Conformational polymorphism in a non-steroidal anti-inflammatory drug, mefenamic acid

Article abstract of DOI:10.1021/cg300812v

For several years, the non-steroidal anti-inflammatory drug mefenamic acid, MA, has been known to exist as dimorphs (I and II). We report a new metastable polymorph (III) of MA obtained during attempted co-crystallization experiments and establish its stability relationship with existing forms. At elevated temperatures I and III convert to II, as evident from DSC experiments. On the basis of the lattice energy calculations in conjunction with thermal analysis, the stability order is proposed to be I > II > III at ambient conditions, whereas at elevated temperature the order is II > I > III. In either condition III is a metastable form and hence transforms to I at ambient conditions and to II at higher temperatures. Also we report the structural studies of a DMF solvate and a cytosine complex.

Full text of DOI:10.1021/cg300812v

Article
pubs.acs.org/crystal
Conformational Polymorphism in a Non-steroidal Anti-inflammatory
Drug, Mefenamic Acid
Sunil SeethaLekshmi and Tayur N. Guru Row*
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India
S
* Supporting Information
ABSTRACT: For several years, the non-steroidal anti-inflammatory drug
mefenamic acid, MA, has been known to exist as dimorphs (I and II). We
report a new metastable polymorph (III) of MA obtained during
attempted co-crystallization experiments and establish its stability
relationship with existing forms. At elevated temperatures I and III
convert to II, as evident from DSC experiments. On the basis of the lattice
energy calculations in conjunction with thermal analysis, the stability order
is proposed to be I > II > III at ambient conditions, whereas at elevated
temperature the order is II > I > III. In either condition III is a metastable
form and hence transforms to I at ambient conditions and to II at higher
temperatures. Also we report the structural studies of a DMF solvate and a
cytosine complex.
itously by co-crystallizing aspirin with levetiracetam from hot
acetonitrile or in the presence of a molar equivalent of
acetamide.6 In a yet another example, Caira et al. reported new
polymorphs of nicotinamide and isonicotinamide obtained
from their attempted co-crystallization of these coformers with
the antitubercular API, isoxyl.7 Thus, co-crystallization offer an
important, though not thoroughly explored, strategy to obtain
new solid state forms of pharmaceutically important molecules
that cannot be obtained otherwise.
Diarylamines, such as mefenamic acid, tolfenamic acid,
flufenamic acid, meclofenamic acid, and diclofenac, are well-
known non-steroidal anti-inflammatory drugs (NSAIDs), and
many of them exhibit polymorphism.8 Mefenamic acid (2-(2,3-
dimethylphenyl)aminobenzoic acid, MA) is a potent prosta-
glandin synthetase inhibitor, commonly used as an analgesic−
antipyretic agent (Scheme 1).9 As per the Biopharmaceutics
Classification System (BCS), MA belongs to Class II type with
low solubility and high permeability. Its poor solubility in water
restricts its utility in clinical trials. The higher hydrophobicity
and tendency to stick to surfaces impel problems during
INTRODUCTION
■
Polymorphism in active pharmaceutical ingredients (APIs) is of
topical interest from both the academic and industrial
viewpoints. However, a lacuna in the understanding of the
mechanism of nucleation and crystal growth at the molecular
level makes the control of polymorphic forms a target still to
achieve. Consequently, most of the observations on poly-
morphs are serendipitous and the studies are heuristic in
nature. In recent times a wide variety of methods have been
employed to control polymorphic behavior in compounds;
these include the use of tailor-made additives, heterogeneous
crystallization, and epitaxial growth on self-assembled mono-
layers.1 Additive-induced crystallization has been adopted since
the early days of crystal engineering to control the growth rate,
size, and shape of crystals. The research groups of Leiserowitz,
Meir Lahav, and a few other pioneers made significant
contributions in employing tailor-made additives/selective
auxiliaries to control crystal growth and thereby to obtain
crystals with definite size and morphology.2 Such additives are
proposed to lessen the free energy barrier to nucleation through
favorable interactions between the substrate and prenucleation
aggregate and hence provide a strategy to obtain the new forms,
otherwise not possible.3 However, due to the lack of systematic
attempts and theoretical backing, such studies are essentially of
serendipitous nature.
Scheme 1. Mefenamic Acid, MA
Co-crystallization provides a potent and promising approach
to alter properties such as hydration, tabletability, solubility, and
bioavailability of pharmaceuticals.4 Though considered initially
as a remedy to reduce the occurrence of polymorphism, co-
crystallization can in fact induce generation of novel
polymorphic forms.5 One of the most debated observations
in the recent history of pharmaceutical polymorphism was the
discovery of the second form of aspirin, obtained serendip-
Received: June 15, 2012
Revised: July 5, 2012
Published: July 10, 2012
© 2012 American Chemical Society
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granulation and tabletting.10 Consequently, quite a lot of efforts
have been made to modify the compositions and to achieve
higher solubility and enhanced bioavailability. The studies on
the inclusion complex with cyclodextrin and cobalt(II)
complexes in the presence/absence of various N-heterocycles
revealed the possibility of alternate approaches to enhance the
stability, solubility, and binding propensity of MA.11 For several
years, MA has been known to exist as dimorphs (I and II). The
crystal structure of I, crystallizing from the majority of solvents,
was reported in 1976.12 Although there exist some mentions
about the 3D coordinates of II in the literature, no such
information is available in Cambridge Structural Database
(CSD).16,17 In this article, we report the metastable polymorph,
III, and the structural studies of II, together with a DMF
solvate and a molecular complex with cytosine.
EXPERIMENTAL SECTION
The chemicals were purchased from Sigma-Aldrich and used without
further purification. The solvents used for crystallization were of
analytical grade.
■
Crystal Preparation. The polymorph II and the MA-DMF
solvate, 4, were obtained by the slow evaporation of, respectively,
CHCl3 (chloroform) and DMF (N,N-dimethylformamide) solutions.
Co-crystallization experiments with adenine in a 1:1 DMF/methanol
mixture followed by slow evaporation at room temperature yielded the
metastable form III. A reaction with cytosine as a coformer yielded the
corresponding molecular complex, 5.
Single Crystal X-ray Diffraction. Single crystals were chosen
carefully using an Olympus microscope supported by a rotatable
polarizing stage. Single crystal diffraction data for the compounds were
collected on an Oxford single-crystal X-ray diffractometer (Micro-
source: Mova; Detector: Eos) with a four-circle κ goniometer
employing a graphite-monochromatized Mo Kα (λ = 0.71073 Å)
radiation. The diffraction intensities were corrected for Lorentz and
polarization effects. The data were reduced using CrysAlisRED
(programs available with the diffractometer), and an analytical
absorption correction (after Clark and Reid) was applied.13 Structure
solution and refinements were performed using SHELX97 using the
WinGX suite.14 The ORTEPs are provided in the Supporting
Information (Supplementary Figure S1).
Powder X-ray Diffraction. The phase purity of the bulk sample
was evaluated by comparing the experimental PXRD pattern with the
simulated one. X-ray powder diffraction data were collected on a
Philips X'pert Pro X-ray powder diffractometer equipped with
X'cellerator detector. The scan range, step size, and time per step
were 2θ = 5° to 30°, 0.02°, and 25 s, respectively.
Figure 1. Intermolecular interactions in (a) III, (b) II, and (c) I.
cooling of a supersaturated solution of MA in DMF.15,20b
Nevertheless, none of the aforementioned routes could yield
crystals suitable for single crystal diffraction studies. Lee and co-
workers reported an additive-induced method, using structur-
ally similar flufenamic acid in ethanol, to obtain the crystals of
II.16 Besides, there were reports on the preparation of the
polymorphs of MA using certain functionalized metallic islands
as individual templates to prepare the polymorphs of MA.17
However, owing to the lack of a reliable crystal data for II, we
performed a large number of crystallizations to explore an
alternate pathway to obtain single crystals of II by adopting
different crystallization conditions and employing numerous
solvents or solvent mixtures. The solubility of MA being less in
the majority of the solvents, the crystallization experiments
generally yield I. Conversely, slow evaporation of a chloroform
solution in a less humid condition yielded single crystals of II.
In the crystal, the imino bridge and the alkylated phenyl ring
are disordered with a population distribution of 55:45. Since
the disorder remains even at low temperature (100 K), it could
be of static nature. Akin to III, carobxylic acid makes symmetric
dimers that are further stabilized through various C−H···π and
π···π interactions (Figure 1b). The structural features of I is
comparable to those of II and III. The phenyl ring with the
carboyxylic acid functionality and the imino bridge is coplanar,
brought about by a strong intramolecular N−H···O hydrogen
bond (H···O, 1.82 Å). The MA molecules make symmetric
Thermal Analysis. DSC/TG experiments were carried out using a
Mettler Toledo TG/DSC-1 thermal analyzer, with a heating rate of 5
°C/min in the range of 35−250 °C, under N2 atmosphere.
RESULTS AND DISCUSSION
■
Polymorphs of Mefenamic Acid. Attempted co-crystal-
lization of MA with adenine from a DMF/methanol mixture at
ambient conditions led to the serendipitous observation of the
third polymorph, III. The block-like crystals of III were
obtained concomitantly with the crystals of adenine trihydrate
and the DMF solvate of MA. The polymorph III crystallizes in
the triclinic space group, P1, with a molecule in the asymmetric
̅
unit. The symmetric O−H···O (1.66 Å) hydrogen bonded acid
dimer is further stabilized through numerous C−H···π and π···π
interactions (Figure 1a). Notably, the crystals obtained from
DMF or a 1:1 DMF/methanol turned out to be of I and the
DMF solvate. Accordingly, it can be inferred that the presence
of adenine plays an imperative role in the crystallization of III.
Form II is generally prepared either by heating crystals of I
above the transition temperature (165−175 °C) or by the rapid
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dimers, and the adjacent dimers are linked through C−H···π
(2.77 Å) interactions involving aromatic C−H and the alkylated
phenyl ring (Figure 1c).
Mefanic Acid-DMF Solvate, 4. One molecule each of MA
and DMF constitute the asymmetric unit and the molecules
form asymmetric dimers through O−H···O and C−H···O
hydrogen bonds (H···O, 1.62 and 2.41 Å, respectively) (Figure
2; Supplementary Table S1). In three dimensions the molecular
synthon, and additional C−H···π and π···π interactions
complement the structure formation.
Analysis of Torsion Angles. The polymorphic forms exhibit
major differences in the torsion angles, as evident from an
overlay of the molecules (Figure 5a). The conformational
polymorphism in MA is determined by three torsion angles
(Figure 5b): twisting of the carboxylic group with respect to the
axis τ1(O72−C7−C1−C2), rotation of the phenyl ring along the
axis τ2(C1−C2−N2−C8), and flipping of the 2,3-dimethylphenyl
ring along the axis τ3(C2−N2−C8−C9). The observed torsional
shift is tabulated in Table 2. While the crystal forms exhibit
comparable values for τ1 and τ2, the conformational variation is
dictated by τ3. Though the intramolecular N−H···O interaction
restricts the free rotation of the carboxylic acid containing
aromatic ring, one can anticipate that the presence of an imino
bridge makes the rotation of the dimethyl-substituted phenyl
ring energetically less demanding.
Thermal Analysis and Phase Stability. In order to obtain an
understanding of the relative stability relationships between
different solid phases of MA, thermal analyses (both DSC and
TG) were carried out. As known from the earlier studies, I
exhibit an endothermic peak in the temperature range of 178−
180 °C that corresponds to the enantiotropic phase transition
to II.15a,18 The melting endotherm is observed with an onset
temperature of 229 °C (Figure 6b). Similar characteristic
endothermic phase transition is observed for III, in the
temperature range of 175−178 °C followed by a melting
endotherm at 227 °C. However, no such events are observed
for II, prior to the melting (onset temperature: 229 °C). At
high temperature I and III convert to II. However, at ambient
conditions, over a period of time, II and III revert to I. Thus,
while II is stable at elevated temperature, I is the stable form at
ambient conditions. Slurry experiments at ambient conditions
also corroborate the stable nature of I. Under ambient
conditions no transformation relating II and III is observed.
Though II was obtained from CHCl3, solvent drop grinding of
MA with CHCl3 or crystallization in humid conditions yielded
only I, as evident from PXRD analysis (Supplementary Figure
S2).
Better solubility of MA in CHCl3 provides an opportunity to
the molecules to assemble/reassemble to yield the high
temperature form II; however, in humid conditions the
experiments preferentially yielded I. Thus, it may be assumed
that under humid conditions the rate of transformation of II →
I could be higher than the rate of formation of II, making it
difficult to obtain II. Thermogravimetry together with PXRD
analysis of 4 confirms the desolvation, with onset at 45 °C,
followed by its transformation to I (Supplementary Figures S3
and S4).
Figure 2. Interactions in the solvate, 4.
units make a close packed structure, stabilized through several
C−H···π and π···π interactions. Upon removing from the
mother liquor the crystals effloresce rapidly to yield I, as is
evident from a PXRD analysis (Supplementary Figure S4).
Mefenamic Acid-Cytosine Complex, 5. Crystallization of
MA with cytosine from a DMF/methanol mixture yielded a 1:2
molecular complex, 5, along with the crystals of 4. The
carboxylic acid of MA is deprotonated, while one of the
cytosine units is protonated. Symmetry-independent cytosine
molecules form dimers through N−H···O/N+−H···N inter-
actions (H···O, 1.74 and H···N, 1.84 Å, respectively), which
extends as a molecular tape, as shown in Figure 3a. The
carboxylate functionality of MA make N−H···O− (H···O−, 1.59
Å) interactions with the adjacent tapes and hence act as clips
that bind the tapes (Figure 3b).
Lattice Energy Calculations. Lattice energy of I and III were
calculated using the Forcite module of Material Studio 4.4 with
COMPASS27 force field.19 I and III are energetically close; III
being less stable by 0.56 kcal/mol. The disorder in II restricts
from obtaining a reliable quantity for the lattice energy.
However, calculation of the crystal lattice energies based on the
sublimation and solution calorimetric experiments, II is
apparently more stable than I.20 Thus, as per the lattice energy
calculation, the stability of the polymorphic forms are in the
order II > I > III. This observed order of stability can be
correlated with the conformational energy.21 Among the three,
the conformational arrangement of III is the least stable, with
8.867 kJ/mol less stable, as compared to I. For II, two different
orientations are possible due to the disorder and the
Figure 3. Crystal structure of 5. (a) Cytosine tapes. (b) Interactions
between cytosine and acid units.
All three polymorphs (I−III) of MA crystallize in the triclinic
space group (P1) with a molecule in the asymmetric unit
̅
(Table 1); such an observation is relatively rare, wherein all the
polymorphic forms consist of Z′ = 1. The simulated PXRD
patterns of the polymorphs are given in Figure 4. Although the
polymorphs exhibit significant variations in the unit cell
dimensions, the hydrogen bonds in the polymorphs are
comparable; the carboxylic acid makes a symmetric O−H···O
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Table 1. Crystallographic Information of Various Solid-State Forms of MA
a
I
II
III
4
5
formula
CCDC no.
formula wt
crystal system
space group
a (Å)
C15H15NO2
C15H15NO2
848899
C15H15NO2
846433
C15H15NO2, C3H7NO
848900
C15H14NO2, (C4H6N3O) (C4H5N3O)
848901
463.50
triclinic
241.28
241.28
241.28
314.38
triclinic
triclinic
triclinic
triclinic
P1
̅
P1
̅
P1
̅
P1
P1
̅
̅
14.556
6.811
7.657
119.57
103.93
91.3
7.7584(5)
9.2772(6)
9.3991(4)
106.308(5)
91.847(4)
101.856(5)
632.52(6)
2
7.723(2)
7.9340(10)
11.2320(10)
83.590(10)
80.940(10)
67.510(10)
626.96(19)
2
7.4730(10)
9.559(2)
13.306(2)
105.070(3)
103.780(3)
103.410(3)
846.5(2)
2
6.966(5)
7.321(5)
23.801(9)
86.950(9)
83.940(8)
67.850(8)
1117.8(12)
2
b(Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å3)
631.766
2
Z
Dcalc (g cm−3
)
1.267
1.278
1.233
1.377
T (K)
298(2)
0.084
298(2)
298(2)
0.084
298(2)
0.098
μ (mm-1)
0.085
2θ range (deg)
total reflns
50.48
50.48
49.98
50.50
12155
12135
8036
9014
unique reflns, Rint
reflns used
2294
2287
2969
4017
1942
1460
1990
2892
no. of parameters
GOF on F2
final R1, wR2
250
169
220
333
1.162
1.037
1.005
1.146
0.089, 0.302
0.042, 0.109
0.045, 0.124
0.072, 0.149
a
Literature values for I (Refcode XYANAC).
Table 2. Torsion Angle Values (deg) of Various Forms of
MA
II
a
a
angle
I
a
b
III
τ1
τ2
τ3
∠O72−C7−C1−C2
∠C1−C2−N2−C8
∠C2−N2−C8−C9
178.60
−179.34
−119.99
−177.43
176.32
68.20
−177.43
−179.57
−81.03
−177.38
−179.55
−80.82
a
MA molecules of II with (a) 55% occupancy and (b) 45% occupancy.
Polymorph II is known to exhibit higher solubility than I in
several solvents and hence preferable for pharmaceutical
formulations.20a,22 However, our results together with some
earlier reports confirm that II is metastable at ambient
conditions and transforms to I. The rate of transformation is
sensitive to relative humidity (RH) and the solvent systems
(faster in the least polar mixtures).23 This metastable nature
negates the utility of II in pharmaceutical formulations. The
present study, through the crystallization in different solvents,
solvent drop grinding and slurry experiments, confirms that at
ambient conditions the order of stability is I > II > III. At
Figure 4. PXRD patterns (simulated) of the polymorphs of MA.
stabilization energy is intermediate to I and III. The
conformational energy is provided in Table 3.
Figure 5. (a) Overlay of the molecules of I (red), II (55% occupancy, blue; 45% occupancy, green), and III (yellow). (b) Numbering scheme used
for the analysis of torsion angles.
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Figure 6. Polymorphs of MA: (a) phase transformation and (b) DSC plots.
Table 3. Conformational Energies of I−III
whereas for II and III it is almost perpendicular (80°). This
angular shift (see Figure 7) is having profound influence in the
nature of weak interactions (C−H···π and π···π) present in
these forms. In I there is fairly significant C−H···π contacts
stabilizing the dimers, whereas in II and III such contacts are
weaker. However the contribution from π···π interactions
follow the opposite trend. To be precise, the percentage of C−
H···π and π···π interactions are 25.4% and 2.1% in I; 21.18%
and 5.04% in II; and 20.3% and 4.7% in III, respectively
(Figure 8).
hartree
kcal/mol
kJ/mol
I
−786.0826765
−786.0810805
−786.0793395
−786.0792989
0
0
a
b
II
II
1.001
2.094
4.192
8.761
8.867
III
2.119
b
a
MA molecules of II with 55% occupancy. MA molecules of II with
45% occupancy.
higher temperatures through enantiotropic transformation, the
order is changed to II > I > III. In either conditions III is a
metastable form and hence transform to I at ambient
conditions whereas to II at higher temperatures.
CONCLUSION
■
A new metastable polymorph (III) of mefanamic acid has been
obtained during attempted co-crystallization experiments.
Together with the structural studies, we established the stability
relationship of III with respect to the existing polymorphs.
Crystallization experiments in different solvents, solvent drop
grinding, and slurry experiments confirm that at ambient
conditions the order of stability is I > II > III. At higher
temperatures, through enantiotropic transformation, the order
is changed to II > I > III. In either condition III is a metastable
form and hence transforms to I at ambient conditions and to II
at higher temperatures. Thus it can be inferred that co-
crystallization of an API with suitable coformers could lead to a
new polymorph of either API or the coformer. Indeed, these
occur serendipitously, though the methods could be considered
for the generation of new polymorphic forms of a drug
molecule. The induction of the polymorphic modification
appears as a consequence of the well understood morphological
control of crystallization; however, the specific control on the
use of solvent combinations needs to be clearly worked out.
Hirshfeld Surface Analysis. Hirshfeld surface (HS) analysis
allows the fast identification of the shortest intermolecular
contacts and subsequently their quantification.24 Hirshfeld
surfaces and fingerprint plots (FP) were generated for the
polymorphs and exhibited significant divergence confirming the
distinction in the polymorphic forms. In all of the three forms
the types of interactions available are similar, although their
contribution to the structure stabilization varies. While the
contribution of the carboxylic acid dimer in III is 14.7%, it is
12.9% and 14.9% for I and II, respectively. This O−H···O
intermolecular interactions appear as a pair of sharp spikes of
equal lengths in the 2D fingerprint plots. In all the forms, the
contribution of the H···H contacts is higher than 50%. The flat
regions of HS depict parts of the molecule involved in π···π
stacking. The contribution of π···π interactions in the
stabilization of II and III is approximately 100% more as
compared to I. This is consistent with the twisted conformation
adopted by I, which can significantly hinder the possible π···π
stacking. In I the angle between the two planar grouping (the
ring containing carboxylic acid and 2,3-dimethylphenyl) is 62°,
Figure 7. Angle between the planar grouping consisting of phenyl rings bearing the carboxyl group (red) and 2,3-dimethylphenyl group (green): I
(62°); II (80°), and III (80°).
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Figure 8. Hirshfeld surfaces, fingerprint plots (labels showing regions of important interactions), and contribution of interactions in the polymorphs
of MA.
(b) Edgar, R.; Schultz, T. M.; Rasmussen, F. B.; Feidenhans’l, R.;
ASSOCIATED CONTENT
* Supporting Information
This material is available free of charge via the Internet at
■
Leiserowitz, L. J. Am. Chem. Soc. 1999, 121, 632−637. (c) Ahn, S.;
S
Matzger, A. J. J. Am. Chem. Soc. 2012, 134, 3208−3214. (d) Kirchner,
M. T.; Blaser, D.; Boese, R.; Desiraju, G. R. CrystEngComm 2009, 11,
̈
http://pubs.acs.org.
229−231. (e) Bhat, M. N.; Dharmaprakash, S. M. J. Cryst. Growth
2002, 236, 376−380. (f) Yu, L. J. Am. Chem. Soc. 2003, 125, 6380−
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AUTHOR INFORMATION
Corresponding Author
*Tel: +91 80 2293 2796. Fax: +91 80 2360 1310. E-mail:
ssctng@sscu.iisc.ernet.in.
■
(3) (a) Lee, E. H.; Boerrigter, S. X. M.; Rumondor, A. C. F.;
Chamarthy, S. P.; Byrn, S. R. Cryst. Growth Des. 2008, 8, 91−97.
(b) Chadwick, K.; Chen, J.; Myerson, A. S.; Trout, B. L. Cryst. Growth
Des. 2012, 12, 1159−1166.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
̈
■
(4) (a) Almarsson, O.; Hickey, M. B.; Peterson, M. L.; Morissette, S.
S.S. thanks University Grants Commission (UGC) for the
award of a Dr. D. S. Kothari postdoctoral fellowship. T.N.G.R.
thanks DST for the award of a J. C. Bose fellowship.
L.; McNulty, C.; Soukasene, S.; Tawa, M.; MacPhee, M.; Remenar, J.
F. Cryst. Growth Des. 2003, 3, 927−933. (b) Morissette, S. L.;
̈
Almarsson, O.; Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo,
A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R. Adv. Drug Delivery Rev.
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