High Solubility Piperazine Salts of the Nonsteroidal Anti-Inflammatory Drug (NSAID) Meclofenamic Acid

Abstract

Meclofenamic acid (MFA) is the most potent antiinflammatory
drug among the fenamic acids. We report (1) two
cocrystals of MFA with isonicotinamide (INA) and 4,4′-bipyridine
(BPY); (2) polymorphs of MFA and piperazine (PPZ) 1:1 salt
(orthorhombic P212121 O and monoclinic P21/c M), MFA−PPZ−
H2O 1:1:1 salt hydrate, MFA−PPZ 2:1 salt; and (3) MFA and 2-
aminopyridine (2-APY) 1:1 salt, MFA and 4-aminopyridine (4-APY)
1:1:1 salt hydrate. Sublimation of MFA gave single crystals for X-ray
diffraction which provided good quality data for refinement and all
atomic coordinates. The cocrystal and salt structures are assembled via
neutral O−H···O, O−H···N, N−H···O, N−H···N, and ionic O−
H···O−, N+−H···O− hydrogen bonds. The disorder of the methyl group in the MFA crystal structure is absent in the cocrystal
and salt structures, which contain different conformers (A or B) of methyl group orientation. The solubility of MFA−INA (1:1)
and MFA−BPY (1:0.5) cocrystals is 2.9 and 7.6 times higher than that of MFA at 37 °C in 50% EtOH−water. Interestingly,
MFA−PPZ-M 1:1 salt and its 1:1:1 hydrate are 2724- and 1334-fold more soluble than MFA. Both of these salts transformed in
50% EtOH−water slurry at 37 °C to MFA−PPZ 2:1 salt after 24 h, which in turn transformed to MFA after another 24 h
of slurry stirring. Remarkably, the dissolution rate of MFA−PPZ-M (1:1) salt in water is just slightly lower than that of the
marketed sodium meclofenamate.

Full text

High Solubility Piperazine Salts of the Nonsteroidal
Anti-Inflammatory Drug (NSAID) Meclofenamic Acid
Palash Sanphui, Geetha Bolla, and Ashwini Nangia*
School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Central University P.O., Hyderabad 500046, India
*
SSupporting Information
ABSTRACT: Meclofenamic acid (MFA) is the most potent anti-
inflammatory drug among the fenamic acids. We report (1) two
cocrystals of MFA with isonicotinamide (INA) and 4,4′-bipyridine
(BPY); (2) polymorphs of MFA and piperazine (PPZ) 1:1 salt
(orthorhombic P212121O and monoclinic P21/cM), MFA−PPZ−
H2O 1:1:1 salt hydrate, MFA−PPZ 2:1 salt; and (3) MFA and 2-
aminopyridine (2-APY) 1:1 salt, MFA and 4-aminopyridine (4-APY)
1:1:1 salt hydrate. Sublimation of MFA gave single crystals for X-ray
diffraction which provided good quality data for refinement and all
atomic coordinates. The cocrystal and salt structures are assembled via
neutral O−H···O, O−H···N, N−H···O, N−H···N, and ionic O−
H···O−,N
+−H···O−hydrogen bonds. The disorder of the methyl group in the MFA crystal structure is absent in the cocrystal
and salt structures, which contain different conformers (A or B) of methyl group orientation. The solubility of MFA−INA (1:1)
and MFA−BPY (1:0.5) cocrystals is 2.9 and 7.6 times higher than that of MFA at 37 °C in 50% EtOH−water. Interestingly,
MFA−PPZ-M 1:1 salt and its 1:1:1 hydrate are 2724- and 1334-fold more soluble than MFA. Both of these salts transformed in
50% EtOH−water slurry at 37 °C to MFA−PPZ 2:1 salt after 24 h, which in turn transformed to MFA after another 24 h
of slurry stirring. Remarkably, the dissolution rate of MFA−PPZ-M (1:1) salt in water is just slightly lower than that of the
marketed sodium meclofenamate.
■INTRODUCTION
About 40% of new molecular entities coming out of the drug
discovery pipeline will never advance in the development chain
because of biopharmaceutical issues, such as poor aqueous
solubility, low dissolution rate, low permeability, and first-pass
metabolism in the liver. An enhancement of drug solubility for
therapeutic agents can improve their bioavailability. Identifying
the optimum solid form of an active pharmaceutical ingredient
(API) is always desirable for clinical use.
1
Over 80% of all drugs
are marketed as tablets, and oral administration is the most
preferred drug delivery route. Different solid-state forms, such
as polymorphs, amorphous, cocrystals, salts, and their hydrates,
can be crystallized to improve physicochemical properties of
drug substances. Crystal engineering is particularly well suited
to cocrystallization of drugs with safe coformers.
2
The advan-
tage of cocrystals and salts for improving physical properties
such as solubility, bioavailability, stability, etc.
3
is that the struc-
ture of the drug molecule is unchanged but the modification
is at the supramolecular level (intermolecular interactions,
hydrogen bonding, molecular packing). A practical advantage is
that the extent of solubility enhancement for cocrystals (4−20
times) is an order of magnitude higher than that for poly-
morphs (2−3 times). Pharmaceutical salts of course are the
most preferred formulation for solubility enhancement (100−
1000 times).
4
On the downside, salts are more likely to form
hydrates (often a drawback in terms of stability) compared to
cocrystals. The ΔpKarule, wherein ΔpKa=pKa(conjugate acid
of base) −pKa(acid), is a useful guide to know beforehand if
an acid−base complex will give a neutral cocrystal (ΔpKa<3)
or an ionic salt (ΔpKa> 3). A more practical cutoff for organic
salts is ΔpKa< 0 for cocrystal, ΔpKa> 3 for salts, and the range
0<ΔpKa< 3 being an unpredictable zone wherein multiple
proton states could be observed.
5
Meclofenamic acid (MFA)
6
(Figure 1) is a nonsteroidal anti-
inflammatory, antipyretic, analgesic drug used in the treatment
of postoperative and traumatic inflammation and swelling
by the inhibition of prostaglandin biosynthesis pathway.
6a
It is
a selective cyclo-oxygenase-2 (COX-2) inhibitor.
6b
Similar to
Received: January 2, 2012
Revised: February 17, 2012
Published: February 24, 2012
Figure 1. Two conformers (A and B) of meclofenamic acid (MFA)
present in crystal structures.
Article
pubs.acs.org/crystal
© 2012 American Chemical Society 2023 dx.doi.org/10.1021/cg300002p |Cryst. Growth Des. 2012, 12, 2023−2036

diclofenac, MFA is also used as a KCNQ2/Q3 potassium
channel opener, depressor of cortical neuron activity, and
exhibits anticonvulsant activity.
6e
MFA also has a transient
effect on platelet aggregation, but unlike aspirin, it does not
cause bleeding.
6h
It is a BCS class II drug of low solubility
(30 mg/L) and high permeability (log Pow = 5).
7
Novel gel and
cream formulations of MFA provide maximal topical activity to
the drug.
6e
Exposure of dilute solutions of MFA to visible
or UV light resulted in fairly rapid decomposition.
6f
Because of
its low aqueous solubility
7
and thus bioavailability, the sodium
salt of MFA (solubility > 250 g/L)
7b
is sold commercially as
100 mg capsules under brand names Meclomen, Melvon,
Movens, and Arquel. Fábián et al.
8
recently published cocrystals
of flufenamic acid, niflumic acid, tolfenamic acid, and
mefenamic acid with nicotinamide, but they mentioned some
difficulty with MFA. Our results on cocrystals and salts of MFA
demonstrate that organic salts of APIs can exhibit comparable
dissolution rates to traditional metal ion salts. The novel
cocrystals and salts of MFA with isonicotinamide (INA), 4,4′-
bipyridine, piperazine, aminopyridine, etc. were prepared by
solvent-assisted grinding, and their solubility was measured in a
USP dissolution tester. Crystal structures, phase transforma-
tions, and solubility of MFA cocrystals and salts are discussed.
■RESULTS AND DISCUSSION
The sodium salt of MFA was obtained from Sigma-Aldrich,
India, and converted to the free acid with aq. HCl. The Na salt
of MFA is readily soluble in water. Vijayan et al.
9
(1981)
published the first crystal structure of MFA but it had a high R-
factor of 0.135. The same authors reported crystal structure of
the 1:1 complex of MFA with choline hydrate and ethanol-
amine.
10
The disorder in the methyl group orientation of MFA
(Figure 1) persisted at low temperature. We have now obtained
good quality single crystals of MFA by sublimation and col-
lected data at 298 and 100 K. There are no reports on crystal
structures of MFA and its salt/cocrystal in the interim period.
Crystallographic parameters for all crystal structures are listed
in Table 1. ORTEP diagrams are displayed in Figure S1,
Supporting Information.
■CRYSTAL STRUCTURE DESCRIPTION
Meclofenamic Acid (MFA). MFA consists of two aryl
moieties, the N-2,6-dichloro-3-methylphenyl group and the N-
2-benzoic acid group. The aryl rings are twisted almost in a
perpendicular orientation of an 82°dihedral angle between the
two ring planes. This twist relieves steric congestion of ortho-
substituted phenyls at the secondary amine. MFA was crys-
tallized by slow sublimation at 190−200 °C over 4−5hto
afford diffraction quality single crystals which was solved in the
triclinic space group P1̅with one molecule in the asymmetric
unit. Similar to other fenamic acids, for example, mefenamic
acid and tolfenamic acid,
11
two MFA molecules form a centro-
symmetric carboxylic acid dimer of O−H···O hydrogen bond
(O···O, 2.632(4) Å) in the R22(8) ring motif.
12
An intra-
molecular N−H···O hydrogen bond (N···O, 2.679(4) Å) of
R11(6) ring motif (Figure 2) rigidifies the molecule. Hydrogen
bond parameters in crystal structures are listed in Table 2.
The 3-methyl group is disordered over two positions with un-
equal site occupancy factor (sof conformer B= 0.58(1) and
A= 0.42(1); see Figure 1) at 298 K (RT structure). X-ray reflec-
tions for MFA crystal were collected at 100 K (LT structure)
in an attempt to resolve the disorder issue (R-factor 0.110).
The disorder of the Me group persisted, now with sof of
conformer B= 0.577(15) and A= 0.423(15). The elongated
thermal ellipsoid of Cl2 (chlorine atom 2) perpendicular to the
aromatic plane in the RT structure could be modeled as Cl2A
and Cl2B (chlorine 2A and 2B) with sof of 0.55(3) and 0.45(3)
in the LT structure. The RT structure of MFA is described in
this paper because it has better refinement parameters and
lower R-factor (0.083).
Meclofenamic Acid−Isonicotinamide Cocrystal (1:1,
MFA−INA). MFA−INA (1:1) cocrystal was prepared by solid-
state grinding, and the resulting solid was crystallized from aceto-
nitrile to afford the single crystal X-ray structure in monoclinic
space group P21/c, which contained conformer A of MFA. The
carboxylic acid dimer in the reference drug crystal structure is
replaced by carboxylic acid−pyridine heterosynthon (O···N,
2.657(4) Å, ∠O−H···N, 174°) as the main bimolecular R22(7)
ring motif (Figure 3a). Different synthons present in the novel
solid phases are displayed in Scheme 1. INA molecules aggre-
gate via the carboxamide dimer (N···O, 2.926(4) Å, ∠N−H···O,
169°) at the secondary level. Such 4-molecule supra-
molecular units are connected via C−Cl···Ointeraction(3.25Å)
in a ladder motif along the b-axis (Figure 3b).
Meclofenamic Acid−4,4′-Bipyiridine Cocrystal (1:0.5,
MFA−BPY). MFA−BPY (1:0.5) cocrystal (crystallized from
acetonitrile) was solved in monoclinic space group P21/cand
contains MFA conformer A. The acid−pyridine heterosynthon
(O···N, 2.668(4) Å, ∠O−H···N, 178°;R
22(7) ring motif) is
supported by an auxiliary C−H···O hydrogen bond (C···O,
3.194(6) Å) between the pyridine ortho C−H to the carbonyl
of carboxylic acid (Figure 4a). The trimolecular units in the
cocrystal make a stepladder motif along the c-axis (Figure 4b).
MFA−BPY (1:1) is a cocrystal based on C−O bond distances
of 1.215(8) Å and 1.316(7) Å in the carboxylic acid group and
∠C−N−C bond angle of 115.7(5)°in the pyridine ring.
Piperazinium Meclofenamate Salt Polymorphs (1:1,
MFA−PPZ-M and MFA−PPZ-O). Piperazinium meclofena-
mate salt (1:1) crystallized as monoclinic (P21/c) and ortho-
rhombic (P212121) polymorphs concomitantly from acetonitrile
solvent. There is one molecule each of meclofenamate anion
(conformer B) and piperazinium cation in the asymmetric unit.
Compared to the cocrystal, proton transfer occurred in the salt
structure from carboxylic acid to the N−H base of piperazine.
In the monoclinic structure (MFA−PPZ-M), each piperazine
molecule forms four hydrogen bonds with two meclofenamates
and two piperazinium cations through ionic N+−H···O−
(N···O, 2.677(4) Å) and neutral N−H···N(N···N, 2.851(4) Å)
and N−H···O(N···O, 2.949(4) Å) hydrogen bonds (Figure 5a).
The carboxylate C−O bond distances are 1.236(4) Å and
1.271(4) Å and piperazinium ∠C−N−C is 112.0(3)°suggest-
ing an ionized species. The C−O bond distances difference
(ΔCO) is less than 0.1 Å compared to the neutral species.
The packing of meclofenamate anions (conformer A) and
piperazinium cations is similar in the orthorhombic poly-
morph (MFA−PPZ-O). Each piperazine molecule forms
four hydrogen bonds with two meclofenamate anions and
two piperazinium cations through N+−H···O−(2.698(3) Å),
N−H···N (2.858 (3) Å), and N−H···O (2.960 (3) Å) hy-
drogen bonds (Figure 5b). C−O bond distances (1.226(6) Å,
1.263(5) Å) and ∠C−N−C angle (111.8(3)°) are consistent
with a salt species.
5
In both polymorphs, six piperazine cations
are sandwiched between three meclofenamate anions along the
c-axis. A minor difference between the two polymorphs is
the orientation of the methyl group in MFA, that is, conformer
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A or B. Piperazine is a small cyclic diamine that is pharma-
ceutically acceptable and has anthelmintic activity.
13
Piperazine
(pKa= 9.72) can act both as a neutral and a cationic co-
former to give a cocrystal or salt product with an acidic API.
The Cambridge Structural Database (CSD ver. 5.32, 2010,
November 2011 update)
14
contains about 20 organic cocrystals
and 25 salts or salt hydrates of piperazine (Table S1, Supporting
Information). Surprisingly, there is only one piperazinium
Table 1. Crystallographic Parameters of MFA and Its Cocrystals and Salts
MFA-100K MFA-RT MFA−INA (1:1) MFA−BPY (1:0.5) MFA−PPZ-M (1:1)
empirical formula C14H10Cl2NO2C14H10Cl2NO2C14H11Cl2NO2·C6H6N2OC
14H11Cl2·0.5(C10H8N2)C
14H10Cl2NO2·C4H11N2
formula weight 295.13 295.13 418.27 374.23 382.28
crystal system triclinic triclinic monoclinic monoclinic monoclinic
space group P1̅P1̅P21/cP21/cP21/c
T(K) 100 298 298 298 298
a(Å) 8.5209(11) 8.566(3) 7.5327(13) 7.4180(6) 16.3805(13)
b(Å) 8.8775(11) 8.968(3) 31.313(5) 8.2144(6) 8.3717(5)
c(Å) 9.1986(12) 9.378(3) 9.601(3) 28.770(2) 14.4609(11)
α(°) 104.265(2) 103.090(6) 90 90 90
β(°) 103.337(2) 103.194(6) 121.439(16) 97.099(7) 102.347(8)
γ(°) 91.569(2) 92.538(6) 90 90 90
V(Å3) 653.56(14) 679.7(4) 1932.2(7) 1739.6(2) 1934.8(3)
Dcalcd (g cm−3) 1.500 1.442 1.438 1.429 1.312
μ(mm−1) 0.492 0.473 0.363 0.388 0.351
θrange 2.36−25.89 2.47−25.77 2.59−29.03 2.75−29.10 2.74−26.31
Z224 4 4
range h−9to+9 −9to+9 −9to+9 −8to+8 −20 to +20
range k−10 to +10 −10 to +10 −39 to +39 −9to+9 −10 to +10
range l−10 to +10 −10 to +10 −11 to +12 −31 to +31 −18 to +18
reflections collected 5863 6239 9616 8621 8452
total reflections 2153 2227 3944 2487 3956
observed reflections 1954 1698 1932 1726 1574
R1[I>2σ(I)] 0.1106 0.0833 0.0567 0.0892 0.0641
wR2(all) 0.2193 0.1910 0.1547 0.2088 0.1850
goodness-of-fit 1.209 1.122 0.915 1.127 0.933
diffractometer SMART BRUKER SMART BRUKER Oxford CCD Oxford CCD Oxford CCD
MFA−PPZ- O (1:1) MFA−PPZ (2:1) MFA−PPZ−H2O (1:1:1) MFA−2-APY (1:1) MFA−4-APY−H2O (1:1:1)
empirical formula C14H10Cl2NO2·C4H11N22(C14H10Cl2NO2)·C4H12N2C14H10Cl2NO2·C4H11N2·H2OC
14H10Cl2NO2·C5H7N2C14H10Cl2NO2·C5H7N2·H2O
formula weight 382.28 678.42 400.29 390.26 408.27
crystal system orthothombic triclinic monoclinic monoclinic monoclinic
space group P212121P1̅P21/cP21/nP21/c
T(K) 298 298 298 298 298
a(Å) 7.929(3) 7.9109(3) 16.137(4) 14.675(4) 16.227(4)
b(Å) 8.168(3) 11.1289(4) 8.4889(15) 7.1318(15) 8.4770(15)
c(Å) 28.381(15) 18.1180(7) 15.596(3) 18.605(6) 15.686(4)
α(°) 90 81.943(3) 90 90 90
β(°) 90 80.424(4) 114.94(3) 110.73(3) 116.18(3)
γ(°) 90 88.809(3) 90 90 90
V(Å3) 1838.1(13) 1557.36(11) 1937.1(7) 1821.2(8) 1936.2(7)
Dcalcd (g cm−3) 1.381 1.447 1.373 1.423 1.401
μ(mm−1) 0.370 0.425 0.358 0.375 0.360
θrange 2.86−26.31 2.74−26.31 2.77−24.71 2.77−29.22 2.78−26.37
Z42 4 4 4
range h−9to+9 −9to+9 −18 to +18 −18 to +18 −20 to +20
range k−10 to +10 −13 to +13 −9to+9 −8to+8 −10 to +10
range l−35 to +35 −22 to +22 −18 to +18 −23 to +23 −19 to +19
reflections
collected 5203 12514 6934 7324 8218
total reflections 3366 6346 3283 3721 3958
observed
reflections 1540 3882 1942 2081 2641
R1[I>2σ(I)] 0.0597 0.0687 0.0868 0.0459 0.0609
wR2(all) 0.0663 0.1770 0.2540 0. 1228 0.1608
goodness-of-fit 0.865 1.030 1.046 0.919 1.038
diffractometer Oxford CCD Oxford CCD Oxford CCD Oxford CCD Oxford CCD
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monocation (Refcode CUKVOU) listed with a carboxylate
counterion up to the recent update of the CSD; there are
73 refcodes for piperazinium dication (Table S2, Supporting
Information). We report three piperazinium monocations with
meclofenamate anion in MFA−PPZ-M, MFA−PPZ-O, and
MFA−PPZ−H2O crystal structures. Furthermore, there are no
examples of piperazine salts which are polymorphic. MFA−PPZ
(1:1) is the first example of piperazine salt polymorphs with 3D
coordinates determined. Crystal density (1.312, 1.381 g cm−3),
packing fraction (64.2, 68.0%, calculated in Platon), and lattice
energy (−176.93, −186.39 kcal mol−1, calculated using Com-
pass force field in Cerius2)
15
of monoclinic and orthorhombic
polymorphs suggest that the orthorhombic form should be
Table 2. Hydrogen Bonds in Crystal Structures (Neutron-Normalized Distances)
crystal forms interaction H···A (Å) D···A (Å) ∠D−H···A(°) symmetry code
MFA N1−H1··· O1 1.95 2.679 (4) 126 intramolecular
O2−H2··· O1 1.66 2.632 (4) 171 1 −x,2−y,−z
MFA−INA N1−H1··· O1 1.83 2.653(4) 137 intramolecular
O2−H2··· N3 1.68 2.657(4) 174 x,y,−1+z
N2−H2A··· O3 1.93 2.926(4) 169 1 −x,−y,1−z
MFA−BPY N1−H1··· O1 1.84 2.640(4) 133 intramolecular
O2−H2··· N2 1.69 2.668(4) 178 x,−1+y,z
C15−H15···O1 2.41 3.194(4) 129 x,1+y,z
MFA−PPZ-M N1−H1··· O1 1.75 2.604(4) 140 intramolecular
N2−H2··· O1 1.68 2.677(4) 171 x, 1/2 −y,1/2 + z
N2−H2··· O2 2.53 3.231(4) 126 x,1/2 −y,1/2 + z
N2−H2A··· N3 1.89 2.851(4) 159 −x,−1/2 + y,1/2 −z
N3−H3A··· O2 1.99 2.949(4) 157 x, 3/2 −y, 1/2 + z
MFA−PPZ-O N1−H1··· O1 1.79 2.619(3) 137 intramolecular
N2−H2··· O1 1.71 2.698(3) 164 1 −x, 1/2 + y, 1/2 −z
N2−H2··· O2 2.48 3.246(3) 133 1 −x, 1/2 + y, 1/2 −z
N2−H2A··· N3 1.85 2.858(3) 178 1/2 + x, 1/2 −y,−z
N3−H3A··· O2 1.97 2.960(3) 165 −x, 1/2 + y, 1/2 −z
C6−H6··· Cl1 2.71 3.201(4) 107 intramolecular
MFA−PPZ (2:1) N1−H1··· O1 2.05 2.682 (3) 119 intramolecular
N2−H2··· O3 1.99 2.642 (3) 120 intramolecular
N3−H3A··· O1 1.70 2.690(3) 164 1 −x,1−y,1−z
N3−H3B··· O4 1.74 2.731(3) 167 1 −x,−y,1−z
N4−H4A··· O2 1.77 2.750(3) 162 −1+x,y,z
N4−H4B··· O3 1.72 2.695(3) 162 1 −x,1−y,1−z
C29−H29B···O3 2.49 3.318(3) 132 1 −x,1−y,1−z
C32−H32B···Cl3 2.67 3.446(3) 128 1 −x,1−y,1−z
MFA−PPZ−H2ON1−H1···O1 1.91 2.699(3) 133 intramolecular
N3−H1A···N2 1.99 2.939(4) 155 1 −x, 1/2 + y, 1/2 −z
N3−H1B···O1 1.90 2.842(4) 154 x, 1/2 −y,−1/2 + z
N2−H2···O3 2.10 3.029(4) 152 1 −x,−1/2+ y, 1/2 −z
O3−H3A···O1 1.87 2.796(4) 155 x,y,z
O3−H3B···O2 1.72 2.692(4) 170 1 −x,−y,1−z
C16−H16B···O2 2.43 3.488(4) 167 1 −x,−y,1−z
C17−H17B···O3 2.35 3.356(4) 155 1 −x, 1/2 + y, 1/2 −z
C3−H3···Cl1 2.67 3.607(4) 145 x,−1/2 −y, 1/2 + z
MFA−2-APY N1−H1···O1 1.88 2.631(3) 128 intramolecular
N2−H2···O1 1.64 2.642(3) 175 1 −x,−y,−z
N3−H3A···O2 1.84 2.841(3) 173 1 −x,−y,−z
N3−H3B···O2 1.92 2.897(3) 164 −1/2 + x, 1/2 −y, 1/2 + z
MFA−4-APY−H2ON1−H1···O2 1.79 2.603(4) 135 intramolecular
N2−H2···O3 1.92 2.837(4) 149 x, 1/2 −y, 1/2 + z
N3−H3A···O1 2.07 3.017(4) 156 1 −x, 1/2 + y, 1/2 −z
N3−H3B···O3 2.00 2.993(4) 169 x, 3/2 −y, 1/2 + z
O3−H3C···O1 1.78 2.761(4) 173 x, 1/2 −y,−1/2 + z
O3−H3D···O2 1.75 2.713(4) 166 1 −x,−1/2 + y, 1/2 −z
C17−H17···O1 2.48 3.301(4) 131 1 −x,1−y,1−z
Figure 2. Centrosymmetric carboxylic acid dimer in MFA. The methyl
group is disordered in the crystal structure of MFA with sof 0.58(1)
and 0.42(1).
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more stable. However, differential scanning calorimetry (DSC)
measurements (discussed later) indicate that the melting point
of the monoclinic form is higher and we show that MFA−PPZ-M
is the stable polymorph.
Piperazinium Meclofenamate Salt (2:1, MFA−PPZ).
Piperazinium meclofenamate salt (2:1) was obtained when the
components were ground with a few drops of EtOH added.
The crystal structure of MFA−PPZ (2:1) was solved in P1̅space
group with two crystallographic meclofenamate anions (conformer
A and B) and two half piperazinium cations in the asymmetric
unit. The two conformers of MFA are arranged in an alternate
fashion ABAB parallel to the b-axis, and piperazinium cations are
sandwiched between the anion layers. Each piperazinium dication
forms four N+−H···O−ionic hydrogen bonds (N3+−H3A···
O1−, 2.690(3) Å; N3+−H3B···O4−, 2.731(3) Å; N4+−H4A···
O2−, 2.750(3) Å and N4+−H4B···O3−, 2.695(3) Å with
meclofenamate anions A and B (shown in thick bond and ball
and stick models, Figure 6). This is the only crystal structure of
MFA salts with both conformers A and B in the same lattice.
Piperazinium Meclofenamate Salt Hydrate (1:1:1,
MFA−PPZ−H2O). Piperazinium meclofenamate salt hydrate
(1:1:1) was obtained during grinding of MFA with piperazine
hydrate or MFA and piperazine in the presence of water.
It crystallized in the monoclinic space group P21/cwith conformer B.
Two meclofenamate anions and two water molecules form ring
motifofgraphsetnotationR
44(12). Water molecules
are present as spacers between two meclofenamates. Two
piperazinium cations form N+−H···O hydrogen bonds (N2+−
H2···O3, 3.029(4) Å) with water (Figure 7a). The N−H···N/O
hydrogen bond network (N3+−H1B···O1−,2.842(4)Å,N3
+−
H1A···N2, 2.939(4) Å) is shown in Figure 7b. Water molecules
reside in channels along the c-axis (Figure 7c). Thermogravimetric
analysis (TGA) (Figure S2, Supporting Information) confirmed
Scheme 1. Different Hydrogen Bond Synthons in Crystal Structures
a
a
(1) Acid−acid dimer R22(8), (2) acid−pyridine R22(7) ring motif, (3) carboxylate−aminopyridinium R22(8) ring motif, (4) carboxylate−
piperazinium−carboxylate salt, (5) carboxylate−piperazinium salt, (6) carboxylate−water tetramer R44(12) ring motif.
Figure 3. (a) Acid−pyridine heterosynthon in MFA−INA (1:1)
cocrystal. (b) Acid−pyridine heterosynthon, amide dimer homosyn-
thon, and C−Cl···O interaction along the b-axis in crystal structure.
Figure 4. (a) Acid−pyridine heterosynthon form termolecular unit in
MFA−BPY (1:0.5) cocrystal structure. (b) Ladder structure along the
c-axis.
Figure 5. Crystal packing in (a) monoclinic form of MFA−PPZ-M
(1:1) viewed along the b-axis, and (b) orthorhombic polymorph
MFA−PPZ-O (1:1) along the a-axis. The main difference is in the
orientation of Me group in MFA, that is, conformer B (in M) and A
(in O).
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the stoichiometry as a monohydrate (calc. 4.68%, obsd. 4.71%).
A mefenamic acid piperazine salt hydrate (2:1:4) was recently
reported,
16
but its crystal structure is completely different
from our results because of hydrogen bonding to four water
molecules.
2-Aminopyridinium Meclofenamate Salt (1:1, MFA−2-
APY). The organic cation and anion form R22(8) ring motif
(Scheme 1) between amino-pyridinium and carboxylate via
N−H···O bonds (N···O, 2.642(3) Å, 2.841(3) Å). Such dimer
units are connected via amino N−H···O(N···O 2.897(3) Å)
hydrogen bond (Figure 8a). The molecular packing extends via
Cl···Cl type I interaction
17
(3.472(2) Å, θ1=θ2= 135.8°) and
C−H···Cl interaction (H···Cl, 2.92(3) Å) in a zigzag chain
along the b-axis (Figure 8b). Carboxylate C−O bond distances
(1.252(3), 1.263(3) Å) and pyridinium ∠C−N−C bond angle
(121.7(2)°) are consistent with a salt structure.
4-Aminopyridinium Meclofenamate Salt Hydrate
(1:1:1, MFA−4-APY−H2O). Proton transfer occurred from
MFA to pyridine base in this salt hydrate. The expected
carboxylate−pyridinium R22(7) ring motif is absent presumably
due to stronger H bonds of carboxylate with water molecules.
Two water molecules now make a dimeric R44(12) ring motif
12
capped with two carboxylates (Scheme 1) through O−H···O−
(O···O, 2.761(4) Å, 2.713(4) Å) hydrogen bonds. The 4-APY
cation interacts with two water molecules through both ion-
ic N+−H···O(N···O, 2.837(4) Å) (Figure 9a) and neutral
N−H···O(N···O, 2.993 (4) Å) and one meclofenamate ion
through N−H···O−(N···O, 3.018 (4) Å) hydrogen bonds
(Figure 9b). Water molecules are strongly hydrogen bonded in
channels formed by MFA and 4-APY ions along the c-axis
(Figure 9c). Carboxylate nature (C−O1.261,1.266Åand∠C−
N−C121.1°) and water stoichiometry by TGA (Figure S2,
Supporting Information) were confirmed (calc 4.40%, obsd.
4.40%) in the monohydrate salt. Hydrogen bonding and unit cell
parameters similarity of MFA−PPZ−H2O and MFA−4-APY−
H2O (1:1:1) suggest 2D isostructurality and isomorphism, but
there are differences in the 3D packing (Figure 7c vs 9c).
The conformation of MFA is different in crystal structures
(Table 3). Both conformers A and B are well distributed
in cocrystals/salts. A small contribution from an alternate con-
formation could be detected in a few cases (e.g., MFA−INA
cocrystal) by the unassigned difference electron density (Q
peaks of about 0.5−0.7 electron), but it was difficult to refine
it as Me group occupancy. The small amount of Me group
disorder in these structures is difficult to model accurately. The
intramolecular N−H···O hydrogen bond locks the anthranilic
acid fragment in a planar conformation, while the phenyl ring
bearing the Cl and Me groups can rotate around the N−C
bond. The formation of cocrystal or salt followed the ΔpKa
rule,
5
that is, ΔpKa> 3 gives salt, ΔpKa< 0 is for cocrystal, and
the region 0 < ΔpKa< 3 is a difficult to predict zone. The pKa
’s
(calculated using SPARC calculator in water medium) are listed
in Table 4. The acid−acid dimer of MFA crystal structure is
replaced by acid−pyridine heterosynthon in MFA−INA and
MFA−BPY. Charge assisted N+−H···O−hydrogen bonds
reproducibly give salts of MFA and piperazine/aminopyridine
base. The N base inserts between the carboxylic acid groups to
replace the carboxylic acid O−H···O homosynthon with the
pyridinium/piperazinum−carboxylate charge assisted N+−H···O−
Figure 6. Two crystallographic molecules of meclofenamate (A = thick
bond, B = ball-stick) and two half molecules of piperazine cations form
N+−H···O−hydrogen bonds in the 2:1 salt of MFA−PPZ.
Figure 7. (a) Tetramer R44(12) ring motif between two meclofenamate anions and two water molecules in MFA−PPZ−H2O (b) A piperazinium
cation is surrounded by two similar cations, one water molecule, and one meclofenamate anion. (c) Water molecules are present in channels along
the c-axis.
Figure 8. (a) Pyridine (NH+)···−OOC synthon in MFA−2-APY
(conformer B of drug). (b) Cl···Cl and C−H···Cl interactions connect
the molecules in a 1D wavelike chain.
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heterosynthon. This strong heterosynthon in MFA salts/
cocrystals is a reliable tool for crystal engineering.
Powder X-ray Diffraction. Powder X-ray diffraction
(PXRD)
18
is a reliable characterization technique to establish
the formation of new solid materials. Rapid “fingerprinting”of
the product phase (cocrystal/salt) compared to characteristic
peaks in the starting materials (drug, coformer) is possible
by eye-balling of the line patterns. PXRD of new materials
prepared in this work (Figure S3, Supporting Information)
confirms the purity and homogeneity of each crystalline phase
by an excellent overlay of the experimental PXRD with the
calculated lines from the crystal structure. Calculated PXRD
line patterns of MFA−PPZ-M and MFA−PPZ-O salt poly-
morphs (prepared in mixed state) are compared in Figure S4,
Supporting Information.
Thermal Analysis. A change in the melting point of
cocrystal/salt in the DSC thermogram is usually indicative of
a new phase. Any dissociation/decomposition and/or phase
changes upon heating are indicated by endo-/exotherm in the
DSC trace. The monoclinic and orthorhombic polymorphs of
MFA−PPZ (1:1) melt at 162.6 and 145.8 °C suggesting that
the high melting monoclinic form is more stable (Figure 10).
The metastable orthorhombic form could not be reproduced in
bulk scale purity. The DSC of polymorphic mixture (O + M)
and pure monoclinic form are shown to compare their thermal
behavior. Melting points are listed in Table 5. Dehydration of
MFA−PPZ−H2O resulted in an anhydrate that matched with
the stable monoclinic form (MFA−PPZ-M). The dissociation
of the cocrystal/salt to MFA above 240 °C is indicated by
the broad endotherm after melting (see Figure S5, Supporting
Figure 9. (a) Two meclofenamate anions (conformer A) and two water molecules form R44(12) ring through O−H···O−hydrogen bond in MFA−
4-APY−H2O. (b) 4-Aminopyridinium cation interacts with one meclofenamate anion and two water molecules through N−H···O−and N+−H···O
hydrogen bonds. (c) Water molecules reside in channels formed along the c-axis.
Table 3. Torsion Angles (°) in MFA Crystal Structures
∠C2−C7−N1−C8
(deg)
∠C7−N1−C8−C9
(deg)
∠C7−N1−C8−C13
(deg)
∠C7−C2−C1−O1
(deg)
∠C7−C2−C1−O2
(deg) conformer of MFA
in crystal structure
MFA 173.46(2) 92.72(3) 86.44(3) 1.54(4) 177.71(2) disorder
MFA−INA 163.21(2) 99.01(2) 81.84(2) 4.52(3) 174.63(2) A
MFA−BPY 172.84(1) 86.50(1) 93.76(1) 3.71(2) 175.45(1) A
MFA−PPZ-M 165.93(1) 98.87(1) 83.43(2) 4.20(2) 176.64(1) B
MFA−PPZ-O 167.98(3) 66.12(4) 115.44(3) 0.16(4) 179.45(2) A
MFA−PPZ 157.82(1), 161.44(1) 98.31(1), 84.42(1) 84.52(1), 95.47(1) 6.28(1), 14.42(1) 171.35(1), 165.67(1) A + B
MFA−PPZ−H2O 167.43(2) 108.04(3) 74.59(3) 8.59(3) 173.55(2) B
MFA−2-APY 177.91(7) 71.22(11) 111.85(9) 6.49(11) 174.43(7) B
MFA−4-APY−H2O 171.60(4) 84.65(5) 98.50(5) 5.55(6) 176.02(4) A
Table 4. Coformers Attempted to Make Cocrystal/Salts with
MFA and ΔpKaValues
a
pKa/pKb(water) ΔpKacocrystal/salt
meclofenamic acid 4.56
isonicotinamide 4.17 0.39 1:1 cocrystal
4,4′-bipyridine 4.61 0.05 1:0.5 cocrystal
piperazine 9.72 5.16 1:1 salt polymorphs
piperazine 9.72 5.16 1:1:1 salt hydrate
piperazine 9.72 5.16 2:1 salt
2-amino pyridine 6.68 2.12 1:1 salt
4-amino pyridine 8.59 4.03 1:1:1 salt hydrate
a
pKa
’s were calculated in water using SPARC pKacalculator, http://
archemcalc.com/sparc/test/login.cfm?CFID=11677&CFTOKEN=
94786654.
Figure 10. DSC endotherm comparisons for MFA−PPZ (1:1) salt
polymorphs monoclinic (M) and orthorhombic (O).
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Information). The dissociation of salts/cocrystals to MFA is
similar to that for Diclofenac.
21e
FT-IR and FT-Raman Spectroscopy. Spectroscopic
analysis (IR and Raman)
19
showed clear differences in hydrogen
bonding of salt/cocrystal compared to the pure components.
Such peak shifts are useful to know specific functional groups
which are involved in intermolecular interactions. Generally
speaking, for fenamic acids,
19b
NH stretch appears at 3300−
3350 cm−1. The band at about 3335 cm−1arises from the
amino group internally hydrogen bonded to the CO of MFA.
Carboxylic acid CO stretch is normally at 1700−1720 cm−1,
but due to intramolecular hydrogen bonds in MFA the CO
stretch is red-shifted at 1655 cm−1. Bands due to C−O stretch
and O−H bend appear at 1256 cm−1and 1400 cm−1. The car-
boxylate anion in salts showed two bands, a strong asymmetric
stretch at 1650−1550 cm−1, and a weaker symmetric stretch
near 1450 cm−1. FT-IR and FT−Raman frequencies are sum-
marized in Tables 6 and 7.
Solid State NMR Spectroscopy. ss-NMR spectroscopy
20
of MFA−PPZ (1:1), MFA−PPZ monohydrate (1:1:1), and
MFA−PPZ (2:1) was informative about local short-range order
in these solid-state structures (Figure 11, Table S3). Two peaks
at δ18.34 and 20.06 ppm represent the methyl group of MFA
which is disordered over two positions. The chemical shifts in
the NMR spectra of MFA−PPZ-M (1:1) and MFA−PPZ−
H2O (1:1:1) salts are similar because the same conformer B of
MFA is present in both structures. There is an extra 13C peak in
MFA−PPZ (2:1) for piperazinium cation at δ37.33 ppm,
methyl carbon at 21.23 ppm, and carboxylate peak at δ175.07
ppm, consistent with the crystal structure which showed two
MFA conformers A and B and two nonequivalent piperazinium
cations. The downfield region peaks in the ss-NMR spectrum
of salts (COO−) are shifted relative to the free acid (COOH).
Solution Mediated Phase Transformations. Solution
mediated phase transformations
21
are common in pharmaceuti-
cals, that is, the transformation of one phase to another in a
suspension or slurry medium. Such phase changes can also
occur upon wet granulation and thus need to be monitored in
dosage formulation. 50% EtOH−water solvent was used be-
cause the drug and cocrystals/salts are soluble in this medium.
The same solvent system was used for solubility and dissolu-
tion experiments (discussed next). Piperazinium meclofenamate
(1:1) and (1:1:1) salt hydrate converted to piperazinium
meclofenamate (2:1) after 24 h slurry in 50% EtOH−water at
37 °C (Figures 12 and 13). The product 2:1 salt converted to
MFA after another 24 h in the same slurry medium (Figure 14).
Fini et al.
21e
reported 1:1 and 2:1 salts of diclofenac-pirperazine
while our work was in review. Their 1:1 salt transforms to the
less soluble 2:1 salt after one week in distilled water during
slurry experiments, similar to our results. We surmise that the
more soluble coformer piperazine dissociates from the salt in
the aqueous medium and the less soluble drug MFA preci-
pitates after 48 h. The dissociation of piperazine from the salt
occurs in stages: half equivalent in 24 h (1:1 to 2:1 salt),
and then another half equivalent in next 24 h (to give MFA)
as confirmed by PXRD of the solid residue. The stability of
Table 5. Melting Point of Cocrystal/Salt Compared with
MFA and Coformers
mp of MFA/
coformer (°C) mp of cocrystal/salt (°C)
(DSC, Tonset)
MFA 257−260
MFA−INA 155−158 176.8
MFA−BPY 110−114 207.1
MFA−PPZ-M 106−108 169.3
MFA−PPZ-O 106−108 144.4
MFA−PPZ−H2O 106−108 97.3, 163.3
MFA−PPZ 106−108 171.9
MFA−2-APY 57−60 145.6
MFA−4-APY−H2O 157−161 93.6, 111.7
Table 6. FT-IR Stretching Modes (νs,cm
−1) of MFA and Its Cocrystals/Salts
a
N−H stretch CO stretch N−H bend C−O stretch (asym) C−O stretch (sym)
MFA 3335.1 1655.4 1575.3 1437.4 1256.6
MFA−INA 3447.0, 3227.2 1694.8 1559.5 1449.5 1261.5
MFA−BPY 3245.9 1675.4 1600.4, 1581.4 1451.0 1259.7
MFA−PPZ-M 3216.9 1582.4 1452.9 1289.1
MFA−PPZ−H2O 3208.4, 3172.6 1576.4 1452.1 1282.5
MFA−PPZ 3497.3, 3267.0 1577.8 1452.5 1287.6
MFA−2-APY 3268.5, 3199.8 1577.7 1449.1, 1458.1 1288.1, 1255.0
MFA−4-APY−H2O 3436.7, 3346.2, 3301.2 1574.7 1455.2 1288.0
a
IR spectrum of MFA−PPZ-O salt could not be recorded due to insufficient sample and contamination from the stable monoclinic polymorph in the
bulk phase.
Table 7. FT-Raman Stretching Modes (νs,cm
−1) of MFA and Its Cocrystal/Salts
a
C−H stretch CO stretch N−H bend C−O stretch (asymm) C−O stretch (sym)
MFA 3079.6, 2925.2 1655.2 1577.5 1439.1 1242.3
MFA−INA 3071.4 1675.0 1602.1 1449.2 1243.2
MFA−BPY 3086.9, 3053.6 1663.2 1582.3 1450.8 1239.8
MFA−PPZ-M 3070.8, 2983.6 1580.1 1448.4 1271.6
MFA−PPZ−H2O 3079.2, 3002.6 1581.1 1450.2 1274.4
MFA−PPZ 3070.1, 2973.4 1582.5 1445.5 1281.0
MFA−2-APY 3073.5, 2924.5 1579.4 1448.4 1273.2
MFA−4-APY−H2O 3059.7, 2924.4 1573.7 1453.4 1267.1
a
Raman spectrum of MFA−PPZ-O salt could not be recorded due to insufficient sample and contamination from the stable monoclinic polymorph
in the bulk phase.
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Figure 12. PXRD comparison of MFA−PPZ-M (black) after 24 h slurry with the calculated X-ray lines of MFA−PPZ-M (red) and MFA−PPZ 2:1
salt (blue) in 50% EtOH−water medium. The monoclinic polymorph undergoes solvent mediated phase transformation from MFA−PPZ-M to
MFA−PPZ salt after 24 h.
Figure 11. Solid state 13C NMR spectra of MFA−PPZ-M (1:1, pink) and MFA−PPZ−H2O (1:1:1, green) and MFA−PPZ (2:1, yellow) salts along
with the pure components. The peaks in the salt are shifted relative to the pure components because of carboxylic acid to carboxylate in MFA. The
regions of main chemical shift differences are indicated in red line border.
Crystal Growth & Design Article
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variable stoichiometry salts in slurry medium may be related
to their hydrogen bonding in the crystal structures: the 1:1 salt
contains one N+−H···O−and one N−H···O hydrogen bond
between meclofenamate and piperazinium, whereas one meclo-
fenamate interacts with a dipiperazinium through two N+−
H···O−hydrogen bonds in the 2:1 salt. The stronger ionic
H bonds result in greater stability of the 2:1 salt over the 1:1
salt. MFA−PPZ monohydrate (1:1:1) showed similar results.
The cocrystals, on the other hand, were more stable to slurry
conditions: MFA−INA transformed to 86% MFA and 14%
cocrystal remained after 24 h, as confirmed by PXRD. A cali-
bration sample of 85% MFA and 15% cocrystal suggested that
the standard deviation of PXRD is ±3%. MFA−BPY cocrystal
was unusually stable for up to 72 h in 50% EtOH−water
medium (Figure S6, Supporting Information). These stability
trendsmaybeascribedtocongruentandincongruent
Figure 14. PXRD comparison of MFA−PPZ 2:1 (black) after 24 h slurry with the calculated X-ray lines of MFA−PPZ 2:1 (red) and MFA (blue) in
50% EtOH−water medium. MFA−PPZ 2:1 salt transforms to pure MFA after 24 h.
Figure 13. PXRD comparison of MFA−PPZ−H2O (black) after 24 h slurry with the calculated X-ray lines of MFA−PPZ−H2O (red) and MFA−
PPZ 2:1 (blue) in 50% EtOH−water medium. The hydrate MFA−PPZ−H2O transforms to MFA−PPZ salt after 24 h.
Crystal Growth & Design Article
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systems.
22
When the solubility of the drug and the coformer are
similar in the same medium (both are insoluble/less soluble),
such systems are congruent and tend to be stable. For incon-
gruent systems, the high solubility coformer leaches into the
solvent medium in which it readily dissolves, and in this way
the salt/cocrystal dissociates faster. The soluble cocrystals will
usually have a highly soluble coformer partner and this in turn
makes the salt/cocrystal of limited stability. This in effect puts a
limit to the stability of more soluble pharmaceutical cocrystals
in the slurry medium. The stability order in aqueous slurry
medium is (less to more stable): MFA−PPZ (1:1) < MFA−
PPZ monohydrate (1:1:1) < MFA−PPZ (2:1) < MFA−INA
(1:1) < MFA−BPY (1:0.5). Solution-mediated phase transfor-
mations
21
can occur during dissolution and solubility measure-
ments (discussed next), and the above stability order will help
to explain any unusual trends.
Solubility and Dissolution Experiments. The rate of
dissolution and solubility of the solid drug in water or aqueous
solvent mixtures is necessary for good oral bioavailability. The
aqueous solubility of the drug must be at least 100 mg/L
for fast dissolution of the tablet.
1c
The aqueous solubility of
MFA is 30 mg/L and other fenamic acids (e.g., mefenamic acid,
tolfenamic acid and diclofenamic acid) are also low solubility
BCS class II drugs. The sodium salt of meclofenamic acid
(MFA-SS) is marketed as capsules (solubility > 250 g/L). The
aqueous solubility for cocrystals and salts of MFA were
measured in 50% EtOH−water medium at 37 °C (Table 8).
Although solubility is a good indicator of drug bioavailability,
the method is applicable only for those solid-state drug forms
which are stable in the test medium/wet slurry. The intrinsic
dissolution rate (IDR) is a kinetic parameter and is a useful
indicator for those solid forms which undergo phase trans-
formation or dissociation during the experiment. Most drugs
exert their therapeutic effect during 4−6−8 h of oral admin-
istration, and IDR is related to drug dissolution in such cases.
IDR measurements showed that piperazine salts reached peak
concentration within 30−45 min of drug dissolution (Figure 15).
The most stable 2:1 MFA−PPZ salt exhibited a gradual in-
crease in dissolution rate up to 24 h. The cumulative amount of
MFA dissolved (mg cm−2) vs time (min) was plotted to com-
pare the IDR of piperazine meclofenamates (Figure 15a). The
highest solubility of MFA−PPZ-M (1:1) is driven by the high
solubility of piperazine > MFA−PPZ−H2O (1:1:1) because
hydrates are generally less soluble than anhydrate drugs >
(MFA−PPZ (2:1) due to lower piperazine content. In contrast
to salts, MFA−INA (1:1) and MFA−BPY (1:0.5) cocrystals
exhibited poor dissolution rates (Figure 15b), but they were
quite stable for over 24 h (Figure S6, Supporting Information).
The highest solubility salt MFA−PPZ (1:1) was compared
Table 8. Solubility and Dissolution Rate of MFA and Its
Cocrystals and Salts
a
solid form
absorption
coefficient
(ε,mM
−1cm−1)
equilibrium solubility
after 24 h slurry in
50% EtOH−water
(mg L−1)IDR ((mg cm−2)
min−1)
a
MFA 6.94 203.11 0.03074
MFA−INA 4.10 581.43 (x 2.9) 0.04858 (x 1.6)
MFA−BPY 5.74 1638.07 (x 7.6) 0.03822 (x 1.2)
MFA−PPZ-M 3.38 553223.061 (x 2724) 27.4976 (x 894.5)
MFA−PPZ 7.95 10211.954 (x 50) 0.31477 (x 10.2)
MFA−PPZ−H2O 4.82 270966.397 (x 1334) 9.8044 (x 318.9)
a
Number in parentheses indicates how many times higher solubility/
IDR compared to reference drug.
Figure 15. Intrinsic dissolution rate (IDR) measurements of (a)
MFA−PPZ-M (1:1), MFA−PPZ−H2O (1:1:1) and MFA−PPZ (2:1)
performed up to 3 h, (b) MFA−PPZ (2:1), MFA−INA (1:1), MFA−
BPY (1:0.5) and MFA over 24 h in 50% EtOH−water medium, and
(c) MFA−PPZ-M (1:1) and MFA-SS (sodium salt of MFA) over
22 min in distilled water. The amount of MFA dissolved in the test
medium was monitored by UV−vis spectroscopy.
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with MFA-SS in aqueous medium; IDR of sodium salt is 28.76
and piperazinium salt is 13.72 (mg cm−2) min−1(Figure 15c).
The marketed sodium salt of MFA has 2.1 times higher IDR
than the equimolar piperazine salt. PXRD of the residue of
MFA−PPZ-M dissolution experiment after 11 min matched
with the 2:1 salt (70%) and monohydrate (30%), the 1:1 salt
showed transformation to piperazine salt hydrate and 2:1 salt,
whereas the MFA sodium salt transformed to its hydrate after
8 min in the dissolution medium. These results suggest that 1:1
MFA−PPZ-M is more stable than the marketed sodium salt
to hydration in aqueous medium. PXRD of melofenamic acid
sodium salt after 24 h of slurry stirring in water (Figure S7,
Supporting Information) is different from the starting material
(MFA-SS, Sigma-Aldrich). Thermogravemetric analysis and Karl
Fischer titration method indicate a water content of 13.92%
(2.8−2.9 equivalent) in MFA-SS hydrate (Figure S8, Supporting
Information) formed in the aqueous medium, a value that was
confirmed by DSC. The aqueous solubility of sodium salt of
MFA (>250 g/L)
7b
is 46 times greater than the value for MFA−
PPZ-M 1:1 salt in water (5.4 g/L), but its dissolution rate is two
times faster in the first 30 min of measurement.
■CONCLUSIONS
MFA is the most potent nonsteroidal anti-inflammatory drug.
A few cocrystals and salts of MFAs were crystallized using crystal
engineering principles. All new crystalline phases were charac-
terized by X-ray diffraction, IR and ss-NMR spectroscopy, and
DSC/TGA. MFA exists in two different conformers A and B
due to m-tolyl group rotation about the N−C bond. Whereas
the crystal structure of MFA has disordered methyl groups, the
drug molecule is in an ordered orientation in its cocrystals and
salts, perhaps rigidified due to stronger hydrogen bonding. The
dissolution rate and solubility of MFA−PPZ-M 1:1 salt is the
highest among the novel solid-state forms studied and slightly
lower than the marketed sodium salt of MFA. Their stability to
hydration is comparable in aqueous medium. Thus, meclofena-
mate piperazinium has an equivalent dissolution and stability
profile to the marketed sodium salt. Four different piperazinium
salts were crystallized: monoclinic and orthorhombic poly-
morphs of MFA−PPZ (1:1), its monohydrate, and MFA−PPZ
(2:1). This is the first example of polymorphic and variable
stoichiometry piperazinium salts with X-ray crystal structures
solved to good accuracy.
■EXPERIMENTAL SECTION
MFA and INA were purchased from Sigma-Aldrich (Hyderabad,
Andhra Pradesh, India) and used directly for experiments. All other
chemicals were of analytical or chromatographic grade. Melting points
were measured on a Fisher-Johns melting point apparatus. Water
filtered through a double deionized purification system (AquaDM,
Bhanu, Hyderabad, India) was used in all experiments. Single crystals
were obtained via slow evaporation of stoichiometric amounts of
starting materials in an appropriate solvent. Cocrystals and salts were
characterized by infrared spectroscopy (IR), powder X-ray diffraction
(PXRD), differential scanning calorimetry (DSC), thermogravimetric
analysis (TGA), and single crystal X-ray diffraction (SC-XRD).
Meclofenamic Acid, MFA. Normally cracked crystals of MFA
appeared after crystallization from organic solvents. Sublimation of
MFA at 190−200 °C produced good quality block shaped crystal after
2−3 h. Melting point 257−260 °C (literature value).
7a,23
Meclofenamic Acid−Isonicotinamide, MFA−INA (1:1) Co-
crystal. MFA (100 mg, 0.34 mmol) and INA (41.5 mg, 0.34 mmol)
were ground in a mortar pestle for 15 min using acetonitrile as solvent-
assisted grinding. After a new solid phase was confirmed by IR and
PXRD, the bulk material was dissolved in acetonitrile. Good quality
single crystals appeared at ambient conditions after 2−3 days, mp
175−177 °C.
Meclofenamic Acid−4,4′-Bipyridine, MFA−BPY (1:0.5) Co-
crystal. MFA (100 mg, 0.34 mmol) and BPY (26.5 mg, 0.17 mmol)
were ground in a mortar pestle for 15 min using acetonitrile as solvent-
assisted grinding. After a new solid phase was confirmed by IR and
PXRD, the bulk material was dissolved in acetonitrile. Thick plate
crystals were harvested at ambient conditions after 2−3 days, mp 204−
207 °C.
Piperazinium Meclofenamate, MFA−PPZ (1:1) Salt Poly-
morphs. MFA (100 mg, 0.34 mmol) and piperazine (29.3 mg,
0.34 mmol) were ground in a mortar pestle for 15 min using acetonitrile
as solvent-assisted grinding. After a new solid phase was confirmed by IR
and PXRD, the bulk material was dissolved in acetonitrile. Block
(monoclinic, form M) and thick long needle (orthorhombic, form O)
crystals were harvested concomitantly at ambient conditions after 2−3
days. Monoclinic form (plate) was obtained exclusively from CH3NO2
solvent; mp of monoclinic and orthorhombic forms are 162−166 °C
and 144−147 °C, respectively.
Piperazinium Meclofenamate, MFA−PPZ (2:1) Salt. MFA
(100 mg, 0.34 mmol) and piperazine (29.3 mg, 0.34 mmol) were
ground in a mortar pestle for 15 min using acetonitrile as solvent-
assisted grinding. After a new solid phase was confirmed IR and
PXRD, bulk material was dissolved in EtOH. Suitable thick plate
(triclinic) crystals were harvested at room temperature after 3−4 days,
mp 166−169 °C.
Piperazinium Meclofenamate Monohydrate, MFA−PPZ−
H2O (1:1:1) Salt. MFA (100 mg, 0.34 mmol) and piperazine hydrate
(35.4 mg, 0.34 mmol) were ground in a mortar pestle for 15 min After
a new solid phase was confirmed by IR and PXRD, the bulk material
was dissolved in nitromethane, mp of salt 154−158 °C and dehydra-
tion temperature 92−95 °C.
2-Aminopyridinium Meclofenamate, MFA−2-APY (1:1) Salt.
MFA (100 mg, 0.34 mmol) and 2-aminopyridine (32 mg, 0.34 mmol)
were ground in a mortar pestle for 15 min using acetonitrile as solvent-
assisted grinding. After a new solid phase was confirmed by IR and
PXRD, the bulk material was dissolved in acetonitrile. Plate crystals
were harvested after 2−3 days at ambient condition, mp 143−146 °C.
4-Aminopyridinium Meclofenamate Monohydrate, MFA−
4-APY−H2O (1:1:1) Salt. MFA (100 mg, 0.34 mmol) and 4-amino-
pyridine (32 mg, 0.34 mmol) were ground in a mortar pestle for
15 min using acetonitrile as solvent-assisted grinding. After a new solid
phase was confirmed by IR and PXRD, bulk material was dissolved in
acetonitrile. Suitable thick plate crystals were harvested after 2−3 days
at ambient condition, mp 104−108 °C and dehydration temperature
80−84 °C.
Single Crystal X-ray Diffraction. A single crystal obtained from
the crystallization solvent(s) was mounted on the goniometer of
Oxford CCD X-ray diffractometer (Yarnton, Oxford, UK) equipped
with Mo−Kαradiation (λ= 0.71073 Å) source. Data reduction was
performed using CrysAlisPro 171.33.55 software.
24
Crystal structures
were solved and refined using Olex2−1.0
25
with anisotropic displace-
ment parameters for non-H atoms. Hydrogen atoms were experi-
mentally located through the Fourier difference electron density maps
in all crystal structures. All O−H, N−H, and C−H atoms were geo-
metrically fixed using HFIX command in SHELX-TL program of
Bruker-AXS.
26
A check of the final cif file with PLATON
27
did not
show any missed symmetry. X-Seed
28
was used to prepare the figures
and packing diagrams. Crystallographic parameters of both structures
are summarized in Table 1. Hydrogen bond distances in Table 2 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 0.82 Å, C−
H 1.083 Å). Crystallographic .cif files (CCDC Nos. 859220−859229)
are available at www.ccdc.cam.ac.uk/data_request/cif or as part of the
Supporting Information.
Powder X-ray Diffraction. Bulk samples were analyzed by PXRD
on a Bruker AXS D8 diffractometer (Bruker-AXS, Karlsruhe,
Germany). Experimental conditions: Cu−Kαradiation (λ=1.54056
Å); 40 kV; 30 mA; scanning interval 5−50°2θat a scan rate of
1°min−1; time per step 0.5 s. The experimental PXRD patterns and
Crystal Growth & Design Article
dx.doi.org/10.1021/cg300002p |Cryst. Growth Des. 2012, 12, 2023−20362034

calculated X-ray lines from the single crystal structure were compared
to confirm the purity of the bulk phase using Powder Cell.
29
Thermal Analysis. DSC and TGA were performed on a Mettler
Toledo DSC 822e module and a Mettler Toledo TGA/SDTA 851e
module, respectively. Samples were placed in open alumina pans for
TGA and in crimped but vented aluminum sample pans for DSC.
A typical sample size is 4−6 mg for DSC and 9−12 mg for TGA.
The temperature range was 30−250 °C at 2 K min−1for DSC and
10 K min−1for TGA. Samples were purged with a stream of dry N2
flowing at 150 mL min−1for DSC and 50 mL min−1for TGA.
Vibrational Spectroscopy. A Thermo-Nicolet 6700 FT-IR
spectrometer (Waltham, MA, USA) with a NXR FT-Raman Module
(Nd:YAG laser source, 1064 nm wavelength) was used to record IR
and Raman spectra. IR spectra were recorded on samples dispersed in
KBr pellets. Raman spectra were recorded on samples contained
in standard NMR diameter tubes or on compressed samples contained
in a gold-coated sample holder.
Solid-State NMR Spectroscopy. Solid-state 13C NMR (ss-NMR)
spectroscopy provides structural information about differences in
hydrogen bonding, molecular conformations, and molecular mobility
in the solid state. The solid-state 13C NMR spectra were obtained on
a Bruker Ultrashield 400 spectrometer (Bruker BioSpin, Karlsruhe,
Germany) utilizing a 13C resonant frequency of 100 MHz (magnetic
field strength of 9.39 T). Approximately 100 mg of crystalline sample
was lightly packed into a zirconium rotor with a Kel-F cap. The cross-
polarization, magic angle spinning (CP-MAS) pulse sequence was used
for spectral acquisition. Each sample was spun at a frequency of 5.0 ±
0.01 kHz and the magic angle setting was calibrated by the KBr
method. Each data set was subjected to a 5.0 Hz line broadening factor
and subsequently Fourier transformed and phase corrected to produce
a frequency domain spectrum. The chemical shifts were referenced to
TMS using glycine (δglycine = 43.3 ppm) as an external secondary
standard.
Dissolution and Solubility Measurements. Intrinsic dissolution
rate (IDR) and solubility measurements were carried out on a USP-
certified Electrolab TDT-08 L Dissolution Tester (Electrolab, Mumbai,
MH, India). A calibration curve was obtained for all the new solid
phases including MFA by plotting absorbance vs concentration UV−vis
spectra curves on a Thermo Scientific Evolution EV300 UV−vis spec-
trometer (Waltham, MA, USA) for known concentration solutions in
50% EtOH−water medium. The mixed solvent system (EtOH−water)
was selected for its higher solubility of MFA in this medium. The slope
of the plot from the standard curve gave the molar extinction coeffi-
cient (ε) by applying the Beer−Lambert’s law. Equilibrium solubility
was determined in 50% EtOH−water medium using the shake-flask
method.
27
To obtain the equilibrium solubility, 100 mg of each solid
material was stirred for 24 h in 5 mL of 50% EtOH−water at 37 °C,
and the absorbance was measured at 318 nm. The concentration of the
saturated solution was calculated at 24 h, which is referred to as the
equilibrium solubility of the stable solid form.
100 mg of the solid (drug, cocrystal, salt) was taken in the intrinsic
attachment and compressed to a 0.5 cm2pellet using a hydraulic press
at a pressure of 2.5 ton/inch2for 2 min. The pellet was compressed to
provide a flat surface on one side and the other side was sealed. Then
the pellet was dipped into 900 mL of 50% EtOH−water medium at
37 °C with the paddle rotating at 150 rpm. At a regular interval of 5−
10 min, 5 mL of the dissolution medium was withdrawn and replaced
by an equal volume of fresh medium to maintain a constant volume.
Samples were filtered through 0.2 μm nylon filter and assayed for drug
content spectrophotometrically at 318 nm on a Thermo-Nicolet
EV300 UV−vis spectrometer. There was no interference to MFA
UV−vis maxima at 318 nm by coformers INA and bipyridine which
absorb strongly at 250−270 nm. Piperazine is UV−vis inactive. The
amount of drug dissolved in each time interval was calculated using the
calibration curve. The linear region of the dissolution profile was used
to determine the intrinsic dissolution rate (IDR) of the compound
(= slope of the curve, that is, the amount of drug dissolved divided by
the surface area of the disk (0.5 cm2) per minute). The dissolution
rates for MFA, its cocrystals, and salts were computed from their IDR
values. Similarly IDR experiments of MFA−PPZ-M and MFA-SS salts
were carried out in distilled water and absorbance was measured at
318 nm in a UV−vis spectrophotometer.
■ASSOCIATED CONTENT
*
SSupporting Information
Crystallographic information files; Refcodes of cocrystals and
salts of piperazine (Table S1) and piperazinium dications
with carboxylate anions (Table S2); 13C solid-state NMR of
piperazinium meclofenamate salts compared to values for the
pure coformers (Table S3); ORTEP diagrams (Figure S1);
TGA results (Figure S2); PXRD results (Figures S3, S6, S7);
comparison of calculated X-ray diffraction lines of monoclinic
and orthorhombic forms of piperazinium meclofenamate (1:1)
salts (Figure S4); DSC endotherm (Figure S5); DSC and TGA
thermograms (Figure S8). 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
We thank the DST (SR/S1/OC-67/2006), JC Bose fellowship
(SR/S2/JCB-06/2009), and CSIR (01(2410)/10/EMR-II) for
research funding, and DST (IRPHA) and UGC (PURSE grant)
for providing instrumentation and infrastructure facilities. P.S.
and G.B. thank the UGC for fellowship. We thank Dr. Naba
Kamal Nath for his assistance to resolve disorder issues in
crystal structure refinement of MFA.
■REFERENCES
(1) (a) Lipinski, C. Am. Pharm. Rev. 2002,5, 82. (b) Vippagunta,
S. R.; Brittain, H. G.; Grant, D. J. W. Adv. Drug Delivery Rev. 2001,48,
3. (c) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid-State Chemistry of
Drugs, 2nd ed.; SSCI, Inc.: West Lafayette, IN, 1999.
(2) (a) Desiraju, G. R. Crystal Engineering: The Design of Organic
Solids; Elsevier: Amsterdam, 1989. (b) Desiraju, G. R. Angew. Chem.,
Int. Ed. 2007,46, 8342. (c) Blagden, N.; Matas, M. D.; Gavan, P. T.;
York., P. Adv. Drug Delivery Rev. 2007,59, 617.
(3) (a) Karki, S.; Friščić, T.; Fábián, L.; Laity, P. R.; Day, G. M.;
Jones, W. Adv. Mater. 2009,21, 3905. (b) Childs, S. L.; Chyall, L. J.;
Dunlap, J. T.; Smolenskaya, V. N.; Stahly, B. C.; Stahly, G. P.
J. Am. Chem. Soc. 2004,126, 13335. (c) Remenar, J. F.; Morissette,
S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.; Guzmán, H. R.;
Almarsson, O
̈J. Am. Chem. Soc. 2003,125, 8456. (d) Cheney, M. L.;
Shan, N.; Healey, E. R.; Hanna, M.; Wojtas, L.; Zaworotko, M. J.; Sava,
V.; Song, S.; Sanchez-Ramos, J. R. Cryst. Growth Des. 2010,10, 395.
(e) Sanphui, P.; Goud, N. R.; Khandavilli, U. B. R.; Nangia, A. Cryst.
Growth Des. 2011,11, 4135.
(4) (a) Portell, A.; Barbas, R.; Font-Bardia, M.; Dalmases, P.;
Prohens, R.; Puigjaner, C. CrystEngComm 2009,11, 791. (b) Thakuria,
R.; Nangia, A. CrystEngComm 2011,13, 1759. (c) Banerjee, R.; Bhatt,
P. M.; Ravindra, N. V.; Desiraju, G. R. Cryst. Growth Des. 2005,5,
2299.
(5) (a) Aakeröy, 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.
(6) (a) Flower, R. J. Pharm. Res. 1974,26, 33. (b) Moser, P.;
Salimann., A.; wissenberg., I. J. Med. Chem. 1990,33, 2358. (c) Bowen,
E. J.; Eland, J. H. D. Proc. Chem. Soc. 1963, 202. (d) Narsinghania, T.;
Chaturvedi, S. C. Biorg. Med. Chem. Lett. 2006,16, 461. (e) Peretz, A.;
Degani, N.; Nachman, R.; Uziyel, Y.; Gibor, G.; Shabat, D.; Attali, B.
Crystal Growth & Design Article
dx.doi.org/10.1021/cg300002p |Cryst. Growth Des. 2012, 12, 2023−20362035

Mol. Pharmacol. 2005,67, 1053. (f) Belsole, S. C.; Chester, N. J. U.S.
Patent 1986, 4602040. (g) Philip, J.; Szulczewski, D. H. J. Pharm. Sci.
1973,62, 1479. (h) http://www.elephantcare.org/Drugs/meclofen.htm.
(7) (a) http://www.drugbank.ca/drugs/DB00939. (b) http://www.
orgyn.com/resources/genrx/D001710.asp.
(8) Fábián, L.; Hamill, N.; Eccles, K. S.; Moynihan, H. A.; Maguire,
A. R.; McCausland, L.; Lawrence, S. E. Cryst. Growth Des. 2011,11,
3522.
(9) Murthy, H. M. K.; Vijayan, M. Acta Crystallogr. 1981,B37, 1102.
(10) Dhanraj, V.; Vijayan, M. Biochim. Biophys. Acta 1987,924, 135.
(11) (a) Takasuka, M.; Nakai, H.; Shiro, M. J. Chem. Soc., Perkin
Trans. II 1982, 1061. (b) McConnell, J. F.; Company, F. Z. Cryst.
Struct.Commun. 1976,5, 861. (c) Lόpez-Mejías, V.; Kapyf, J. W.;
Matzger, A. J. J. Am. Chem. Soc. 2009,131, 4554.
(12) (a) Etter, M. C.; Macdonald, J. C. Acta Crystallogr. 1990,B46,
256. (b) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew.
Chem., Int. Ed. Engl. 1995,34, 1555.
(13) (a) Stahl, P. H., Wermuth, C. G., Eds.; Handbook of Pharma-
ceutical Salts: Properties, Selection and Use; Verlag Helvetica Chimica
Acta: Zürich, 2002. (b) Generally Regarded as Safe: http://www.cfsan.
fda.gov/∼rdb/opa-gras.html and http://www.cfsan.fda.gov/∼dms/
grasguid. html.
(14) Cambridge Structural Database, Ver. 5.32, 2010, November
2011 update, Cambridge Crystallographic Data Center, UK, www.
ccdc.cam.ac.uk.
(15) Cerius2Materials Studio, http://accelrys.com/products/cerius2,
Lattice energy calculation of crystal structures.
(16) Fonari, M. S.; Ganin, E. V.; Vologzhanina, A. V.; Antipin, M. Y.;
Kravtsov, V. C. Cryst. Growth Des. 2010,10, 3647.
(17) (a) Hathwar, V. R.; Roopan, S. M.; Subashini, R.; Khan, F. N.;
Guru Row, T. N. J. Chem. Sci. 2010,122, 677. (b) Nath, N. K.; Saha,
B. K.; Nangia, A. New J. Chem. 2008,32, 1693. (c) Rajput, L.;
Chernyshev, V. V.; Biradha, K. Chem. Commun. 2010,46, 6530.
(18) (a) Karki, S.; Friščić, T.; Fábián, L.; Jones, W. CrystEngComm
2010,12, 4038. (b) Remenar, J. F.; Peterson, M. L.; Stephens, P. W.;
Zhang, Z.; Zimenkov, Y.; Hickey, M. B. Mol. Pharmaceutics 2007,4,
386. (c) André, V.; Fernandes, A.; Santos, P. P.; Duarte, M. T. Cryst.
Growth Des. 2011,11, 2325.
(19) (a) Silverstein, R. M. Spectrometric Identification of Organic
Compounds, 6th ed.; John Wiley & Sons, Inc.: New York, 2002;
pp 71−143. (b) Gilpin, R. K.; Zhou, W. Vib. Spectrosc. 2005,37, 53.
(c) Romero, S.; Escalera, B.; Bustamante, P. Int. J. Pharm. 1999,178,
193. (d) Smith, E. Dent, G. Modern Raman Spectroscopy: A Practical
Approach; John-Wiley: New York, 2005.
(20) (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) Li,
Z. J.; Abramov, Y.; Bordner, J.; Leonard, J.; Medek, A.; Trask, A. V.
J. Am. Chem. Soc. 2006,128, 8199.
(21) (a) Greco, K.; Mcnamara, D. P.; Bogner, R. J. Pharm. Sci. 2011,
100, 2755. (b) Murphy, D.; Rodríguez-Cintrón, F.; Langevin, B.; Kelly,
R. C.; Rodríguez-Hornedo, N. Int. J. Pharm. 2002,246, 121. (c) Ferrari,
E. S.; Davey, R. J. Cryst. Growth Des. 2004,4, 1061. (d) Cherekuvada,
S.; Babu, N. J.; Nangia, A. J. Pharm. Sci. 2011,100, 3233. (e) Fini, A.;
Cavallari, C.; Bassini, G.; Ospitalli, F.; Morigi, R. J. Pharm. Sci. 2012,
DOI: 10.1002/jps.23052.
(22) (a) Friščić, T.; Childs, S. L.; Rizvi, S. A. A.; Jones, W.
CrystEngComm 2009,11, 418. (b) Alhalaweh, A.; Velega, S. P. Cryst.
Growth Des. 2010,10, 3302. (c) Rodríguez-Hornedo, N.; Nehm, S. J.;
Seefeldt, K. F.; Pagán-Torres, Y.; Falkiewicz, C. J. Mol. Pharmaceutics
2006,3, 362. (d) Goud, N. R.; Gangavaram, S.; Suresh, K.; Pal, S.;
Manjunatha, N. G.; Nambiar, S. J. Pharm. Sci. 2012,101, 664.
(23) Fawzi, M.; Mahjour, M. U.S. Patent, 5,373,022, 1994.
(24) CrysAlis CCD and CrysAlis RED, versions 1.171.33.55; Oxford
Diffraction: Oxford, 2008.
(25) Diffraction Ltd, Yarnton, Oxfordshire, UK.
(26) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. OLEX2: A complete structure solution, refinement
and analysis program. J. Appl. Crystallogr. 2009,42, 339.
(27) SMART, version 5.625 and SHELX-TL, version 6.12; Bruker
AXS Inc.: Madison, Wisconsin, USA, 2000.
(28) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool;
Utrecht University: Utrecht, Netherlands, 2002. Single-crystal struc-
ture validation with the Program PLATON. J. Appl. Crystallogr. 2003,
36,7.
(29) Barbour, L. J. X-Seed, Graphical interface to SHELX-97 and POV-
Ray, Program for Better Quality of Crystallographic Figures; University of
Missouri-Columbia: Missouri, USA, 1999
(30) Kraus, N.; Nolze, G. Powder Cell, version 2.3, A Program for
Structure Visualization, Powder Pattern Calculation and Profile Fitting;
Federal Institute for Materials Research and Testing: Berlin, Germany,
2000.
(31) Glomme, A.; Marz, J.; Dressman, J. B. J. Pharm. Sci. 2005,94,1.
Crystal Growth & Design Article
dx.doi.org/10.1021/cg300002p |Cryst. Growth Des. 2012, 12, 2023−20362036