibit low aqueous solubility (Thayer 2010).
During drug discovery programs, dimethyl sulfoxide (DMSO) is
widely used as the solvent of water insoluble drug candidates for
biological in vitro and in vivo studies (Santos et al. 2003).
However, recent studies have questioned the safety of DMSO
even at low concentrations (Galvao et al. 2014; Li et al. 2016).
Therefore, it is desirable to find nontoxic and biocompatible alter-
natives for DMSO.
In addition to challenges in pharmacological tests, when
administered through the oral route, poorly soluble drugs usually
face with problems such as large dose, insufficient bioavailability,
delayed onset of action, and erratic absorption (Pouton 2006).
About 40% of marketed drugs are poorly water soluble (Takagi
et al. 2006). Therefore, finding efficient ways to improve solubility
and dissolution rate is essential for translating promising new
drug candidates into effective therapies and even improving effi-
cacy of marketed drugs.
2.3.1. DESs as solvents for pharmacological evaluations of
drug candidates
An ideal vehicle/solvent for in vitro and in vivo bioactivity tests of
candidate drug molecules must be nontoxic, inert, and possess
high solvation properties. Recently some studies have explored
DESs as suitable solvents for in vitro pharmacological studies of
drug candidates. In this context, Rozema et al. (2015) investigated
the possibility of dissolving salsalate, a poorly water-soluble
compound, in a DES composed of choline chloride–propylene gly-
col–water (1:1:1) as an alternative to DMSO for in vitro pharmaco-
logical tests. When this DES was used as the solvent, salsalate
remained soluble in the aqueous medium of cell culture in higher
concentrations in comparison to DMSO. These higher dissolved
concentrations allowed authors to generate full dose-response
curves for salsalate. In addition, as DMSO, the studied DES was
nontoxic in concentrations up to 1%, and did not influence the
cellular viability. However, one drawback of the studied DES was
chemical instability of salsalate in it whereas salsalate was stable
in DMSO up to three months. Another study showed that
dissolving of phenolic antioxidants in DESs, as alternatives for
DMSO or ethanol, could result in higher antioxidant activities in
fibroblast cell model (Durand et al. 2017). The improvement
mechanisms probably were through an enhancement of cell
membrane permeation capacity, or an optimization of activity
within the intracellular medium.
In the same line, Shamseddin et al. (2017) studied suitability of
various DESs to dissolve resveratrol and compared in vitro
pharmacological activities of the compound dissolved in the
selected DES with resveratrol dissolved in DMSO. Resveratrol, a
powerful antioxidant, is a low-water soluble compound with low
oral bioavailability (Pujara et al. 2017). Among the studied DESs,
1,2-propanediol–choline chloride–water (1:1:1) showed the lowest
cytotoxicity and exhibited highest solvency for resveratrol.
Resveratrol dissolved in this DES could show ten times higher
in vitro pharmacological activity when compared with the com-
pound dissolved in DMSO. This higher activity in the presence of
DES was attributed to improvements in resveratrol diffusion,
transport and, cellular uptake.
2.3.2. DESs as carriers for solubilization of poorly soluble drugs
In 2009, Morrison et al. (2009) introduced, for the first time, the
use of DESs as drug solubilization vehicles. Since then, several
studies have explored the potential of DESs as pharmaceutical sol-
vents (Table 2). Until now, most of the studies have used choline
chloride based DESs probably because they are the most common
DESs. As it can be seen in Table 2, solubility of poorly soluble
APIs in DESs can dramatically be higher by 6- to 2200-fold com-
pared to their water solubility. Generally, a solvent must be able
to dissolve greater than 1 mg/mL of an API to be utilized in
pharmaceutical processing (Marrucho et al. 2014). Considering this
criteria, DESs can play an important role as solvents and cosol-
vents in drug delivery applications.
Lu et al. (2016) reported the solubility of aspirin, acetamino-
phen, naproxen, ketoprofen, and ibuprofen in 17 types of DESs.
The studied APIs could be dissolved 17- to 5477 times better by
DESs than by water. In addition to DES composition, solubility
also was dependent to molar ratios of the components of DES. All
five drugs showed the highest solubility in tetra propyl ammo-
nium bromide–propylene glycol (1:2). The authors could not find
meaningful correlations between drug solubility and physico-
chemical properties of DESs including viscosity, polarity, and pH.
Also to be mentioned is the work of Palmelund et al. (2019), who
measured solubilities of 11 APIs in water, conventional pharma-
ceutical solvents, and six DESs with different HBAs and HBDs. The
results showed that for water insoluble APIs such as indometh-
acin, aprepitant, celecoxib, cinnarizine, and flufenamic acid the
solubility was higher in a DES than in water. As an example, solu-
bility of celecoxib was about 104 times higher in choline chlori-
de–lactic acid–water (1:0.9:0.6) than water. Furthermore, for some
of the studied APIs, the solubility was higher in a DES than com-
monly used pharmaceutical solvents; glycerin, ethanol, and poly-
ethylene glycol 300. These data suggest that DESs may be useful
as carriers for solubilization of poorly soluble drugs. Many more
of such head to head comparisons should be performed between
solubility of APIs in DESs and conventional pharmaceutical sol-
vents to evaluate real potential of DESs.
The chemical structure of the components of a DES and their
molar ratio strongly affect solvation properties, probably by
changing polarity and pH, and introducing new intermolecular
interactions. Some studies have reported the dependence of the
API solubility in DESs to these structural features (Morrison et al.
2009; Lu et al. 2016; Palmelund et al. 2019). Jelin ski et al. (2019)
 PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 785

Table 2. Examples of solubility of APIs in water and DESs.

Solubility in Solubility in
API Log P DES (molar ratio) DES (mg/mL) water (mg/mL) Solubility ratioa Reference
Acetylsalicylic acid 1.1 Propylene glycol–choline chloride (2:1) 202 7.03 29 (Lu et al. 2016)
Acetaminophen 0.5 Propylene glycol–choline chloride (2:1) 324 19.95 16 (Lu et al. 2016)
Ketoprofen 3.1 Propylene glycol–choline chloride (2:1) 253.40 0.34 744 (Lu et al. 2016)
Naproxen 3.2 Propylene glycol–choline chloride (2:1) 45.26 0.06 754 (Lu et al. 2016)
Ibuprofen 4 Propylene glycol–choline chloride (2:1) 183.3 0.07 190 (Lu et al. 2016)
Itraconazole 5.7 Malonic acid–choline chloride (1:1) 22 <0.001 >22 000 (Morrison et al. 2009)
AMG517 – Malonic acid–choline chloride (1:1) 0.4727 <0.0001 >4727 (Morrison et al. 2009)
Griseofulvin 2.2 Malonic acid–choline chloride (1:1) 1 0.007 143 (Morrison et al. 2009)
Danazol 4.2 Malonic acid–choline chloride (1:1) 0.16 <0.0005 >320 (Morrison et al. 2009)
Benzoic acid 1.9 Urea–choline chloride (2:1) 229 3 76 (Morrison et al. 2009)
Berberine 1.3 Proline–urea (2:1) 12.3 2.1 6 (Sut et al. 2017)
Rutin 0.9 Proline–choline chloride (1:2) 2.643 0.12 22 (Faggian et al. 2016)
Itraconazole 5.7 Glycolic acid–cholinchloride (2:1) 6.7 <0.001 >6700 (Li and Lee 2016)
Piroxicam 3.1 Glycolic acid–cholinchloride (2:1) 9.9 0.023 430 (Li and Lee 2016)
Posaconazole 5.5 Glycolic acid–cholinchloride (2:1) 76.8 0.012 6400 (Li and Lee 2016)
Lidocaine 2.4 Glycolic acid–cholinchloride (2:1) 100.60 3.63 28 (Li and Lee 2016)
Daidzein 2.5 Borneol–menthol (1:3) 0.400 0.008 50 (Shen et al. 2011)
Imipenem 3.9 Trimethylglycine–urea (2:3) 11.32 9.92 1.1 (Olivares et al. 2018)
Clavulanic acid 1.5 Trimethylglycine–urea (2:3) 173.62 289.44 0.6 (Olivares et al. 2018)
a
The ratio of solubility of API in DES to solubility in water.

Figure 6. Solubility of curcumin in NADESs based on choline chloride and

selected HBDs at different molar ratios. Molar ratio (choline chloride: HBD). Data
ski et al. (2019).
were taken from Jelin
measured solubility of curcumin in NADESs based on choline
chloride as HBA and sugars and sugar alcohols as HBD. As it can
be seen from Figure 6, changing HBD type and molar ratio have
significant effect on curcumin solubility. The authors did not pro-
vide possible explanations behind the obtained results. Further
studies are needed to shed a mechanistic light on the influence
of different structural parameters of DESs on their solvency.
Presence of water can greatly influence the properties of DESs
such as viscosity, polarity, and solvency power (Shekaari et al.
2018). Generally, solubility of poorly water soluble drugs in DESs is
significantly decreased by addition of water (Figure 7). The trend of
decrease in solubility is dependent on drug structure and DES type
(Lu et al. 2016). The added water can weaken intermolecular inter-
actions, especially hydrogen-bonding interactions, between the
components of DES. It has been shown that high amounts of water
(>50%) can completely rupture the hydrogen bonds and destroy
the supramolecular structure of DES (Dai et al. 2015).
Despite an exponentially increasing number of published data
on APIs solubility in DESs, the study of solute-solvent interactions
and solubilization mechanisms of APIs by DESs has received little
attention to date. Gutierrez et al. (2018) utilized density functional
theory and molecular dynamics methods to investigate the solv-
ation process of lidocaine in choline chloride–lactic acid (1:1) and
b-alanine–lactic acid (1:1). The results of analyses indicated that
the drug molecule interacts with components of DESs in solution
through formation of a combination of hydrogen bonding and
Figure 7. Solubility of itraconazole and benzoic acid in malonic acid–choline
chloride (1:1) containing different percentage of water. Data were taken from
Morrison et al. (2009).
nonspecific van der Waals interactions. The same research group
subsequently showed that lidocaine forms strong hydrogen bonds
with arginine and organic acids when dissolves in arginine–gluta-
mic acid (1:1), arginine–oxalic acid (1:1), and arginine–tartaric acid
(1:1) (Gutierrez et al. 2019).
Taking into account the large number of possible DESs and in
the absence of predictive tools considerable time- and labor-
intensive experimental work is needed to identify the best DES
solvent for a given API. Therefore, computational methods are
necessary to speed the screening process. Recently Palmelund
et al. (2019) performed a computational approach based on the
conductor-like screening model for real solvents (COSMO-RS) to
predict solubility of APIs in DESs. The API solubility calculated by
COSMO-RS was found in good agreement with experimentally
measured one. The authors concluded that COSMO-RS can help
to determine DESs with high solvation capacity for a given API.
Turning now to in vivo studies, to date, only very few studies
have assessed the oral pharmacokinetics of poorly soluble APIs dis-
solved in DESs (Faggian et al. 2016; Sut et al. 2017). Berberine is a
natural plant alkaloid with antidiabetic, antihypertensive, cholesterol
lowering, and anti-inflammatory effects (Jin et al. 2016). It exhibits
low oral bioavailability (less than 1%) due to low solubility and
poor membrane permeability (Zhaojie et al. 2014). As an attempt
to solve the solubility problem, a series of 38 DESs were prepared
786 S. EMAMI AND A. SHAYANFAR
Figure 8. Solubility of berberine in: water, (A) proline–malic acid (1:2), (B) proli-
ne–urea (2:1), and (C) proline–malic acid–lactic acid–water (1:0.2:0.3:0.5). Data
were from (Sut et al. 2017).
Figure 9. Plasma concentration-time profiles of berberine; (Water) suspended in
water, (A) dissolved in proline–malic acid (1:2), (B) dissolved in proline–urea (2:1),
and (C) dissolved in proline–malic acid–lactic acid–water (1:0.2:0.3:0.5) in mice
(n ¼ 15, mean ± SD) The figure was adapted with permission from (Sut et al.
2017) Copyright (2017) MDPI.
and used to dissolve berberine (Sut et al. 2017). From the several
DESs studied, three DESs with higher solvency power for the drug
(Figure 8) were selected for pharmacokinetic studies. To assess the
bioavailability, mice were orally gavaged with berberine suspended
in water or dissolved in the selected DESs. Dissolving berberine in
DESs, especially in proline–malicacid–lactic acid–water (1:0.2:0.3:0.5),
led to significant increases in oral bioavailability of berberine
(Figure 9). The maximum plasma concentration and the area under
the mean plasma concentration-time curve values of berberine dis-
solved in this DES were approximately 6- and 4-fold higher than
those of berberine suspension. Improvements in the bioavailability
were attributed to solubilization of the drug by DESs. Many more
such in vivo studies in animal models and then in human subjects
are required to verify the real potential of DESs in improving bio-
availability of poorly soluble APIs.
2.4. Self-assembly of amphiphiles in DESs
Molecular self-assembly is the spontaneous and reversible associ-
ation of amphiphilic molecules by means of non-covalent interac-
tions such as hydrogen bonding, van der Waals, electrostatic, or
hydrophobic forces to adopt well-defined patterns or structures
(Dehsorkhi et al. 2014). Amphiphilic molecules including surfac-
tants (Svenson 2004), block copolymers (Mai and Eisenberg 2012),
lipids (Antonietti and Fo €rster 2003), and some peptides (Zhang
et al. 2002) can self-assemble into a number of various supra-
molecular nanostructures such as liposomes, micelles, vesicles,
tubes, fibers, and lamellas in the solution. Using self-assembled
structures as drug carriers are of great interest in pharmaceutical
sciences due to their advantages such as solubilization potential,
targeted delivery, intracellular delivery, prolonged delivery,
improved permeability through membrane barriers, and possibility
of delivery of both hydrophilic and lipophilic drugs (Ariga et al.
2011; Cui et al. 2016).
Self-assembly only occurs in very limited number of solvents.
Prior to introduction of ionic liquids, only 17 solvents including
water and some H-bonding molecular solvents had been shown
to support self-assembly of amphiphilic molecules (Greaves and
Drummond 2013). Although ionic liquids have begun to attract
interests as self-assembly media, their limitations necessitate
exploring for better alternatives (Greaves and Drummond 2008).
Possibility of the presence of solvophobic interactions in DESs
make them appropriate media for generating ordered structures
of amphiphilic molecules (Bryant et al. 2016). Self-assembly of cat-
ionic (Sanchez-Fernandez et al. 2016), anionic (Pal et al. 2014),
and zwitterionic surfactants (Sanchez-Fernandez et al. 2018) have
been reported in DESs. Sodium lauryl sulfate (SLS), an anionic sur-
factant, forms micelles in pure choline chloride–urea (1:2) (Arnold
et al. 2015). The behavior of SLS differs greatly in this DES in com-
parison to water. Micelles of SLS in the DES are cylindrical in com-
parison to its spherical micelles in water. In addition, critical
micelle concentration of SLS in choline chloride–urea (1:2) is four
times lower than its CMC in water. As another example, Li et al
(Li et al. 2018) showed that a cationic surfactant cetylpyridium
bromide could form various aggregates, including micelles, hex-
agonal, bicontinuous cubic and lamellar phases in choline chlori-
de–glycerol (1:2) and choline chloride–ethylene glycol (1:2).
Self-assembly of a series of single-chain n-alkyltrimethylammo-
nium based cationic surfactants has been shown in choline chlori-
de–glycerol (1:2) by using fluorescence probe, electrical
conductivity, surface tension, small-angle X-ray/dynamic light scat-
tering, and transmission electron microscopy methods (Pal et al.
2015). The authors reported that hexadecyl trimethylammonium
bromide self-assembled as aggregates with a mean size of about
36 nm in the DES (Figure 10).
Beside to surfactants, self-assembly of lipids has also been
reported in DESs. By using solvent penetration experiments and
small-angle X-ray scattering, Bryant et al. (2016) were able to
show that phosphatidylcholine lipids dissolved in choline chlori-
de–urea (1:2) DES self-assemble to vesicles above phase transition
temperature of lipids. In another study, the same authors reported
that DESs composed of alkylammonium halide salts and glycerol
or ethylene glycol support self-assembly of phosphatidylcholine
lipids (Bryant et al. 2017). These findings may expand applications
of biocompatible DESs to develop self-assembled drug carriers
and open new ways for designing drug delivery systems.
2.5. Application of DESs in dermal and transdermal
drug delivery
Drug delivery across the skin offers distinct advantages over other
routes of administration. The advantages are being non-invasive,
better patient compliance, avoiding pre-systemic gastrointestinal
and hepatic metabolism, lower side effects, direct access to target

Figure 10. Transmittance electron microscopy images for hexadecyl trimethylammonium bromide [20 mM (left) and 50 mM (right)] in choline chloride–glycerol (1:2).
The figure was adapted with permission from (Pal et al. 2015). Copyright (2015) Wiley-VCH.
Figure 11. Schematic presentation of the preparation of an oil in water emulsion based on a deep eutectic mixture of lidocaine and prilocaine.
or diseased site, and capability for sustained and controlled deliv-
ery (Brown et al. 2006).
The major challenge in designing delivery systems for treat-
ment of dermatological diseases (topical or dermal delivery) or for
systemic delivery through skin (transdermal delivery) is low per-
meability of skin (Alvarez-Roman et al. 2003). The human skin
inherently possesses significant barrier properties to protect body
organs from entrance of foreign toxins and minimize water loss.
The stratum corneum (SC), the non-living, outermost layer of the
skin, especially hinders the permeation of most APIs (Prausnitz
et al. 2004). Only a limited number of drugs with low molecular
weight (<500 Da) and optimum lipophilicity (Log P ¼ 1–3), can
effectively penetrate through the intact skin (Naik et al. 2000).
Therefore, appropriate permeability enhancement strategies
should be used for hydrophilic drugs and macromolecules.
Various strategies such as chemical penetration enhancers
(Pham et al. 2016), physical methods (Nanda et al. 2006), and ves-
icular carriers (Dubey et al. 2006) have been investigated to
improve skin permeability of APIs. These strategies are mainly
based on disrupting the SC barrier or altering the lipid structure.
Toxicity and skin irritation of chemical enhancers and infections,
burns, and scars related to physical methods have necessitated
the introduction of effective and safe enhancement approaches
(Karande and Mitragotri 2009; Banerjee et al. 2017).
Due to the low toxicity and being liquid at room temperature,
eutectic mixtures have been investigated for dermal and transder-
mal drug delivery applications. For these purposes, some
researches have focused on converting solid APIs to API-DESs (oil
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 787
at room temperature) by using appropriate excipients and others
have used DESs as the carrier for APIs.
2.5.1. Using API-DESs for dermal and transdermal drug delivery
From the historical point of view, the first applications of API-
DESs in the field of drug delivery seems to has been reported for
topical and transdermal delivery. In 1889, Jules-Aristide Bonain
discovered that phenol, cocaine hydrochloride, and menthol in
equivalent proportions form a room temperature liquid and used
the formed liquid mixture for topical anesthesia (Fiala et al. 2010).
Later in 1984, it was reported that lidocaine and prilocaine forms
a 1:1 eutectic mixture with the melting point of 18
C (Brodin
et al. 1984). Then, this API-DES was formulated as an oil in water
emulsion (Figure 11) called EMLAV (Eutectic Mixture of Local
R
Anesthetics) cream and was consequently approved by FDA for
local anesthesia in 1992 (Nyqvist-Mayer et al. 1986; Eichenfield
et al. 2002). The analgesic effectiveness of emulsion formulation
based on the API-DES is higher than either prilocaine or lidocaine
applied alone (Gajraj et al. 1994). EMLAV cream still is the most
R
widely used topical anesthetic. In the same line, an aerosol-deliv-
ery form containing lidocaine–prilocaine eutectic-like mixture
(FortacinTM) was approved to be used for treatment of premature
ejaculation in the European Union in 2016 (Porst and Burri 2017).
These marketed examples highlight the great potential of the
API-DESs in the area of dermal and transdermal drug delivery.
The mentioned successful examples have motivated research-
ers to attempt eutectic formation approaches for transdermal
delivery of other drugs. API-DESs could enhance the transdermal
788 S. EMAMI AND A. SHAYANFAR

Table 3. API-DESs reported for transdermal delivery applications.

Tm of
API Coformer Mole ratio Tm of API coformer Tm/Tg of API-DES Reference
Ibuprofen Menthol 3:7 76 41 19 (Stott et al. 1998)
Ibuprofen Methyl nicotinate 1:1 (w/w) 76 41 a (Woolfson et al. 2000)
Itraconazole Phenol 1:1 168 39 <0 (Park et al. 2012)
Lidocaine Camphor 1:1 (w/w) 68 175 33 (Gala et al. 2015)
Lidocaine Tetracaine 1:1 (w/w) 68 41 30 (Gala et al. 2015)
Lidocaine Decanoic acid 1:1 68 32 61 (Bica et al. 2011)
Lidocaine Hexanoic acid 1:1 68 3 56 (Bica et al. 2011)
Lidocaine Linoleic acid 1:1 68 5 71 (Bica et al. 2011)
Lidocaine Oleic acid 1:1 68 13 47 (Bica et al. 2011)
Lidocaine Stearic acid 1:1 68 69 43 (Bica et al. 2011)
Lidocaine Ibuprofen 1:1 68 76 27 (Wang et al. 2014)
Lidocaine Menthol 3:7 (w/w) 68 41 26 (Kang et al. 2000)
Lidocaine Phenyl salicylate 3:2 68 41 18 (Lazerges et al. 2010)
Lidocaine Prilocaine 1:1 68 38 18 (Brodin et al. 1984)
Paeonol Menthol – 52 41 a (Wang et al. 2017)
Propranolol Capric acid 3.5:6.5 (w/w) 92 32 15 (Stott et al. 2001)
Propranolol Lauric acid 3:7 (w/w) 92 43 16 (Stott et al. 2001)
Testosterone Menthol 1:4 154 41 39 (Kaplun-Frischoff and Touitou 1997)
a
Liquid at room temperature

permeability of propranolol, testosterone, ibuprofen, itraconazole,
and lidocaine (Table 3). The enhancement mechanisms have been
suggested to be related to penetration enhancing capability of
coformers (such as menthol), melting point depression, and
increased membrane solubility (Stott et al. 1998; Fiala et al. 2010).
Indeed, the oily liquid phase (API-DES) containing high drug con-
centration acts as a reservoir, and thus may provide higher driving
force for diffusion of drug molecules in to the skin (Nyqvist-Mayer
et al. 1986). For example, formation of an API-DES of testosterone,
a lipophilic molecule, with menthol, a known permeation enhan-
cer, at the molar ratio of 4:1 resulted in drastic melting point
depression of testosterone from 153.7 to 39.9
C. The permeation
of this API through mice skin was eightfold higher in the form of
API-DES than the aqueous solution of testosterone. The increase
in permeation was attributed to improved solubility of testoster-
one in hydroalcoholic vehicle and reducing barrier properties of
SC by menthol (Kaplun-Frischoff and Touitou 1997). Despite these
promising results, there are still many unanswered questions
about the nature of API-DESs, physicochemical stability, compati-
bility with excipients, and formulating these liquids as an accept-
able final dosage form.
Hydrogen bond formation between an API and coformer is
considered as the driving force of the melting point depression
and API-DES formation. Theoretically, API-DES formation is pos-
sible for a considerable number of pharmaceutical molecules that
are either hydrogen bond donors or quaternary ammonium salts
(Abbott et al. 2017). However, until now API-DES discovery has
been performed mainly by experimental work of the mixing of
APIs with different coformers in different ratios. Very recently,
Wolbert et al. (2019) performed a thermodynamic modeling to
predict eutectic composition and eutectic temperature of an API/
coformer eutectic system. Melting points, melting enthalpies, and
thermodynamic activity coefficients of the API and coformer were
used to construct the prediction. The predictions were made for
11 combinations of three APIs and six coformers. The predicted
eutectic compositions and eutectic temperatures were in good
agreement with experimental data indicating the applicability of
the proposed model for rapid screening of API-DES formation.
Certainly, there is abundant room for further progress in develop-
ing rational strategies in order to guide the process of synthesis
of API-DESs and selection of optimal one for a given application.
It will also be interesting to see whether it is possible to tailor
API-DES properties by changing counterpart.
The chemical structure of the molecule remains unaffected
when a solid API is converted to a liquid API-DES. This can be a
great advantage for API-DESs from drug development and regula-
tory decision making because pharmaceutical properties can be
modified without structural change of the API. However, there are
no established regulatory authority guidelines regarding API-DESs.
The answer to the question of do regulatory bodies treat API-
DESs as new chemical entities requiring extensive preclinical
pharmacological and toxicology studies or see them as new for-
mulations? is crucial. The answer could significantly affect the
interest of industry towards research on API-DESs.
2.5.2. DESs as transdermal delivery vehicles
Another interesting area of research is using DESs as carriers/
vehicles with penetration enhancing power in dermal and trans-
dermal drug delivery systems. In this context, Mitragotri group
(Zakrewsky et al. 2014) synthesized a range of ILs and DESs and
investigated their cytotoxicity, skin irritation, antimicrobial effect
on bacterial biofilm, and delivery of antibiotics through the skin.
The best results were obtained for choline–geranate (1:2) DES.
This DES showed the lowest toxicity for epithelial cells, minimum
of skin irritation, excellent antimicrobial activity against bacterial
biofilms, and highest efficiency in improving transdermal delivery
of model hydrophilic molecules. For example, the skin permeation
of cefadroxil, a hydrophilic antibiotic with a log P of –0.4, was
improved by fivefold when dissolved in choline–geranate (1:2) in
comparison to aqueous solution of the drug. The mechanism of
permeability enhancement was proposed to be the extraction of
lipids from SC. The results suggest that choline–geranate (1:2)
would be a promising carrier for dermal delivery of antibiotics for
the eradication of biofilm-associated infections.
Biological macromolecules such as proteins and peptides have
very low transdermal permeability due to their large sizes (Benson
and Namjoshi 2008). Encouraged by low toxicity, low irritability,
and good penetration enhancing property of choline–geranate
(1:2) observed for hydrophilic antibiotics, Mitragotri’s group fur-
ther investigated the efficacy of the DES in enhancing permeation
of proteins across skin. The research group (Banerjee et al. 2017)
studied ex vivo skin permeability of bovine serum albumin (MW
66 kDa), ovalbumin (MW 45 kDa), and insulin (MW 5.8 kDa)

Figure 12. Percent change in blood glucose level with time after administration
of various formulations in nondiabetic rats. Topical application of choline–gera-
nate (1:2) (CAGE) alone (0 U kg1 insulin, green triangles); insulin in buffer
(Insulin-PBS, 10 U mL1 as 25 U kg1 body weight, red squares); insulin in choli-
ne–geranate (1:2) (10 U mL1 with total dose 25 U kg1 body weight, blue
circles); and subcutaneous insulin injection (1 U kg1 insulin, magenta inverted
triangles) was performed. The figure was adapted with permission from
(Banerjee et al. 2017). Copyright (2017) Wiley-VCH.
dissolved in choline–geranate (1:2). The DES significantly
improved skin penetrations of these macromolecules and was
more efficient than commonly used chemical penetration
enhancers; diethylene glycol monoethyl ether and ethanol. The
results of infrared spectroscopy studies of SC suggested that chol-
ine–geranate (1:2) enhances permeability by the extraction of SC
lipids. In the further step, the authors investigated in vivo blood
glucose lowering efficacy of insulin dissolved in choline–geranate
(1:2) applied to the skin of nondiabetic rats (Figure 12). When
insulin was dissolved in the DES resulted in 25 and 40% decrease
in blood glucose in 2 and 4 h, respectively, compared to no sig-
nificant reduction in blood glucose level by insulin dissolved in
phosphate buffer.
Glabridin is a water insoluble polyphenolic flavonoid with anti-
oxidant, anti-inflammatory, and skin lightening properties. Liu
et al. (2017) used a menthol–camphor (1:1) DES as the oil phase
(vehicle) for developments of oil in water nanoemulsion of this
drug. Menthol and camphor have been reported as nontoxic,
nonirritating, and efficient transdermal penetration enhancers
(Sapra et al. 2008). These natural terpenes form a water-immis-
cible DES with hydrophobic properties. The menthol–camphor
DES can act as the penetration enhancer as well as the solvent
for transdermal delivery of water insoluble compounds. The
authors compared permeability properties of eutectic-based nano-
emulsion with nanoemulsion formulated with isopropyl myristate
and aqueous solution of the drug. Isopropyl myristate is a com-
monly used lipophilic vehicle and penetration enhancer in trans-
dermal delivery (Engelbrecht et al. 2012). The solubility of
glabridin in the DES was about two times higher than its solubil-
ity in isopropyl myristate. More importantly, in vitro skin perme-
ability of eutectic based nanoemulsion was about 3-and 7-times
higher than isopropyl myristate-based nanoemulsion and aqueous
solution of the drug, respectively.
Although DESs have the ability to dissolve solutes with wide
range of chemical nature but unlike their analogues ILs, the num-
ber of published works on utilizing DESs as solvent/vehicle for
transdermal drug delivery are rare yet. We predict that more data
will be generated in near future by introducing new DESs, specif-
ically hydrophobic ones. DESs can be used as dual-function sol-
vents in this area. Taking the advantage of large number of
possible combinations, a researcher would select a DES based
vehicle with desired properties such as wound healing, occlusive,
penetration enhancing, or antibacterial, depending on a spe-
cific condition.
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 789
3. Challenges and limitations of DESs
In the previous sections we briefly reviewed the potential
pharmaceutical applications of DESs. However, to be selected as
solvents or processing materials by pharmaceutical industry, DESs
should compete with currently used drug delivery systems and
organic solvents. In the oncoming section, discussions will be con-
ducted to investigate some important challenges and limitations
that stand in the way of pharmaceutical applications of DESs.
3.1. Cost
Without a doubt, cost is a major factor that should to be consid-
ered for commercial use of DESs. To our knowledge, the commer-
cialization potential of DESs has not been investigated yet. As the
field matures, studies need to be performed to techno-economic
analysis of DESs. At the current stage, it seems that the cost of
starting materials and method of synthesis are the largest contrib-
utors in the way of commercial applications of DESs (Chen et al.
2014). Many DES components are cost effective, some of which
are routinely used in pharmaceutical applications as excipients.
For example, choline chloride, a common component of DESs, is
produced in megaton scales at a reasonably low cost (Jablonsky
et al. 2019). From preparation point of view, DESs have a simple
and easy to scale up production method. Therefore, one person
can assume that perhaps not all but at least some DESs can be as
inexpensive as conventional organic solvents (Cruz et al. 2017). In
addition, if a DES is being considered as a component of a drug
delivery system, the advantages of the prepared formulation may
outweigh the possible higher costs.
3.2. Structure and classification
The structure determines the function. Although recently the
number of studies focusing on resolving structures of DESs is
increasing (Zahn 2017; McDonald et al. 2018) but the basic ques-
tion of what is the liquid structure of a DES yet continue to be
largely unanswered. The lack of enough structural information
also makes it difficult to establish a generally accepted definition
and classification of DESs. We clearly need to know more about
the liquid structure, dynamic, and molecular interactions of DESs
to establish the structure  property relationships and rationally
design tailored DESs.
3.3. High viscosity
Generally, due to the strong hydrogen networks, DESs have
100–1000 times higher viscosities than water and common
organic solvents (Tang and Row 2013). High viscosity is a limiting
factor for DESs applications and can cause problems in pharma-
ceutical operations such as handling, mixing, and filling. Thus,
strategies are needed to reduce the viscosity to a suitable level.
Among others, viscosity of a DES can be affected by temperature
and the presence of a third component such as water. Increasing
the temperature leads to strong decrease in viscosity. For
example, the viscosity of choline chloride-urea (1:2) was decreased
from 1100 to 200 cP when temperature was increased from 20 to
40
C (Abbott et al. 2003). Studies have also shown that addition
of small amounts of water, up to 10%, to DESs can significantly
reduce their viscosity while maintaining their solvency power. For
example, addition of 10% of water to choline chloride-urea (1:2)
DES decreased the viscosity to 1/550 of its original value
(Guajardo et al. 2017).
790 S. EMAMI AND A. SHAYANFAR

Table 4. Summary of studies conducted on toxicity of DESs.

HBA HBD Biological system Results Reference

Choline chloride Sugars and alcohols
Urea, acetamide, glycerol, and
ethylene glycol
Urea, triethylene glycol,
glycerol, and
ethylene glycol
Urea, acetamide, sugars
and alcohols
Glucose, glycerol, and
oxalic acid
Glycerol, ethylene glycol,
triethylene glycol, and urea
Citric acid, Fructose, glucose, sucrose,
trimetyl glycerol, and malonic acid
glycine
Oxalic acid, urea, sugars,
Glycerol, proline, sugars
Glucose, malic acid,
and proline
Methyltriphenyl Glycerol, ethylene glycol,
phosphonium triethylene glycol
bromide
Human cell line Toxic to cells, More toxic than their (Ahmadi et al. 2018)
starting materials
Bacteria and aquatic Strong anti-bacterial activity, (Wen et al. 2015)
organism Considerable toxic effects on cells
Bacteria and aquatic No inhibition on bacterial growth, More (Hayyan, Hashim, Al-Saadi,
organism toxic than their starting materials et al. 2013; Hayyan,
Hashim, Hayyan,
et al. 2013)
Bacteria No inhibition on bacterial growth by (Zhao et al. 2015)
amine-, alcohol- and sugar-based
DESs, Inhibition on bacterial growth
by acid-based DESs
Human and fish Low cytotoxicity for choline chloride- (Radosevic et al. 2015)
cell lines glucose and choline chloride-
glycerol, Moderate cytotoxicity for
choline chloride-oxalic acid
Human cell line Relatively high cytotoxicity, More toxic (Hayyan et al. 2015)
than their starting materials
Human and mouse Relatively nontoxicity by DESs of (Hayyan et al. 2016)
cell lines choline chloride with sugars and
water, cytotoxicity by choline
chloride-malonic acid
Bacteria and human Inhibition on bacterial growth by most (Radosevic et al. 2018)
cell line of DESs, No toxicity by Most DESs,
High toxicity by choline chloride-
oxalic acid
Bacteria and aquatic Inhibition on bacterial growth, More (Hayyan, Hashim, Al-Saadi,
organism toxic than their starting materials, et al. 2013; Hayyan,
Dependence of cytotoxicity of DESs Hashim, Hayyan,
on the structure of components et al. 2013)

3.4. Hygroscopicity non-toxic, eco-friendly, biodegradable, and benign solvents alter-

Hygroscopicity is the tendency of a material to take up water
vapor from the surrounding air (Newman et al. 2008). Generally,
possibility of water sorption is increased, when a crystalline sub-
stance is converted to a liquid form because environmental water
can easily dissolve in the disordered liquid state (Balk et al. 2015).
Due to their vast hydrogen bonding networks and hydrophilic
nature, most of DESs are hygroscopic and the adsorption of mois-
ture from air has been reported for some of them (Hammond
et al. 2017). For example, choline chloride-urea (1:2) could absorb
about 4% of water after 24 h exposure to a relative humidity of
64% and 20
C (Zhao et al. 2011). Another study showed that
DESs based on choline chloride and carboxylic acids took up
10–20% of water when were stored for 30 days in contact with air
(Florindo et al. 2014).
The presence of water can dramatically affect the structure
and physicochemical characteristics of DESs (Dai et al. 2015).
Introducing of water could enormously reduce the viscosity of
DESs (Yadav and Pandey 2014). Polarity and the ability of DESs to
solubilize solutes are other affected properties (Pandey and
Pandey 2014). As mentioned earlier, presence of water, even in
low amounts, can cause dramatic changes in solvency power of
DESs. In addition, it is predictable that chemical stability of DES
and incorporated API will be reduced by contamination of
DESs with water. For these reasons, it is crucial to evaluate hygro-
scopicity of DESs and their water content should be carefully
monitored and controlled.
3.5. Toxicity
Most of the components of DESs are non-toxic, biodegradable,
and pharmaceutically acceptable therefore, DESs are assumed as
native for ILs and other organic solvents (Wen et al. 2015).
However, these assumptions have been disputed by recent stud-
ies. Table 4 summarizes the results of DESs toxicity in different
biological systems. As it can be seen different DESs exhibit differ-
ent degrees of toxicity depending on the structure of compo-
nents. Furthermore, some DESs are much more toxic than their
starting materials. For detailed discussion on the topic, the reader
is referred to a recent comprehensive literature review (Juneidi
et al. 2018) on the topic.
Although there are limited published data on toxicity of DESs
but what these data suggest is that one should not consider DESs
a priori as non-toxic solvents simply by looking at the toxicity pro-
files of their staring components. It seems that there is no general
answer to the toxicity question and for each DES in-depth investi-
gations are required to determine the toxicity, biocompatibility,
and biodegradability profiles before applying it to pharmaceutical
applications.
3.6. Long-term stability of APIs in DESs
The long term stability of APIs in the forms of API-DESs or as dis-
solved in DESs is another inherent concern. Until now, there are
very limited studies that evaluate physicochemical stability of APIs
in DESs under stressed storage conditions of elevated tempera-
ture and/or high humidity. Generally speaking, APIs in solid state
are more physicochemical stable than liquid state and transform-
ing solid APIs to liquid forms can increase the risk of instabilities
(Balk et al. 2015). In the case of APIs dissolved in DESs, enhanced
chemical stability has been reported for some hydrolysis-sensitive
APIs such as aspirin (Lu et al. 2016), imipenem and clavulanic acid
(Olivares et al. 2018), salvialonic acid B (Chen et al. 2016), and car-
thamin (Dai et al. 2014) in short-term storage times in comparison

Table 5. Summary of potentials and challenges of pharmaceutical applications
of DESs.
Potentials Challenges
Easy method of preparation Hygroscopicity
Readily available components Absence of techno-economic
analysis data
Numerous number of possible Long term stability of dissolved APIs
combinations
Solvency for biopolymers and Toxicity and safety profile
water insoluble APIs
Non-volatile and non-inflammable High viscosity
Dual-function solvents Unresolved structural properties
Supporting self-assembly of Absence of structure-property
amphiphile molecules relationships
Reaction media to design tailor
made materials
Biodegradable
Enhancing Permeability of APIs
through biological barriers
to their water stability. As an example, in a time period of seven
days, the stability of imipenem and clavulanic acid in trimethyl
glycine–urea (1:1.5) DES, was 7 and 2.5 times higher, respectively,
compared to water (Olivares et al. 2018). In another study it was
reported that photostability of curcumin dissolved in chloride–gly-
cerol (1:1) was significantly higher than curcumin dissolved in
methanol and curcumin powder (Jelin ski et al. 2019). However,
these improved stabilities cannot be extrapolated to other APIs
and in each case comprehensive long-term stability data should
be provided.
4. Concluding remarks
This paper provides an overview about current advances made
over the last decade in utilizing of DESs and API-DESs for pharma-
ceutical formulation and drug delivery applications. Table 5 sum-
marizes the potentials and challenges of DESs in pharmaceutical
engineering.
In the field of drug solubilization, published data show that
DESs can effectively dissolve water insoluble APIs and may find
applications in early pharmacological and toxicological evaluations
of drug candidates and development of effective pharmaceutical
products. However, more studies should investigate solute-solvent
interactions and solubilization mechanisms and propose models
to predict API solubility in DESs. Furthermore, in vivo behavior of
API dissolved in DES remains largely unknown. Therefore,
researchers should plan to conduct studies on cell cultures, ani-
mal models, and human subjects to assess the bioavailability
enhancing potential.
Regarding transdermal drug delivery, most studies have
focused on API-DESs and there are scare studies about utilizing
DESs as delivery vehicles. DESs, as dual-function solvent, can act
as penetration enhancer, wound healing, or antibacterial in add-
ition to their solvent role. On the hand, many APIs can be
designed as API-DESs. The successful case of local anesthetics
(EMLA) indicates that API-DESs are not far from clinical applica-
tions and more designer API-DESs can contribute to improve
pharmaceutical properties of problematic APIs such as solubility,
permeability, and polymorphism. Indeed, the most promising area
of API-DESs applications seems to be in dermal and transdermal
drug delivery.
Also, DESs can help to design innovative and sophisticated
materials with pharmaceutical interest such as inorganic nanoma-
terials, functionalized nanomaterials, self-assembled delivery
vehicles, and polymer and biopolymer based drug delivery
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 791
systems. In particular, the ability of DESs to dissolve various types
of biopolymers ranging from DNA to proteins and polysaccharides
makes them an ideal option to process the biopolymers.
Despite these promising results, deeper studies on the interac-
tions and building principles are needed in order to gain insight
into the properties of DESs and to. Reasonable data should
become available regarding toxicity, biocompatibility, biodegrad-
ability, and safety. Also, appropriate strategies should be devel-
oped to reduce viscosity, overcome hygroscopicity, and determine
long-term physicochemical stability.
We searched ClinicalTrialsRegister.eu and ClinicalTrials.gov
using the terms, ‘deep eutectic solvents’ OR ‘eutectic’ to retrieve
possible eutectics under clinical investigations. There were 38
studies all of them were about eutectic mixtures of local anes-
thetics. This indicate that until now, most of the conducted stud-
ies have investigated DESs from a proof-of-concept point of view,
and no considerable attempts have been invested to translate the
findings of basic science to real-world pharmaceutical product
development. Overall, we expect that DESs and API-DESs will find
real applications in the field of drug delivery in the near future.
Disclosure statement
No potential conflict of interest was reported by the author(s).
ORCID
Shahram Emami http://orcid.org/0000-0002-5182-1728
Ali Shayanfar http://orcid.org/0000-0001-7507-9057
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