Confused ionic liquid ions - A "liquification" and dosage strategy for pharmaceutically active salts

Article abstract of DOI:10.1039/b925147b

We present a strategy to expand the liquid and compositional ranges of ionic liquids, specifically pharmaceutically active ionic liquids, by simple mixing with a solid acid or base to form oligomeric ions.

Full text of DOI:10.1039/b925147b

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Confused ionic liquid ions—a ‘‘liquification’’ and dosage strategy
for pharmaceutically active saltsw
a
Katharina Bicaz and Robin D. Rogers*ab
Received (in Austin, TX, USA) 30th November 2009, Accepted 17th December 2009
First published as an Advance Article on the web 20th January 2010
DOI: 10.1039/b925147b
We present a strategy to expand the liquid and compositional
ranges of ionic liquids, specifically pharmaceutically active ionic
liquids, by simple mixing with a solid acid or base to form
oligomeric ions.
et al. presented dimeric and oligomeric anions in the protic
N-methylpyrrolidine–acetic acid system, with the highest
degree of ionicity being present for the oligomeric species
[(AcO)3H2]ꢀ.10 However, oligomeric anions can also be seen
in Lewis acidic ILs that are composed of monomeric, dimeric,
and mixꢀed-valent anions such as AlCl4ꢀ, Al2Cl7ꢀ, and
AlCl3Cl9 or for halides, e.g., iodides complexed to I2, with
oligomeric species based on [I3]ꢀ, [I5]ꢀ, [I7]ꢀ, and [I9]ꢀ.11,12
Here, we present results which suggest the formation of
oligomeric hydrogen bonded cations or anions in pharma-
ceutically active ILs. Such a strategy can have profound effects
for improving the properties of salts of APIs, for example, in
modification of stoichiometry for dosage options, in lique-
faction for drug delivery, etc. However, we also recognize that
such a strategy might be generally used by the IL community
to provide relatively easy modification of melting points and
other physical properties as part of an overall ‘tuning’ strategy
for a particular solvent/material need.
The pharmaceutical industry relies predominantly on the solid
crystalline or amorphous state for the manufacture and delivery
of active pharmaceutical ingredients (APIs), despite the increasing
instances of problems associated with the solid form of many
drugs including polymorphic conversion, low solubility, and
low bioavailability, and the tendency of amorphous forms to
spontaneously crystallize.1,2
We have recently questioned the reliance of the pharma
industry on solid APIs and suggested that in some instances a
liquid salt form (i.e., an ionic liquid, IL, loosely defined as salts
with melting points below 100 1C) might prove beneficial.3,4
An IL form of an API not only eliminates problems associated
with polymorphism by virtue of being a liquid, but can also
dramatically influence a drug’s solubility. Dual-functional ILs
composed of two active ions may even lead to synergistic
effects and we note recent commercialization efforts along
these lines.5 In our own ongoing search for new ILs and new
IL APIs, we have found that by carefully generating oligo-
meric ions with ‘confused’ protons (compared with simple
eutectics such as mixtures of quaternary ammonium halides
and hydrogen bond donors),6 we can dramatically increase the
liquid range of a classic salt.
Hydrogen-bonded homoconjugated oxoanions (Aꢀ hydrogen-
bonded to their corresponding acid to form HA2ꢀ) are
frequently found in transition metal complexes and can be
classified as weakly coordinating anions.7 The O–H–O bond in
carboxylic acid–carboxylate systems is considered to be a low-
barrier hydrogen bond with considerable covalent character,
an overall bond length of 2.5 A or below, and to have an
unusually strong interaction energy (Z10 kcal molꢀ1).8
Given the importance of weakly coordinating anions for
ILs, surprisingly few explicit studies of oligomeric ILs can be
found in the literature, although evidence for their presence is
found in the context of protic ILs.9 Only recently McFarlane
We chose to first test our hypothesis by attempting the
formation of an oligomeric anion based on salicylate (Salꢀ)
with the permanent cation tetrabutylphosphonium (P(Bu)4+);
thus allowing us to ignore hydrogen bonding between cation
and anion (Scheme 1). Salicylic acid, a key ingredient of skin-
care products, has antiseptic, preservative, analgesic, and
anti-inflammatory properties, covering a broad spectrum of
applications,13 and P(Bu)4+ has known antimicrobial effects.14
Tetrabutylphosphonium salicylate [1] was easily prepared
by reaction of salicylic acid with a solution of tetrabutylphos-
phonium hydroxide in H2O and obtained as a colorless, rather
hygroscopic solid with a moderate melting point of 57 1C.15
However, when tetrabutylphosphonium hydroxide was reacted
with two equivalents of salicylic acid, a clear liquid with only a
glass transition at ꢀ46 1C was obtained. These results prompted
us to look for new synthetic methods that would allow us to
eliminate any influence of trace solvent and to explore the
dependence of thermal properties on composition.
Solid 1 and solid salicylic acid (mp = 158.1 1C) were ground
or melted under an atmosphere of dry nitrogen to form several
new liquid compositions. Each liquid form was studied
by differential scanning calorimetry (DSC; Table S1 in ESIw).
a The Queen’s University of Belfast, QUILL,
School of Chemistry and Chemical Engineering, Belfast,
Northern Ireland BT9 5AG
b The University of Alabama, Department of Chemistry and Center for
Green Manufacturing, Tuscaloosa, AL 35487, USA.
E-mail: rdrogers@as.ua.edu
w Electronic supplementary information (ESI) available: Synthetic
procedures, characterization and copies of TGA and DSC plots. See
DOI: 10.1039/b925147b
Scheme 1 Proposed formation of oligomeric ions based on salicylate/
z Current address: Institute of Applied Synthetic Chemistry,
Vienna University of Technology, 1060 Vienna, Austria.
salicylic acid.
ꢁc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 1215–1217 | 1215

View Article Online
Fig. 2 1H-NMR spectra of P(Bu)4Sal [1] (bottom) and P(Bu)4Sal2H1
(top).
proton-bound isomeric tautomers are typically characterized
by an unusual downfield shift of the delocalized proton of
>15 ppm in aprotic, low-polarity solvents.8c,17,18 When we
performed low temperature NMR spectroscopy of P(Bu)4Sal [1]
19
and P(Bu)4Sal2H1 in a mixture of CDClF2/CDF3 at 173 K,
Fig. 1 DSC traces of P(Bu)4Sal–SalH salts.
we observed a broad peak at 19.2 ppm for P(Bu)4Sal2H1 as is
typical for short, strong hydrogen bonds of the type O–H–O,
thus indicating the presence of a hydrogen-bonded oligomeric
anion with strong interaction energy (Fig. 2).
The addition of excess salicylic acid resulted in dramatic
reductions in the melting point; an excess of only 0.1 equiv.
salicylic acid reduced the observed melting point from 57 1C
(P(Bu)4Sal, mole fraction salicylic acid wSalH = 0) to 48 1C
(P(Bu)4Sal1.1H0.1, wSalH = 0.09). The addition of 0.4 equiv.
salicylic acid (P(Bu)4Sal1.4H0.4 (wSalH = 0.29)) resulted in the
complete elimination of the melting point to yield a free
flowing liquid (Fig. 1), despite the fact that both 1 and the
free acid are solid at room temperature.
The formation of oligomeric ions as discussed above, need
not be carried out using the parent acid (corresponding to
homoconjugated oxoanions [HA2]ꢀ), but can also be observed
for heteroconjugated oxoanions of the type [HAA0]ꢀ. We have
demonstrated this with the non-steroidal anti-inflammatory
drug (NSAID) ibuprofen and the UV-protector cinnamic acid
as examples of solid biologically active acids with a reasonable
pKa difference (DpKa o 2) to allow a permaꢀnent hydrogen
exchange in the mixed dimeric anion [HAA0] . When these
solid acids were reacted with one equiv. of P(Bu)4Sal [1], we
obtained liquid products with only a glass transition: ꢀ45.01 1C
ibuprofen; ꢀ43.81 1C cinnamic acid.
A point of saturation was observed with 2 equiv. of salicylic
acid at a composition of P(Bu)4Sal3H2 (wSalH = 0.67) and slow
precipitation of crystalline salicylic acid was observed after
some time. Between the first liquid composition and satura-
tion, a glass transition temperature at Bꢀ50 1C that is slightly
shifted to higher temperature with increasing salicylic acid, is
the only observed transition.
Since the majority of all APIs can be considered as protic
acids or bases,1 we were curious whether the addition of excess
acid to a salt comprised of the conjugate base of a protic acid
or addition of excess base to a salt comprised of the conjugate
acid of a protic base (Scheme 2) would (a) result in oligomeric
ions and (b) if the presence of such oligomers would signifi-
cantly alter the physical properties of the salt. We investigated
this possibility with the addition of excess acid or base to
lidocainium salicylate [2] (Scheme 2). Here, we hoped to not
only expand the scope of the oligomeric anions to the corres-
ponding oligomeric cations, but to also provide a method
which would allow the individual dosing of two or more active
compounds in one liquid salt form, that is, obviating the need
for stoichiometric component ions.
Thermogravimetric analysis (TGA) of PBu4Sal [1] showed a
single decomposition with high thermal stability (Tonset5%
=
308 1C), however, a two-step decomposition is obtained for
the corresponding salts with oligomeric anions. The thermal
stability decreases with increasing excess salicylic acid, gradually
approaching the decomposition temperature of pure salicylic
acid (Fig. S2, Table S1 in ESIw).
The striking behavior observed above can be explained by a
fast proton exchange between anion and corresponding acid
and the formation of hydrogen-bonded oligomeric anions as
previously described for salicylic acid–salicylate systems.16 The
permanent delocalizatꢀion of a ‘‘confused’’ proton in the
homoconjugated HA2 anion apparently prevents the salt
ꢀ
Lidocainium salicylate [2] was prepared by anion metathesis
from lidocainium hydrochloride monohydrate and sodium
salicylate and was obtained as a very viscous liquid with only
from crystallizing. In addition, the homoconjugated HA2
anion should be more weakly coordinating (i.e., a weaker
base) than Aꢀ, thereby affecting the various physicochemical
properties of the IL. However, whereas McFarlane et al.
reported a characteristic maxima in conductivity and viscosity
for the oligomeric anions [(AcO)3H2]ꢀ in the protic N-methyl-
pyrrolidine–acetic acid system,10 we observed a constant
decrease of conductivity and increase of viscosity (Table S1
in ESIw) with addition of salicylic acid, thus indicating that
liquefaction of the solid IL P(Bu)4Sal [1] is achieved at the cost
of ionicity.
The presence of the oligomeric anion could be demonstrated
by NMR spectroscopy. Low-barrier hydrogen bonds in
Scheme 2 Proposed oligomeric ion approach.
ꢁc
This journal is The Royal Society of Chemistry 2010
1216 | Chem. Commun., 2010, 46, 1215–1217

View Article Online
6 (a) A. P. Abbott, D. Boothby, G. Capper, D. L. Davies and
R. K. Rasheed, J. Am. Chem. Soc., 2004, 126, 9142;
(b) A. P. Abbott, J. C. Barron, K. S. Ryder and D. Wilson,
Chem.–Eur. J., 2007, 13, 6495; (c) A. P. Abbott, G. Capper,
D. L. Davies, K. J. McKenzie and S. U. Obi, J. Chem. Eng. Data,
2006, 51, 1280; (d) A. P. Abbott, G. Capper and S. Gray,
ChemPhysChem, 2006, 7, 803; A. P. Abbott, G. Capper, D. L.
Davies, R. Rasheed and V. Tambyrajah, Chem. Commun., 2003, 70.
7 O. G. Polyakov, B. G. Nolan, B. P. Fauber, S. M. Miller,
O. P. Anderson and S. H. Strauss, Inorg. Chem., 2000, 39, 1735.
8 (a) P. Gilli, V. Bertolasi, V. Ferretti and G. Gilli, J. Am. Chem.
Soc., 1994, 116, 909; (b) G. A. Kumar, Y. Pan, C. J. Smallwood
and M. A. McAllister, J. Comput. Chem., 1998, 19, 1345;
(c) A. Bruck, L. J. McCoy and K. V. Kilway, Org. Lett., 2000,
¨
2, 2007; (d) K. M. Harmon, K. E. Shaw and S. M. Sadeki, J. Mol.
Struct., 2000, 526, 191; (e) P. Barczynski, I. Kowalczyk,
M. Grundwald-Wyspianska and M. Szafran, J. Mol. Struct.,
1999, 484, 117; (f) C. L. Perrin and J. B. Nielson, J. Am. Chem.
Soc., 1997, 119, 12734; (g) C. L. Perrin and J. B. Nielson, Annu.
Rev. Phys. Chem., 1997, 48, 51ꢀ1.
Fig. 3 DSC traces of lidocainium salicylate [2] and oligomers.
9 For examples: (a) H(TFA)2
: M. Yoshizawa, W. Xu and
C. A. Angell, J. Am. Chem. Soc., 2003, 125, 15411;
(b) H(TFSI)2 : A. Noda, M. A. B. H. Susan, K. Kudo,
S. Mitsushima, K. Hayamizu and M. Watanabe, J. Phys. Chem.
B, 2003, 107, 4024; M. A. B. H. Susan, A. Noda, S. Mitsushima
and M. Watanabe, Chem. Commun., 2003, 938; H. Nakamoto,
ꢀ
a glass transition at 19.8 1C observable in the DSC.12 When
excess salicylic acid or excess lidocaine (free base) was ground
with 2 in a manner analogous to that above, a less dramatic
but similar reduction of the glass transition temperatures
in both directions, until saturation and solid samples are
obtained, was observed (Fig. 3).
A. Noda, K. Hayamizu, S. Hayashi, H. Hamaguchi and
M. Watanabe, J. Phys. Chem. C, 2007, 111, 1541; (c) HF2
ꢀ
:
R. Hagiwara, K. Matsumoto, Y. Nakamori, T. Tsuda, Y. Ito,
H. Matsumoto and K. Momota, J. Electrochem. Soc., 2003, 150,
D195; R. Hagiwara and Y. Ito, J. Fluorine Chem., 2000, 105, 221;
R. Hagiwara, Y. Nakamori, K. Matsumoto and Y. Ito, J. Phys.
Chem. B, 2005, 109, 5445; K. Matsumoto and R. Hagiwara,
J. Fluorine Chem., 2007, 128, 317; Y. Saito, K. Hirai,
K. Matsumoto, R. Hagiwara and Y. Minamizaki, J. Phys. Chem.
B, 2005, 109, 2942; C. Rijksen and R. D. Rogers, J. Org. Chem.,
2008, 73, 5582; (d) HCl2ꢀ: J. W. Shuppert and C. A. Angell,
J. Chem. Phys., 1977, 67, 3050; (e) HNO32ꢀ: A. C. Angell, W. Xu,
J.-P. Belieres and M. Yoshizawa, PCT Int. Appl. 2004/114445 Aꢀ1,
In conclusion, oligomeric ion formation has a tremendous
influence on physical properties that allows expansion of the
liquid ranges of some solid salts. We are aware that the term
‘‘ionic liquids’’ for this type of liquid salt formulation might be
controversial and has to be verified by further investigation
concerning ionicity and simple eutectic behavior (these studies
are currently ongoing in our lab). However, it is important to
note that the concept of oligomeric ions enables liquefaction of
solid ILs (or other salts) by simply changing the stoichiometry
or complexity of the ions and the strategy need not employ the
parent of the anion or cation in use. This can be particularly
useful for pharmaceutically active salts or ILs, since, although
some efforts towards the prediction of the state of ILs have
been made,4 the design of IL pharmaceuticals will benefit from
this strategy to modify the physical properties of a given salt
form once obtained.
2004; (f) H(HCO)2ꢀ, H(CH3CH2COO)2ꢀ and H((CH3)3CCOO)2
:
F. Kohler, H. Atrops, H. Kalali, E. Liebermann, E. Wilhelm,
F. Ratkovics and T. Salamon, J. Phys. Chem., 1981, 85, 2520.
10 K. M. Johansson, E. I. Izgorodina, M. Forsyth, D. R. MacFarlane
and K. R. Seddon, Phys. Chem. Chem. Phys., 2008, 10, 2972.
11 (a) S. P. Wicelinski and R. J. Gale, Anal. Chem., 1988, 60, 2228;
(b) P. Wasserscheid and W. Keim, Angew. Chem., Int. Ed., 2000,
39, 3772.
12 (a) O. Bortolini, M. Bottai, C. Chiappe, V. Contec and
D. Pieraccini, Green Chem., 2002, 4, 621; (b) M. Deetlefs,
K. R. Seddon and M. Shara, Phys. Chem. Chem. Phys., 2006, 8,
642.
13 K. Wu, Anti-Inflammatory Anti-Allergy Agents Med. Chem., 2007,
6, 278.
14 (a) A. Cieniecka-Ros"onkiewicz, J. Pernak, J. Kubis-Feder,
A. Ramani, A. J. Robertson and K. R. Seddon, Green Chem.,
2005, 7, 855; (b) R. Grade and B. M. Thomas, PCT Int. Appl.,
4874526, 1989.
15 K. Bica, C. Rijksen, M. Nieuwenheuzen and R. D. Rogers, Phys.
Chem. Chem. Phys., 2010, accepted (manuscript number
B923855G).
16 N. S. Golubev, S. N. Smirnov, P. Schah-Mohammedi,
I. G. Shenderovich, G. S. Denisov, V. A. Gindin and
H. H. Limbach, Russ. J. Gen. Chem., 1997, 67, 1082 (Zh. Obshch.
Khim., 1997, 67, 1150).
Notes and references
1 Handbook of Pharmaceutical Salts, ed. P. H. Stahl and
C. G. Wermuth, Wiley-VCH, Weinheim, 2002; S. M. Berge,
L. D. Bighley and D. C. Monkhouse, J. Pharm. Sci., 1977, 66, 1.
2 H. G. Brittain, J. Pharm. Sci., 2002, 91, 1573.
3 (a) W. L. Hough and R. D. Rogers, Bull. Chem. Soc. Jpn., 2007, 80,
2262; (b) W. L. Hough, M. Smiglak, H. Rodriguez,
R. P. Swatloski, S. K. Spear, D. T. Daly, J. Pernak, J. E. Grisel,
R. D. Carliss, M. D. Soutullo, J. H. Davis Jr. and R. D. Rogers,
New J. Chem., 2007, 31, 1429; (c) R. D. Rogers, D. T. Daly,
R. P. Swatloski, W. L. Hough, J. H. Davis, M. Smiglak, J. Pernak
and S. K. Spear, PCT Int. Appl., 2007044693, 2007.
4 P. M. Dean, J. Turanjanin, M. Yoshizawa-Fujita,
D. R. MacFarlane and J. L. Scott, Cryst. Growth Des., 2009, 9,
1137.
5 (a) Chem. Eng. News, October 5 2009, 87(40), p. 26; (b) Etodolac
Patch (MRX-7EAT) in Phase I clinical trials in the US. http://www.
medrx.co.jp/english/newsrelease.html (last accessed 15/12/09).
17 N. S. Golubev, S. N. Smirnov, V. A. Gindin, G. S. Denisov,
H. Benedict and H. Limbach, J. Am. Chem. Soc., 1994, 116, 12055.
18 P. M. Tolstoy, P. Schah-Mohammedi, S. N. Smirnov,
N. S. Golubev, G. S. Denisov and H. Limbach, J. Am. Chem.
Soc., 2004, 126, 5621.
19 J. S. Siegel and F. L. A. Annet, J. Org. Chem., 1988, 53,
2629.
ꢁc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 1215–1217 | 1217