API ionic liquids: Probing the effect of counterion structure on physical form and lipid solubility

Article abstract of DOI:10.1039/d0ra00386g

Lipid based formulations (LBFs) are extensively utilised as an enabling technology in drug delivery. The use of ionic liquids (ILs) or lipophilic salts (LS) in drug delivery has also garnered considerable interest due to unique solubility properties. Conversion of active pharmaceutical ingredients (API) to ILs by pairing with an appropriately lipophilic counterion has been shown to decrease melting point of the salt complex and improve solubility in LBFs. However, the relationship between the structure of the counterion, the physicochemical properties of the resulting salts and solubility in LBFs has not been systematically explored. This study investigates the relationship between alkyl sulfate counterion structure and melting temperature (T_m or T_g) in addition to LBF solubility, utilizing cinnarizine and lumefantrine as model weakly basic APIs. Three series of structurally diverse alkyl sulfate counterions were chosen to probe this relationship. Pairing cinnarizine and lumefantrine with a majority of these alkyl sulfate counterions resulted in a reduction in melting temperature and enhanced solubility in model medium chain and long chain LBFs. The chain length of the alkyl sulfate plays a crucial role in performance, and consistently branched alkyl sulfate counterions perform better than straight chain alkyl sulfate counterions, as predicted. Most interestingly, trends in counterion performance were found to be consistent across two APIs with disparate chemical structures. The findings from this study will facilitate the design of counterions which enhance solubility of ionisable drugs and unlock the potential to develop compounds previously restrained by poor solubility.

Full text of DOI:10.1039/d0ra00386g

RSC Advances
View Article Online
View Journal | View Issue
PAPER
API ionic liquids: probing the effect of counterion
structure on physical form and lipid solubility†
Cite this: RSC Adv., 2020, 10, 12788
a
Erin Tay,‡b Tri-Hung Nguyen,c Hywel D. Williams,a
*
Leigh Ford,
‡
c
b
de
*
Hassan Benameur, Peter J. Scammells and Christopher J. H. Porter
Lipid based formulations (LBFs) are extensively utilised as an enabling technology in drug delivery. The use of
ionic liquids (ILs) or lipophilic salts (LS) in drug delivery has also garnered considerable interest due to unique
solubility properties. Conversion of active pharmaceutical ingredients (API) to ILs by pairing with an
appropriately lipophilic counterion has been shown to decrease melting point of the salt complex and
improve solubility in LBFs. However, the relationship between the structure of the counterion, the
physicochemical properties of the resulting salts and solubility in LBFs has not been systematically
explored. This study investigates the relationship between alkyl sulfate counterion structure and melting
temperature (Tm or Tg) in addition to LBF solubility, utilizing cinnarizine and lumefantrine as model
weakly basic APIs. Three series of structurally diverse alkyl sulfate counterions were chosen to probe this
relationship. Pairing cinnarizine and lumefantrine with a majority of these alkyl sulfate counterions
resulted in a reduction in melting temperature and enhanced solubility in model medium chain and long
chain LBFs. The chain length of the alkyl sulfate plays a crucial role in performance, and consistently
branched alkyl sulfate counterions perform better than straight chain alkyl sulfate counterions, as
predicted. Most interestingly, trends in counterion performance were found to be consistent across two
APIs with disparate chemical structures. The findings from this study will facilitate the design of
counterions which enhance solubility of ionisable drugs and unlock the potential to develop compounds
previously restrained by poor solubility.
Received 14th January 2020
Accepted 18th March 2020
DOI: 10.1039/d0ra00386g
rsc.li/rsc-advances
(i) improved uniformity of high potency/low dose drugs, (ii) fast
onset of action, (iii) taste-masking, (iv) ability to deliver drugs
Introduction
with low melting points, (v) modied release proles, (vi)
increased drug permeability and (vii) capacity to meet the
market needs of consumer preference,5–9 and oen a combina-
tion of these. Notably, in these broader LBF applications,
advantages may accrue for both poorly water soluble and water-
soluble drugs.
The use of ionic liquids (ILs) in drug development has
received increasing interest in recent years due to their versa-
tility and desirable physicochemical properties, such as
improved thermal stability, low vapour pressure, and the ability
to dissolve organic, inorganic, and polymeric materials.10 ILs
may be dened as salts with a melting (Tm)/glass transition (Tg)
point below 100 ꢀC, with a subset of ILs referred to as room-
temperature ionic liquids (RTILs), which are liquid at or
below ambient temperature.11 The highly tunable nature of ILs
(i.e. the ability to alter both the cation and the anion) has led to
their use in a wide variety of applications ranging from catal-
ysis12 to solar cells13 to drug delivery.14
Lipid-based formulations (LBFs) are widely utilised to improve
the oral exposure of an increasing number of poorly water-
soluble drugs that are emerging from the drug discovery pipe-
line.1,2 LBFs increase oral exposure by circumventing drug
dissolution, recruiting endogenous solubilisation processes,
and by promoting the uptake of certain drugs into the
lymphatic system, thereby avoiding hepatic rst pass metabo-
lism.3,4 In addition to their capacity to boost exposure, LBFs
have a range of broader pharmaceutical benets. These include:
aOral Drug Delivery Innovation, Chemical Division, Lonza Pharma Biotech
Nutrition, Melbourne, Australia
&
bMedicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash
University, 381 Royal Parade, Parkville, Victoria 3052, Australia
cOral Drug Delivery Innovation, Chemical Division, Lonza Pharma Biotech & Nutrition,
Strasbourg, France
dDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical
Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
eARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash
University, 381 Royal Parade, Parkville, Victoria 3052, Australia. E-mail:
chris.porter@monash.edu; leigh.ford@lonza.com
The use of ILs in drug delivery has been described in the
formation of novel microemulsions15 and use as permeation
enhancers for transdermal delivery.16 More relevant to this work
is the conversion of ionisable APIs themselves into ILs to
† Electronic supplementary information (ESI) available: Experimental section,
characterization details, and additional gures. See DOI: 10.1039/d0ra00386g
‡ These authors contributed equally to this work.
12788 | RSC Adv., 2020, 10, 12788–12799
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
improve delivery.17,18 Examples of this application also include reduced ion symmetry to frustrate crystal packing (reduced
instances where the counterion itself is bioactive leading to Madelung constant) and (v) increased conformation degrees of
dual-function active pharmaceutical ingredient ionic liquids freedom (branching, chiral centres etc.). Notably, the structural
(API ILs).19–22 Ionic liquids are therefore an attractive option in factors which affect Tm have a complex interrelation and are
drug delivery, in particular for their tendency to form amor- therefore difficult to predict a priori.38,39
phous or liquid salts circumventing issues of poly-
Studies by Seddon and co-workers have previously shown the
morphism11,20,22,23 and potentially enhancing solubility.24 When relationship between the chain length of alkyl substituents on
pairing an API with a counterion of low polarity in order to the properties of N-alkyl-methylimidazolium ILs ([Cnmim]+
improve solubility in lipids the complex can be referred to as Xꢁ).40 As predicted, the symmetrical imidazolium (N-methyl) IL
a lipophilic salt (LS) or hydrophobic ion pair (HIP).25–28 This had the highest melting point. As the length of the alkyl chain
alternate denition also recognises the fact that LSs with increased the melting point decreased until n ¼ 10, beyond
melting points above 100 ꢀC (and therefore not strictly ionic which the melting point started to increase rapidly, presumably
liquids) may also have benet.
as van der Waals forces became more signicant. Similar trends
series of imidazolium hexa-
API ILs when utilised in combination with LBFs have been were also observed in
a
shown previously to enhance drug exposure.14,29,30 The conver- urophosphate ILs. Interestingly, in some cases, branched alkyl
sion to API ILs can enhance solubility in LBFs and ultimately substituents with short chain lengths resulted in increased
result in greater oral exposure of the API, by exploiting the melting point, highlighting the difficulties in predicting prop-
benets of LBFs described earlier.25 This may be particularly erties from rst principles.41
important during drug development where toxicity screening of
Reducing crystal lattice energy is, of course, only one aspect
lead compounds requires delivery of large doses (up to 2000 mg of increasing solubility in lipid systems. Interactions between
kgꢁ1) where dissolution of standard API forms may not be the solute and solvent (in this case the IL and the lipid excipi-
feasible.31 Despite the utility of API ILs, the relationship ents) are also key and must overcome the energy required to
between counterion structure and IL physical properties has not break solute–solute interactions. Solubility thus follows the
been well established. The melting temperature of the API IL is common adage ‘like dissolves like’.1 We hypothesise that by
largely determined by the strength of the crystal lattice where judicious choice of lipophilic counterion, it is possible to both
the stronger the forces holding the ions together, the higher this reduce the crystal lattice energy and increase favourable inter-
temperature. The relationship between salt structure and actions with lipid excipients, both factors combining to
crystal lattice energy, and therefore melting temperature has enhance solubility and therefore drug loading, generating
been discussed elsewhere.24,32–34 Utilising thermodynamic a high performance API IL form. A systemic study of structure/
considerations of the free energy of the solid and liquid phases solubility relationships has therefore been undertaken to
leads to the following equation.
address this aim.
In this study, the relationship between IL structure and
physicochemical properties has been assessed using two model
drugs, cinnarizine (1) and lumefantrine (2) (Fig. 1) that have
been converted to similar salts by us and others.14,42,43
Compounds 1 and 2 are both ionisable and weakly basic (pKa's >
ðDEm þ PDVmÞ
¼
DSm
Tm
where Tm reects the melting point (or Tg – glass transition
point for amorphous solids) of the system, DEm is the change in
energy on melting (reective of the relative energies of the
liquid and solid phases), P is the external pressure, DVm is the
change in volume, and DSm is the entropy change on melting.
When considering the effect modifying the counterion will have
on Tm, the two most important factors to consider are DEm and
DSm.35 The change in energy on melting (DEm) is affected by
several factors relating to the counterion: including charge,
charge delocalization, size, and symmetry (loosely described by
the Madelung constant, M).36 van der Waals (or London
dispersion) forces also contribute to Em. Entropic changes will
also be affected by counterion structure, for instance, the
greater the number of motional and congurational degrees of
freedom a counterion has, the larger the entropy and the lower
the Tm. Factors such as chain branching and asymmetry (which
increase packing frustration) lead to an increase in entropy on
melting.36,37 Considering these factors, counterions may be
rationally designed to reduce lattice energy and improve solu-
bility. Therefore, ideal counterions theoretically have (i) higher
molecular weight and are sterically hindered (leading to distally
separated ions), (ii) decreased localised charge density (more
diffuse charges), (iii) limited hydrogen bonding potential, (iv)
ꢀ
8), have melting points <150 C and workable organic solvent
solubility and are therefore excellent candidates for this study.
API IL were formed by pairing the model drugs with three series
of alkyl sulfate counterions. The rst series examined the effect
of counterion chain length within linear alkyl sulfates, the
second series utilised branched counterions in the hope of
increasing rotational freedom (increasing entropy), and the
third series shied the position of the head group along a C10
Fig. 1 The two model APIs – cinnarizine (1) and lumefantrine (2).
RSC Adv., 2020, 10, 12788–12799 | 12789
This journal is © The Royal Society of Chemistry 2020

View Article Online
RSC Advances
Paper
chain, reducing symmetry of the counterion with the aim of mixture diluted with methanol (40 mL). The cloudy solution was
reducing the Madelung constant of the system. All compounds stirred vigorously as 5 mL sat. aq. Na2CO3 was added dropwise.
were evaluated for physical form, melting point and solubility of Aer stirring at room temperature for 30 min, solid Na2SO4 was
the API IL in a type IIIA LBF (as classied by Pouton)44 which is added and stirring was continued for a further 20 min. The
representative of a formulation type widely used in industry.
solution was ltered and concentrated in vacuo. The resulting
Alkyl sulfates were selected as counterions in this study in residue was dried under house vacuum. The crude material
large part because of their low pKa. As the ILs formed in this (3.02 g) was taken up in CH2Cl2 (20 mL) and shaken, then
study are protic (i.e. rely on proton transfer between ions), ltered through a 0.2 mm microlter. The ltrate was concen-
a large DpKa value between API and counterion increases the trated in vacuo and placed under high vacuum to afford an off
likelihood of salt formation and reduces the chance of disso- white solid (2.92 g, 99%).
ciation in solution.45–47 Sulfates also have favourable charge
Synthesis of API ILs. All API ILs were prepared utilising the
distribution, reducing electrostatic interactions between the standard method described below and were determined to be
anion and cation, which promotes reduced melting tempera- >95% pure as determined by HPLC (HPLC traces are provided in
ture. Alkyl sulfates traditionally have low toxicity and appear in ESI†).
many commercial products, such as household cleaning prod-
API$HCl (1 mmol) and sodium alkyl sulfate (1 mmol) or
ucts and cosmetics.48 Additionally, alkyl sulfates can be easily sodium docusate (1 mmol) were weighed out, and solids were
accessed through simple sulfation of a plethora of commercially dissolved in a biphasic solution of CH2Cl2 and water (1 : 1 – 100
available alcohols in one step.
mL). The resulting mixture was stirred vigorously at ambient
An understanding of the structure/solubility relationship of temperature overnight (protected from light in the case of
counterions utilised in the synthesis of API ILs is expected to lumefantrine salts). This biphasic mixture was transferred to
facilitate the design of counterions tailored for specic APIs to a separating funnel and the organic phase was collected. The
promote solubility and to unlock utility in LBFs whilst main- aqueous phase was further extracted (2 ꢂ 50 mL – CH2Cl2). The
taining low toxicity.
combined organics were backwashed with cold distilled water
(20 mL) until a negative AgNO3 (0.02 M aq.) precipitate test
result was obtained. The organic solution was dried with
Na2SO4, ltered and concentrated in vacuo. The resulting
material was placed under high vacuum until uniform mass was
obtained.
Results and discussion
Synthesis and characterisation
Synthesis of API HCl salts
Synthesis of cinnarizine$HCl.14 Cinnarizine free base (6.5 g,
Solubility assessment of API ILs. The equilibrium solubility
17.6 mmol) was dissolved in diethyl ether (300 mL) with of the API free base, HCl salt and API IL forms, in two model
vigorous stirring and HCl (8.85 mL, 2.0 M in diethyl ether) was LBFs (medium chain and long chain SEDDs) were evaluated.
added slowly at room temperature. The resulting mixture was Details of the method can be found in ESI,† the formulation
allowed to stir at ambient temperature for 4 h. The cloudy compositions are provided in Table 1.
solution was ltered under vacuum and the white precipitate
was washed with ice cold portions of diethyl ether (total volume
– 100 mL). The resulting white solid was dried under high
vacuum (7.05 g, 99%).
Physical characterisation of cinnarizine salt forms
Three series of counterions were prepared by systematically
increasing either alkyl chain length in linear alkyl sulfates
(series one) and branched alkyl sulfates (series two). The posi-
tion of the head group was also varied (series three) in order to
probe the effect this had on packing, and by extension API IL
Synthesis of lumefantrine$HCl. Lumefantrine free base (5.21 g,
9.85 mmol) was suspended in diethyl ether (300 mL) with
vigorous stirring and HCl (4.95 mL, 2.0 M in diethyl ether) was
added slowly at room temperature. The resulting mixture was
protected from the light and allowed to stir at ambient
temperature for 4 h. The cloudy solution was ltered under
vacuum and the yellow precipitate was washed with ice cold
portions of Et2O (total volume – 100 mL). The resulting yellow
solid was dried under house vacuum protected from the light
(5.45 g – 98%).
Table 1 Composition of the medium-chain and long-chain self-
emulsifying drug delivery systems (SEDDS) used in equilibrium solu-
bility studies. All formulations contained ꢃ1% butylated hydrox-
ytoluene as an antioxidant
Synthesis of counterions. Sodium salts of the counterions
were prepared from the corresponding alcohols under modied
sulfation conditions,49 except for sodium 1-octyl sulfate, sodium
docusate and sodium lauryl sulfate which were commercially
available. An example synthetic method is provided below.
Sodium 2-hexyl-1-decyl sulfate. 2-Hexyl-1-decanol (2.08 g,
8.58 mmol) was weighed into a dry microwave vial, followed by
sulfamic acid (1.0 g, 10.30 mmol). Anhydrous pyridine (12 mL)
was added and the resulting suspension heated to 95 ꢀC for 16 h
in an oil bath. The solution was cooled, and the resulting
LBF
Component
(% w/w)
Medium chain SEDDS
Glyceryl tricaprylate/caprate
Glycerol monocaprylocaprate
Polyoxyl 35 castor oil
Ethanol
30%
30%
30%
10%
30%
30%
30%
10%
Long chain SEDDS
Soybean oil
Glyceryl monolinoleate
Polyoxyl 35 castor oil
Ethanol
12790 | RSC Adv., 2020, 10, 12788–12799
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 2 Physical state and melting point of cinnarizine free base, HCl
salt and series one sulfates
assessed by hot stage microscopy in order to evaluate the effect
of counterion on physical form (crystalline or amorphous) and
glass transition (amorphous) or melting (crystalline) point, the
data are presented in Tables 2–7.
The physical properties of the rst series of cinnarizine ILs
are summarised in Table 2. As expected cinnarizine hydro-
chloride (1a) had the highest melting temperature (201–210 ꢀC),
due to strong electrostatic interactions between the protonated
API and the chloride ion, which is small and has a non-diffuse
ꢀ
charge, followed by cinnarizine free base (1) (122–123 C). For
the cinnarizine IL series, only the 1-hexyl sulfate (1b) was a solid
at room temperature (melting point: 35–36 ꢀC). The short chain
hexyl sulfate was likely unable to disrupt packing in the crystal
lattice to the extent of the other counterions, hence the higher
melting point and solid physical state. All other cinnarizine (C8–
C
18) sulfates (1c–h) were viscous liquids at room temperature,
precluding more detailed analysis of the effect of structure on
melting point. Cinnarizine 1-octyldecyl sulfate (1h) showed
signs of crystallization aer long term storage (>6 months at
ꢀ
ꢁ20 C), suggesting the possibility of a more stable (and less
#
Name
Physical state
Tm/Tg (ꢀC)
soluble) crystalline form. It remains possible that the other
isolated ILs may also have more thermodynamically stable
crystal forms, however, we were unable to isolate such forms of
the other salts (over 6 months storage at ꢁ20 C).
1
Free base
Hydrochloride
Crystalline
Crystalline
Amorphous
Viscous oil
Viscous oil
Viscous oil
Viscous oil
Viscous oil
Viscous oil
122–123
207
35–36
<25
<25
<25
1a
1b
1c
1d
1e
1f
1-Hexyl sulfate (C6)
1-Octyl sulfate (C8)
1-Decyl sulfate (C10
1-Dodecyl sulfate (C12
1-Tetradecyl sulfate (C14
1-Hexadecyl sulfate (C16
1-Octadecyl sulfate (C18
ꢀ
Four counterions were designed for the second series
(Table 3), increasing the chain length at each branch by two
carbons. The alkyl sulfates were obtained in one step from the
corresponding alcohol. Of the ILs formed, only cinnarizine 2-
ethyl-1-hexyl sulfate (1i) was a solid at room temperature, and
had a melting point of 40–42 ꢀC, no birefringence was observed
under polarized microscopy, suggesting an amorphous nature.
)
)
)
)
)
<25
1g
1h
<25
<25a
a
Cinnarizine 1-octadecyl sulfate showed signs of crystallization aer
long term storage.
properties. Cinnarizine was chosen as the primary model
compound due to its favourable pKa and moderate Tm.
Table 3 Physical state and melting point of cinnarizine series two
sulfates
The lipophilic salts were prepared utilising a biphasic
metathesis reaction, from the API$HCl salt and the sodium salt
of the counterion, to generate pure (>95%) product without
further purication. Series one probed the performance of ILs
containing linear alkyl sulfates with varying chain lengths
(increasing by two carbons from C6 to C18). We predicted that
salts with sulfates bearing alkyl chain lengths similar to those
found in the lipidic excipients would show favourable solubility
(and potentially physical stability) in the lipid formulations (i.e.
C8–C10 for MC-SEDDS and C16–C18 for LC-SEDDS). Series two,
which consisted of branched alkyl sulfate counterions, could be
compared with the corresponding compounds from series one
(with identical numbers of carbons) to determine the overall
effect of branching, but additionally allowed evaluation of the
optimal chain length within the branched series. It was pre-
dicted that branching of the alkyl chains would frustrate
packing in the crystal lattice in line with previous observa-
tions,14,50 but also maximise entropy within the system.2 The
third series was prepared in order to determine how varying the
position of the sulfate group along a C10 chain (affecting the
Madelung constant) would alter crystal packing and by exten-
sion solubility. The physical properties of the salt forms were
#
Name
Physical state
Tm/Tg (ꢀC)
1
Free base
Hydrochloride
2-Ethyl-1-hexyl sulfate
2-Butyl-1-octyl sulfate
2-Hexyl-1-decyl sulfate
2-Octyl-1-dodecyl sulfate
Crystalline
Crystalline
Amorphous
Viscous oil
Viscous oil
Viscous oil
122–123
207
40–42
<25
1a
1i
1j
1k
1l
<25
<25a
a
Cinnarizine 2-octyl-1-dodecyl sulfate showed signs of crystallization
aer long term storage.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 12788–12799 | 12791

View Article Online
RSC Advances
Paper
Table 4 Physical state and melting point of cinnarizine series three
sulfates
Fig. 2 Equilibrium solubility in MC-SEDDS and LC-SEDDS for cin-
narizine (1), cinnarizine HCl (1a) and cinnarizine series one sulfates (1-
hexyl sulfate 1b, 1-octyl sulfate 1c, 1-decyl sulfate 1d, 1-dodecyl sulfate
1e, 1-tetradecyl sulfate 1f, 1-hexadecyl sulfate 1g and 1-octadecyl
sulfate 1h). Data are expressed as solubility in cinnarizine free base
equivalents, and are n ¼ 3, mean ꢄ SD, except for cinnarizine 1-hexyl
sulfate (1b) and cinnarizine 1-octyl sulfate (1c) in MC-SEDDS, and
cinnarizine 1-decyl sulfate in both MC- and LC-SEDDS (1d), which
were n ¼ 1. *IL was miscible in formulation. # addition of IL to
formulation formed 3 immiscible layers, so comparative data could not
be obtained.
#
Name
Physical state
Tm/Tg (ꢀC)
1
Free base
Crystalline
Crystalline
Viscous oil
Amorphous
Amorphous
Amorphous
Amorphous
122–123
207
<25
27–28
27–28
27–29
27–29
1a
1d
1m
1n
1o
1p
Hydrochloride
1-Decyl sulfate
2-Decyl sulfate
3-Decyl sulfate
4-Decyl sulfate
5-Decyl sulfate
(LC-SEDDS) self-emulsifying drug delivery systems (composi-
tions shown in Table 1). The equilibrium solubility values for
the linear alkyl sulfate series of cinnarizine compounds are
shown in Fig. 2, note that for highly miscible salts solubility was
dened as the measured concentration at 1 : 1 mass API IL:
LBF.
As predicted, cinnarizine hydrochloride (1a) had the lowest
solubility in both MC- and LC-SEDDS, followed by the free base
(1). The values were consistent with previously published
values14 and reect their higher melting points relative to the IL
forms. Cinnarizine 1-hexyl sulfate (1b), 1-octyl sulfate (1c), and
1-decyl sulfate (1d) were miscible in MC-SEDDS. These IL forms
have alkyl chains with similar lengths to those found in glyceryl
Interestingly, the branched cinnarizine 2-ethyl-1-hexyl sulfate
was a semi-solid, whereas the linear 1-octyl sulfate was a liquid.
This was unexpected, particularly considering the increased
solubility of the branched compound in LC-SEDDS (see below).
The reason for the increased melting point of cinnarizine 2-
ethyl-1-hexyl sulfate is not currently understood. The 2-butyl-1-
octyl sulfate (1j), 2-hexyl-1-decyl sulfate (1k), and 2-octyl-1-
dodecyl sulfate (1l) ILs were viscous liquids at room tempera-
ture. The longer alkyl chain sulfates in 1j, 1k, 1l provide more
extensive branching and likely contributed to the liquid state of
these salts as the counterions were better able to disrupt
packing of the crystal lattice. The evidence that a crystal form of
1l exists (formed on long term storage), may be explained by
increased van der Waals interactions due to the longer alkyl
chain.
tricaprylate/caprate and glycerol monocaprylocaprate (C8–C10
)
and are expected to have favourable interactions with the
excipients. As the chain length increased past C10 the solubility
values in MC-SEDDS decreased, likely as intermolecular van der
Waals interactions between counterions became more signi-
cant. Given the miscibility of the shorter chain cinnarizine ILs
in MC-SEDDS, it was not possible to differentiate between them.
The reduced solubility of the ILs in LC-SEDDS, however,
provided more discrimination. Of the straight chain alkyl
sulfates, only the 1-decyl sulfate (1d) was miscible in LC-SEDDS.
Interestingly C10 was the optimal chain length for linear sulfates
paired with cinnarizine in both LBFs despite the different
chemical structure of the constituent excipients, suggesting the
API IL structure impacts solubility more than the formulation
composition. The C10 alkyl chain may represent a compromise
between favourable non-polar interactions before van der Waals
forces become prevalent. The 1-octyl sulfate (1c) and 1-dodecyl
sulfate (1e) had similar solubility values with both exhibiting
higher solubility than either the free base (1) or the
Series three of the cinnarizine ILs (varying sulfate position)
had very similar melting points (Table 4). Only the 1-decyl
sulfate (1d) was a viscous liquid at room temperature, while the
remaining salts were semi-solid, but became less viscous upon
ꢀ
heating to 27–29 C. This was surprising as these counterions
were expected to disrupt the crystal lattice more than the
straight chain 1-decyl sulfate due to increased asymmetry. All
salts in this series were amorphous as determined a lack of
birefringence under cross-polarised light microscopy.
Equilibrium solubility of cinnarizine salts in model lipid-
based formulations
The equilibrium solubility of the cinnarizine salt forms was
measured in model medium-chain (MC-SEDDS) and long-chain
12792 | RSC Adv., 2020, 10, 12788–12799
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Interestingly, this compound showed signs of crystallization on
long term storage (>6 months) suggesting the presence of
a more stable crystalline form, consistent with other long chain
alkyl sulfate salts (Fig. 3).
All cinnarizine ILs utilising counterions from the series three
were miscible in both MC-SEDDS and LC-SEDDS (data in ESI†).
This is in spite of the fact that the melting temperatures were
higher than many ILs in other series. In an effort to better
determine how the placement of the sulfate group in the alkyl
chain affected crystal packing and therefore solubility, the
solubility of all these salts was also evaluated in glyceryl
tricaprylate/caprate, the hypothesis being that solubility in the
single excipient would be lower and allow better discrimination
of the API IL solubility. The free base (1) and hydrochloride salt
(1a) solubility were also included as a reference (Fig. 4).
Surprisingly 1 showed high solubility in glyceryl tricaprylate/
caprate, while the hydrochloride salt (1a) was practically
insoluble.
Fig. 3 Equilibrium solubility in MC-SEDDS and LC-SEDDS for cin-
narizine (1), cinnarizine HCl (1a) and cinnarizine series two sulfates (2-
ethyl-1-hexyl sulfate 1i, 2-butyl-1-octyl sulfate 1j, 2-hexyl-1-decyl
sulfate 1k and 2-octyl-1-dodecyl sulfate 1l). Data are n ¼ 3, mean ꢄ SD.
*IL was miscible in formulation.
For the ILs, there was a great degree of variability in indi-
vidual data sets and a clear solubility advantage was not
observed with cinnarizine series three salts under these condi-
tions. It was further hypothesised that pairing these counter-
ions with an API with inherently lower solubility might allow
differentiation between the counterions (see later).
hydrochloride salt (1a) (but lower than 1d). In general, solubility
values in model lipid formulations decreased dramatically as
chain length of the counterion increased past C12, representing
the length beyond which van der Waals interactions of the API
IL with other molecules of API IL become favoured over inter-
action with the excipients. Consistent with previous work,14
there was generally greater solubility of the API IL in MC-SEDDS
when compared to LC-SEDDS,51 though 1d and 1e showed
similar performance in both formulations reecting the higher
inherent solubility of these salts and favourable interactions
with the excipient sidechains.
For the branched alkyl sulfates (series two), the 2-ethy-1-
hexyl sulfate (1i), 2-butyl-1-octyl sulfate (1j), and 2-hexyl-1-
decyl (1k) sulfate were miscible in MC-SEDDS, indicating that
branching in the alkyl chain increased solubility, likely through
disruption of packing in the crystal lattice. The branched alkyl
sulfates all showed high solubility values in LC-SEDDS (relative
to series one salts) while only cinnarizine 2-hexyl-1-decyl sulfate
(1k) was found to be miscible. Cinnarizine 2-octyl-1-dodecyl
sulfate (1l) had the lowest solubility in the series.
Fig. 5 outlines the solubility of all the examined cinnarizine
compounds, allowing for comparison of counterions grouped
by # of carbons across different series. As all cinnarizine C10
sulfates were miscible in MC-SEDDS and LC-SEDDS, only one
data set is shown. The cinnarizine compounds are displayed
with increasing number of carbons from le to right, and with
the straight chain length ILs (designated with an L) shown rst,
followed by the branched chain counterions (designated with
a B). The coloured groupings signify counterions with the same
number of carbons. There was a decreasing trend in solubility
as the number of carbons in the counterion chain increased
past C10. Additionally, as predicted, branching of the coun-
terion resulted in higher solubility in LBF when compared to
the straight chain counterparts. This effect was most dramatic
for the C16 salts in LC-SEDDS, where cinnarizine 2-hexyl-1-decyl
sulfate (1k) had a solubility of 261 mg gꢁ1 and 249 mg gꢁ1 in
MC-SEDDS and LC-SEDDS, respectively, whereas the linear
variant cinnarizine 1-hexadecyl sulfate (1g) had a greatly
reduced solubility of 99 and 17 mg gꢁ1 in MC-SEDDS and LC-
SEDDS, respectively. Interestingly, no signicant improvement
was observed in MC-SEDDS or LC-SEDDS when branching
occurred in the C12 IL (1e and 1j). This may reect the fact that
the solubility of the linear cinnarizine 1-dodecyl sulfate was
considerably higher than cinnarizine 1-hexadecyl sulfate.
Given the results outlined above, subsequent studies sought
to determine whether the structural trends observed with cin-
narizine were conserved with another API. This was expected to
highlight the degree to which the structure of the API had an
effect on overall LS properties and performance compared with
counterion structure. If the API structure was found to have
minimal impact, this would allow for more general selection of
counterions when generating API IL forms.
Fig. 4 Equilibrium solubility of cinnarizine (1), cinnarizine (1a) and
cinnarizine series three sulfates (1-decyl sulfate 1d, 2-decyl sulfate 1m,
3-decyl sulfate 1n, 4-decyl sulfate 1o and 5-decyl sulfate 1p) in glyceryl
tricaprylate/caprate. Data are n ¼ 3, ꢄSD.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 12788–12799 | 12793

View Article Online
RSC Advances
Paper
Fig. 5 Equilibrium solubility in MC-SEDDS and LC-SEDDS of all cinnarizine compounds. As all of the third series of cinnarizine compounds were
miscible, only one IL is shown. L – refers to linear alkyl sulfates. B – refers to branched alkyl sulfates. All data are n ¼ 3, ꢄSD, except for cinnarizine
1-hexyl sulfate and cinnarizine 1-octyl sulfate in MC-SEDDS, and all cinnarizine decyl sulfate in both MC-SEDDS and LC-SEDDS, which were n ¼
1. *IL was miscible in formulation. # addition of IL to formulation formed three immiscible layers, so data was not obtained. Cinnarizine docusate
is miscible in MC-SEDDS and LC-SEDDS formulations (unpublished data).
Lumefantrine was chosen as a second model API and paired (Table 5). Unlike cinnarizine ILs, most lumefantrine salts were
with counterions selected from series one to three, which solid at room temperature, suggesting greater difficulty in dis-
showed favourable performance with cinnarizine. The physical rupting the lumefantrine crystal lattice, in spite of the fact that
characterization data for these compounds are compiled in the melting points of lumefantrine HCl (2a) and free base (2)
Tables 5–7
were similar to that of cinnarizine. Lumefantrine hydrochloride
Three of the counterions from the linear alkyl series with (2a) had the highest melting range (180–200 ꢀC), followed by the
cinnarizine were selected for pairing with lumefantrine as they free base (2) (133–140 ꢀC). Lumefantrine 1-octyl sulfate (2b) had
improved solubility in the formulations to the greatest extent the highest melting range among the ILs. Presumably, the C8
alkyl chain disrupted crystal packing less than the longer chain
analogues. The 1-decyl sulfate (2c) and 1-dodecyl sulfate (2d)
ꢀ
ꢀ
Table 5 Physical state and melting point of lumefantrine series one
sulfates
salts had similar melting ranges, 111–125 C and 115–128 C,
respectively, suggesting a small window of improvement with
linear alkyl sulfate salts of lumefantrine. All compounds in
Table 5 showed birefringence under cross-polarised light
microscopy, indicating that all compounds possessed some
degree of crystallinity, consistent with a lack of crystal lattice
disruption.
Examining the branched series of lumefantrine salts
(Table 6), the 2-hexyl-1-decyl sulfate (2g) had the highest
melting range (133–135 ꢀC), which may be explained by greater
van der Waals interactions of the longer alkyl chains. The
truncated 2-butyl-1-octyl sulfate (2f) had a reduced melting
point range (117–136 ꢀC), followed by 2-ethyl-1-hexyl sulfate (2e)
(111–119 ꢀC), here the branched C8 alkyl sulfate had a lower
melting/glass transition point than the linear 1-octyl sulfate, in
contrast to the trend observed for the cinnarizine ILs.
Interestingly 2f had a similar melting range to the dodecyl
sulfate IL (2d), a trend also observed in the cinnarizine salts.
Lumefantrine docusate (2h) is shown for comparison as it
contains sidechains with similar branching to that in this series
(c.f. 2e). 2h had the lowest melting point in this series, high-
lighting the ability of the docusate to disrupt crystal
packing.17,18,47,52,53 Only the docusate salt lacked birefringence
#
Name
Physical state
Tm/Tg (ꢀC)
2
Free base
HCl
1-Octyl sulfate
1-Decyl sulfate
1-Dodecyl sulfate
Crystalline
Crystalline
Crystalline
Crystalline
Crystalline
133–140
180–200
147–155
111–125
115–128
2a
2b
2c
2d
12794 | RSC Adv., 2020, 10, 12788–12799
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 6 Physical state and melting point of lumefantrine series two Table 7 Physical state and melting point of lumefantrine series three
sulfates
sulfates
#
Name
Physical state
Tm/Tg (ꢀC)
#
Name
Physical state
Tm/Tg (ꢀC)
2
Free base
HCl
2-Ethyl-1-hexyl sulfate
2-Butyl-1-octyl sulfate
2-Hexyl-1-decyl sulfate
Docusate
Crystalline
Crystalline
Crystalline
Crystalline
Crystalline
Amorphous
133–140
180–200
111–119
117–136
133–135
52–60
2
Free base
HCl
Crystalline
Crystalline
Crystalline
Crystalline
Amorphous
Amorphous
Amorphous
133–140
180–200
111–125
107–121
42–46
2a
2e
2f
2g
2h
2a
2c
2i
2j
2k
2l
1-Decyl sulfate
2-Decyl sulfate
3-Decyl sulfate
4-Decyl sulfate
5-Decyl sulfate
40–47
51–53
under cross-polarised light microscopy, while the other three
lipophilic salts displayed varying degrees of crystallinity.
Unlike their cinnarizine counterparts, all lumefantrine ILs
from series three were solid at room temperature (Table 7).
Lumefantrine 1-decyl sulfate (2c) (111–125 ꢀC) had a similar
the centre of the alkyl chain, in effect forming a more branched
counterion, is more likely to disrupt packing.
ꢀ
melting range to the 2-decyl sulfate salt (2i) (107–121 C), and
Equilibrium solubility of lumefantrine salts in model lipid-
based formulations
both displayed birefringence, indicating they were crystalline.
The 5-decyl sulfate IL (2l) however, had a considerably lower
melting range (51–53 ꢀC), and this was also the case for both the
3-decyl sulfate salt (2j) (42–46 ꢀC) and the 4-decyl sulfate salt (2k)
(40–47 ꢀC). Lumefantrine compounds 2j, 2k and 2l lacked
birefringence under cross-polarised light microscopy, indi-
cating that they were amorphous. For lumefantrine salts in
series three the differences in melting point were more signif-
icant. In this case, moving the position of the sulfate group
down the ten-carbon chain resulted in a decrease in melting/
glass transition point, most notably when moving from the 2-
position to the 3-position. There was a slight increase in glass
transition point when moving from the 4-position to the 5-
position. Shiing the sulfate group along the ten-carbon chain
is expected to increase asymmetry in the counterion and
appears to have signicantly disrupted packing in the crystal
lattice, thus decreasing melting/glass transition point. The 5-
decyl sulfate counterion is likely more symmetrical than the 3-
or 4-decyl sulfate, which may explain the slight increase in
melting point. This data suggests that the position of the head
group is highly important in crystal packing in the case of
lumefantrine and that having the sulfate group situated towards
From the linear alkyl sulfate series, the 1-octyl sulfate, 1-decyl
sulfate, and 1-dodecyl sulfate counterions were selected and the
solubility of the corresponding salts of lumefantrine were
assessed. In contrast to the cinnarizine data, where the cin-
narizine ILs generally had higher solubility in LBF than either
the free base or hydrochloride salt, the lumefantrine ILs from
series one showed little solubility advantage (Fig. 6). Indeed,
lumefantrine free base (2) showed the greatest solubility in the
formulations, with the exception of lumefantrine 1-decyl sulfate
(2c) in MC-SEDDS. It is possible that due to the highly planar
and aromatic structure of lumefantrine, disruption of crystal
packing may be more difficult than is the case with cinnarizine.
This is consistent with the relatively small reduction in melting
point of series one lumefantrine ILs when compared to the free
base. In contrast, the salts of cinnarizine from series one
resulted in marked decreases in melting point, consistent with
larger increases in LBF solubility.
Within the lumefantrine IL series, however, the trends in
solubility for the 1-octyl sulfate (2b), 1-decyl sulfate (2c), and 1-
dodecyl sulfate salts (2d) in both MC-SEDDS and LC-SEDDS
were similar to cinnarizine, such that lumefantrine 1-decyl
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 12788–12799 | 12795

View Article Online
RSC Advances
Paper
Fig. 6 Equilibrium solubility in MC-SEDDS and LC-SEDDS for lume-
fantrine (2), lumefantrine HCl (2a), and lumefantrine series one sulfates
(1-octyl sulfate 2b, 1-decyl sulfate 2c and 1-dodecyl sulfate 2d). Data
are n ¼ 3, ꢄSD.
Fig. 8 Equilibrium solubility in MC-SEDDS and LC-SEDDS for lume-
fantrine (2), lumefantrine HCl (2a) and lumefantrine series three
sulfates (1-decyl sulfate 2c, 2-decyl sulfate 2i, 3-decyl sulfate 2j, 4-
decyl sulfate 2k and 5-decyl sulfate 2l). Data are n ¼ 3.
sulfate had the highest solubility in MC-SEDDS compared to the
other lumefantrine compounds. This is consistent with the
hypothesis that the C10 counterion has the most favourable
interactions with the lipid excipients. It also suggests that
counterion structure/solubility trends may be consistent, inde-
pendent of drug structure.
For the branched series (Fig. 7), lumefantrine 2-ethyl-1-hexyl
sulfate (2e) and lumefantrine 2-hexyl-1-decyl sulfate (2g) had
higher solubilities in MC-SEDDS and LC-SEDDS compared to
the free base and hydrochloride salt. Similar to the cinnarizine
counterparts (1i and 1k) both had higher solubility in both MC-
SEDDS and LC-SEDDS compared to the 2-butyl-1-octyl sulfate IL
in LC-SEDDS, again suggesting the trends may be independent
of drug structure. The high solubility of 2g is surprising given its
relatively high melting point and number of carbons (and
considering the low solubility of the linear C12 sulfate 2d and
therefore the expectation that a linear C16 sulfate would be
lower still). Interestingly, this counterion also performed well
for cinnarizine. Lumefantrine 2-ethyl-1-hexyl sulfate (2e)
outperformed the linear C8 alkyl sulfate (2b) in both MC-SEDDS
and LC-SEDDS presumably due to its ability to disrupt packing
and increased entropy on melting.
The solubility of lumefantrine docusate (2h) was also eval-
uated to explore the effects of more extensive branching on
solubility (see later in Fig. 9). We have shown previously that
branching acts to disrupt packing and increase solubility, the
docusate counterion has two branched alkyl ester substituents
and was therefore expected to disrupt crystal packing to an even
greater degree than simple branched alkyl sulfates. Consistent
with this hypothesis, and the depressed melting point of
lumefantrine docusate, the docusate IL was miscible in both
MC-SEDDS and LC-SEDDS. This is in spite of the presence of the
ester groups which are potential H-bond donors and are oen
undesirable (due to strong interactions in the solid state) in
traditional ILs. In the context here in lipid formulations, the
ester groups present in the docusate counterion do not appear
to be problematic and in fact may form favourable interactions
with the excipients and enhance solubility.27 When compared to
the straight chain lipophilic salts with the same number of
carbons, the solubility of the branched ILs was therefore higher
in both systems (see Fig. 9), again consistent with the trends
observed with the equivalent cinnarizine salts. The effect of
branching of the counterion on IL solubility was further
exemplied by lumefantrine docusate, which was miscible in
both MC-SEDDS and LC-SEDDS, consistent with its low glass
transition point.
As all cinnarizine ILs from the series three were miscible in
both formulations, these counterions were paired with lume-
fantrine in an attempt to increase solubility and better differ-
entiate performance (Fig. 8). Apart from lumefantrine 1-decyl
sulfate (2c), all series three lumefantrine ILs displayed higher
solubilities in LBF compared to both the free base and hydro-
chloride salt. In general, solubility increased as the position of
the sulfate group moved further down the carbon chain, with
the highest solubility for lumefantrine 4-decyl sulfate (2k)
(66 mg gꢁ1 in MC-SEDDS and 53 mg gꢁ1 in LC-SEDDS), before
Fig. 7 Equilibrium solubility in MC-SEDDS and LC-SEDDS for lume-
fantrine (2), lumefantrine HCl (2a) and lumefantrine series two sulfates
(2-ethyl-1-hexyl sulfate 2e, 2-butyl-1-octyl sulfate 2f and 2-hexyl-1-
decyl sulfate 2g). Data are n ¼ 3, ꢄSD.
12796 | RSC Adv., 2020, 10, 12788–12799
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Fig. 9 Equilibrium solubility of all lumefantrine compounds in MC-SEDDS and LC-SEDDS separated by # of carbons in the counterion. Data are
n ¼ 3, ꢄSD. *IL was miscible in formulation.
decreasing when the sulfate group was in the 5-position (2l). the increase in entropy in the crystal lattice resulting from
This is consistent with the effect caused by greater branching in higher degrees of freedom of the counterion.
the counterion structure. Notably, whilst lumefantrine 4-decyl
Solubility trends for cinnarizine and lumefantrine salt forms
sulfate showed the highest solubility, the sodium salt of 4- and generally reected trends in melting point, where the salts with
5-decyl sulfate showed signs of decomposition on long term lower melting/glass transition points generally had higher
ꢀ
storage at 25 C, this occurred via displacement of the sulfate solubility in LBF [one exception being cinnarizine 2-ethyl-hexyl
group by water, liberating the parent alcohol and sulfuric acid, sulfate (1i) vs. cinnarizine 1-octyl sulfate (1c)] (a plot of Tm/Tg vs.
as determined by comparison with 1H NMR spectrum of the solubility for lumefantrine salts can be found in ESI†). For both
decomposed counterion with the pure parent alcohol, speci- APIs, increasing branching of the counterion and increasing
cally the appearance of a multiplet at 3.55–3.62 ppm (CDCl3) asymmetry typically reduced melting point and increased
and a noted decrease in pH (0–1) of the material. This decom- solubility in LBFs.
position was also observed in the salt form on long term storage
In summary, this study provides new insights into the
ꢀ
(25 C). The instability of the counterions may therefore limit complex relationship between IL counterion structure, API IL
practical use. Interestingly, however, this was not observed in physical properties and solubility in model LBFs. The data
long term storage of the cinnarizine salts. Fig. 9 shows all conrm the need for rational counterion selection to realise the
lumefantrine ILs grouped by # of carbons, highlighting the full potential of the IL form. Interestingly, many structure/
benet of branched alkyl sulfates.
solubility trends were consistent across two APIs, further
highlighting that certain counterions (typically C10 counterions
and those with branched structures) may be effective in signif-
icantly improving IL solubility in LBFs across a broad range of
API structures. LBF solubility was enhanced up to 8-fold for
cinnarizine ILs compared to the free base, and up to 18-fold for
lumefantrine docusate compared to the free base form. This
highlights the power of ILs to improve lipid solubility and
unlocks the potential to deliver greater doses of API despite
poor inherent solubility.
Conclusions
Isolation of two weakly basic drugs as ILs with alkyl sulfate
counterions in many cases reduced the melting point relative to
the free base and enhanced drug solubility in LBF. The coun-
terion structure played a key role in the physicochemical
properties of the salt, as predicted by thermodynamic consid-
erations. For cinnarizine and lumefantrine ILs, the reduction in
melting point was more pronounced with C8–C12 alkyl chains.
Conflicts of interest
C
10 was the optimal chain length for counterions for both drugs
This article describes intellectual property in the use of ionic
liquids/lipophilic salts in drug delivery that has been assigned
to Lonza. Authors L. F., H. D. W. and H. B. are from Lonza.
and increasing linear chain length past C12 generally resulted in
reduced solubility.
While the majority of the cinnarizine lipophilic salts were
liquid at room temperature, this was not the case for the
lumefantrine ILs, in spite of the fact that the melting points of
the APIs are similar. For lumefantrine, the ILs with branched
Acknowledgements
counterions consistently had lower melting points and higher Erin Tay is funded by an Australian Postgraduate Award. We
solubilities than their straight-chain counterparts, reecting kindly thank Dr Jason Dang for acquiring all HRMS data. We
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 12788–12799 | 12797

View Article Online
RSC Advances
Paper
thank Colin Pouton and Vincent Jannin for helpful discussions 22 J. Stoimenovski and D. R. MacFarlane, Chem. Commun.,
related to this work.
2011, 47, 11429–11431.
23 J. Stoimenovski, D. R. MacFarlane, K. Bica and R. D. Rogers,
Pharm. Res., 2010, 27, 521–526.
24 P. M. Dean, J. Turanjanin, M. Yoshizawa-fujita,
D. R. Macfarlane and J. L. Scott, Cryst. Growth Des., 2009,
9, 1137–1145.
Notes and references
1 H. D. Williams, N. L. Trevaskis, S. A. Charman,
R. M. Shanker, W. N. Charman, C. W. Pouton and 25 H. D. Williams, L. Ford, A. Igonin, Z. Shan, P. Botti,
C. J. H. Porter, Pharmacol. Rev., 2013, 65, 315–499.
2 O. M. Feeney, M. F. Crum, C. L. McEvoy, N. L. Trevaskis,
H. D. Williams, C. W. Pouton, W. N. Charman,
M. M. Morgen, G. Hu, C. W. Pouton, P. J. Scammells,
C. J. H. Porter and H. Benameur, Adv. Drug Delivery Rev.,
2019, 142, 75–90.
C. A. S. Bergstrom and C. J. H. Porter, Adv. Drug Delivery 26 H. D. Lu, P. Rummaneethorn, K. D. Ristroph and
Rev., 2016, 101, 167–194.
R. K. Prud'homme, Mol. Pharm., 2018, 15, 216–225.
3 C. J. H. Porter, N. L. Trevaskis and W. N. Charman, Nat. Rev. 27 J. Griesser, G. Hetenyi, M. Moser, F. Demarne, V. Jannin and
Drug Discovery, 2007, 6, 231–248. A. Bernkop-Schnurch, Int. J. Pharm., 2017, 520, 267–274.
4 H. Mu, R. Holm and A. Mullertz, Int. J. Pharm., 2013, 453, 28 S. H. Choi and T. G. Park, Int. J. Pharm., 2000, 203, 193–202.
¨
215–224.
29 H. D. Williams, L. Ford, S. Han, K. J. Tangso, S. F. Lim,
D. M. Shakleford, D. T. Vodak, H. Benameur,
C. W. Pouton, P. J. Scammells and C. J. H. Porter, Mol.
Pharm., 2018, 15, 5678–5696.
5 D. J. Hauss, Adv. Drug Delivery Rev., 2007, 59, 667–676.
6 E. T. Cole, D. Cade and H. Benameur, Adv. Drug Delivery Rev.,
2008, 60, 747–756.
´
7 V. Jannin, J. Musakhanian and D. Marchaud, Adv. Drug 30 Y. Sahbaz, T. H. Nguyen, L. Ford, C. L. McEvoy,
Delivery Rev., 2008, 60, 734–746.
8 E. V. Hersh, L. M. Levin, S. A. Cooper, G. Doyle, J. Waksman,
H. D. Williams, P. J. Scammells and C. J. H. Porter, Mol.
Pharm., 2017, 14, 3669–3683.
D. Wedell, D. Hong and S. A. Secreto, Clin. Ther., 2000, 22, 31 S. Parasuraman, J. Pharmacol. Exp. Ther., 2011, 2, 74–79.
1306–1318.
32 D. R. MacFarlane, M. Kar and J. M. Pringle, Fundamentals of
Ionic Liquids: From Chemistry to Applications, Wiley, 2017.
9 R. G. Strickley and R. Oliyai, in Solvent Systems and Their
Selection in Pharmaceutics and Biopharmaceutics, ed. P. 33 A. R. Katritzky, R. Jain, A. Lomaka, R. Petrukhin, U. Maran
Augustijns and M. Brewster, Springer, New York, NY, 2007,
vol. VI.
and M. Karelson, Cryst. Growth Des., 2001, 1, 261–265.
34 A. S. Prakash, J. Excipients Food Chem., 2011, 2, 28–40.
10 D. Dobler, T. Schmidts, I. Klingenhofer and F. Runkel, Int. J. 35 E. I. Izgorodina, U. Bernard, P. Dean, J. Pringle and
Pharm., 2013, 441, 620–627. D. Macfarlane, Cryst. Growth Des., 2009, 9, 4834–4839.
11 A. Balk, U. Holzgrabe and L. Meinel, Eur. J. Pharm. 36 H. Tokuda, K. Hayamizu, K. Ishii, M. A. B. H. Susan and
Biopharm., 2015, 94, 291–304.
12 C. P. Mehnert, Chem.–Eur. J., 2005, 11, 50–56.
13 M. Gorlov and L. Kloo, Dalton Trans., 2008, 2655–2666.
M. Watanabe, J. Phys. Chem. B, 2004, 108, 16593–16600.
37 H. Tokuda, K. Hayamizu, K. Ishii, M. A. B. H. Susan and
M. Watanabe, J. Phys. Chem. B, 2005, 109, 6103–6110.
14 Y. Sahbaz, H. D. Williams, T. H. Nguyen, J. Saunders, 38 J. A. P. Coutinho, P. J. Carvalho and N. M. C. Oliveira, RSC
L. Ford, S. A. Charman, P. J. Scammells and C. J. Porter,
Mol. Pharm., 2015, 12, 1980–1991.
15 S. Kandasamy, M. Moniruzzaman, M. Sivapragasam,
Adv., 2012, 2, 7322–7346.
39 E. I. Izgorodina, Theoretical Approaches to Ionic Liquids: From
Past History to Future Directions, 2012.
´
M. R. Shamsuddin and M. I. A. Mutalib, Sep. Purif. 40 I. Lopez-Martin, E. Burello, P. N. Davey, K. R. Seddon and
Technol., 2018, 196, 149–156. G. Rothenberg, ChemPhysChem, 2007, 8, 690–695.
16 D. Monti, E. Egiziano, S. Burgalassi, P. Chetoni, C. Chiappe, 41 W. M. Reichert, J. D. Holbrey, R. P. Swatloski, K. E. Gutowski,
A. Sanzone and S. Tampucci, Int. J. Pharm., 2017, 516, 45–51.
A. E. Visser, M. Nieuwenhuyzen, K. R. Seddon and
17 W. L. Hough, M. Smiglak, H. Rodriguez, R. P. Swatloski,
R. D. Rogers, Cryst. Growth Des., 2007, 7, 1106–1114.
S. K. Spear, D. T. Daly, J. Pernak, J. E. Grisel, R. D. Carliss, 42 K. Patel, V. Sarma and P. Vavia, Daru, J. Pharm. Sci., 2013, 21,
M. D. Soutullo, J. H. Davis and R. D. Rogers, New J. Chem.,
2007, 31, 1429–1436.
18 W. L. Hough and R. D. Rogers, Bull. Chem. Soc. Jpn., 2007, 80,
2262–2269.
27–37.
43 N. M. Pinkerton, A. Grandeury, A. Fisch, J. Brozio,
B. U. Riebesehl and R. K. Prud'homme, Mol. Pharm., 2013,
10, 319–328.
19 W. L. Hough-Troutman, M. Smiglak, S. Griffin, W. Matthew 44 C. W. Pouton, Eur. J. Pharm. Sci., 2006, 29, 278–287.
Reichert, I. Mirska, J. Jodynis-Liebert, T. Adamska, J. Nawrot, 45 M. Yoshizawa, W. Xu and C. A. Angell, J. Am. Chem. Soc.,
M. Stasiewicz, R. D. Rogers and J. Pernak, New J. Chem., 2009,
33, 26–33.
20 J. L. Shamshina, P. S. Barber and R. D. Rogers, Expert Opin.
Drug Delivery, 2013, 10, 1367–1381.
21 K. Bica, C. Rijksen, M. Nieuwenhuyzen and R. D. Rogers,
Phys. Chem. Chem. Phys., 2010, 12, 2011–2017.
2003, 125, 15411–15419.
46 J. Stoimenovski, P. M. Dean, E. I. Izgorodina and
D. R. Macfarlane, Faraday Discuss., 2011, 154, 335–352.
47 D. N. Moreira, N. Fresno, R. Perez-Fernandez, C. P. Frizzo,
P. Goya, C. Marco, M. A. P. Martins and J. Elguero,
Tetrahedron, 2015, 71, 676–685.
´
´
12798 | RSC Adv., 2020, 10, 12788–12799
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
`
¨
48 A. Wibbertmann, I. Mangelsdorf, K. Gamon and R. Sedlak,
F. Carriere, A. Mullertz, C. J. H. Porter and C. W. Pouton, J.
Ecotoxicol. Environ. Saf., 2011, 74, 1089–1106.
Pharm. Sci., 2012, 101, 3360–3380.
49 R. Mogul, E. Johansen and T. R. Holman, Biochemistry, 2000, 52 M. Morgen, A. Saxena, X.-Q. Chen, W. Miller, R. Nkansah,
39, 4801–4807.
A. Goodwin, J. Cape, R. Haskell, C. Su, O. Gudmundsson,
M. Hageman, A. Kumar, G. S. Chowan, A. Rao and
V. K. Holenarsipur, Eur. J. Pharm. Biopharm., 2017, 117,
212–223.
50 H. D. Williams, Y. Sahbaz, L. Ford, T. H. Nguyen,
P. J. Scammells and C. J. H. Porter, Chem. Commun., 2014,
50, 1688–1690.
¨
51 H. D. Williams, P. Sassene, K. Kleberg, J.-C. Bakala-N'Goma, 53 F. Alves, F. S. Oliveira, B. Schroder, C. Matos and
M. Calderone, V. Jannin, A. Igonin, A. Partheil, D. Marchaud,
E. Jule, J. Vertommen, M. Maio, R. Blundell, H. Benameur,
I. M. Marrucho, J. Pharm. Sci., 2013, 102, 1504–1512.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 12788–12799 | 12799