Transforming aspirin into novel molecular salts of salicylic acid

Article abstract of DOI:10.1007/s11224-013-0326-x

Aspirin is one of the most widely used analgesic, antipyretic, and anti-inflammatory drugs. Herein we disclose a way to transform aspirin into novel multicomponent crystal forms of salicylic acid, also a long-known analgesic with anti-inflammatory properties, among others, covering a broad spectrum of applications, including skin care products. A salicylic acid:salicylate ammonium salt and a salicylate:2-methyl-4-oxopentan-2-aminium molecular salt are concomitantly formed in acetone/ammonia solutions, resulting from aspirin decomposition. Furthermore the 2-methyl-4-oxopentan-2-aminium cation results from a sequence of in situ reactions: (i) imine formation, in which acetone is known to undergo under basic pH conditions; (ii) nucleophilic attack of α-carbon of the deprotonated acetone to the imine yielding 4-amino-4-methylpentan-2-one; and (iii) protonation of 4-amino-4-methylpentan-2- one. In the structures obtained for the novel multicomponent crystal forms, the strong charge-assisted N⁺-H···O/O^- hydrogen bonds between the drug molecule and the co-former play a key function in the supramolecular arrangement. The typical R²₂(8) carboxylic···carboxylic homosynthon observed in salicylic acid was inhibited by the salt formation. These results are in agreement with the results of a careful survey on the Cambridge Structural Database. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11224-013-0326-x

Struct Chem
DOI 10.1007/s11224-013-0326-x
ORIGINAL RESEARCH
Transforming aspirin into novel molecular salts of salicylic acid
•
Vania Andre Ines Martins Sılvia Quaresma
•
•
ˆ
´
ˆ
Marta Martins M. Teresa Duarte
´
•
Received: 24 April 2013 / Accepted: 7 August 2013
Ó Springer Science+Business Media New York 2013
Abstract Aspirin is one of the most widely used analgesic,
antipyretic, and anti-inflammatory drugs. Herein we disclose
a way to transform aspirin into novel multicomponent crystal
forms of salicylic acid, also a long-known analgesic with
anti-inflammatory properties, among others, covering a
broad spectrum of applications, including skin care products.
A salicylic acid:salicylate ammonium salt and a salicylate:2-
methyl-4-oxopentan-2-aminium molecular salt are con-
comitantly formed in acetone/ammonia solutions, resulting
from aspirin decomposition. Furthermore the 2-methyl-4-
oxopentan-2-aminium cation results from a sequence of
in situ reactions: (i) imine formation, in which acetone is
known to undergo under basic pH conditions; (ii) nucleo-
philic attack of a-carbon of the deprotonated acetone to the
imine yielding 4-amino-4-methylpentan-2-one; and (iii)
protonation of 4-amino-4-methylpentan-2-one. In the
structures obtained for the novel multicomponent crystal
forms, the strong charge-assisted N?–HꢀꢀꢀO/O- hydrogen
bonds between the drug molecule and the co-former play a
key function in the supramolecular arrangement. The typical
R22ð8Þ carboxylicꢀꢀꢀcarboxylic homosynthon observed in
salicylic acid was inhibited by the salt formation. These
results are in agreement with the results of a careful survey on
the Cambridge Structural Database.
Keywords Aspirin ꢀ Salicylic acid ꢀ Molecular salts ꢀ
Acetone reactions ꢀ Supramolecular anion
Introduction
Salicylic acid, also known as ortho-hydroxybenzoic acid or
2-hydroxybenzoic acid (Fig. 1), was used as early as 400
b.c. as an analgesic and is naturally prevalent in willow
leaves, as well as in poplar and birch trees [1]. Salicylic
acid has antiseptic, preservative, analgesic, and anti-
inflammatory properties, covering a broad spectrum of
applications, including skin care products [2, 3].
On the other hand, aspirin, acetylsalicylic acid, or,
under IUPAC designation, 2-acetoxybenzoic acid was
first synthesized in 1853 and by the turn of the nineteenth
century became the world’s best selling drug [4, 5]. It is
a salicylate drug, often used as an analgesic to relieve
minor aches and pains, as an antipyretic to reduce fever,
and as an anti-inflammatory medication. Aspirin also has
an antiplatelet and is used long-term, at low doses, to
help prevent heart attacks, strokes, and blood clot for-
mation in people at high risk for developing this condi-
tion [6–22].
Aspirin is known to exist in two polymorphic forms:
form I (Fig. 2a) [23] and form II [24] (Fig. 2b), and their
supramolecular arrangements are related to each other by a
relative shift of adjacent layers along the crystallographic
c axis in space group P21/c [8, 25].
Electronic supplementary material The online version of this
article (doi:10.1007/s11224-013-0326-x) contains supplementary
material, which is available to authorized users.
Salicylic acid has some similarities to aspirin, not only
on its analgesic action but also in its chemical structure,
molecular and crystal packing arrangements [24–28]. The
formation of the centrosymmetric homosynthon R22ð8Þ
forming carboxylic acid dimers also occurs in salicylic acid
as observed in both aspirin polymorphs [29]. Salicylic acid
´
V. Andre (&) ꢀ I. Martins ꢀ S. Quaresma ꢀ M. Martins ꢀ
M. T. Duarte
Departamento de Engenharia Quımica, Centro de Quımica
´
Estrutural, Instituto Superior Tecnico, Universidade de Lisboa,
´
´
Av. Rovisco Pais 1, 1049-001 Lisbon, Portugal
e-mail: vaniandre@ist.utl.pt
123

Struct Chem
forms were obtained: an ammonium salt1 with a supramo-
lecular anion2 formed by salicylic acid and salicylate (1)
and a molecular salt (see footnote 1) between salicylate and
2-methyl-4-oxopentan-2-aminium (2). These crystal forms
were structurally characterized, but as they were always
concomitantly obtained (Fig. 3), we were unable to further
characterize their separate thermal behavior and stability.
Graph-set notation will be used to characterize the
description of these novel crystal forms [58].
Fig. 1 a Salicylic acid and b aspirin
supramolecular arrangement is further characterized by an
intramolecular hydrogen bond between the hydroxyl and
Salicylic acid:salicylate ammonium salt, 1
carboxylic groups forming
a S(6) synthon [30–32]
The asymmetric unit of the ammonium salt consists on one
neutral molecule of salicylic acid, one salicylate anion, and
one ammonium cation (Fig. 4). The anionic nature of the
salicylate was determined by the C–O distances [59]
(Fig. 2c). All these features lead to a less flexible molecule
with reduced intermolecular hydrogen-bonding capacity,
which likely explains the low tendency for polymorphism,
as opposed to its isomers, p- and m-hydroxybenzoic acids
[3, 33].
˚
[1.272(2) and 1.267(2) A] and confirmed by the location of
all four hydrogen atoms from electron density map around
the nitrogen. This crystal form of global formula
[NH4]?ꢀ[(SA)(HSA)]- is a salt in which the anion is
actually a supramolecular anion (see footnote 2) formed
between neutral and deprotonated salicylic acid, having
direct intermolecular hydrogen-bonding between them.
Both salicylic acid and salicylate display intramolecular
Two ammonium salts [34, 35] and five new aspirin
multicomponent crystal forms have been reported: with
5-methoxysulfadiazine (1:1) [27], sulfadimidine (1:1) [28],
carbamazepine [24, 36], DABCO [37], and D-theanine
[38]. In all of them aspirin synthons were disrupted due to
the formation of O–HꢀꢀꢀO, N–HꢀꢀꢀO, and/or N–HꢀꢀꢀN
interactions with the co-formers.
˚
S(6) interactions via O–HOHꢀꢀꢀOCOOH [2.641(4) A] and O–
Also several multicomponent crystal forms of salicylic
acid have been reported [37, 39–53] with several co-
formers such as meloxicam [42], temozolomide [43], car-
bamazepine [45, 46], theophylline [47], caffeine [48, 49],
creatinine [50], as well as some b-cyclodextrine clathrates
[54]. In most of these forms, the formation of ring synthons
is common, except in the salt examples where the depro-
tonation of the carboxylic group makes it much more
unlikely.
˚
HOHꢀꢀꢀOCOO– [2.513(4) A], respectively. In the crystal pack-
ing we find no direct contacts between symmetry equivalent
fragments. Salicylic acid interacts with the salicylate by both
the hydroxyl and carboxyl groups [O–HOHꢀꢀꢀOCOO
–
˚
˚
2.974(5) A and O–HCOOHꢀꢀꢀOCOO– 2.597(4) A] and connects
with the ammonium cations through N–HꢀꢀꢀOCOOH interac-
˚
tions [N–HꢀꢀꢀOCOOH 3.141(6) A]. The salicylate is further
hydrogen-bonded to the cations by two N–HꢀꢀꢀOCOO
–
˚
[3.226(6), 2.732(5), and 2.859(6) A] and one N–HꢀꢀꢀOOH
Taking this into consideration, we decided to further
search for new multicomponent forms of aspirin using
mono-, di-, and tricarboxylic acids and aminoacids as co-
formers. In these studies, besides the intended supramo-
lecular rearrangements, we have also induced traditional
covalent reactions, yielding new multicomponent crystal
forms of salicylic acid.
˚
[2.934(6) and 2.964(6) A]. Thus each ammonium cation
connects to four salicylates and one salicylic acid molecule. A
layer is formed in the ab plane, where tapes of alternated sal-
icylic acid and salicylateare assistedbythe ammonium cations
that lie in the space between them (Fig. 5). Details on the
hydrogen bonds present 1 are given in Table 1.
The direct interactions between salicylic acidꢀꢀꢀsalicylate
were not seen in the salt reported by Downie and Speak-
man [34] where both entities interact directly with the
Results and discussion
ammonium cation and water molecules. The N–HꢀꢀꢀOCOO
–
and N–HꢀꢀꢀOOH depicted in the salt reported herein are
similar to the ones reported in the two ammonium salts
previously reported [34, 35].
Polymorphic and multicomponent crystal form screenings
of both aspirin and salicylic acid have been extensively
reported previously. To expand these studies we decided to
attempt the co-crystallization of aspirin with mono-, di-, and
tricarboxylic acids and aminoacids, but these efforts were
unsuccessful. Instead, we induced aspirin’s in situ decom-
position into salicylic acid when doing a salt screening in
basic pH media. Two concomitant new multicomponent
1
We have used a long-used definition of salts (inorganic counterion)
versus molecular salt (organic counterion) [55, 56].
2
We have used the definition of supramolecular anion when referring
to a supramolecular aggregate that as a whole has a negative charge,
as used by Braga and co-workers [57].
123

Struct Chem
Fig. 2 a Aspirin polymorph I: R22 synthon formed by the carboxylic
groups (green) and R22 synthon formed by the C–HꢀꢀꢀO interactions
(purple); b Aspirin polymorph II: R22 synthon formed by the carboxylic
groups (green) and C–HꢀꢀꢀO interactions (purple) giving rise to
catemeric chains; c salicylic acid R22 synthon formed by the carboxylic
moiety (green) and the S(6) synthon (blue) (Color figure online)
˚
and 1.252(3) A) in the carboxylate moiety and the location
of three hydrogen atoms on the nitrogen from the electron
density map.
The 2-methyl-4-oxopentan-2-aminium cation is formed
in situ by a sequence of reactions: (i) imine formation that
acetone is known to undergo under basic pH conditions;
(ii) nucleophilic attack giving rise to 4-amino-4-methyl-
pentan-2-one; and (iii) 4-amino-4-methylpentan-2-one
protonation (Scheme I).
Both the salicylate and the 2-methyl-4-oxopentan-2-
aminium cation display intramolecular interactions: O ꢁ
Â
Ã
HOH ꢀ ꢀ ꢀ OꢁCOO ꢁ 2:502ð3ÞA in the first case and N?–
˚
˚
HꢀꢀꢀOCO [2.811(4) A] for the cation (Fig. 7).
2-Methyl-4-oxopentan-2-aminium cations build pairs
via N?–HꢀꢀꢀOCO [2.905(4) A] interactions that give rise to
˚
R22ð4Þ synthons. Furthermore, each cation connects with
two different anions through different N?–HꢀꢀꢀOCOO
–
˚
Fig. 3 Experimental powder diffraction pattern obtained for the bulk
sample at 293 K (pink) and calculated powder diffraction patterns for
1 (blue) and 2 (green) at 150 K, showing that the bulk obtained is a
mixture of both forms (Color figure online)
[2.757(4) and 2.775(4) A] hydrogen bonds forming tetra-
mers based on R24ð8Þ motifs. There are no direct interac-
tions between salicylates. These interactions give rise to
chains that grow along the a axis (Fig. 7; Table 1).
Salicylate:2-methyl-4-oxopentan-2-aminium molecular
salt, 2
Experimental
The asymmetric unit of this crystalline consists of one
salicylate and one 2-methyl-4-oxopentan-2-aminium cation
(Fig. 6). The assessment of the molecular salt nature was
done both by the analysis of the C–O distances (1.260(3)
Synthesis
Reagents and solvents were acquired from Sigma-Aldrich.
(b)
(a)
O
O
-
H
O
O
+
.
.
NH4
OH
H
O
Fig. 4 a [NH4]?.[(SA)(HSA)]- salt, 1; b molecular diagram of 1. Ellipsoids are set at 50 % probability
123

Struct Chem
Fig. 5 Crystal packing of 1
depicting a tapes formed by
salicylic acid (purple) and
salicylate (blue) assisted by the
ammonium cations (yellow) in a
view along a; b space filling
representation of the tapes; c the
tapes assisted by the ammonium
cations in a view along
c. Hydrogen atoms not involved
in hydrogen-bonding are not
displayed for clarity (Color
figure online)
Table 1 Hydrogen bond details for 1 and 2
˚
d(D–H) (A)
˚
˚
ˆ
Structure
Sym. op.
D–HꢀꢀꢀA
d(HꢀꢀꢀA) (A)
d(DꢀꢀꢀA) (A)
(DHA) (°)
1
x, y, z
O ꢁ HOH ꢀ ꢀ ꢀ OꢁCOOꢁ
0.82
1.78
2.513(4)
2.934(6)
3.226(6)
2.732(5)
2.859(6)
2.641(4)
2.974(5)
2.964(6)
3.141(6)
2.597(4)
2.775(4)
2.502(3)
148
N
N
N
N
þ ꢁ H ꢀ ꢀ ꢀ OOH
þ ꢁ H ꢀ ꢀ ꢀ OꢁCOO
þ ꢁ H ꢀ ꢀ ꢀ OꢁCOO
þ ꢁ H ꢀ ꢀ ꢀ OꢁCOO
-1 ? x, y, z
0.78(4)
1.06(4)
1.06(4)
0.98(5)
0.82
2.22(4)
2.58(4)
1.68(4)
2.01(4)
1.93
153(4)
119(3)
173(3)
144(4)
145
1 - x, -1/2 ? y, 1/2 - z
1 - x, -1/2 ? y, 1/2 - z
2 - x, -1/2 ? y, 1/2 - z
x, y, z
ꢁ
ꢁ
ꢁ
O ꢁ HCOOH ꢀ ꢀ ꢀ OCOOH
O ꢁ HOH ꢀ ꢀ ꢀ OꢁCOOꢁ
1 - x, -1/2 ? y, 1/2 - z
x, y, z
0.82
2.44
124
þ ꢁ H ꢀ ꢀ ꢀ OOH
0.86(5)
0.86(5)
0.82
2.30(4)
2.49(4)
1.78
134(3)
133(4)
176
N
N
þ ꢁ H ꢀ ꢀ ꢀ OCOOH
1 - x, 1/2 ? y, 1/2 - z
-1 ? x, -1 ? y, z
1 - x, 1 - y, 1 - z
x, y, z
O ꢁ HCOOH ꢀ ꢀ ꢀ OꢁCOOꢁ
N
þ ꢁ H ꢀ ꢀ ꢀ OꢁCOO
ꢁ
2
0.99(3)
0.82
1.84(3)
1.77
158(3)
148
O ꢁ HOH ꢀ ꢀ ꢀ OꢁCOO ꢁ Oꢁ
HOH ꢀ ꢀ ꢀ OꢁCOOꢁ
N
N
N
þ ꢁ H ꢀ ꢀ ꢀ OꢁCOO
þ ꢁ H ꢀ ꢀ ꢀ OCO
þ ꢁ H ꢀ ꢀ ꢀ OCO
ꢁ
x, y, z
0.98(3)
0.94(3)
0.94(3)
1.79(3)
2.16(3)
2.21(3)
2.757(4)
2.811(4)
2.905(4)
173(3)
125.6(8)
130(2)
x, y, z
-x, 1 - y, 1 - z
Fig. 6 a Salicylate:2-methyl-4-
oxopentan-2-aminium
molecular salt, 2; b molecular
diagram of 2. Ellipsoids are set
at 50 % probability
(a)
(b)
O
-
+
NH3
O
O
.
H
O
123

Struct Chem
Scheme 1 General mechanisms for (I) imine formation; (II) deprotonation of acetone a-carbon; and (III) nucleophilic attack to the imine giving
rise to 4-amino-4-methylpentan-2-one
Fig. 7 Crystal packing of 2
depicting a the R22ð4Þ synthons
formed by pairs of 2-methyl-4-
oxopentan-2-aminium cations;
b the tetramers formed by R22ð8Þ
synthons between two cation–
anion pairs and the
intramolecular interactions
shown in blue; c chain of
cations and anions based on the
previously mentioned R22ð4Þ
(blue) and R22ð8Þ (purple)
synthons growing along
a. Hydrogen atoms not involved
in hydrogen-bonding were
omitted for clarity (Color figure
online)
50 mg of aspirin was dissolved in a 1:1 blend of
ammonia and acetone. The solution was left to crystallize
at room temperature and after 3 days colorless crystals of 1
(needle) and 2 (plate) were concomitantly formed in sim-
ilar proportion.
APEX II diffractometer with graphite-monochromated
˚
radiation (Mo Ka, k = 0.71069 A). The X-ray generator
was operated at 50 kV and 30 mA and the X-ray data
collection was monitored by the APEX2 program. All data
were corrected for Lorentzian, polarization and absorption
effects using SAINT [60] and SADABS [61] programs.
Crystals suitable for X-ray diffraction study were mounted
on a loop with FomblinÓ protective oil.
SIR97 [62] and SHELXS-97 [63] were used for structure
solution and SHELXL-97 [63] was used for full-matrix least-
squares refinement on F2. These three programs are included
in the package of programs WINGX-Version 1.80.05 [64].
Characterization
Single-crystal X-ray diffraction
X-ray data were collected at 150 K on a Bruker AXS-
KAPPA APEX II diffractometer. Bruker AXS-KAPPA
123

Struct Chem
Conclusions
Table 2 Crystallographic details for 1 and 2
1
2
In this study we demonstrated that aspirin tends to
decompose into salicylic acid in high pH (basic) environ-
ments. Furthermore, multicomponent crystal forms with
salicylic acid were easily formed.
Chemical formula
Mr
C7H6O3ꢀC7H5O3ꢀNH4 C7H5O3ꢀC6H14NO
293.27
253.29
Temperature (K)
150(2)
150(2)
˚
Wavelength (A)
0.71069
Needle, colorless
0.2 9 0.04 9 0.02
Monoclinic
P21/c
0.71069
Plate, colorless
0.2 9 0.1 9 0.04
Monoclinic
P21/c
As mentioned in the introduction, several multicompo-
nent crystal structures with aspirin have been reported [67]
as well as several salicylic acid co-crystals [37, 39–46, 48–
54, 68]. From a Cambridge Structural Database [69] survey
including multicomponent forms of salicylates and organic
cations containing amines presented in supplementary
information (Tables S1, S2), we observed that the typical
R22ð8Þ homosynthon is commonly disrupted by direct
anion–cation interactions of the type N?–HꢀꢀꢀO/O-, con-
sidering from primary to aromatic amines. This is also
observed in both forms discussed herein, where the N?–
HꢀꢀꢀO/O- interactions play a main role, forming different
ring synthons. Also due to the presence of charges in 1 and
2, most of the hydrogen-bond interactions are charge-
assisted which reinforces the supramolecular arrangements,
like those found in the survey. The intramolecular S(6)
synthon is never disrupted, indicating that it is a very
strong intramolecular hydrogen bond, which may be one of
the causes for the lack polymorphs of salicylic acid. This
synthon is also present in most of the structures analyzed in
the survey reinforcing its strength.
Morphology, color
Crystal size (mm)
Crystal system
Space group
˚
a (A)
3.857(7)
13.171(6)
26.849(3)
90
7.504(6)
8.545(4)
22.273(4)
90
˚
b (A)
˚
c (A)
a (°)
b (°)
g (°)
91.393(3)
90
92.897(2)
90
3
˚
V (A )
1364(3)
4
1426.4(13)
4
Z
Calculated density
(Mg m-3
1.429
1.180
)
Absorption coefficient 0.113
(mm-1
0.087
)
Reflections collected/ 13048/2756
unique
11036/2694
Rint
0.1
0.0653
0.932
GoF
0.895
Final R indices
[I [ 2r(I)]
R1 = 0.0505,
wR2 = 0.0991
R1 = 0.0517,
wR2 = 0.1156
Supporting information
The crystal structures reported in the manuscript entitled
‘‘Transforming aspirin into novel molecular salts of sali-
MERCURY 3.0 [65] was used for packing diagrams. PLA-
TON [66] was used for hydrogen bond interactions. Crys-
tallographic details for 1 and 2 are given in Table 2.
ˆ
´
ˆ
´
cylic acid,’’ authored by Vania Andre, Ines Martins, Sılvia
Quaresma, Marta Martins and M. Teresa Duarte, have been
deposited at the Cambridge Crystallographic Data Centre
and allocated the deposition numbers: CCDC 914535 and
CCDC 914536.
Non-hydrogen atoms were refined anisotropically using a
full-matrix least-squares refinement. All the hydrogen atoms
were inserted in idealized positions and allowed to refine
riding in the parent carbon atom, except for those bonded to
the N atoms, which were located in a difference map.
Acknowledgments The authors acknowledge funding of the pro-
jects POCI/QUI/58791/2004, PEst-OE/QUI/UI0100/2013, PTDC/
CTM-BPC/122447/2010, and post-doc grant SFRH/BPD/78854/2011
X-ray powder diffraction
ˆ
by Fundac¸a˜o para a Ciencia e a Tecnologia.
Data were collected in a D8 Advance Bruker AXS h - 2h
diffractometer, with a copper radiation source (Cu Ka,
k = 1.5406 A) and a secondary monochromator, operated
at 40 kV and 30 mA.
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