Solubility and stability advantage of aceclofenac salts

Article abstract of DOI:10.1021/cg301825u

The nonsteroidal anti-inflammatory drug aceclofenac was screened with pharmaceutically acceptable coformers to discover novel solid forms of improved solubility. First, the X-ray crystal structure of aceclofenac (ACF) was analyzed to contain the rare carboxylic acid catemer O-H···O synthon, stabilized by auxiliary C-H···O and Cl···O interactions. Slurry grinding of aceclofenac with different coformers in a fixed stoichiometry resulted in salts with cytosine (1:1), piperazine (1:0.5), l-lysine (1:1), and γ-aminobutyric acid (1:1). The problem of drug cyclization to give the inactive indolinone byproduct is avoided in the mild conditions of salt formation. All the salts were characterized by spectroscopic methods, thermal analysis, and X-ray diffraction. Aceclofenac-l-lysine salt showed 135 times faster intrinsic dissolution rate (IDR) and 127 times higher area under the curve (AUC) compared to aceclofenac. ACF-LYS is a high solubility salt that is stable in the accelerated International Conference on Harmonization (ICH) conditions of 40 C and 75% relative humidity for 8 months.

Full text of DOI:10.1021/cg301825u

Article
pubs.acs.org/crystal
Solubility and Stability Advantage of Aceclofenac Salts
N. Rajesh Goud, Kuthuru Suresh, and Ashwini Nangia*
School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Central University P.O., Hyderabad 500 046, India
S
* Supporting Information
ABSTRACT: The nonsteroidal anti-inflammatory drug aceclofenac was
screened with pharmaceutically acceptable coformers to discover novel solid
forms of improved solubility. First, the X-ray crystal structure of aceclofenac
(ACF) was analyzed to contain the rare carboxylic acid catemer O−H···O
synthon, stabilized by auxiliary C−H···O and Cl···O interactions. Slurry
grinding of aceclofenac with different coformers in a fixed stoichiometry
resulted in salts with cytosine (1:1), piperazine (1:0.5), L-lysine (1:1), and γ-
aminobutyric acid (1:1). The problem of drug cyclization to give the inactive
indolinone byproduct is avoided in the mild conditions of salt formation. All
the salts were characterized by spectroscopic methods, thermal analysis, and
X-ray diffraction. Aceclofenac-L-lysine salt showed 135 times faster intrinsic
dissolution rate (IDR) and 127 times higher area under the curve (AUC)
compared to aceclofenac. ACF−LYS is a high solubility salt that is stable in
the accelerated International Conference on Harmonization (ICH)
conditions of 40 °C and 75% relative humidity for 8 months.
basic conditions to give the inactive indolinone byproduct12,13
(Scheme 1).
The modification of solid-state properties of a drug molecule
The cyclized product (indolinone) was also isolated during
INTRODUCTION
■
through polymorph, salt, cocrystal etc. can significantly
our attempts to form the sodium or potassium salt of ACF with
modulate its solubility, dissolution, and bioavailability.1 Where-
bases such as Na2CO3, NaOH, KOH, K2CO3, etc. The ORTEP
as solubility modulation through cocrystallization2 has received
diagram of the cyclized product is shown in Figure S1
considerable attention in the past decade, salt formation is the
(Supporting Information). Therefore, unlike the other
traditional and widely accepted technology for improving the
solubility, solid form stability, and filterability of solid dosage
members of its class, such as indomethacin and diclofenac,
which are marketed as their sodium salt trihydrate and
forms. Moreover, salt formation is the preferred approach for
potassium salt respectively, ACF is marketed as a neutral drug.
aqueous solubility enhancement of liquid formulations of a
A systematic study of ACF using crystal engineering14
drug for parenteral administration.3 A current challenge in the
principles has not been reported in the literature. This is
pharmaceutical industry is to improve the physicochemical
surprising because the supramolecular synthon15 strategy would
properties of poorly soluble drugs without changing their
chemical structure.2b,4
A c e c l o f e n a c ( 2 - ( 2 , 6 - d i c h l o r o p h e n y l a m i n e ) -
phenylacetoxyacetic acid, ACF hereafter) is an orally effective
nonsteroidal anti-inflammatory drug (NSAID) with remarkable
offer diverse options for solubility modulation of such
chemically labile drug molecules. Hence we set out to address
the poor solubility of ACF by developing cocrystals and salts
based primarily on the robustness of functional groups and acid
constants (pKa) of the coformers.2,16 The ability of the COOH
group in ACF to assemble cocrystals with complementary
functional groups such as carboxamide, pyridine, etc. through
the corresponding heterosynthon17 is well documented for
pharmaceutical cocrystals. In this background, mechanochem-
ical and slurry grinding18 of ACF with selective GRAS
coformers19 was carried out, and the products were
characterized for cocrystal/salt/hydrate formation.
anti-inflammatory, analgesic, and antipyretic properties.5 It
belongs to the class of phenyl acetic acid derivatives and was
found to be the most tolerated drug among NSAIDs with a
lower incidence of adverse gastrointestinal effects. ACF is a
BCS class II drug with poor aqueous solubility of 58 μg/mL.6
The solubility of ACF has been improved by making a
triethanolamine salt7 and arginate salt8 as well as solid
dispersion techniques.9 A pharmaceutical cocrystal of ACF
with nicotinamide was recently reported10 and characterized by
FT-IR and differential scanning calorimetry (DSC). However
no solubility and dissolution information on the cocrystal is
known in the literature. Other reports describe the formation of
ACF derivatives11 and solid form stability of salts in water.12
Very few reports on the solid forms of ACF, especially salts, is
discussed perhaps due to its degradation in strongly acidic or
We report salts of ACF with piperazine (PIP), cytosine
(CYT), L-lysine (LYS), and γ-aminobutyric acid (GABA) (see
Scheme 2). A salt hydrate with piperazine and a cocrystal
Received: December 13, 2012
Revised: February 19, 2013
Published: February 21, 2013
© 2013 American Chemical Society
1590
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601

Crystal Growth & Design
Article
Scheme 1. Transformation of ACF Under Strongly Acidic or Basic Conditions Produces The Inactive Indolinone Derivative
Scheme 2. ACF and Coformers Used in this Study
Table 1. Coformers Resulting in Salts/Cocrystals with ACF
and Their ΔpKa Values
a
pKa in water
ΔpKa
cocrystal/salt
ACF
BIP
3.46
4.61
1.15
2.47
6.26
6.26
6.76
6.83
1:0.5:0.5 cocrystal hydrate
1:1 salt
CYT
PIP
5.93
9.72
1:0.5 salt
PIP
9.72
1:0.5:1 salt hydrate
1:1 salt
LYS
GABA
10.29
10.22
1:1 salt
a
pKa’s were calculated using Marvin 5.10.1, 2012, ChemAxon (http://
www.chemaxon.com).20d
hydrate with 4,4′-bipyridine (BIP) are also disclosed. These
solid forms were characterized by X-ray diffraction, spectro-
scopic, and thermal techniques. We were unable to obtain
single crystals of ACF−LYS and ACF−GABA for X-ray
diffraction. They were characterized by powder X-ray
diffraction (PXRD) pattern, and the stoichiometry was
The crystallographic parameters (Table 2) and hydrogen
bonding distances (Table 3) are listed.
Crystal Structure Description. Aceclofenac (ACF). ACF
consists of two aryl moieties, the N-2,6-dichlorophenyl group
and the N-phenylacetyloxyacetic acid group. The aryl rings are
inclined at a dihedral angle of 67°. This twist in the ortho-
substituted phenyl rings at the secondary amine relieves steric
hindrance. Dissolution of ACF in toluene and leaving the
solution for slow evaporation afforded diffraction quality single
crystals which were solved and refined in space group P21/n
(see ORTEP diagram in Figure S3a). In contrast to the other
members of its class, such as diclofenac22 and indomethacin,23
where the carboxylic acid forms a centrosymmetric O−H···O
dimer, ACF extends through catemeric O−H···O hydrogen
bond along the b-axis (O1···O2, 1.90 Å, 135°) resulting in a
tape motif (Figure 1a). The carboxylic acid catemer motif is, as
such, rare and is formed compared to the frequent dimer
synthon only when auxiliary C−H···O interactions from an
acidic or activated carbon donor nearby the acid moiety provide
auxiliary stabilization to the C−H···O catemer chain.24 Similar
stabilizing interactions were observed in ACF through an
activated CH group and Cl···O interactions. While the CH2
group between the phenyl ring and the ester moiety forms a
weak C−H···O interaction (C4···O2, 2.29 Å, 174°) between
the molecules connected via the C(4) chain (Figure 1a), the
CH2 group between the ester and acid functional moieities
connects the interlayer catemer tapes through centrosymmetric
1
determined by H NMR (see NMR spectra in Figure S2).
Preparation of the amorphous phase of ACF−LYS is reported
in the patent literature.12 The crystalline salt prepared in this
study is thermodynamically stable and exhibited a solubility
enhancement of 135 times compared to the pure drug.
RESULTS AND DISCUSSION
■
Salt formation is an acid−base reaction involving transfer of
proton from acid to base: A−H + B → (A−) (B+−H). The “rule
of three”20 is a useful guide to predict salt formation between
organic acids and bases. Thus salt formation requires a
difference of at least three pKa units between the conjugate
base (B+−H) and the acid (A−H); i.e., if (Δ pKa < 0) then it
would most certainly result in a cocrystal, and if (ΔpKa > 3)
then the product will be a salt. An intermediate value between 0
and 3 is an unpredictable zone with multiple proton states
possible to give a salt, cocrystal, or salt cocrystal. ACF is a
moderately strong acid (pKa 3.46), and salt formation is
expected with coformers of sufficient basicity. With the parent
compound being reactive in strongly acidic or basic conditions,
the coformers selected should be such that they can form a salt
or cocrystal but not too strong for cyclization to give the
inactive indolinone (Scheme 1). The pKa values of ACF, salt/
cocrystal formers and ΔpKa values are listed in Table 1. The
ΔpKa “rule of three” was observed to give salts for CYT, PIP,
LYS, and GABA and a cocrystal for BIP in this study.
25
2
C2−H2A···O4 (2.32 Å, 171°) R2 (10) motif (Figure 1b,c).
An intermolecular Cl···O interaction (3.12 Å) between adjacent
molecules fortifies the catemer motif. The detailed role of C−
H···O interactions in the catemer structure is possible to
elucidate now with complete H atom locations. Acemetacin, a
molecule with a similar acetyloxyacetic acid group, was recently
reported to have a catemer chain polymorph.26 An intra-
molecular N−H···O hydrogen bond (N1···O4, 2.13 Å, 147°) of
S(7) type makes the molecule rigid. We have not found a dimer
type structure of ACF so far.
The X-ray crystal structure of a guest free form of ACF is
reported but with incomplete proton location in the structure.21
For a better understanding of the hydrogen bonding motifs, X-
ray reflections on a crystal of the guest free form were collected
at 100 K to obtain the complete crystal structure. Surprisingly
there are no structural reports on any salts or cocrystals of ACF.
1591
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601

Crystal Growth & Design
Article
Table 2. Crystallographic Parameters of ACF Salts
ACF
ACF−BIP−H2O (1:0.5:0.5)
ACF−CYT (1:1)
ACF−PIP (1:0.5)
ACF−PIP−H2O (1:0.5:1)
emp form
form wt
cryst syst
sp gr
C16H13Cl2NO4
354.17
monoclinic
P21/n
C42H36Cl4N4O9
882.55
monoclinic
P21/c
C20H18Cl2N4O5
465.28
C18H18Cl2N2O4
397.24
monoclinic
P21/n
C18H20Cl2N2O5
415.26
monoclinic
P21/c
monoclinic
P21/n
T (K)
a (Å)
100(2)
12.284(3)
8.198(2)
15.484(4)
90
100(2)
7.5085(5)
11.9908(8)
22.2488(15)
90
100(2)
11.2960(10)
8.7429(8)
20.8507(19)
90
100(2)
9.1898(11)
5.5983(7)
34.890(4)
90
100(2)
14.555(4)
14.950(4)
8.557(3)
90
b (Å)
c (Å)
α (°)
β (°)
γ (°)
96.174(4)
90
91.5690(10)
90
98.0120(10)
90
94.038(2)
90
92.473(4)
90
Z
4
2
4
4
4
V (Å3)
rflns collect
unique rflns
obsd rflns
parameters
R1
1550.3(7)
15306
2002.4(2)
18720
2039.1(3)
20400
1790.5(4)
17574
1860.1(9)
18911
3030
3520
4019
3515
3674
2305
3315
3791
3143
3504
216
288
300
247
264
0.0535
0.1288
1.047
0.0293
0.0770
1.056
0.0361
0.0499
0.1112
1.130
0.0335
0.0825
1.103
wR2
0.0880
GOF
1.102
Aceclofenac−4,4′-Bipyridine−Hydrate (ACF−BIP−HYD).
Crystallization of ACF and BIP in a 1:0.5 stoichiometry in a
MeOH−CH3CN solvent mixture afforded single crystals of
ACF−BIP hydrate which solved and refined in the monoclinic
space group P21/c in a 1:0.5:0.5 ratio. The water O atom was
refined with s.o.f. of 0.5 (Figure S3b). The most acidic COOH
donor in ACF is hydrogen bonded to the most basic pyridine N
acceptor of BIP through an O−H···N hydrogen bond
(O1···N2, 1.62 Å, 172°) (Figure 2a), consistent with Etter’s
hydrogen bond pairing rules.27 ACF molecules in adjacent
layers are connected through water molecules acting as bridges
(O5−H5A···O2, 1.81 Å, 181°, and O5−H5B···O2, 1.88 Å,
151°) (Figure 2b). Auxiliary Cl···O interactions provide
support to the crystal structure.
Piperazinium−Aceclofenate Salt (ACF−PIP). This molec-
ular salt crystallized in space group P21/n with one molecule of
aceclofenate anion and a half molecule of piperazinium cation
in the asymmetric unit (Figure S3d). The piperazinium cation
forms two N+−H···O− ionic hydrogen bonds, N2+−H1A···O1−
(1.68 Å, 169°) and N2+−H1A···O2− (2.46 Å, 124°). C−O
bond distances and C−N−C bond angles are consistent with
those for a salt species20 (Figure 4). Piperazine is a
pharmaceutically acceptable cyclic diamine with anthelminthic
activity. Given its high basicity (pKa = 9.72), it can act both as a
neutral and a cationic coformer to give a cocrystal or a salt
depending on the acidity of the parent API. Three
monocationic forms of piperazine with anti-inflammatory
drug meclofenamic acid were reported from our group.29 In
this work two dicationic forms of piperazine, ACF−PIP and
ACF−PIP−HYD, are added.
Cytosinium−Aceclofenate Salt (ACF−CYT). Single crystals
of 1:1 cytosinium aceclofenate salt were obtained from EtOH−
CH3CN. The X-ray crystal structure of ACF−CYT was solved
and refined in space group P21/n (Table 1, see ORTEP in
Figure S3c). The major difference between this crystal structure
and that of ACF−BIP−HYD is that the proton is transferred
from the COOH group of ACF to the basic N2 nitrogen of
CYT via an ionic N2−H1A+···O1− hydrogen bond (1.71 Å,
180°) resulting in a salt. The protonation state of the carboxylic
acid and the basic nitrogen in acid−base structures can be
difficult to predict in multicomponent structures. There are
several cases of borderline proton location and a continuum of
O···H···N hydrogen bond states have been noted.28 The
electron density maps of X-ray diffraction showed that the
acidic H atom is transferred and covalently bonded to the
cytosine N, making a hydrogen bond with the COO− acceptor.
The two C−O distances are near equal (1.246(2) Å, 1.267(2)
Å) in the carboxylate group. Hydrogen bonding is mediated by
Piperazinium−Aceclofenate Monohydrate Salt (ACF−
PIP−HYD). This 1:0.5:1 salt hydrate crystal obtained from
EtOH−CH3CN (Figure S3e) was solved in space group P21/c.
One side of the dicationic piperazinium molecule is connected
to aceclofenate anion through N+−H···O− ionic hydrogen
bond, N2+−H1A···O1− (1.67 Å, 175°), and on the other side
ACF and water molecules bridge through N2+−H2C···O5
(1.84 Å, 144°) and O5−H5B···O1− (1.83 Å, 171°) hydrogen
6
bonds respectively, resulting in a R4 (12) ring motif (Figure 5).
Crystal structural analysis gave an idea of the packing
efficiency and bond strength of ACF salts compared to the
neutral molecule. As discussed earlier, ACF can form major
bonding interactions through its ester, amine, and acid
functional groups. Structural analysis showed that the N−H
and ester functional groups are held together by an intra-
molecular hydrogen bond in ACF and its solid forms.
Therefore, the homomeric and heteromeric interactions in
ACF and its solid forms are primarily due to the hydrogen
bonding interactions at the COOH functional group. In ACF,
the acid protons form a catemeric O1−H1A···O2 interaction
(1.90 Å) with a neighboring molecule stabilized by auxiliary C−
H···O interactions (Figure 1). In ACF−BIP−HYD, a
heteromeric O1−H1A···N2 hydrogen bond (1.62 Å) with
2
the two-point carboxylate···aminopyrimidine synthon of R2 (8)
geometry. Two ACF molecules are hydrogen-bonded to two
4
CYT molecules via the carboxylate···amine R2 (8) motif. The
N3 nitrogen of CYT forms a N3−H3A···O1 hydrogen bond
with the O1 carboxylate oxygen (1.74 Å, 173°) of ACF (Figure
3).
1592
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601

Crystal Growth & Design
Article
Table 3. Hydrogen Bond Distances and Angles in ACF and Salts (N−H, O−H, and C−H Distances Were Neutron-Normalized)
D−H···A
D···A (Å)
H···A (Å)
D−H···A (deg)
symmetry code
ACF
O1−H1A···O2
N1−H1B···Cl1
N1−H1B···O4
C2−H2A···O4
C4−H4B···O2
2.690(3)
2.968(3)
3.025(3)
3.397(4)
3.366(3)
1.90
2.63
2.13
2.32
2.29
135
100
147
171
174
3/2 − x , −1/2 + y, 1/2 − z
a
a
1 − x, −y, −z
3/2 − x, 1/2 + y, 1/2 − z
ACF−BIP−H2O (1:1:0.5)
O1−H1A···N2
N1−H1B···Cl1
N1−H1B···O4
O5−H5A···O2
O5−H5B···O2
C4−H4A···O5
2.5970(16)
2.9726(12)
3.0095(16)
2.794(3)
1.63
173
113
148
168
151
121
2 − x, −1/2 + y, 1/2 − z
a
2.55
2.28
a
1.81
1 − x, 1/2 + y, 1/2 − z
−1 + x, 1/2 − y, −1/2 + z
1 − x, −1/2 + y, 1/2 − z
2.786(3)
1.88
3.097(3)
2.48
ACF−CYT (1:1)
N2−H1A···O1
N1−H1B···Cl1
N1−H1B···O3
N3−H3A···O1
N4−H4C···O2
N4−H4D···O2
C4−H4B···O2
C14−H14···O5
2.7150(19)
3.0163(15)
2.9175(19)
2.7420(18)
2.857(2)
1.71
180
103
144
173
178
141
174
128
1 − x, 2 − y, −z
a
2.63
2.04
a
1.74
1/2 + x, 3/2 − y, 1/2 + z
1 − x, 2 − y, −z
a
1.85
2.7902(19)
3.521(2)
1.93
2.44
1 − x, 2 − y, −z
−1 + x, y, z
3.213(2)
2.43
ACF−PIP (1:0.5)
N2−H1A···O1
N2−H1A···O2
N1−H1B···Cl1
N1−H1B···O3
N2−H2C···O2
C2−H2A···O1
C4−H4A···Cl1
2.673(3)
3.142(3)
3.013(2)
2.924(3)
2.653(3)
3.497(3)
3.510(3)
1.68
169
124
103
145
173
164
137
x, 1 + y, z
x, 1 + y, z
a
2.46
2.62
2.04
a
1.65
x, 1 + y, z
x, −1 + y, z
x, 1 + y, z
2.44
2.64
ACF−PIP−H2O (1:0.5:1)
N2−H1A···O1
N1−H1B···Cl2
N1−H1B···O4
N2−H2C···O5
O5−H5A···O2
O5−H5B···O1
C2−H2B···O4
C2−H2B···O3
C4−H4A···O1
C17−H17B···O2
C18−H18A···O4
2.6792(19)
2.9949(17)
2.970(2)
1.67
2.60
2.12
1.84
1.73
1.83
2.26
2.47
2.51
2.32
2.38
175
103
141
144
178
171
102
150
163
140
134
−x, −y, 1 − z
a
a
2.724(2)
a
2.7106(19)
2.8090(19)
2.693(2)
x, 1/2 − y, 1/2 + z
x, 1 + y, 1 + z
a
3.446(2)
x, −1/2 − y, −1/2 + z
x, −1/2 − y, 1/2 + z
x, 1 + y, z
3.561(2)
3.231(2)
3.222(2)
x, 1/2 − y, 1/2 + z
a
Intramolecular hydrogen bond.
BIP is observed. The layered motif of ACF molecules in ACF−
BIP−HYD is further stabilized by water bridges. The complete
transfer of acidic proton to the basic nitrogen resulted in a short
and ionic bond in the salt structures. Apart from the bifurcated
N−H···O− interactions (1.68 Å in ACF−PIP and 1.67 Å in
Conformational Flexibility. The chemical diagram of ACF
(Scheme 2) suggests that this conformationally flexible
molecule (rotation at C−N and CH2−COO moieties) can
adopt different conformations in the solid-state. Significant
differences were observed in the conformations of ACF in its
guest free form and salt/cocrystal structures. The different
conformations due to free rotation about single bonds,30 mainly
the acetoxyacetic acid group, are shown in Figure 6. Selected
torsional angles are listed in Table S1.
2
ACF−PIP−HYD), a two point R2 (8) ring motif between
carboxylate and aminopyrimidine moieties strengthens the
crystal structure of ACF−CYT. Therefore all the solid forms of
ACF are stabilized by stronger and shorter ionic interactions
which will impart improved physicochemical properties. This
latter point is confirmed in our solubility and solid form
stability studies of ACF salts (discussed later) where the salts
(except ACF−PIP) were found to be stable in accelerated
International Conference on Harmonization (ICH) conditions
and positively modulated the solubility of the parent drug.
Powder X-ray Diffraction. PXRD31 is a reliable character-
ization tool to establish the formation of novel solid forms. It
can unambiguously distinguish the resulting product phases
from its starting materials through the unique diffraction line
pattern. The PXRD of the novel solid forms prepared in this
work (Figure S4) confirm the bulk solid phase purity and
homogeneity of each crystalline phase which showed an
1593
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601

Crystal Growth & Design
Article
Figure 1. (a) Catemeric O−H···O hydrogen bonds extend the ACF molecules in a tape motif supported by auxiliary C−H···O and Cl···O
interactions. The strong O−H···O H bond is marked by a rectangle (red) and the weak C−H···O and Cl···O interactions by a circle (green). (b)
Weak C−H···O’s connecting the adjacent catemer tapes. (c) Molecules in adjacent layers are connected through by a centrosymmetric C−H···O
2
R2 (10) motif.
excellent overlay of the experimental powder pattern with the
calculated lines from the crystal structure. ACF−LYS and
ACF−GABA were compared with the starting components to
establish novel product phases. Their single crystal X-ray
structures are not available for comparison.
Changes in the bonding patterns hint at the functional groups
involved and efficiently complement the diffraction methods for
the characterization of solid-state forms. In the IR spectrum of
ACF, the COOH functional group is present as a monomer,
and hence the carbonyl group appears as a sharp peak at 1771.4
cm−1. The ester and amine functional moieties are connected to
each other through intramolecular hydrogen bonds and appear
at 1716.6 cm−1 and 3318.9 cm−1. The bands due to C−O
stretch and O−H bend appear at 1256.4 cm−1 and 1400.0
cm−1. These hydrogen bonding functional groups showed
significant changes in their vibrational modes on salt/cocrystal
formation (Figure S6). In ACF−BIP−HYD, the N−H
stretching frequency shifted to 3296.2 cm−1, and its bending
frequency appeared at 1602.2 cm−1. Due to its hydrogen
bonding to the acid moiety of ACF, the CN stretch in BIP
shifted from 1408.5 cm−1 to 1416.9 cm−1 in the cocrystal. The
acid moiety exists as a carboxylate anion in all salts,
characterized by the strong asymmetric stretch at 1650−1450
cm−1, and a weaker symmetric stretch near 1350−1250 cm−1 in
their IR spectra. The asymmetric and symmetric stretching
frequencies of carboxylate salt appear at 1492.2 cm−1 and
1232.4 cm−1 in ACF−CYT, 1450.8 cm−1, and 1245.6 cm−1 in
ACF−PIP, 1453.7 cm−1 and 1292.5 cm−1 in ACF−PIP−HYD,
1453.3 cm−1 and 1242.1 cm−1 in ACF−LYS, and 1452.1 cm−1
and 1241.1 cm−1 in ACF−GABA as compared to the 1771.4
cm−1 stretching peak of carboxylic acid in ACF. The Raman
Thermal Analysis. The DSC of cocrystal/salt showed a
unique melting point compared to that of the starting
components; a TGA trace established the stoichiometry of
water or solvent in the case of hydrates and solvates. The
thermal measurements complement the XRD patterns to
confirm the formation of the novel crystalline forms. The
characteristic melting/decomposition profiles are shown as
endo-/exotherm in the DSC heating curve. The DSC trace of
each novel solid form prepared in this work (Figure 7) showed
a unique melting behavior which distinguishes it from the
starting materials. We did not notice any correlation between
the melting point of the coformer and its corresponding salt,
similar to recent cocrystal systems15a,16 (Table 4). The water
stoichiometry in ACF−BIP−0.5HYD and ACF−PIP−HYD
bulk phases was confirmed by TGA and HSM experiments
(Figure S5), which showed an excellent match with the
calculated amount of water in the crystal structure.
Vibrational Spectroscopy. Changes in the hydrogen
bonding patterns of the starting materials on forming
cocrystals/salts are expected to influence the energies of
vibrational modes associated with the functional groups.32
1594
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601

Crystal Growth & Design
Article
Figure 2. (a) ACF and BIP molecules are connected through O−H···N hydrogen bond. (b) Adjacent ACF layers are connected through water
bridges in a tetramer O−H···O motif.
Figure 4. ACF and PIP molecules are connected through one point
N−H···O− hydrogen bond.
2
4
Figure 3. R2 (8) and R2 (8) N−H···O hydrogen bond ring motifs in
the crystal structure of ACF−CYT salt.
cm−1, 1237.0 cm−1 in ACF−PIP−HYD, 1425.2 cm−1, 1234.7
cm−1 in ACF−LYS, and 1420.9 cm−1, 1234.2 cm−1 in ACF−
GABA compared to the monomeric carboxylic acid peak at
1726.4 cm−1 for ACF. Thus both IR and Raman spectra of
cocrystal and salts exhibited significant differences in their
stretching and bending frequencies (Tables S2 and S3) which
established their unique intermolecular bonding pattern. They
complement the diffraction techniques to confirm the novelty
of salts.
spectra also showed similar changes in the product phases
compared to the starting components (Figure S7). In ACF−
BIP-HYD, the Raman shift for N−H stretching frequency was
observed at 3299.7 cm−1, and its bending frequency at 1611.5
cm−1 indicating changes in hydrogen bonding. The Raman
asymmetric and symmetric stretching frequencies of the
carboxylate group appeared at 1414.2 cm−1, 1254.9 cm−1 in
ACF−CYT, 1450.8 cm−1, 1237.0 cm−1 in ACF−PIP, 1451.7
1595
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601

Crystal Growth & Design
Article
Table 4. Melting Point of ACF Salts/Cocrystals and the
a
Coformers
s.
no.
ACF salts/
cocrystal
melting point
melting point
(°C)
coformer
(°C)
1
ACF−BIP−
132.4
4,4′-bipyridine
110−114
HYD
2
3
4
ACF−CYT
ACF−PIP
185.2
164.2
166.2
cytosine
320−325
106
piperazine
piperazine
ACF−PIP−
106
HYD
5
6
ACF−LYS
ACF−GABA
201.0
135.5
L-lysine
196
203
γ-aminobutyric
acid
a
Melting point of ACF 151.4 °C.21
order in crystalline and amorphous solids.33 13C ss-NMR
analysis of the novel solid forms of ACF showed clear
differences in the product phases when compared with the
starting components. On the basis of the extent of proton
transfer, the position of the COOH carbon atom differed in ss-
NMR spectra. Whereas the neutral COOH peak appeared at
174.1 ppm in the parent drug, it showed a clear downfield shift
in salts where it exists as a carboxylate anion (Figure S8). In
ACF−BIP−HYD, there is no proton transfer from ACF to the
coformer. Hydrogen bonding of the COOH donor to the
pyridyl nitrogen of BIP showed a downfield shift to 174.8 ppm.
In salts, larger downfield shifts were observed due to complete
proton transfer. The chemical shift of COO− carbon in salts
was shifted downfield to 176.5 ppm in ACF−CYT, 174.4 in
ACF−PIP, 174.8 in ACF−PIP−HYD, 175.1 ppm in ACF−
LYS, and 174.9 ppm in ACF−GABA (Table S4).
Solid Form Stability. Solid form stability of salts was
measured under accelerated stability ICH34 conditions of 40 °C
and 75% relative humidity (RH). PXRD was recorded on all
the solid forms at monthly intervals for up to 8 months. ACF−
CYT, ACF−PIP−HYD, ACF−LYS, and ACF−GABA were
found to be as stable as the reference drug ACF in the 8
months period by PXRD. The final PXRD patterns of the solids
6
Figure 5. R4 (12) hydrogen bond ring motif in the crystal structure of
ACF−PIP−HYD salt hydrate.
Figure 6. An overlay diagram of the ACF molecule extracted from the
guest free form and salts. Color codes: violet = ACF, magenta = ACF−
BIP−HYD, green = ACF−CYT, red = ACF−PIP, and blue = ACF−
PIP−HYD.
ss-NMR Spectroscopy. ss-NMR spectroscopy can non-
destructively provide detailed information about the differences
in hydrogen bonding, molecular environment, and short-range
Figure 7. DSC heating curves show a sharp melting endotherm for each solid form which is indicative of high purity and homogeneity.
1596
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601

Crystal Growth & Design
Article
are shown in Figure 8 and the intermediate PXRD patterns are
in Figure S9. However, ACF−PIP was found to convert to
ACF−PIP−HYD within 3 days (Figure S9f). The crystalline
phase stability studies demonstrate good stability of ACF−
CYT, ACF−PIP−HYD, ACF−LYS, and ACF−GABA and with
the added advantage of higher solubility compared to ACF
(solubility curves are discussed later in the paper). We did not
observe any peaks for byproducts such as diclofenac and/or
indolinone shown in Scheme 1 (Figure S9g).
Crystalline and Amorphous ACF−LYS Salt. Due to their
excess thermodynamic functions, amorphous forms tend to be
less stable compared to their crystalline counterparts.35 The
amorphous form of ACF−LYS salt was prepared by
lyophilization.12 The amorphous nature of the product was
characterized by PXRD and DSC (Figure S10a,b). PXRD of the
amorphous solid kept in accelerated ICH conditions (40 °C,
75% RH) for 24 h matched the crystalline salt (Figure S10c).
The same result was observed on slurry grinding of amorphous
material in water for 24 h (Figure 9). Stabilization of the
amorphous phase is possible, for example, itraconazole as
Sporanox beads.36
Figure 9. PXRD pattern of ACF−LYS amorphous form slurry ground
in water for 24 h showed complete conversion to the stable crystalline
salt.
Solubility and Dissolution. An important goal of drug
development is to maintain optimum physicochemical
parameters which have a major impact on its efficacy. Solubility
and permeability of a drug molecule determine its mode of
administration into the body. Solubility remains a major
concern for BCS class II drugs since it largely limits
bioavailability.37 Hence, physical or chemical modifications
are necessary for such drugs in order to modulate solubility and
improve therapeutic efficacy. Solubility and dissolution studies
were carried out on ACF (a BCS class II drug) salts to evaluate
the solubility advantage. Equilibrium solubility of ACF, ACF−
CYT, ACF−PIP-HYD, and ACF−LYS was determined in 25%
EtOH−water medium because the concentration of ACF in
pure water is very low. The equilibrium solubility experiment
was performed for 48 h. Solubility of ACF−PIP and ACF−
GABA could not be determined since the former converted to
its more stable hydrate and the latter dissociated into the
starting components due to the incongruent solubilities of ACF
and GABA.38 The stable ACF−CYT, ACF−PIP−HYD, and
ACF−LYS salts exhibited 16.3, 3.5, and 156.5 times higher
solubility than the reference drug ACF. PXRD plots of the
residue at the end of the equilibrium solubility experiment
(Figure S11) confirm that there is no phase transformation or
degradation of the salt during the solubility experiment.
Figure 8. Comparison of PXRD plots of salts kept in the stability
chamber at 40 °C and 75% RH for 8 months with the PXRD of the
starting salts. All salts were stable for up to 8 months except ACF−PIP
(shown in Figure S9f).
Dissolution rate is a time-dependent phenomenon, and this
method is preferable for those drugs which undergo phase
transformation during the equilibrium solubility experiment.
1597
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601

Crystal Growth & Design
Article
IDR gives an idea of the peak concentration and the amount of
the drug dissolved in a short time period (30 min to 2 h) before
it undergoes any phase transformation/dissociation.39 IDR
experiments on ACF salts were performed in 25% EtOH−
water for 1.5 h by the rotating disk intrinsic dissolution rate
(DIDR) method40 at 37 °C. ACF−LYS showed 135-fold higher
IDR than ACF followed by ACF−GABA (×112.7), ACF−CYT
(×11.6), ACF−PIP (×3.4), and ACF−PIP−HYD (×x2.6). As
expected, ACF−PIP converted to its hydrate and ACF−GABA
dissociated into the starting components in the IDR experiment
(Figure S12); the other salts are stable. We did not observe any
trend between the melting point of the salt and its dissolution
rate; i.e., the lower the melting point, the higher the IDR,
similar to those reported for cocrystals.15a,16a,41 The dissolution
rates are better correlated to the coformer solubility (a kinetic
parameter) rather than the melting point42 (thermodynamic).
ACF−CYT did not follow this order. Intrinsic dissolution rate
curves are displayed in Figure 10, and dissolution rates, melting
example, ibuprofen lysinate salt is marketed under the brand
name Neoprofen.43
CONCLUSIONS
■
Slurry grinding of ACF with carefully selected GRAS coformers
resulted in novel salts of higher solubility, dissolution, and
comparable solid form stability. The chemical transformation of
ACF to the indolinone derivative under extreme acidic and
basic pH was avoided by the use of weak organic bases. A large
ΔpKa of >6 resulted in salts with piperazine, lysine, and GABA,
and moreover even a small ΔpKa of 2.5 for cytosine also gave a
salt. A reason for favorable salt formation with cytosine could
be the two-point synthon between 2-aminopyrimidine and
COOH group, which facilitates proton transfer. All the salts
were characterized by thermal, spectroscopic and diffraction
techniques. The stoichiometry of ACF−LYS and ACF−GABA
for which single X-ray crystal data could not be obtained was
established by 1H NMR. The intrinsic dissolution rate of ACF−
lysine is 135 times, solubility is 156 times, and AUC value is
127 times higher than that of the reference crystalline drug.
Solid form stability at accelerated ICH conditions of 40 °C and
75% RH showed that ACF−LYS is stable for over 8 months.
The ultimate aim of this work, to improve the solubility of ACF
without affecting its solid form stability or cause chemical
transformations, was achieved through salt formation using
mildly basic coformers. Further physicochemical studies on
ACF−LYS salt for drug development are ongoing.
EXPERIMENTAL SECTION
■
ACF was obtained from Dalian HongRiDongSheng Import & Export
Co. Ltd. (China). Coformers (purity > 99.8%) were purchased from
Sigma-Aldrich (Hyderabad, India). Solvents (purity > 99%) were
purchased from Hychem Laboratories (Hyderabad, India). Water
filtered through a double deionized purification system (Aqua DM,
Bhanu, Hyderabad, India) was used for all experiments.
Preparation of ACF Solid Forms. ACF (212.4 mg) and 4,4′-BIP
(46.8 mg) in a 1:0.5 molar ratio were slurry ground in 5 mL of EtOH
for 3 h. The formation of cocrystal hydrate was confirmed by PXRD,
DSC, and TGA. Thirty milligrams of this material was dissolved in 5
mL of EtOH and left for slow evaporation at ambient conditions.
Single crystals suitable for X-ray diffraction were obtained after 4−5
days.
ACF (212.4 mg) and CYT (66.6 mg) in a 1:1 molar ratio were
slurry ground in 5 mL of EtOH for 3 h. Salt formation was confirmed
by PXRD. Thirty milligrams of this material was dissolved in 5 mL of
EtOH−CH3CN 1:1 solvent mixture and left for slow evaporation at
ambient conditions. Single crystals suitable for X-ray diffraction were
obtained after 4−5 days.
ACF (70.8 mg) and PIP (8.6 mg) in a 1:0.5 molar ratio was
dissolved in 5 mL of acetone and left for slow evaporation at ambient
conditions. Single crystals suitable for X-ray diffraction were obtained
Figure 10. Intrinsic dissolution rate curves of ACF salts in 25%
EtOH−water.
points, and coformer solubility are listed in Table 5. The
amount of dissolved ACF after 1.5 h (AUC0−1.5) is 105.33 mg
h/L for ACF, 218.5 mg h/L for ACF−PIP−HYD, 836.5 mg h/
L for ACF−CYT, and 13451.1 mg h/L for ACF−LYS. The
AUC value, which indicates the total dissolved ACF in a given
time period, is the highest for ACF−LYS (×127.7 times greater
than ACF). ACF−LYS salt having the highest dissolution rate
and good solid form stability in solubility and humidity
experiments is a promising candidate as a soluble ACF salt.
Moreover, the salt former L-lysine is completely safe. For
a
Table 5. Intrinsic Dissolution Rates of ACF Salts along with Their Molar Extinction Coefficient (ε), and Melting Point
molar extinction
coefficient, ε /mM cm
equilibrium
solubility (g/L)
intrinsic dissolution rate, IDR
M.P.
(°C)
area under the curve,
AUC0−1.5h (mg h)/L
solubility of coformer
in water (g/L)
compound
(mg/cm2)/min (× 10−3
)
ACF
9.41
11.61
8.33
0.174
0.022
151.4
185.2
164.2
162.4
105.3
0.058
7.7
ACF−CYT
ACF−PIP
2.85 (× 16.37)
0.256 (×11.64)
0.076 (×3.46)
0.057 (×2.59)
836.5 (×7.9)
316.3 (×3.0)
218.5 (×2.1)
1000
1000
ACF−PIP−
9.57
1.01 (× 3.56)
HYD
ACF−LYS
9.26
27.23 (× 156.51)
2.97 (×135.0)
2.48 (× 112.7)
201.0
135.5
13451.1 (×127.7)
6431.1 (×61.1)
1500
1300
ACF−
10.28
GABA
a
The number of times enhancement of IDR and AUC with respect to ACF is given in parentheses.
1598
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601

Crystal Growth & Design
Article
after 4 h. The starting materials were crystallized in above conditions
repeatedly to obtain the bulk material.
many). Mo−Kα X-radiation (λ = 0.71073 Å) was used to collect X-ray
reflections on the single crystal at 100 K. Data reduction was
performed using the Bruker SAINT software.45 Intensities for
absorption were corrected using SADABS,46 the Siemens area detector
absorption correction program (Bruker-AXS). Crystal structures were
solved and refined using SHELX-9747 with anisotropic displacement
parameters for non-H atoms. Hydrogen atoms on O and N were
experimentally located in difference electron density maps. All C−H
atoms were fixed geometrically using HFIX command in SHELX-TL
(Bruker-AXS). The stoichiometry of water molecule in ACF−BIP−
H2O was fixed to 0.5 s.o.f. and hydrogens attached to it were fixed
using the DFIX command. A check of the final CIF file using
PLATON48 did not show any missed symmetry. Hydrogen bond
distances shown in Table 3 are neutron normalized to fix the D−H
distance to its accurate neutron value in the X-ray crystal structures
(O−H 0.983 Å, N−H 1.009 Å, and C−H 1.083 Å). X-Seed49 was used
to prepare packing diagrams. Crystallographic .cif files (CCDC Nos.
915223−915227) are available at www.ccdc.cam.ac.uk/data or as part
of Supporting Information.
ACF (70.8 mg) and PIP (8.6 mg) in a 1:0.5 molar ratio were slurry
ground in 5 mL of EtOH for 3 h. The salt hydrate was formed based
on PXRD, DSC, and TGA. Thirty milligrams of this material was
dissolved in 5 mL of EtOH−CH3CN 1:1 solvent mixture and left for
slow evaporation at ambient conditions. Single crystals suitable for X-
ray diffraction were obtained after 4−5 days.
ACF (212.4 mg) and LYS (87.6 mg) in a 1:1 molar ratio were slurry
ground in 5 mL of EtOH for 3 h. Salt formation was confirmed by
1
PXRD and H NMR.
ACF (212.4 mg) and GABA (61.8 mg) in a 1:1 molar ratio were
slurry ground in 5 mL of EtOH for 3 h. Salt formation was confirmed
1
by PXRD and H NMR.
To a solution of 292 mg of LYS in 20 mL of water, 708 mg of ACF
was added with stirring. The solution was filtered through Whatmann
filter paper and lyophilized. The ACF−LYS salt residue was obtained
as an amorphous powder.
1H NMR Spectroscopy. All ground products were characterized
by 1H NMR to confirm their stoichiometry (Figure S6). Proton NMR
spectra were recorded on Bruker Avance 400 MHz spectrometer
(Bruker-Biospin, Karlsruhe, Germany). Chemical shifts are quoted in δ
scale and J coupling in Hz.
Solid Form Stability. About 200 mg of each solid compounds was
placed in an open Petri dish and stored without a lid in a Thermolab
T-908 stability chamber (Thermolab Instruments, Mumbai, India)
premaintained at 40 °C and 75% RH (as per the WHO/ICH
guidelines) for 8 months. Solid form stability and integrity of the
samples were assessed periodically every week by PXRD.
1
ACF−LYS (1:1). H NMR (D2O): 1.28 (2H, quintet, J 7.5), 1.51
(2H, quintet, J 7.5), 1.68 (2H, q, J 7.5), 2.78 (2H, t, J 7.5), 3.79 (2H,
s), 4.28 (2H, s), 6.21 (1H, d, J 8), 6.83 (1H, t, J 8), 7.0 (1H, t, J 8),
7.11 (1H, t, J 8), 7.19 (1H, d, J 8), 7.39 (2H, d, J 8). COOHs and NHs
of ACF and LYS exchange in solvent.
Dissolution and Solubility Measurements. The solubility
curves of ACF salts were measured using the Higuchi and Connor
method50 in 25% ethanol−water medium at 30 °C. First, the
absorbance of a known concentration of the salt was measured at
the given λmax (ACF 274 nm, ACF−CYT 270 nm, ACF−PIP 273 nm,
ACF−PIP−HYD 273 nm, ACF−LYS 275 nm, ACF−GABA 274 nm)
in 25% ethanol−water on Thermo Scientific Evolution 300 UV−vis
spectrometer (Thermo Scientific, Waltham, MA). These absorbance
values were plotted against several known concentrations to prepare
the concentration versus intensity calibration curve. From the slope of
the calibration curves, molar extinction coefficients for ACF salts were
calculated. An excess amount of the sample was added to 6 mL of 25%
ethanol−water. The supersaturated solution was stirred at 300 rpm
using a magnetic stirrer at 30 °C. After 24 h, the suspension was
filtered through Whatman’s 0.45 μm syringe filter. The filtered aliquots
were diluted sufficiently, and the absorbance was measured at the
given λmax. IDR experiments were carried out on USP-certified
Electrolab TDT-08L dissolution tester (Mumbai, India). Dissolution
experiments were performed for 1.5 h in 25% ethanol−water at 37 °C.
Prior to IDR estimation, standard curves for all the compounds were
obtained spectrophotometrically at their respective λmax. The
calculated molar extinction coefficients were used to determine the
IDR values. For IDR measurements, 200 mg of the compound was
taken in the intrinsic attachment and compressed to a 0.5-cm2 disk
using a hydraulic press 4.0 ton/in.2 pressure for 5 min. The intrinsic
attachment was placed in a jar of 500 mL of medium preheated to 37
°C and rotated at 150 rpm. Five milliliters of the aliquot was collected
at specific time intervals, and the concentration of the aliquots was
determined with appropriate dilutions from the predetermined
standard curves of the respective compounds. The IDR of the
compound was calculated in the linear region of the dissolution curve
(which is the slope of the curve or amount of drug dissolved/surface
area of the disk) per unit time. The identity of the undissolved material
after the dissolution experiment was ascertained by PXRD. The nature
of the solid samples after disk compression and solubility/dissolution
measurements was verified by PXRD.
1
ACF−GABA (1:1). H NMR (DMSO-d6): 1.70 (2H, quintet, J 7.5),
2.27 (2H, t, J 7.5), 2.74 (2H, t, J 7.5), 3.81 (2H, s), 4.33 (2H, s), 6.22
(1H, d, J 8), 6.83 (1H, t, J 8), 7.0 (1H, t, J 8), 7.18 (1H, t, J 8), 7.20
(1H, d, J 8), 7.49 (2H, d, J 8). COOHs and NHs of ACF and GABA
exchange in solvent.
Vibrational Spectroscopy. Thermo-Nicolet 6700 Fourier trans-
form infrared spectrophotometer with NXR-Fourier transform Raman
module (Thermo Scientific, Waltham, Massachusetts) was used to
record IR and Raman spectra. IR was recorded on sample dispersed in
KBr pellet. Raman spectra were recorded on sample contained in
standard NMR diameter tube or on compressed sample contained in a
gold-coated sample holder. Data were analyzed using the Omnic
software (Thermo Scientific, Waltham, Massachusetts).
Solid-State NMR Spectroscopy. Solid-state 13C NMR spectra
were recorded on Bruker Avance 400 MHz spectrometer (Bruker-
Biospin, Karlsruhe, Germany, operating at 100 MHz for 13C nucleus).
ss-NMR measurements were carried out on Bruker 4-mm double
resonance CP-MAS probe in zirconia rotors with a Kel-F cap at 5.0
kHz spinning rate with a cross-polarization contact time of 2.5 ms and
a delay of 8 s. 13C NMR spectra were recorded at 100 MHz and
referenced to the methylene carbon of glycine, and then recalibrated to
the TMS scale (δglycine = 43.3 ppm).
Thermal Analysis. DSC was performed on a Mettler-Toledo DSC
822e module, and thermogravimetric analysis (TGA) was performed
on a Mettler Toledo TGA/SDTA 851e module (Mettler-Toledo,
Columbus, Ohio). Samples were placed in sealed pin-pricked alumina
pans for TG experiments and in crimped but vented aluminum pans
for DSC experiments. The typical sample size is 3−5 mg for DSC and
8−12 mg for TGA. The temperature range for the heating curve was
30−220 °C, and the sample was heated at a rate of 5 °C/min. Samples
were purged in a stream of dry nitrogen flowing at 80 mL/min for
DSC and 50 mL/min for TGA.
Powder X-ray Diffraction. PXRD of all the samples was recorded
on Bruker D8 Advance diffractometer (Bruker-AXS, Karlsruhe,
Germany) using Cu−Kα X-radiation (λ = 1.5406 Å) at 40 kV and
30 mA power. XRD patterns were collected over the 2θ range 5−50°
at a scan rate of 1°/min. Powder Cell 2.444 (Federal Institute of
Materials Research and Testing, Berlin, Germany) was used for
Rietveld refinement of experimental PXRD and calculated lines from
the X-ray crystal structure.
ASSOCIATED CONTENT
* Supporting Information
■
S
Crystallographic information (.cif files); ORTEP of indolinone
1
(Figure S1); H NMR spectra of ACF−LYS and ACF−GABA
(Figure S2); ORTEP of ACF, ACF−BIP−H2O (1:0.5:0.5),
ACF−CYT (1:1), ACF−PIP (1:0.5), ACF−PIP-H2O (1:0.5:1)
(Figure S3); powder XRD patterns of all solid forms (Figure
X-ray Crystallography. X-ray reflections were collected on Bruker
SMART-APEX CCD diffractometer (Bruker-AXS, Karlsruhe, Ger-
1599
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601

Crystal Growth & Design
Article
S. S.; Patil, S. S.; Mevekari, F. I.; Satpute, A. S. Int. J. Adv. Pharm. Sci.
2010, 1, 299.
(10) Sevukarajan, M.; Thanuja, B.; Riyaz, S.; Rahul, N. J. Pharm. Sci.
S4), DSC, TGA, and HSM of ACF−BIP−HYD, ACF−PIP−
HYD (Figure S5); IR spectra of all solid forms (Figure S6);
Raman spectra of all solid forms (Figure S7); ss-NMR spectra
of all solid forms (Figure S8); 6 months accelerated stability
experiments of all solid forms (Figure S9); DSC and PXRD
comparisons of ACF−LYS amorphous and crystalline salt and
PXRD comparison of amorphous to crystalline ACF−LYS salt
conversion in humidity experiments (Figure S10); PXRD of
ACF, ACF−CYT, ACF−PIP−HYD, ACF−PIP, ACF−LYS,
ACF−GABA at 24 h of slurry experiment (Figure S11); PXRD
of ACF−PIP and ACF−GABA at 90 min of dissolution
experiment (Figure S12); torsion angles of all solid forms
(Table S1), IR vibrational frequencies of ACF and salts (Table
S2); Raman vibrational frequencies of ACF and salts (Table
S3); and 13C ss-NMR chemical shifts of ACF and salts (Table
S4). This material is available free of charge via the Internet at
http://pubs.acs.org.
Res. 2011, 3, 1288.
(11) Casas, A. V.; Rue du, R. New 2-((2,6-dichlorophenyl)amine)-
phenylacetoxyacetyl derivatives, the process for preparing the same
and their use in therapeutics. Patent No. EP0119932A1, European
Patent Office, Barcelona, 1984.
(12) Sallmann, A. New Salts of 2-[(2,6-dichlorophenyl)amine]-
phenylacetoxyacetic acid with organic basic cations. Patent No.
US005708024A, United States patent office, 1998.
(13) Azhlawar, S.; Ravi, T. K. Int. J. Pharm. Pharm. Sci. 2011, 3, 245.
(14) (a) Desiraju, G. R.; Vittal, J. J.; Ramanan, A. Crystal Engineering.
A Textbook; World Scientific Publishing: Singapore, 2011. (b) Desiraju,
G. R. Crystal Engineering. The Design of Organic Solids;; Elsevier:
Amsterdam, 1989.
(15) (a) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9,
2950. (b) Jones, W.; Motherwell, W. D. S.; Trask, A. V. MRS Bull.
̈
2006, 31, 875. (c) Almarsson, O; Zaworotko, M, J. Chem. Commun.
2004, 17, 1889.
AUTHOR INFORMATION
(16) (a) Stanton, M. K.; Bak, A. Cryst. Growth Des. 2008, 8, 3856.
(b) Stanton, M. K.; Tufekcic, S.; Morgan, C.; Bak, A. Cryst. Growth
Des. 2009, 9, 1344. (c) Bak, A.; Gore, A.; Yanez, E.; Stanton, M.;
Tufekcic, S.; Syed, R.; Akrami, A.; Rose, M.; Surapaneni, S.; Bostick,
T.; King, A.; Neervannan, S.; Ostovic, D.; Koparkar, A. J. Pharm. Sci.
2008, 97, 3942.
(17) (a) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311.
(b) Walsh, R. D. B.; Bradner, M. W.; Fleischman, S.; Morales, L. A.;
Moulton, B.; Rodríguez-Hornedo, N.; Zaworotko, M. J. Chem.
Commun. 2003, 186.
(18) (a) Trask, A. V.; Jones, W. Top. Curr. Chem. 2005, 254, 41.
(b) Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 20, 2372.
(19) GRAS chemicals list may be accessed at www.fda.gov/Food/
FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/
GRASSubstancesSCOGSDatabase/default.htm.
(20) (a) Aakeroy, C. B.; Fasulo, M. E.; Desper, J. Mol. Pharmaceutics
2007, 4, 317. (b) Sarma, B.; Nath, N. K.; Bhogala, B. R.; Nangia, A.
Cryst. Growth Des. 2009, 9, 1546. (c) Childs, S. L.; Stahly, G. P.; Park,
A. Mol. Pharmaceutics 2007, 4, 323. (d) Cruz-Cabeza, A. J.
CrystEngComm 2012, 14, 6362.
■
Corresponding Author
*E-mail: ashwini.nangia@gmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
N.R.G. and K.S. thank CSIR and UGC for a fellowship. We
thank the Department of Science and Technology (J.C. Bose
fellowship SR/S2/JCB-06/2009) and Council of Scientific and
Industrial Research (Pharmaceutical Cocrystals Project 01/
2410)/10/EMR-II) for funding. DST (IRPHA) and University
Grants Commission (UGC-PURSE grant) are thanked for
providing instrumentation and infrastructure facilities at
University of Hyderabad (UOH).
REFERENCES
■
(21) Alvarez-Larena, A.; Piniella, J. F.; Carrasco, E.; Ginebreda, A.;
Julia, S.; Germain, G. J. Crystallogr. Spec. Res. 1992, 22, 323.
(22) Perlovich, G. L.; Surov, A, O.; Hansen, L. K.; Bauer-Brandl, A. J.
Pharm. Sci. 2007, 96, 1031.
(23) (a) Chen, X.; Morris, K. R.; Griesser, U. J.; Byrn, S. R.; Stowell,
J. G. J. Am. Chem. Soc. 2002, 124, 15012. (b) Cox, P. J.; Manson, P. L.
Acta Crystallogr. 2003, E59, 986.
(1) Huang, L. F.; Tong, W. Q. Adv. Drug Delivery Rev. 2004, 56,
321−334.
(2) (a) Goud, N. R.; Gangavaram, S.; Suresh, K.; Pal, S.; Manjunatha,
S. G.; Nambiar, S.; Nangia, A. J. Pharm. Sci. 2012, 101, 664. (b) Babu,
N. J.; Nangia, A. Cryst. Growth Des. 2011, 11, 2662. (c) Blagden, N.; de
Matas, M.; Gavan, P. T.; York, P. Adv. Drug Delivery Rev. 2007, 59,
617.
(24) (a) Kuduva, S. S.; Craig, D. C.; Nangia, A.; Desiraju, G. R. J. Am.
Chem. Soc. 1999, 121, 1936. (b) Das, D.; Jetti, R. K. R.; Boese, R.;
Desiraju, G. R. Cryst. Growth Des. 2003, 3, 675. (c) Das, D.; Desiraju,
G. R. Chem. − Asian J. 2006, 1, 231.
(25) (a) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1555. (b) Etter, M. C. Acc. Chem. Res.
1990, 23, 120. (c) Etter, M. C. J. Phys. Chem. 1991, 95, 4601.
(26) Sanphui, P.; Bolla, G.; Das, U.; Mukherjee, A. K.; Nangia, A.
CrystEngComm 2013, 15, 34.
(3) (a) Berge, S. M.; Bighley, L. D.; Monkhouse, D. C. J. Pharm. Sci.
1977, 66, 1. (b) Sweetana, S.; Akers, M. J. J. Pharm. Sci. Tech. 1996, 50,
330.
(4) (a) Thayer, A. M. Chem. Eng. News 2013, 91, 10. (b) Babu, N. J.;
Sanphui, P.; Nangia, A. Chem. Asian J. 2012, 7, 2274. (c) Yan, Y.;
Chen, J. M.; Geng, N.; Lu, T. B. Cryst. Growth Des. 2012, 12, 2226.
(d) Sanphui, P.; Kumar, S. S.; Nangia, A. Cryst. Growth Des. 2012, 12,
4588.
(5) (a) British Pharmacopoeia, The Stationary Office, MHRA, British
Pharmacopoeial Commission Office, London, 2005. (b) Reynolds, J.
E. F. Martindale: The Complete Drug Reference; Pharmaceutical Press:
London, 1999.
(27) (a) Etter, M. C.; Macdonald, J. C.; Bernstein, J. Acta Crystallogr.
1990, B46, 256. (b) Etter, M. C.; Reutzel, S. M. J. Am. Chem. Soc.
1991, 113, 2586.
(28) (a) Stevens, J. S.; Byard, S. J.; Schroeder, S. L. M. J. Pharm. Sci.
2010, 99, 4453. (b) Li, Z. J.; Abramov, Y.; Bordner, J.; Leonard, J.;
Medek, A.; Trask, A. V. J. Am. Chem. Soc. 2006, 128, 8199.
(29) Sanphui, P.; Bolla, G.; Nangia, A. Cryst. Growth Des. 2012, 12,
2023.
(30) (a) Nangia, A. Acc. Chem. Res. 2008, 41, 595. (b) Babu, N. J.;
Cherukuvada, S.; Thakuria, R.; Nangia, A. Cryst. Growth Des. 2010, 10,
1979.
(6) (a) Lee, B.; Jung, H. Pharm. Sci. Suppl. 1999, 4, 14. (b) Kim, T.;
Shin, J.; Lee, B. AAPS Annual Meeting, Denver, Colorado, 2001
(7) Sevukarajan, M.; Parveen, S. S.; Nair, R.; Badivaddin, T. M. J.
Pharm. Sci. Res. 2011, 3, 1280.
(8) Kim, N. W.; Il, J. Novel Amino acid Salt of Aceclofenac having
high bioavailability and Pharmaceutical preparation comprising the
same as Active Ingredient. Patent No. 1020050005894A, Korean
Industrial Property Office, Korea, 2003.
(9) (a) Maulvi, F. A.; Dalwadi, S. J.; Thakkar, V. T.; Soni, T. G.;
(31) (a) Remenar, J. F.; Peterson, M. L.; Stephens, P. W.; Zhang, Z.;
Gohel, M. C.; Gandhi, T. R. Powder Technol. 2011, 207, 47. (b) Shinde,
Zimekov, Y.; Hickey, M. B. Mol. Pharmaceutics 2007, 4, 386. (b) Karki,
1600
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601

Crystal Growth & Design
Article
S.; Frisc
(c) Andre,
Growth Des. 2011, 11, 2325.
̌
i
̌
c,
́
T.; Fab
́ ́
ian, L.; Jones, W. CrystEngComm 2010, 12, 4038.
́
V.; Fernandes, A.; Santos, P. P.; Duarte, M. T. Cryst.
(32) (a) Silverstein, R. M. Spectrometric Identification of Organic
Compounds, 6th ed.; John Wiley & Sons, Inc.: New York, 2002.
(b) Smith, E.; Dent, G. Modern Raman Spectroscopy, A Practical
Approach; John Wiley: New York, 2005.
(33) (a) Vogt, F. G.; Clawson, J. S.; Strohmeier, M.; Edwards, A. J.;
Pham, T. N.; Watson, S. A. Cryst. Growth Des. 2009, 9, 921. (b) Braga,
D.; Maini, L.; de Sanctis, G.; Rubini, K.; Grepioni, F.; Chierotti, M. R.;
Gobetto, R. ChemEur. J. 2003, 9, 5538.
(34) Stability testing of Active Pharmaceutical Ingredients and
Finished Pharmaceutical Products, WHO Technical Report Series, No.
953, http://www.ich.org/fileadmin/Public_Web_Site/ICH_
Products/Guidelines/Quality/Q1F/Stability_Guideline_WHO.pdf
(35) (a) Hancock, B. C.; Zograf, G. J. Pharm. Sci. 1997, 86, 1.
(b) Craig, D. Q. M.; Royall, P. G.; Kett, V. L.; Hopton, M. L. Int. J.
Pharm. 1999, 179, 179. (c) Singhal, D.; Curatolo, W. Adv. Drug
Delivery Rev. 2004, 56, 335.
(36) Sporanox capsules (made by Janssen Pharmaceutica) contain
amorphous itraconazole coated on 0.4−0.5 mm diameter sucrose
spheres. Other inactive ingredients include hydroxypropyl methyl-
cellulose, poly(ethyleneglycol) (PEG) 20 000, and starch.
(37) (a) Takagi, T.; Ramachandran, C.; Bermejo, M.; Yamashita, S.;
Yu, L. X.; Amidon, G. L. Mol. Pharmaceutics 2006, 3, 631. (b) Lipinski,
C. A. Solubility in Water and DMSO: issues and potential Solutions. In
Pharmaceutical Profiling in Drug Discovery for Lead Selection: Borchardt,
R. T.; Kerns, E. H.; Lipinski, C. A.; Thakker, D. R.; Wang, B., Eds.;
AAPS Press: Arlington, VA, 2004; pp 93−125.
(38) Childs, S. L.; Rodríguez-Hornedo, N.; Reddy, L. S.; Jayasankar,
A.; Maheshwari, C.; McCausland, L.; Shipplett, R.; Stahly, B. C.
CrystEngComm 2008, 10, 856.
(39) Dressman, J. B.; Amidon, G. L.; Reppas, C.; Shah, V. P. Pharm.
Res. 1998, 15, 11.
(40) Yu, L. X.; Carlin, A. S.; Amidon, G. L.; Hussain, A. S. Int. J.
Pharm. 2004, 270, 221.
(41) Abramowitz, R.; Yalkowsky, S. H. Pharm. Res. 1990, 7, 942.
(42) Good, D. J.; Rodríguez-Hornedo, N. Cryst. Growth Des. 2009, 9,
2252.
(43) (a) Su, P. H.; Chen, J. Y.; Su, C. M.; Huang, T. C.; Lee, H. S.
Pediatr. Int. 2003, 45, 665. (b) Geisslinger, G.; Dietzel, K.; Bezler, H.;
Nuernberg, B.; Brune, K. Int. J. Clin. Pharmacol. Ther. Toxicol. 1989,
27, 324.
(44) Powder Cell, a program for structure visualization, powder
pattern calculation and profile fitting. http://www.ccp14.ac.uk/
tutorial/powdcell/.
(45) SAINT-Plus, Ver. 6.45; Bruker AXS: Madison, WI, 2003.
(46) Sheldrick, G. M. SADABS, Program for Empirical Absorption
Correction of Area Detector Data; University of Gottingen: Gottingen,
̈
̈
Germany, 1997.
(47) Sheldrick, G. M. SHELX-97, Program for the Solution and
Refinement of Crystal Structures; University of Gottingen: Gottingen,
̈
̈
Germany, 1997.
(48) Spek, A. L. PLATON: A Multipurpose Crystallographic Tool;
Utrecht University: Utrecht, The Netherlands, 2002. Spek, A. L. J.
Appl. Crystallogr. 2003, 36, 7.
(49) (a) Barbour, L. J. Supramol. Chem. 2001, 1, 189. (b) Barbour, L.
J. X-Seed, Graphical Interface to SHELX-97 and POV-Ray; University of
Missouri−Columbia: Columbus, MO, 1999.
(50) Higuchi, T.; Connors, K. A. Adv. Anal. Chem. Instrum. 1965, 4,
117.
1601
dx.doi.org/10.1021/cg301825u | Cryst. Growth Des. 2013, 13, 1590−1601