Polymorphic ammonium salts of the antibiotic 4-aminosalicylic acid

Article abstract of DOI:10.1021/cg300284z

Reaction of the antibiotic 4-aminosalicylic acid with ammonia yields three polymorphic forms of the ammonium 4-aminosalicylate salt [NH₄][C ₆H₃NH₂OH(COO)]. When the reaction is conducted in solution, the three p

Full text of DOI:10.1021/cg300284z

Article
pubs.acs.org/crystal
Polymorphic Ammonium Salts of the Antibiotic 4-Aminosalicylic
Acid
Vania Andre,† M. Teresa Duarte,*,† Dario Braga,‡ and Fabrizia Grepioni‡
̂
́
†Centro de Química Estrutural, DEQ, Instituto Superior Tec
́
nico, Universidade Tec
́
nica de Lisboa, Av. Rovisco Pais 1, 1049-001
Lisbon, Portugal
‡Dipartimento di Chimica “G. Ciamician”, Universita
̀
di Bologna, Via Selmi 2, 40126 Bologna, Italy
S
* Supporting Information
ABSTRACT: Reaction of the antibiotic 4-aminosalicylic acid
with ammonia yields three polymorphic forms of the
ammonium 4-aminosalicylate salt [NH4][C6H3NH2OH-
(COO)]. When the reaction is conducted in solution, the
three polymorphs are obtained concomitantly, while liquid-
assisted grinding and solid−gas reaction result in the formation
of pure Form II. The three polymorphs are characterized by
different patterns of hydrogen bonding interactions between
the structurally rigid anions and the ammonium cations. Solid
products were characterized by single-crystal and powder X-ray
diffraction, variable temperature powder diffraction, calori-
metric techniques (DSC and TGA), and hot-stage microscopy (HSM).
Only one crystal form of this active pharmaceutical
INTRODUCTION
■
ingredient has been reported in the literature, for which single
crystal data were extracted from the CSD.11,12 The crystal
packing of this form is characterized by a S(6) intramolecular
synthon between the hydroxyl and carboxyl groups [O−
HOH···OCOOH], the R22(8)·carboxyl−carboxyl homosynthon
[O−HCOOH···OCOOH], and a N−H···OOH interaction that
gives rise to a three-dimensional (3D) network (Figure 1).
Organic carboxylic acids have received considerable attention
in crystal engineering owing to their potential for the formation
of hydrogen bonds and their predisposition to form a dimeric
carboxyl···carboxyl homosynthon that generates self-comple-
mentary hydrogen-bonding interactions in their crystal
structures.13,14 However, in the presence of an N-containing
heterocyclic moiety, a robust O−HCOOH···Npyridine heterosyn-
thon is preferentially shaped in the resultant multicomponent
crystal form (co-crystal, salt, molecular salt, solvate).15−17
Two ASA co-crystals have been reported with sulfadimi-
dine18 and with a codified compound reported as VX-950,19 as
well as a solvate with dioxane and molecular salts with
morpholine and piperazine.20 Moreover, copper(II)-p-amino-
salicylate complexes with diamine ligands21 and ASA metal-
coordination and hydrogen-bonded networks with silver22 were
reported. In 2011, new supramolecular networks, more
specifically, a hydrated molecular salt and a complex with
Co(II) have been disclosed involving ASA and 4,4′-bipyridine.23
The formation of a complex with polystyrene for application in
4-Aminosalicylic acid (ASA), a nonsteroid anti-inflammatory
drug (NSAID),1 is an antibiotic that has been used since the
1940s in the treatment of tuberculosis. It has also shown to be
safe and effective in the treatment of inflammatory bowel
diseases, namely, distal ulcerative colitis2,3 and Crohn’s disease.4
After oral administration, ASA is rapidly absorbed in the upper
intestinal tract before it reaches the colonic sites, decreasing its
suitability for the treatment of active ulcerative proctitis or left
sided ulcerative colitis.2,5 To overcome this problem, azo6 and
phenol-class azo derivatives7 have been synthesized in the
pursuit of a better ASA prodrug against inflammatory bowel
disease. ASA conjugates of ethylenediaminetetraacetic acid
(EDTA) chelating to Cu(II) were reported as potential anti-
inflammatory pro-drugs and as promising drugs with anticancer
properties, due to proteolytic attack resistance.4
A novel ASA−konjac glucomannan (KGM) pH-sensitivity
complex was synthesized based on the advantage of the
biodegradability of KGM.8 KGM is a high-molecular weight
polysaccharide extracted from the tubers of the amorphophallus
konjac plants that has received recognition for reducing the risk
of developing diabetes and heart diseases.9 The binding number
indicates a 1:1 complexation of the drug ASA with the sugar-
ring of the KGM chain.10
Received: February 27, 2012
Revised: April 23, 2012
© XXXX American Chemical Society
A
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Figure 1. Crystal packing of ASA11,12 showing (a) the pattern of intra- and intermolecular hydrogen bonds at work in the crystal and (b) a view of
the packing along the crystallographic a-axis.
that were added whenever the previous drops had dried. This synthetic
method yielded pure Form II, as determined by XRPD.
the analysis of natural water samples was also recently
published.24
Grinding of HCl and Ammonium Salts (1:1). 0.091 mmol of
ASA·HCl salt obtained as previously described12 were manually
ground for 5 min with 0.102 mmol of a mixture of the three forms of
[NH4][C6H3NH2OH(COO)]. This resulted in the formation of pure
ASA in its known form and NH4Cl, as established by XRPD.
Single Crystal X-ray Diffraction. Data collection for polymorphs
I and II was carried out with an Oxford X’Calibur S CCD
diffractometer equipped with a graphite monochromator (Mo−Kα
radiation, λ = 0.71073) and operated at room temperature. For
polymorph III, data collection was carried out in a Bruker AXS-
KAPPA APEX II diffractometer with graphite-monochromated
radiation (Mo Kα, λ = 0.71073 Å), at room temperature. 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
SAINT32 and SADABS33 programs. Crystals suitable for X-ray
diffraction study were mounted on a loop with Fomblin protective
oil. SIR9734 and SHELXS-97 were used for structure solution, and
SHELXL-9735 was used for full matrix least-squares refinement on F2.
These three programs are included in the package of programs
WINGX-Version 1.80.05.36 MERCURY 2.237 was used for packing
diagrams. PLATON38 was used to calculate hydrogen bonding
interactions.
All non-hydrogen atoms were refined anisotropically. HCH and HOH
atoms were added in calculated positions and refined riding on their
respective C and O atoms.
Crystals of ASA−ammonium salt form III were of bad quality; the
ratio reflections/variables is rather low, hindering a better refinement
of the crystal structure.
X-ray Powder Diffraction (XRPD). XRPD data for solution and
gas−solid diffusion experiments were collected with a Panalytical
X’Pert Pro instrument equipped with an X’Celerator detector and an
Anton Paar TTK 450 low temperature camera. A Cu anode was used
as X-ray source at 40 kV and 40 mA. Data for grinding experiments
were collected in a D8 Advance Bruker AXS θ-2θ diffractometer, with
a copper radiation (Cu Kα, λ = 1.5406 Å) and a secondary
monochromator, operated at 40 kV and 30 mA.
Very recently, two drug−drug multicomponent crystal forms
of ASA have been disclosed with the antituberculosis active
pharmaceutical ingredients (APIs) isoniazid and pyrazinamide.
With isoniazid, a 1:1 co-crystal was formed and with
pyrazinamide a 1:1 monohydrate molecular salt was synthe-
sized. In both systems the O−HCOOH···Npyridine hydrogen bond
is found, as expected.25
In this paper we report the preparation and characterization
of three polymorphic modifications, which we call forms I, II,
and III, of the molecular salt [NH4][C6H3NH2OH(COO)].
Form II was obtained by liquid-assisted grinding (LAG)26,27
and solid vapor diffusion, while conventional solution methods
yielded mixtures.
Polymorphism is a widespread phenomenon observed in
most pharmaceutical ingredients, and it is well established that
different polymorphs frequently display different physical,
chemical, mechanical, and thermal properties that can deeply
affect the bioavailability, stability, and other performance
characteristics of the drug.28 These studies aim to rationalize
a path for the development of new acceptable pharmaceutical
species of ASA, by using different synthetic techniques and
different experimental conditions. The knowledge of the type of
interactions favoring the formation of salts of this API can then
be applied in a future work to the synthesis of crystal forms
with other generally recognized as safe (GRAS) co-formers,
with the intent of obtaining formulations characterized by
better performance.29−31
EXPERIMENTAL SECTION
Synthesis. All reagents were purchased from Sigma (pa reagent
grade) and used without further purification.
■
Solution Technique. 200 mg of ASA were dissolved in 4 mL of a
1:1 (v/v) basic solution of acetone and ammonia 25%, heated to
boiling temperature, and left to cool and crystallize at room
temperature. Crystals were formed after 1 day, corresponding to a
mixture of Forms II and III of [NH4][C6H3NH2OH(COO)], as
proven by X-ray powder diffraction (XRPD). Similar results were
attained using solutions of ammonia/ethanol and ammonia/chloro-
form in analogous conditions. A room temperature solution of
ammonia and acetone left to crystallize yielded a mixture of the three
polymorphic forms reported herein, from which a single crystal of
Form I was selected for X-ray structural determination. Furthermore,
100 mg of ASA were dissolved in 2 mL of ammonia 25% and left to
crystallize at room temperature. Crystals of the three forms were
obtained after 3 days.
The program Mercury 2.223 was used for calculation of X-ray
powder patterns on the basis of the single crystal structure
determinations. The identity of single crystals and the bulk material
obtained from solution and grinding/kneading experiments was always
verified by comparison of the calculated and observed X-ray powder
diffraction patterns.
Hot-Stage Microscopy (HSM). Hot stage experiments were
carried out using a Linkam TMS94 device connected to a Linkam
LTS350 platinum plate. Images were collected, via the imaging
software Cell, with an Olympus BX41 stereomicroscope. Crystals were
placed within an oil drop to allow a better visualization of solvent or
decomposition products release.
Gas−Solid. 200 mg of solid ASA were placed inside a covered box
with ammonia 25% in the bottom, not in direct contact with the solid.
After 3 days pure Form II was obtained, as shown by XRPD.
Liquid-Assisted Grinding. 200 mg of ASA was manually ground for
10 min in an agate mortar with a few drops (40 μL) of ammonia 25%
Differential Scanning Calorimetry (DSC). Calorimetric meas-
urements were performed using a Perkin-Elmer Diamond equipped
with a model ULSP90 intracooler. Temperature and enthalpy
calibrations were performed by using high purity standards (n-decane,
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Table 1. Crystallographic Details for ASA/Ammonium Salts
Forms I, II, and III
I
II
III
chemical formula
C7H6NO3·NH4
170.17
C7H6NO3·NH4
170.17
C7H6NO3·NH4
170.17
Mr
T (K)
293
293
293
morphology, color plate, colorless
block, colorless
plate, colorless
crystal size/mm
0.15 × 0.08 ×
0.03
0.24 × 0.18 ×
0.06
0.10 × 0.06 ×
0.02
crystal system
space group
a (Å)
orthorhombic
P212121
4.7638(5)
6.2178(5)
26.844(3)
90
orthorhombic
P212121
4.8050(4)
12.0290(7)
14.5230(9)
90
monoclinic
P21/n
8.736(6)
3.7600(8)
29.484(8)
94.97(1)
964.8(5)
4
b (Å)
c (Å)
Figure 3. Melting and recrystallization experiments conducted for
polymorphic screening: (top) slow cooling after melting; (middle)
quenching after melting; (bottom) 3-aminophenol pattern calculated
from SCXRD.
β (°)
V (Å3)
800.15(13)
4
839.42(10)
4
Z
d (mg·m−3
)
1.413
1.347
1.172
μ (mm−1
θmin (°)
θmax (°)
reflections
collected/
unique
)
0.112
0.106
0.093
fast (quenching) or slow recrystallization. Most experiments
were conducted under ambient conditions, but also high and
low temperature conditions were tested.
In the solvent screening at ambient conditions a new dioxane
solvate and a morpholine molecular salt were obtained, and
their full characterization was previously reported by us.20 In all
the other solvents no new forms of ASA were detected (Figure
2).
3.03
2.80
4.01
28.50
25.34
25.34
3060/1047
2858/1452
7094/1636
Rint
0.0595
0.906
0.0388
0.863
0.1568
1.202
GOF
threshold
expression
>2σ(I)
>2σ(I)
>2σ(I)
Slurry experiments with water, THF, and acetonitrile yielded
the known form of ASA, indicating that this is the
thermodynamically stable form at ambient conditions. There
is no evidence of the formation of crystalline hydrates, but
mainly amorphous forms were obtained in DMSO, water, and
water/ethanol solutions.
Additional polymorph screening was performed using
melting and recrystallization experiments. Two different
approaches were used: slow cooling to room temperature
after melting and fast cooling by quenching in liquid nitrogen.
In both experiments, decomposition of ASA into 3-amino-
phenol was observed, in agreement with what has been
previously reported (Figure 3).39
R1 (obsd)
wR2 (all)
0.0564
0.0556
0.0341
0.0639
0.1805
0.4694
benzene, and indium). Samples (3−5 mg) were placed in aluminum
open pans. Calorimetric measurements were performed using a
Setaram DSC121.
Thermogravimetric Analysis (TGA). TGA analyses were
performed with a Perkin-Elmer TGA-7. Each sample, contained in a
platinum crucible, was heated in a nitrogen flow (20 cm3 min−1) at a
rate of 5 °C min−1, up to decomposition. Sample weights were in the
range 5−10 mg. Combined TG-DSC measurements were carried out
on a SETARAM TG-DTA 92.
Salt Screening: Three Polymorphic Modifications of
the Molecular Salt [NH4][C6H3NH2OH(COO)]. The prep-
aration of salts was attempted using hydrochloric acid, sodium
hydroxide, and ammonia. The experiments with the acid
resulted in the formation of the already reported hydrochloride
salt;12 experiments with NaOH were done in ethanol or water
solutions and in both cases the sodium salt was detected as an
amorphous phase. After waiting for 1 day to 1 week, HCl was
added to the previous solutions and precipitation took place;
the precipitate was filtered off and always checked by XRPD
and proved to be the ASA hydrochloride salt.
RESULTS AND DISCUSSION
■
Polymorph Screening. After a careful characterization of
the starting material, a thorough polymorphic screening was
performed for 4-aminosalicylic acid using different techniques:
grinding, solvent screening, slurrying, and melting followed by
On the other hand, experiments with ammonia were
successful, and three new polymorphic forms of the molecular
salt [NH4][C6H3NH2OH(COO)] were obtained. All forms
appeared concomitantly from solution, and the solid mixtures,
after solvent evaporation, were stable and the proportion of
forms in the mixture was maintained over time. On the other
hand, pure Form II was obtained when the reaction was
conducted in the solid state (solid−gas and liquid-assisted
grinding).
Forms I and II crystallize in the P212121 orthorhombic space
group, and both asymmetric units contain one ammonium
cation and one [C6H3NH2OH(COO)]− anion. Form III has a
Figure 2. XRPD patterns for the products of solvent screening at
ambient conditions.
C
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Table 2. Hydrogen Bond Details for [NH4][C6H3NH2OH(COO)] Forms I, II, and III
̂
structure
I
sym op
D−H···A
d(D−H) (Å)
d(D···A) (Å)
(DHA) (deg)
x, y, z
O−HOH···OCOO
N−HASA···OOH
N−HASA···OOH
-
0.82
2.552(4)
3.221(5)
3.476(6)
2.849(5)
2.839(6)
2.798(6)
2.749(5)
2.518(2)
3.004(2)
3.151(3)
2.855(2)
2.792(3)
3.167(2)
2.911(3)
2.775(2)
2.51(1)
147
1/2+ x, 1/2 − y, −z
1 + x, 1 + y, z
0.88(3)
0.88(3)
0.92(2)
0.94(4)
0.90(3)
0.94(3)
0.82
153(4)
173(2)
162(3)
164(4)
171(3)
176(2)
148
−x, −1/2+ y, 1/2 − z
x, y, z
N+−Hcation···OCOO
N+−Hcation···OCOO
N+−Hcation···OCOO
N+−Hcation···OCOO
-
-
-
-
1 + x, y, z
1 − x, 1/2 + y, 1/2 − z
x, y, z
II
O−HOH···OCOO-
N−HASA···OCOO
N−HASA···NASA
1/2 − x, 1 − y, 1/2 + z
1/2+x, 1/2-y, 2-z
1 − x, y, z
3/2 − x, 1 − y, 1/2 + z
1/2 − x, 1 − y, 1/2 + z
1/2 − x, 1 − y, 1/2 + z
1 − x, 1/2 + y, 3/2 − z
x, y, z
-
0.92(2)
0.89(2)
0.91(2)
0.96(2)
0.95(3)
0.95(3)
0.95(2)
0.82
173(2)
163(2)
160(2)
162(2)
143(3)
156(3)
161(2)
146
N+−Hcation···OOH
N+−Hcation···OCOO
N+−Hcation···OCOO
N+−Hcation···OCOO
N+−Hcation···OCOO
-
-
-
-
III
O−HOH···OCOO
N−HASA···NASA
-
3/2 − x, 1/2 + y, 1/2 − z
−1 + x, 1 + y, z
1 − x, 1 − y, −z
x, y, z
0.86
3.27(1)
162
N+−Hcation···OCOO
N+−Hcation···OCOO
N+−Hcation···OOH
N+−Hcation···OOH
N+−Hcation···OCOO
N+−Hcation···OCOO
-
-
0.90(4)
0.90(4)
0.90(8)
0.90(8)
0.9(1)
0.9(1)
3.07(1)
127(10)
114(10)
134(15)
116(14)
147(10)
107(9)
3.06(2)
3.13(2)
x, 1 + y, z
2.99(2)
1 − x, −y, −x
−1 + x, y, z
-
-
2.99(2)
2.888(19)
Figure 4. Hydrogen bonding interactions in [NH4][C6H3NH2OH(COO)] Form I: (a) the double chain formed by the [C6H3NH2OH(COO)]−
anions in a view along the a-axis; (b) anionic chains in a view along the b-axis, intercalated by cations (blue spheres); (c) packing in a view along the
c-axis showing the rotation of the [C6H3NH2OH(COO)]− lines (ammonium cations and hydrogen atoms not involved in the represented hydrogen
bonds have been omitted for clarity); (d) detailed view of the hydrogen bonds between the anion and the ammonium cations (intramolecular O−
H···O bond in blue).
similar content in the asymmetric unit but displays a
monoclinic symmetry crystallizing in the P21/n space group.
The intramolecular hydrogen bond observed in the crystal
structure of ASA is maintained in all the salt structures. The
supramolecular arrangement of the three forms is described
(see Table 2 for a list of relevant hydrogen bonding
interactions); X-ray single crystal and powder X-ray diffraction
data are compared for a characterization of the bulk material in
all cases. Thermal characterization of each form was performed
and will be discussed.
Crystal Structure of [NH4][C6H3NH2OH(COO)] Form I.
The amino group on the [C6H3NH2OH(COO)]− anion is
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Figure 5. Supramolecular arrangements in [NH4][C6H3NH2OH(COO)] Form II: (a) hydrogen bonded chains extending along the c-axis direction,
(b) ammonium cations environment, and (c) a view of the packing down the c-axis.
Figure 6. Supramolecular arrangements for [NH4][C6H3NH2OH(COO)] Form III depicting: (a) the Nanion···Nanion interactions (b) the ladder-like
arrangement showing the planes formed by pairs of [C6H3NH2OH(COO)]− anions, and (c) the R44(12) synthon identified by the pink circle, the
R46(12) in the purple circle, and a void indicated by the blue circle.
involved exclusively in two hydrogen bonds with the hydroxyl
groups of two adjacent anions [N−HASA···OOH 3.221(5) and
3.475(6) Å] (see Figure 4a). Thus the hydroxyl groups work
both as acceptors from the amino group and donors in the
intramolecular hydrogen bond [OOH···OCOO- 2.552(4) Å]. The
N−HASA···OOH interactions are responsible for the formation of
double chains along a and b directions; ammonium cations
work as spacers between these double chains (Figure 4a,b). In a
view along the c-axis, it is clear that the lines that give rise to the
double chains are rotated by 81.77° (Figure 4c).
Each ammonium cation is linked to four different anions via
charge-assisted N+−H···O hydrogen bonds with oxygen atoms
belonging to carboxylate groups [N+cation···O−COO- 2.849(5),
2.839(6), 2.798(6), and 2.749(5) Å]; in turn, each anion is
connected to four different ammonium cations: the oxygen
atom involved in the intramolecular O−−H···OOH hydrogen
bond is connected to one ammonium cation, while the second
E
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Figure 7. Overlap of structures of [NH4][C6H3NH2OH(COO)]
Form I (blue), II (magenta), and III (green). a) for the asymmetric
unit; b) crystal packing.
Figure 10. DSC and TGA for pure form II of [NH4][C6H3NH2OH-
(COO)].
c-axis direction, are interconnected through ammonium cations,
each linked to four anions via N+−H···OOH [2.855(2) Å] and
N+(H)···OCOO [2.791(3), 2.911(3), and 2.775(2) Å] inter-
−
actions. As always observed for these anions, also in Form II the
intramolecular hydrogen bond is maintained [OOH···OCOO
2.518(2) Å].
-
Crystal Structure of [NH4][C6H3NH2OH(COO)] Form III.
In [NH4][C6H3NH2OH(COO)] Form III the amino group on
the [C6H3NH2OH(COO)]− anion is exclusively involved in
N−H···N hydrogen bonds with adjacent anions [Nanion···Nanion
3.27(1) Å]; therefore, its donor capacities are not completely
fulfilled (Figure 6a). These contacts link each anion with two
other equivalent anions, forming a ladder-like arrangement
(Figure 6b). The hydroxyl and carboxylate moieties interact
with ammonium cations via N+−H···OOH [3.13(2) and 2.99(2)
Å] and N+−H···O−COO- [3.062(2), 2.99(2), 3.07(2), and
2.89(2) Å] contacts. The intramolecular hydrogen bond is
again maintained [O−HOH···OCOO- 2.51(1) Å]. The combina-
tion of all these interactions gives rise to a supramolecular
arrangement in which voids can be detected, in a view along the
b, as well as the formation of R44(12) and R64(12) synthons
(Figure 6c).
Figure 8. XRPD patterns for (from top to bottom) calculated Forms I,
II, and III at 150 K; experimental acetone, chloroform, and ethanol
solutions, gas−solid reaction and LAG with ammonia.
Unlike what happens in ASA itself, both in I and II the amine
moiety of ASA anion fulfils all its donor capacities. In I, the N−
HASA···OOH interactions are similar to the N−HASA···OOH
observed in ASA packing, but in I both hydrogens of NH2
are involved. On the other hand, in II none of the two
interactions in which the amine moiety is involved is similar to
the one observed in ASA. In III the amine moiety does not
fulfill all its donor capacities, similar to what is observed in the
ASA structure.
Figure 9. DSC and TGA results obtained for the bulk product
containing the three forms of [NH4][C6H3NH2OH(COO)] obtained
from solution.
The R22(8) synthon formed in ASA is disrupted in all these
packings, due to formation of a carboxylate group and the
competition with other active functions. In these structures the
carboxylate moiety is mainly used to connect with the
ammonium cations via charge-assisted N+−H···O−COO- hydro-
gen bonds, originating different synthons in the salts.
oxygen atom takes part in a trifurcate hydrogen bond with three
ammonium cations (Figure 4b). Ammonium cations alternate
with anionic double chains (Figure 4d).
Crystal Structure of [NH4][C6H3NH2OH(COO)] Form II.
The hydrogen bonding pattern in crystalline Form II differs
from the one observed for Form I, as each amine moiety on the
anion is involved in interactions with only one carboxylate
group on an adjacent anion and an amino group on a second
anion [Nanion···OCOO- 3.004(2) Å, and Nanion···Nanion 3.151(3)
Å] (Figure 5a); the resulting infinite chains, extending along the
The intramolecular synthon S(6) [O−H···OCOOH/COO-] is
never disrupted in any of the salicylic acid derivatives and ASA
crystal forms (ASA, ASA/sulfadimidine, and the multi-
component forms disclosed by our group) and, therefore, has
shown once again to be the strongest synthon.
Form III is the polymorph that presents a lower packing
efficiency, with a packing coefficient of only 0.59. On the other
F
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Figure 11. Hot-stage microscopy images obtained with a crystal of Form I at 27, 109, 120, and 138 °C.
Figure 12. Hot-stage microscopy images obtained with a crystal of Form II at 25, 111, 123, and 134 °C.
Figure 13. Hot-stage microscopy images obtained with a crystal of Form III at 25, 109, 119, and 137 °C.
similar to the one observed in carbamazepine Form II.40 In the
latter the VOID depended on the solvent used, while in ASA−
ammonium salt Form III the VOID seems to be independent of
the solvent (ethanol, acetone, chloroform). Crystallization
might be induced by the presence of a solvent, not present in
the structure and not detected in HSM (the only thermal
characterization where isolated pure Form III was tested).
Further comparisons of the three concomitant polymorphs
point out that Forms I, II, and III have similar conformation,
and their supramolecular arrangements are distinct due to the
very different hydrogen bond patterns (Figure 7).
Powder Diffraction, Grinding Experiments, and
Thermal Behavior of [NH4][C6H3NH2OH(COO)] Forms I,
II, and III. Crystallization from acetone and ethanol solutions
systematically yielded concomitantly the three polymorphs,
while from chloroform solutions only I and II were detected by
XRPD. Only Form II was obtained as a pure phase, both by
LAG and gas−solid reaction methods.
Thermal Behavior of [NH4][C6H3NH2OH(COO)] Forms I,
II, and III. Because of the impossibility of obtaining sufficient
quantities of Forms I and II as pure forms, DSC and TGA
measurements were performed on a mixture of the three forms
and on pure Form II. Single crystals of the three forms were
analyzed via hot stage microscopy.
Figure 14. XRPD-VT results for the bulk sample containing Forms I,
II, and III obtained from an acetone solution.
hand, neutral ASA is the most efficient structure in terms of
space filling, with a packing coefficient of 0.73. Forms I and II
represent intermediate situations, with packing coefficients of
0.70 and 0.67, respectively. The low packing efficiency of Form
III can be explained by a sort of a templating effect, somewhat
For a bulk mixture containing the three polymorphs, TGA
data indicate the loss of ammonia between 75 and 120 °C. This
loss is also observed in the DSC analysis that further shows an
endothermic peak at approximately 138 °C, corresponding to
the melting of ASA, immediately followed by decomposition.
Pure II shows a similar behavior as do the mixtures of the three
forms.
HSM experiments were performed on single crystals of each
of the three forms, revealing very similar behaviors. HSM is in
agreement with DSC and TGA data, showing ammonia loss at
temperatures around 100 °C and melting of pure ASA around
120−130 °C.
To complete the thermal characterization of the bulk sample
obtained from solution, -variable-temperature (VT)-XRPD was
also performed on a mixture of the three forms. From this
Figure 15. XRPD pattern resulting from manual grinding of ASA·NH4
and ASA·HCl salts (pink) compared with pure ASA (blue) and the
NH4Cl pattern (gray).
G
dx.doi.org/10.1021/cg300284z | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Notes
technique it was possible to confirm the loss of ammonia and
the transformation of all the salts into ASA.
The authors declare no competing financial interest.
Grinding ASA Ammonium and Hydrochloride Salts.
Using mechanochemistry26 to react the ASA ammonium salt
with the ASA hydrochloride salt, the neutral API was obtained
and the NH4Cl salt was formed (Figure 15).
This is an example of a solid-state metathesis (SSM) process
where the reaction was initiated by grinding. These fast solid
state reactions that have been developed over the past two
decades take advantage of the reaction enthalpy given out in a
specific reaction, and the driving force behind them is the
formation of stable byproducts. Typically in a SSM process a
co-formed salt is obtained along with the desired product, the
high lattice energy of the co-formed salt providing the driving
force for the process.41,42
ACKNOWLEDGMENTS
■
The authors acknowledge funding of the Project PTDC/QUI/
58791/2004 and Ph.D. Grant SFRH/BD/40474/2007 to
Fundaca̧ o para a Ciencia e Tecnologia. FG thanks MiUR for
̂
̃
financial support (PRIN2008).
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AUTHOR INFORMATION
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Corresponding Author
(26) James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.;
Friscic, T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs,
*E-mail: teresa.duarte@ist.utl.pt.
H
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