4-aminosalicylic acid adducts

Article abstract of DOI:10.1021/cg301798s

4-Aminosalicylic acid (p-aminosalicylic acid, PAS), an antituberculosis drug, is a model active pharmaceutical ingredient to study salt and cocrystal formation in a multiple hydrogen-bonding functionality molecule with carboxylic acid, amine, and phenol groups. A cytosine salt CYT⁺-PAS^-, salt cocrystal hydrate CYT⁺-PAS^--CYT-H₂O, and nicotinamide cocrystal hydrate PAS-NAM-H₂O, are described in this article. Furthermore, X-ray crystal structures of PAS sodium dihydrate, sulfate, and mesylate salts and dehydration/rehydration behavior of the sodium salt by powder X-ray diffraction are discussed.

Full text of DOI:10.1021/cg301798s

Article
pubs.acs.org/crystal
4‑Aminosalicylic Acid Adducts
Suryanarayan Cherukuvada,† Geetha Bolla,† Kanishka Sikligar,‡,§ and Ashwini Nangia*,†
†School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Hyderabad 500 046, India
‡Networking Resource Centre, School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Hyderabad 500 046,
India
§Bhaskar Pharmacy College, Yenkapally, Hyderabad 500 075, India
S
* Supporting Information
ABSTRACT: 4-Aminosalicylic acid (p-aminosalicylic acid,
PAS), an antituberculosis drug, is a model active pharmaceut-
ical ingredient to study salt and cocrystal formation in a
multiple hydrogen-bonding functionality molecule with
carboxylic acid, amine, and phenol groups. A cytosine salt
CYT+−PAS−, salt cocrystal hydrate CYT+−PAS−−CYT−H2O,
and nicotinamide cocrystal hydrate PAS−NAM−H2O, are
described in this article. Furthermore, X-ray crystal structures
of PAS sodium dihydrate, sulfate, and mesylate salts and dehydration/rehydration behavior of the sodium salt by powder X-ray
diffraction are discussed.
drugs. Interestingly, PAS exists in an unionized state as 4-
NH2C6H3(OH)COOH, whereas 5-ASA is a zwitterion/inner
INTRODUCTION
4-Aminosalicylic acid, commonly known as p-aminosalicylic
acid (abbreviated as PAS, Figure 1), is a second-line drug used
■
6
salt 5-NH3 C6H3(OH)COO− in the crystal structure (Figure
+
1). In buffer solutions, PAS is known to exist in different ionic
+
states: (a) as a diprotic acid (NH3 C6H3(OH)COOH) below
its pKa1 (= 1.79), (b) as a zwitterion (NH3 C6H3(OH)COO−)
+
at its isoelectric point (pI = 2.71), and (c) as a diprotic base
(NH2C6H3(OH)COO−) above its pKa2 (= 3.63).7 PAS
decarboxylates to 3-aminophenol (NH2C6H4OH) through the
zwitterionic species7 and also upon melting.8
There is a renewed interest in the chemistry of p-
aminosalicylic acid. It was recently shown that PAS inhibits
dihydropteroate synthase in M. tuberculosis by acting as a
replacement substrate and a prodrug that releases active forms
by the enzymes that they eventually inactivate.9 Cocrystals of
PAS with pyrazinamide, isoniazid,10 and sulfadimidine11 are
examples of drug−drug cocrystals, which can become multi-
drug, fixed-dose formulations in the future. An amorphous
form,12 several salts (sodium,8b potassium, hydrochloride,
sulfate, mesylate, ammonium, etc.),13 molecular salts14
(piperazinium, morpholinium), and a dioxane solvate15 of
PAS were reported by different groups, and among these, the
ammonium salt is polymorphic.16 However, crystal structures of
many of these salts are not reported. Because of its rich
functionalities (carboxylic acid, amine, and phenol), PAS could
form a multitude of adducts17 with coformers depending on the
pKa,18 and thereby offer a better understanding of salt and
cocrystal supramolecular assembly.10,14b,18,19 Salts, cocrystals,
and salt cocrystal hydrate of PAS with pyrdine coformers were
Figure 1. (a) 4-Aminosalicylic acid (PAS) exists in an unionized
neutral form and (b) 5-aminosalicylic acid (5-ASA) is a zwitterion in
the crystal structure. Intramolecular O−H···O hydrogen bond is
present in both structures. The molecular structure of 4-ASA is
extracted from the CSD (refcode AMSALA01).6 The reported
structure of 5-ASA (refcode SAQJAV) has no H atoms, and hence,
its X-ray crystal structure was redetermined with 3D coordinates (.cif
file is deposited to CCDC).
in the treatment of multidrug-resistant tuberculosis (MDR-
TB)1 and is on the World Health Organization Model List of
Essential Medicines.2 PAS was found to be also effective toward
ulcerative colitis3 and Crohn’s disease,4 but the more potent
drug in these latter ailments is its isomer 5-aminosalicylic acid4,5
(5-ASA, common name mesalazine or mesalamine, Figure 1).
Both these aminosalicylic acids are amphoteric molecules, and
surprisingly, there are no polymorphs reported for these classic
Received: December 7, 2012
Revised: February 18, 2013
Published: February 19, 2013
© 2013 American Chemical Society
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Table 1. X-ray Crystallographic Parameters
Na+−PAS−−2H2O
2PAS+−SO4
PAS+−CH3SO3
C8H11NO6S
Cyt+−PAS−
C11H12N4O4
Cyt+−PAS−−Cyt−H2O
PAS−NAM−H2O
2−
−
adduct
empirical formula C7H10NNaO5
C14H16N2O10S
404.35
orthorhombic
Pba2
C15H19N7O6
393.37
monoclinic
P21/n
C13H15N3O5
293.28
formula weight
crystal system
space group
211.15
monoclinic
P21/c
249.24
monoclinic
P21/c
264.25
monoclinic
P21/c
triclinic
P1
̅
6
a
Z
16
12
8
16
16
T (K)
a (Å)
b (Å)
c (Å)
298(2)
8.790(4)
14.615(7)
6.955(3)
90
298(2)
15.7940(16)
19.897(2)
5.5179(6)
90
298(2)
5.3525(5)
17.8159(12)
11.0537(10)
90
100(2)
12.6069(17)
13.6925(18)
14.595(2)
90
298(2)
7.4285(6)
22.0769(18)
10.9219(10)
90
100(2)
6.750(2)
7.060(2)
14.809(4)
95.977(4)
97.899(5)
104.722(4)
668.9(3)
1.456
α (deg)
β (deg)
γ (deg)
VÅ3
Dcalc (g cm−3
μ (mm−1
97.799(8)
90
90
99.057(8)
90
110.973(3)
90
101.461(9)
90
90
885.3(8)
1.584
1734.0(3)
1.549
1040.93(15)
1.590
2352.5(5)
1.492
1755.5(3)
1.488
)
)
0.174
0.246
0.325
0.116
0.118
0.114
reflns collected
unique reflns
observed reflns
R1 [I > 2σ(I)]
wR2 [all]
9005
3402
4343
24058
6349
5351
1749
3402
2132
4667
2992
2206
1558
3244
1420
3233
1367
1653
0.0434
0.1015
1.103
0.0443
0.1110
1.135
0.0426
0.0982
0.968
0.0856
0.1405
1.142
0.0517
0.0664
0.851
0.0400
0.0967
1.040
goodness-of-fit
diffractometer
Bruker Smart-Apex Bruker Smart-Apex Oxford Xcalibur Gemini Bruker Smart-Apex Oxford Xcalibur Gemini Bruker Smart-Apex
a
Z = Z″ (no. of crystallographically nonequivalent molecules of any type in the asymmetric unit)23 × no. of independent general positions of the
space group.
recently reported by Goswami et al.20 The absence of
polymorphism in PAS encouraged us to carry out a solid
form screen for a novel zwitterionic form21 of PAS or a new
polymorph. In this study, two cytosine adducts, CYT+−PAS−
salt and CYT+−PAS−−CYT−H2O salt cocrystal hydrate, and a
nicotinamide cocrystal hydrate, PAS−NAM−H2O, were
obtained. X-ray crystal structures of the known sodium
dihydrate PAS8b and its sulfate and mesylate13 salts are added.
RESULTS AND DISCUSSION
■
Solid form screening of PAS to study its supramolecular solid
form space gave salts and salt cocrystal and cocrystal. Attempts
to obtain a zwitterionic form or a polymorph of PAS by
different methods such as evaporative crystallization (solvents
and temperatures), sublimation,22 crystallization from aqueous
HCl solutions of varying pH, exchange of counterions reaction
to give a zwitterion (e.g., NH2C6H3(OH)COO−‘C’+
+
+
X−NH3 C6H3(OH)COOH → NH3 C6H3(OH)COO−
+
+
‘C’+X−, where ‘C’ is a salt former such as cytosine), etc., were
unsuccessful. All the crystallization attempts are summarized in
the experimental section.
Sodium-4-aminosalicylate Dihydrate (Na+−PAS−−
2H2O). When PAS was dissolved in NaOH solution and left
for crystallization at ambient temperature, a dihydrate of the
salt was obtained in the space group P21/c (see X-ray
crystallographic parameters in Table 1 and hydrogen bonds
in Table S1, Supporting Information). The crystal structure is a
coordination compound with the sodium (NaI) residing in a
six-coordinate twisted-octahedral geometry. The six ligand
positions are occupied by three PAS molecules (through
COO−, OH, and NH2 groups), one crystallographic unique
water molecule, and two waters that are shared by a
neighboring NaI atom (Figure 2a). The sodium ions form a
tape with PAS and water molecules and such adjacent tapes
propagate through channel water molecules (Figure 2b).
Figure 2. (a) Tape of sodium PAS and water molecules. (b) Adjacent
tapes are connected by channel waters along the a axis.
Bis-4-ammonium Salicylic Acid Sulfate (2PAS+−
SO42−). A 2:1 PAS sulfate salt was crystallized upon slow
evaporation of a methanolic solution. Each sulfate moiety
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connects the crystallographic unique PAS molecules, which
make a zigzag chain along the b axis through N+−H···O− and
O−H···O bonds (Figure 3a). Such chains extend into a
corrugated sheet-like structure (Figure 3b).
Cytosinium-4-aminosalicylate Cytosine Hydrate
(Cyt+−PAS−−Cyt−H2O). Crystal structure of this adduct
shows a PAS anion, a cytosinium cation, and cytosine and
water molecules, making it a salt cocrystal since cytosine is
present in ionized and unionized states. The ions make
carboxylate−pyridinium heterosynthon (Figure 6a) instead of
carboxylate−aminopyrimidinium present in the previous
structure. The amino-pyrimidinium group of cytosinium cation
makes a self-complementary 3-point synthon with a neutral
cytosine such that the pyrimidinium N−H is shared between
the two moieties (N−H distance: cytosinium cation 1.31(4) Å;
unionized cytosine 1.52(4) Å). A long covalent bond N−H is
typical in a charge-assisted short N+−H···N hydrogen bond.
The 3-point synthon flanked by PAS anions propagates into
infinite tapes through C(6)R24(8) graph set25 motif (Figure 6b).
These tapes form a herringbone structure that makes channels
parallel to the a axis, which is filled with water molecules
(Figure 6c). Very recently, Sridhar et al.26 observed that
whenever the cytosine/acid ratio is 2:1 in the crystal structure,
the 3-point cytosinium−cytosine synthon involving the amino-
pyrimidine group is preferred over the carboxylate−amino-
pyrimidinium synthon, and the same situation is observed in
our structures.
Generally, grinding technique (neat and/or liquid-assisted) is
employed to prepare macroscopic amounts of a multi-
component adduct.27 The cytosine salt and nicotinamide
cocrystal hydrate (discussed next) were reproduced by using
this technique, the former by ethanol-assisted and the latter by
water-assisted grinding, but the cytosine salt cocrystal was not
obtained. The PXRD of the ground material (of PAS and
cytosine in 1:2 ratio subjected to water-assisted grinding) did
not match with the calculated diffraction lines of the salt
cocrystal X-ray crystal structure Cyt+−PAS−−Cyt−H2O. It was
found to be a mixture of Cyt+−PAS− salt and cytosine hydrate
by PXRD profile match (Figure S1, Supporting Information).
The nonformation of cytosine salt cocrystal in certain cases was
noted by Sridhar et al.26 Crystallization of this salt cocrystal
could be due to solution kinetics. The ΔpKa between cytosine
and PAS is 0.77 (pKa pyrimidine-H+ 4.4,28 acid 3.63),7 a value
that is in the 0−3 region in which it is difficult to predict the
extent of proton transfer based on solution pKas.18 In this
situation, both ionized and unionized species can coexist in
solution, and the final crystallization product(s) can be salt or
cocrystal or even salt cocrystal depending upon the species that
precipitate from solution. The products of crystallization are
therefore a result of crystallization conditions (temperature,
concentration, and solvent) and kinetic effects (the species that
is least soluble will precipitate).18d Cruz-Cabeza18c recently
reported that the probability for salt and cocrystal formation is
about equal when ΔpKa ≈ 1.
4-Aminosalicylic Acid−Nicotinamide Hydrate (PAS−
NAM−H2O). Similar to the cytosine case, the pKa difference
between nicotinamide (pKa pyridine-H+ 4.2)29 is 0.57.
Consistent with the Cruz-Cabeza’s study,18c which showed
increasing tendency for cocrystal formation with ΔpKa
approaching zero, a 1:1:1 cocrystal hydrate of PAS and
nicotinamide was crystallized from methanol. The same
cocrystal hydrate was reproduced upon water-assisted grinding
of the components. Neat grinding of PAS and nicotinamide (to
avoid water/moisture) did not afford any anhydrous cocrystal
as monitored by PXRD. In the crystal structure, PAS molecules
connect the amide dimer of nicotinamide molecules through
acid−pyridine synthon and extend into zigzag tapes through
Figure 3. (a) Crystallographic unique PAS molecules (shown in
different colors) make zigzag chains through N+−H···O− and O−
H···O bonds with the sulfate groups. (b) Such molecular chains form a
corrugated sheet in the ab plane.
4-Ammonium Salicylic Acid Mesylate (PAS+−
−
CH3SO3 ). A 1:1 PAS mesylate salt was crystallized upon
slow evaporation of a methanolic solution of the components in
molar ratio. Parallel tapes of N+−H···O− bonded PAS
molecules are connected by mesylate ions through N+−
H···O− and O−H···O hydrogen bonds, which extend into
sheets (Figure 4) parallel to the (102) plane. Such sheets are
connected by oxygens of the mesylate (orthogonal to the
plane) and lie at an interplanar separation of 3.53 Å.
Figure 4. Parallel tapes of PAS molecules connected by mesylate ions
through N+−H···O−, O−H···O, and C−H···O hydrogen bonds in a
layered motif.
Cytosinium-4-aminosalicylate (Cyt+−PAS−). Crystalliza-
tion of PAS and cytosine in a 1:1 ratio from methanol resulted
in two different stoichiometry adducts, a 1:1 salt and a 1:1:1:1
salt cocrystal hydrate, in different batches. The crystal structure
of the 1:1 salt contains two symmetry-independent PAS and
cytosine molecules. The familiar 2-amino-pyrimidinium−
carboxylate heterosynthon24 between cytosine and PAS was
observed (Figure 5a). Adjacent heterodimer units propagate
perpendicular to each other through N−H···O and C−H···O
hydrogen bonds (Figure 5b).
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Figure 5. (a) 2-Amino-pyrimidinium−carboxylate synthon of cytosinium cation and PAS anion in the heterodimer. (b) These finite heterodimers
between symmetry-independent PAS and cytosine molecules (shown in different colors) propagate in an orthogonal fashion.
Figure 7. Zigzag tapes formed by amide dimer nicotinamide molecules
connected through acid−pyridine synthon with PAS molecules extend
into a sheet structure through water molecules.
Na−PAS dihydrate and 2PAS−SO4 were obtained from direct
synthesis, and PAS−NAM hydrate was prepared through water-
assisted grinding. Water of crystallization is present in the
sodium and nicotinamide adducts, but the solvent could not be
conclusively assigned for the sulfate salt from the difference
Figure 6. (a) Carboxylate−pyrimidinium synthon between PAS anion
and cytosinium cation. (b) Cytosinium cation and cytosine are
connected by 3-point synthon of N−H···O and N−H···N hydrogen
bonds and extend into infinite tapes through C(6)R24(8) motif. (c) The
tapes form a herringbone structure, which makes channels along the a
axis for water molecules.
electron density maps. To find out if these adducts will give
anhydrates, their DSC and TGA were recorded to look for
thermal transitions and weight loss (Figures 8 and 9). PAS−
NAM hydrate turns black upon melting and gave 3-amino-
phenol as a byproduct of PAS decomposition.8 The
concomitant release of water was confirmed in TGA (the
weight loss of 21.15% matches with one water and one CO2
molecule, calcd 21.16%, see Figure 8). The dihydrate sodium
salt showed a transition at 80−100 °C prior to the melting
endotherm at 193 °C in DSC. The weight loss in TGA
matched with two water molecules in the dihydrate crystal
(calcd 17.06%, obsd 16.43%; Figure 9a). Controlled
dehydration of the dihydrate salt at 110 °C for 30 min resulted
water molecules (Figure 7) into sheets that lie at an interplanar
distance of 3.26 Å. The water molecules form channels along
the a-axis and connect the sheets through O−H···O hydrogen
bonds.
Thermal Analysis. All adducts, except PAS−cytosine salt
cocrystal, were obtained in bulk quantity, and their solid form
integrity was confirmed by PXRD profile match with the X-ray
crystal structure (Figures S2−S6, Supporting Information).
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formation was monitored by PXRD (Figure 10). Thus, the
PAS-sodium salt was obtained both in hydrate and anhydrate
forms under controlled conditions.
Figure 8. DSC (blue) and TGA (red) of PAS−NAM−H2O. The two
endotherms in DSC are the two weight loss steps in TGA due to
melting and decomposition.
Figure 10. PXRD plots of Na−PAS dihydrate to show the formation
of an anhydrate upon dehydration and its conversion to the original
dihydrate upon rehydration.
Lack of Polymorphism in API. We were somewhat
surprised to note that, despite the presence of three hydrogen
bonding functional groups in 4-ASA, COOH, OH, NH2,
neither a zwitterionic form (similar to 5-ASA,6 see Figure 1)
nor a new polymorph was obtained for the active
pharmaceutical ingredient (API) in our numerous crystalliza-
tion attempts (see experimental section). Apart from the lack of
polymorphism in these classic drugs, another fact that struck us
is that 4-ASA is a neutral molecule and that 5-ASA is
zwitterionic in the crystal structure (see Figure 1). Three
polymorphs of the ammonium salt of 4-ASA16 and multiple
crystal forms (including a polymorphic cocrystal) of 4-ASA
with pyridine coformers20 were recently reported. A computa-
tional study of low energy−high density crystal structures30
should be informative in the search for polymorphs of these
important amino salicylic acids.
CONCLUSIONS
■
The solid form space of PAS was explored and its variable
stoichiometry adducts with cytosine (a salt and salt cocrystal)
and sodium (anhydrate and hydrate salts) were obtained. A
nicotinamide cocrystal hydrate was also obtained and X-ray
crystal structures of a few salts were also determined. PAS has a
tendency to form solvate/hydrate adducts (4 out of 6 structures
studied in this work). PAS-sodium salt was obtained both in
hydrate and anhydrate forms in a controlled and reproducible
way. The difficulty of predicting the cocrystallization product as
salt, cocrystal, or salt cocrystal in the ΔpKa range 0−418 is
complicated in the multifunctional molecule PAS. Cytosine and
nicotinamide adducts fall in the borderline zone. The 2-point
synthon of carboxylate−aminopyrimidinium in the 1:1 cytosine
salt and the 3-point motif of cytosinium−cytosine in the 2:1
cytosine salt cocrystal are consistent with a recent report.26
However, only the former product could be prepared by the
grinding technique. This example highlights the subtle role of
crystallization conditions in obtaining a particular product and
the necessity of design controls for scale-up processes. These
examples add to the diversity of multicomponent crystalline
solids of APIs.17,19
Figure 9. DSC (red) and TGA (blue) of (a) Na−PAS dihydrate and
(b) its anhydrate. The hydrate salt showed water loss at 80−100 °C
before melting, and the anhydrate did not exhibit a visible transition
before melting at 193 °C.
in an anhydrous material (see DSC and TGA in Figure 9b).
Water-assisted grinding of the dehydrated salt gave back the
original dihydrate salt, and the hydrate ↔ anhydrate trans-
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Xcalibur Gemini Eos CCD diffractometer using Cu−Kα radiation (λ =
1.5418 Å). Data reduction was performed using CrysAlisPro (version
1.171.33.55),35 and OLEX2-1.036 was used to solve and refine the
structure. All non-hydrogen atoms were refined anisotropically.
Hydrogen atoms on heteroatoms were located from difference
electron density maps, and all C−H hydrogens were fixed geometri-
cally. The final CIF files and hydrogen bond geometries were validated
in PLATON.34 X-Seed37 was used to prepare packing diagrams:
CCDC Nos. 914456−914462.
Powder X-ray Diffraction. PXRD was recorded on a Bruker D8
Advance diffractometer using Cu−Kα X-radiation (λ = 1.5406 Å) at 40
kV and 30 mA. Diffraction patterns were collected over 2θ range of 5−
50° at scan rate of 1° min−1. Powdercell 2.438 was used to plot the
diffraction patterns.
EXPERIMENTAL SECTION
■
Materials and Methods. 4-Aminosalicylic acid was purchased
from Shanghai Xunxin Chemical Co., Ltd., China, and used without
further purification. All other chemicals were of analytical or
chromatographic grade. Water purified from a mixed bed deionizer
purification system was used for all experiments.
Synthesis of Adducts. a. Sodium-4-aminosalicylate dihydrate
(Na+−PAS−−2H2O). PAS (153 mg, 1 mmol) was dissolved in aqueous
NaOH (40 mg, 1 mmol) solution (3 mL) and left for slow evaporation
at room temperature. Brown colored crystals of plate morphology
were observed after a few days.
b. Bis-4-ammonium Salicylic Acid Sulfate (2PAS+−SO42−) and 4-
Ammonium Salicylic Acid Mesylate (PAS+−CH3SO3 ). PAS and the
−
sulfonic acid (2:1 molar ratio for sulfuric acid and 1:1 for
methanesulfonic acid) were dissolved in acetone in separate flasks
and kept at −20 °C. After 10 min, the two solutions were mixed and
stirred for 5−10 min in an ice-cold bath. The salt was obtained as a
grayish precipitate, which was filtered on a 2.5 μm Whatman filter
paper and washed with acetone and dried. Single crystals of the sulfate
salt were obtained as brownish needles when 30 mg of the salt was
recrystallized from 5 mL of warm methanol at room temperature.
Similarly, the mesylate salt crystallized as brownish plates.
Thermal Analysis. DSC was performed on a Mettler Toledo DSC
1 module calibrated with indium (Tm = 156.60 °C; ΔHf = 28.45 J g−1)
and zinc (Tm = 419.50 °C; ΔHf = 107.50 J g−1) as per the
manufacturer’s specifications. TGA was performed on a Mettler
Toledo TGA/SDTA 851e module calibrated with indium (Tm
=
156.60 °C) and aluminum (Tm = 660.30 °C). The typical sample size
is 3−5 mg for DSC and 8−10 mg for TGA. The temperature range
used in both DSC and TGA is 30−250 °C at 5 °C min−1. Samples
were placed in crimped but vented aluminum pans for DSC, and open
alumina pans for TGA and were purged by a stream of dry nitrogen
flowing at 50 mL min−1.
c. Cytosinium-4-aminosalicylate (Cyt+−PAS−) and Cytosinium-4-
aminosalicylate Cytosine Hydrate (Cyt+−PAS−−Cyt−H2O). PAS (30
mg, 0.2 mmol) and cytosine (22 mg, 0.2 mmol) were dissolved in 6−8
mL of warm methanol and left for slow evaporation at room
temperature. Adducts of 1:1 and 2:1 stoichiometry (both of brown
color) crystallized in plate and needle morphology, respectively, in
different batches. The composition and structure was confirmed by
single crystal X-ray diffraction.
d. 4-Aminosalicylic Acid−Nicotinamide Hydrate (PAS−NAM−
H2O). PAS (30 mg, 0.2 mmol) and nicotinamide (24 mg, 0.2 mmol)
were dissolved in 6 mL of warm ethanol and left for slow evaporation
at room temperature. Brown colored crystals of plate morphology
were harvested after a few days.
Cogrinding. About 200 mg of the components, combined together
as per the stoichiometric ratio in the crystal structure, were ground for
15−20 min using a mortar and pestle. Then, 8−10 drops of the solvent
was added during grinding in the case of solvent-assisted grinding.
PXRD of the ground material was recorded to confirm complete
reaction of the starting materials and formation of a new crystalline
phase. The product was matched with the X-ray crystal structure by
PXRD line overlay.
Polymorph Screening Experiments of PAS. PAS was crystal-
lized from aqueous HCl solutions in the pH range 1.2−4.0, i.e., near its
pKa values,7 to induce internal proton transfer with the intent of
isolating its zwitterionic form. Also, metathesis reaction of Cyt+−PAS−
salt with PAS hydrochloride salt (PAS+−Cl−, prepared as per the
method by Forbes et al.)13 was carried out by ethanol-assisted grinding
to induce crystallization of its zwitterion via the reaction sequence
shown in eq 1 (‘C’ = pharmaceutical salt former). The expectation was
that the Cyt+−Cl− will precipitate and leave a zwitterionic form of PAS
for crystallization by the addition of antisolvent (n-hexane). Apart
from evaporative crystallization in several solvents and sublimation, the
above experiments did not result in any polymorph/zwitterion of PAS
as monitored by PXRD.
ASSOCIATED CONTENT
■
S
* Supporting Information
Table of hydrogen bonds, PXRD patterns, CIF files. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ashwini.nangia@gmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.C., G.B., and K.S. thank the ICMR, UGC, and Networking
Resource Centre for fellowship. We thank the DST J. C. Bose
Fellowship (SR/S2/JCB-06/2009) and CSIR Pharmaceutical
Cocrystals (01(2410)/10/EMR-II) for research funding. DST
(IRPHA) and UGC (PURSE grant) are thanked for providing
instrumentation and infrastructure facilities. We thank N.
Rajesh Goud for the X-ray crystal structure determination of 5-
ASA (mesalamine).
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