Crystal structures and physicochemical properties of four new lamotrigine multicomponent forms

Article abstract of DOI:10.1021/cg301556j

In the present study, four new multicomponent forms of lamotrigine (LTG) with selected carboxylic acids, viz. acetic acid, propionic acid, sorbic acid, and glutaric acid, have been identified. Preliminary solid-state characterization was done by differential scanning calorimetry/ thermogravimetric, infrared, and powder X-ray diffraction techniques. X-ray single-crystal structure analysis confirmed the proton transfer, stoichiometry, and the molecular composition, revealing all of these to be a new salt/salt-cocrystal/salt monosolvate monohydrate of LTG. All four compounds exhibited both the aminopyridine dimer of LTG (motif 4) and cation-anion dimers between protonated LTG and the carboxylate anion in their crystal structures. Further, these new crystal forms were subjected to solubility studies in water, powder dissolution studies in 0.1 N HCl, and stability studies under humid conditions in comparison with pure LTG base. The solubility of these compounds in water is significantly enhanced compared with that of pure base, which is attributed to the type of packing motifs present in their crystal structures as well as to the lowering of the pH by the acidic coformers. Solid residues of all forms remaining after solubility and dissolution experiments were also assessed for any transformation in water and acidic medium.

Full text of DOI:10.1021/cg301556j

Article
pubs.acs.org/crystal
Crystal Structures and Physicochemical Properties of Four New
Lamotrigine Multicomponent Forms
Renu Chadha,*,† Anupam Saini,† Sadhika Khullar,‡ Dharamvir Singh Jain,§ Sanjay K. Mandal,*,‡
and T. N. Guru Row∥
†University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India
‡Department of Chemical Sciences, Indian Institute of Science Education and Research, Mohali, Sector 81, Manauli PO, S.A.S. Nagar,
Mohali (Punjab) 140306, India
§Department of Chemistry, Panjab University, Chandigarh-160014, India
∥Solid State and Structural Chemistry Unit (SSCU), Indian Institute of Science, Bangalore-560012, India
S
* Supporting Information
ABSTRACT: In the present study, four new multicomponent
forms of lamotrigine (LTG) with selected carboxylic acids, viz.
acetic acid, propionic acid, sorbic acid, and glutaric acid, have
been identified. Preliminary solid-state characterization was
done by differential scanning calorimetry/thermogravimetric,
infrared, and powder X-ray diffraction techniques. X-ray single-
crystal structure analysis confirmed the proton transfer,
stoichiometry, and the molecular composition, revealing all of
these to be a new salt/salt-cocrystal/salt monosolvate
monohydrate of LTG. All four compounds exhibited both
the aminopyridine dimer of LTG (motif 4) and cation−anion
dimers between protonated LTG and the carboxylate anion in
their crystal structures. Further, these new crystal forms were subjected to solubility studies in water, powder dissolution studies
in 0.1 N HCl, and stability studies under humid conditions in comparison with pure LTG base. The solubility of these
compounds in water is significantly enhanced compared with that of pure base, which is attributed to the type of packing motifs
present in their crystal structures as well as to the lowering of the pH by the acidic coformers. Solid residues of all forms
remaining after solubility and dissolution experiments were also assessed for any transformation in water and acidic medium.
triazine ring (Scheme 1). Thus, it has multiple competitive
hydrogen-bonding sites, that is, donors and acceptors within its
molecular framework, which makes it a potential target for both
cocrystal and salt formation studies. Various researchers
working on LTG have utilized these strategies of salt,16−25
solvate,21,26−32 or cocrystal formation20,33,34 to improve its
INTRODUCTION
■
A significant portion of the crystalline drugs have very low
solubilities1,2 and, consequently, exhibit low bioavailability. This
situation has, in turn, led to an increased effort aimed at
improving the aqueous solubility of poorly soluble drugs. Since
the fundamental physical properties of crystalline material rely
upon the molecular arrangement within the solid, therefore,
altering the interactions between these molecules directly
impacts the physicochemical properties, such as solubility,
stability, and bioavailability of crystalline active pharmaceutical
ingredients (APIs).3 One of the current strategies focuses on
engineering and screening of crystal phases4−8 through
cocrystal9,10 or salt11,12 formation to optimize these properties
of APIs.
Scheme 1. Molecular Structures of Lamotrigine and All the
Coformers Used in This Study
Lamotrigine (LTG) [3,5-diamino-6-(2,3-dichlorophenyl)-
1,2,4-triazine] is an anticonvulsant drug marketed under the
brand name Lamictal and is indicated for adjunctive treatment
of partial and primary generalized tonic-clonic seizures.13 It is a
BCS class II drug having low solublity in water (0.17 mg/mL at
25 °C),14 which limits its absorption and dissolution rate in
water and thus the bioavailability.15 LTG is a basic molecule
with a diamino-triazine ring having a pKa of 5.7 at N4 of the
Received: October 23, 2012
Revised: December 25, 2012
Published: January 7, 2013
© 2013 American Chemical Society
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were obtained overnight, which were filtered, air-dried, and stored in a
glass vial for analysis.
solubility. The current literature shows that coformers
containing carbonyl and amide functionalities are more likely
to form cocrystals with LTG, viz. nicotinamide, methylpar-
aben,20 acetamide,33 phthalimide, pyromellitic diimide, caffeine,
and isophthaldehyde,34 by hydrogen bonding to its amino
groups, whereas all the carboxylic acids tried so far (succinic
acid, fumaric acid, tartaric acid,19 adipic acid, malic acid,
nicotinic acid,20 acetic acid, 4-hydroxybenzoic acid,33 fluoro-
benzoic acid, 2-thiobarbituric acid21) resulted in the salt
formation at the N4 site of LTG. The present work is in
continuation with our latest publication33 on LTG in which we
investigated the competing intermolecular interactions between
LTG and some pharmaceutically acceptable coformers and
subsequent formation of five different muticomponent forms of
LTG with nicotinamide (1), acetamide (2), acetic acid (3), 4-
hydroxy-benzoic acid (4), and saccharin (5). It has been
learned from the literature20,33 that LTG multicomponent
crystals with disrupted aminopyridine homosynthons may
exhibit better solubility profiles in aqueous medium than
under acidic conditions. To further understand this correlation
between solubility and crystal structures, we searched for more
of such LTG crystalline phases by utilizing some selected
carboxylic acids having a pKa value greater than 4 (so that ΔpKa
(pKa base − pKa acid) is less than 3) in order to identify any
cocrystal formation between LTG and carboxylic acids of
higher pKa values.5 Four new multicomponent crystal forms of
LTG with acetic acid (AA), 6; propionic acid (PA), 7; sorbic
acid (SA), 8; and glutaric acid (GA), 9, are identified, and their
complete structural details have been obtained by single-crystal
X-ray analysis. Out of these four forms, 6 and 7 have been
found to be salts, 8 as a salt-cocrystal, whereas 9 as a salt
isobutanolate monohydrate of LTG. The solubility and
dissolution properties of these salts and LTG pure base were
evaluated in water and 0.1 N HCl, respectively. All four
multicomponent forms were found to exhibit higher solubility
than the single component parent drug in pure water, but the
results were found to be reversed in acidic medium. A
correlation of solubility with the crystal packing arrangement
has been investigated based upon the type of synthons retained
or disrupted in these crystal forms. The stability of the reported
forms was also assessed.
LTG-Glutaric Acid (9). LTG (0.256 g, 1 mmol) was dissolved in a
solution of GA in isobutanol (0.067 g, 0.51 mmol). The mixture was
stirred and warmed on a water bath until a clear solution was obtained,
which was then kept at room temperature undisturbed. Single crystals
of 9 were obtained overnight, which were filtered, air-dried, and stored
in a glass vial for analysis.
Differential Scanning Calorimetry (DSC). Differential scanning
calorimetry analyses of all the samples were conducted using a DSC
Q20 (TA Instruments). The samples (3−5 mg) were placed in sealed
nonhermetic aluminum pans and were scanned at a rate of 5 °C/min
in the range of 25−300 °C under a dry nitrogen atmosphere (flow
rate: 50 cc/min). The data were managed by TA Q series Advantage
software (Universal Analysis 2000).
Thermogravimetric Analysis (TGA). TGA analyses of all the
samples were performed on a Mettler Toledo TGA/SDTA 851e
instrument. Approximately 5 mg of each sample was heated from 25 to
300 °C in an open alumina pan at the rate of 10 °C/min under
nitrogen purge at a flow rate of 50 cc/min. The data were managed by
STAR software (9.00).
Powder X-ray Diffraction (PXRD). PXRD patterns were collected
on an X’Pert PRO diffractometer system (Panalytical, Netherlands)
with a Cu Kα radiation (1.54060 Å). The tube voltage and current
were set at 45 kV and 40 mA, respectively. The divergence slit and
antiscattering slit settings were set at 0.48° for the illumination on the
10 mm sample size. Each sample was packed in an aluminum sample
holder and measured by a continuous scan between 5 and 50° in 2θ
with a step size of 0.017°. The experimental PXRD patterns were
refined using X’Pert High Score software.
Fourier Transform Infrared Spectroscopy (FT-IR). A Spectrum
RX I FT-IR spectrometer (Perkin-Elmer, U.K.) was employed in the
KBr diffuse-reflectance mode (sample concentration: 2 mg in 20 mg of
KBr) for measuring IR spectra of the samples over the range of 4000−
400 cm−1. Data were analyzed using Spectrum software.
Single-Crystal X-ray Diffraction (SCXRD). X-ray diffraction data
set for compound 7 was collected on an Oxford Xcalibur (Mova)
diffractometer equipped with an EOS CCD detector and sealed-tube
monochromated Mo Kα radiation (λ = 0.71073 Å) at 120 K, whereas
X-ray diffraction data sets for compounds 6, 8, and 9 were collected on
a Bruker AXS Kappa Apex II diffractometer equipped with a CCD
detector and sealed-tube monochromated Mo Kα radiation at room
temperature (6, 8) and 150 K (9). In each case, data were processed
and appropriate corrections were made using routine procedures. All
structures were solved by direct methods and refined against F2 using
SHELXL-97.35 Hydrogen atoms in the carboxylic acid groups and
amide groups associated with the formation of either a salt or a
cocrystal of LTG were located based on the difference Fourier map
and were refined isotropically wherever possible. All other hydrogen
atoms except those for the water molecule in 9 were placed
geometrically and refined with an isotropic displacement parameter
fixed at 1.2 times Uq of the atoms to which they were attached. A
residual peak of 1.20 e/Å3 in the final difference Fourier map was
located at 1.06 Å away from the H18 atom, indicating no significance
to the final structure of 8. A considerable effort was put to use five
different data sets collected at three different temperatures (150−296
K) to improve the refinement results for 9; however, solvent molecules
could best be refined isotropically with reasonable thermal parameters,
acceptable metric parameters, and refinement parameters, such as
Rvalues and insignificant residual electron densities, as reported here.
Similarly, a residual peak of 1.168 e/Å3 in the final difference Fourier
map was located at 1.48 Å from the oxygen (O5) atom of isobutanol,
indicating no significance to the final structure of 9. Considering the
fact that the OH (O5) group of isobutanol is hydrogen-bonded to the
carboxylate oxygen (O1), this peak can be assigned to an oxygen of
another water molecule. The WINGX package (version 1.70.01)36 was
used for refinement and production of data tables and ORTEP-337 for
structural visualization. All ORTEP representations were made using
POV-Ray38 showing ellipsoids at the 50% probability level. Analysis of
the H-bonding and other noncovalent interactions was carried out
EXPERIMENTAL SECTION
■
Chemicals. LTG was obtained as a complementary sample from
Rantus Pharma Pvt. Ltd. (India). The guest compounds and
crystallization solvents were of analytical reagent grade and purchased
from various commercial suppliers. All of these were used as received.
Sample Preparation. LTG-Acetic Acid (6). A mixture of LTG
(0.256 g, 1 mmol) and AA (0.060 g, 1 mmol) in a 1:1 molar ratio was
dissolved in 10 mL of ethyl methyl ketone by heating at 70 °C and
stirring to get a clear solution, which was slowly evaporated to get
single crystals of 6 that were filtered, air-dried, and stored in a glass vial
for analysis. In contrast to the 1:1 stoichiometric ratio of LTG and AA
used in preparation of 6, compound 3 (reported in our previous
publication33) was obtained by dissolving LTG in an excess of AA.
Interestingly, both compounds 3 and 6 are well-reproducible when
prepared under controlled solvent conditions.
LTG-Propionic Acid (7). LTG (0.256 g, 1 mmol) was dissolved in an
excess of PA by warming slightly to get a clear solution, which was
slowly evaporated to get single crystals of 7 that were filtered, air-dried,
and stored in a glass vial for analysis.
LTG-Sorbic Acid (8). LTG (0.256 g, 1 mmol) was dissolved in a
solution of SA in acetone (0.112 g, 1 mmol), and the mixture was
stirred at room temperature until a clear solution was obtained, which
was then kept at room temperature undisturbed. Single crystals of 8
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Table 1. Melting Points and pKa Values of LTG and Coformers and the Resulting ΔpKa Values for the LTG Multicomponent
Forms
compound
mp (°C)
216−217
171
pKa
5.70
ΔpKa (pKa base − pKa acid)
LTG (free base)
6
a
a
acetic acid
16.64 (mp) , 118 (bp)
175
4.80
0.90
0.83
0.94
1.36*
7
a
a
propionic acid
−21 (mp) , 141 (bp)
4.87
8
175
sorbic acid
9
135
4.76
185
glutaric acid
97−100
4.34*, 5.22
a
Obtained from Merck Index.
using PARST95 and PLATON39 for all the structures. Packing
diagrams were generated using Mercury-2.3.40
Thermal Analysis Utilizing DSC and TGA. DSC and
TGA scans of LTG and its multicomponent forms are shown in
Figures 1 and 2, respectively. The DSC thermogram of LTG
Equilibrium Solubility Studies. Equilibrium solubility of LTG
free base and all four salts has been determined in water. In each
experiment, a flask containing 5 mL of water was equilibrated at 25 °C
in a constant temperature bath. An excess of the solid phase was added
to the flask, and the resulting slurry was shaken at 200 rpm. An aliquot
of slurry was withdrawn after 24 h, filtered through a 0.22 μm
membrane filter, and diluted suitably, and the concentration was
determined by high-performance liquid chromatography (HPLC).
After the last aliquot was collected, the remaining solids were filtered,
air-dried, and analyzed by DSC, PXRD, and FT-IR spectroscopy.
Powder Dissolution Studies. For the powder dissolution studies,
the starting solids were sieved using a Gilson mesh sieve to provide
samples with an approximate particle size of 150 μm. An excess of the
solid phase was added to the flask containing 20 mL of 0.1 N HCl
maintained at 37 °C, and the resulting slurry was shaken at 200 rpm.
An aliquot of slurry was withdrawn at multiple time points up to 6 h,
filtered through a 0.22 μm membrane filter, and diluted suitably, and
the concentration was determined by HPLC. After the last aliquot was
collected, the remaining solids were filtered, air-dried, and analyzed by
FT-IR spectroscopy.
HPLC Studies. In the solubility and dissolution experiments on
samples of LTG and its salt forms, the solution concentration of LTG
was determined by a Waters Alliance HPLC system, which includes a
Waters 2695 separation module, a Waters 2996 Photodiode Array
Detector, and a 4.6 mm × 150 mm SunFire C18, 5 μm column
(Waters Corporation, Milford, MA). Stock standards of LTG for
solubility and dissolution studies were prepared by dissolving LTG in
1 mL of methanol and making up the volume with water and 0.1 N
HCl, respectively. A 70:30 mixture of phosphate buffer (pH 3.5) and
ACN was used to prepare various concentrations of calibration
standards in a range of 1000−33 000 ng/mL. Separations of drug and
coformers were conducted using the mobile phase of a mixture of
phosphate buffer (pH 3.5) and ACN (70:30) pumped at a flow rate of
0.7 mL/min through the column at a temperature of 30 °C. LTG was
detected at 265 nm. Data acquisition and analysis were performed
using Empower 2.0. software.
Figure 1. DSC thermograms of LTG free base and its muticomponent
forms 6−9 along with the coformers used.
Stability Studies. Accurately weighed samples (approximately 100
mg) of pure LTG and its salt forms were placed in loosely capped glass
vials and kept in a stability chamber at 40 °C and 75% RH for 1 month
and then analyzed by PXRD.
showed a single melting endotherm at 217.1 °C, while that of 6
and 7 showed broad endotherms centered at 170.83 and 175.7
°C, respectively, which are accompanied by a weight loss of
17.91% and 22.27%, respectively, in TGA in a temperature
range of 130−190 °C, followed by a sharp melting endotherm
at 217.3 °C. The broad endotherm indicates the melting of the
complexes with simultaneous release of one molecule of AA
and PA from the crystal lattice of 6 and 7, respectively, as
suggested by their theoretical weight loss of 18.98% and
22.43%, respectively. Therefore, DSC and TGA results suggest
6 and 7 to be multicomponent crystals of LTG with AA and PA
in a 1:1 stoichiometry, respectively. The emergence of a sharp
RESULTS AND DISCUSSION
■
The pKa values of pure drug and coformers used in this study
are summarized in Table 1. It is clear from this table that the
difference in pKa values (ΔpKa) between LTG and the selected
carboxylic acids lies in the range of 0−3, thus suggesting the
formation of complexes that can be either salts or cocrystals.
The molecular structures of all the coformers are given in
Scheme 1, and the melting points of complexes along with
those of the coformers are given in Table 1.
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was observed in TGA of 8 before the final melting of this
complex in the range of 160−180 °C, indicating it to be
anhydrous and a new stable phase complex of LTG with SA.
The DSC scan of 9 showed an endotherm at 180.4 °C
(shown in the inset), followed immediately by another sharp
melting endotherm at 185.4 °C. The first endotherm
corresponds to desolvation and is accompanied by a weight
loss of 12.2% in TGA, which correlates with a theoretical
weight loss of 12.5% for desolvation of one molecule of
isobutanol and one water molecule from the crystal lattice of 9,
suggesting a stoichiometry of 2:1:1:1 for LTG/GA/isobutanol/
H2O. Immediately after desolvation, the melting of 9 occurs at
185.4 °C. The binary mixture of LTG-GA started melting at
100 °C only (melting point of GA, 100.6 °C), suggesting that
peaks appearing in the DSC scan of 9 are not due to any
eutectic melting.
Thus, DSC/TGA have shown the existence of multi-
component crystals of LTG with AA, PA, SA, and GA.
PXRD Analysis. All four multicomponent crystals display
unique crystalline PXRD patterns in comparison to the starting
components, indicating the generation of new solid phases.
These unique peaks corresponding to each of the molecular
complexes are shown in Figure 3. Thus, the formation of new
solid phases in these samples has been identified by a
combination of DSC/TGA and confirmed by PXRD analysis;
however, the transfer of protons and hydrogen bonding in these
solids were ascertained only by FTIR spectroscopy and single-
crystal X-ray diffraction studies.
FT-IR Spectroscopy. FT-IR spectroscopy is an excellent
technique to characterize and distinguish cocrystals from salts,
especially when a carboxylic acid is used as a coformer. LTG
shows an IR absorption frequency for a primary amine N−H
stretch at 3448 and 3316 cm−1, a C−H aromatic stretch at 3210
cm−1, and a primary amine N−H bend at 1620 cm−1 (Figure
Figure 2. TGA curves of compounds 6−9.
melting endotherm at 217.3 °C suggests the transformation of
the original crystal lattice of 6 and 7 to that of pure LTG.
The DSC scan of 8 showed a single, sharp melting
endotherm at 175.3 °C that lies in between the melting
temperatures of starting components (LTG, 217.1 °C; SA,
134.4 °C), whereas two different endotherms corresponding to
the melting point of starting components were observed in the
DSC scan of the binary mixture of LTG-SA, thus ruling out the
probability of any eutectic formation. Further, no weight loss
Figure 3. PXRD patterns of LTG free base, coformers, and their multicomponent forms 6−9.
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4). However, changes were observed in IR peaks of the drug as
well as coformers in FT-IR spectra of all four multicomponent
present, which form salts with sorbate ions and cocrystals with
neutral SA molecules, respectively. Thus, IR analysis suggests
compounds 6, 7, and 9 to be salts, whereas 8 to be a salt-
cocrystal.
Crystal Structure Analysis. On the basis of the
information available in the literature, the crystal structure of
LTG is built from hydrogen-bonded dimeric units of the drug
molecule showing two dominant supramolecular synthon
motifs, the aminopyridine dimer (motif 1) and the amine-
aromatic nitrogen synthon (motif 2).20 However, in all four
complexes discussed here, the incorporation of a comple-
mentary coformer breaks motif 1 as well as motif 2 (except in
complex 8), but conserves motif 4. The four different hydrogen
bond motifs possible for the LTG dimer homosynthon have
been represented well in Scheme 2.33 A proton transfer is also
Scheme 2. All of the Four Hydrogen-Bonding Motifs
(Reproduced with Permission from ref 33. Copyright 2011
The Royal Society of Chemistry)
observed from the carboxylic group to the triazine ring of LTG
in all the four complexes, as suggested by FT-IR results.
Crystallographic data, DC−O distances (i.e., carbon−oxygen
distances in the acid carbonyl group), and hydrogen bond
geometries of compounds 6−9 are given in Tables 2−4,
respectively. The comparison of simulated PXRD patterns with
the experimental powder patterns showed that the single crystal
used to obtain the crystal structure was representative of the
bulk of all the samples, except in case of complex 9, where the
correlation is not fairly good, suggesting that the bulk sample of
9 is not very pure (Figure S1, available as Supporting
Information).
Figure 4. FT-IR spectra of LTG free base, coformers, multicomponent
forms 6−9, and LTG hydrochloride salt obtained after dissolution in
0.1 N HCl medium.
forms, which showed characteristic broad bands between 3300
and 1800 cm−1 corresponding to N−H+ signals of amine
hydrogen-bonded salts (absent in spectra of the drug),
suggesting these to be salts of LTG. Further, the shift of the
carboxylic acid CO stretching frequency of AA, PA, SA, and
GA from 1715, 1717, 1695, and 1697 cm−1 to lower
wavenumbers of 1649, 1693, 1675, and 1660 cm−1 in IR
spectra of 6, 7, 8, and 9, respectively, clearly indicates the salt
formation in these compounds, as the absorption moves to a
lower wavenumber if the oxygen atom attached to carbonyl
become ionized. Besides this, in the IR spectrum of compound
8, the primary N−H stretch and N−H bend of LTG is also
observed, being shifted from 3448 to 3442 cm−1 and from 1620
to 1638 cm−1, respectively. This suggests that, in compound 8,
both the protonated and the neutral LTG molecules are
LTG-AA Salt, 6 (1:1). Complex 6 crystallizes in the
monoclinic space group P1, unlike complex 3 (described in
̅
our previous publication33) that crystallized in the monoclinic
space group P21/c. The asymmetric unit of 3 consisted of one
LTG cation and an AA trimer, out of which only one AA
molecule transferred its proton to the triazine ring of LTG
while the remaining two AA molecules were present in the
neutral form, resulting in a 1:3 LTG-AA salt-solvate. In
contrast, the asymmetric unit of 6 consists of two LTG cations
and two acetate anions (Figure 5). Hence, this complex can be
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Table 2. Crystallographic Data for Compounds 6−9
6
7
8
9
chemical formula
C9H8N5Cl2, C2H3O2 C9H8N5Cl2, C3H5O2 C9H7N5Cl2, C9H8N5Cl2, C6H7O2,
C6H8 O2
C18H16N10Cl4, C5H6O4, C4H10O1,
H2O
stoichiometry
formula wt
temp (K)
wavelength (Å)
cryst syst
space group
a (Å)
1:1
1:1
1:1:1:1
2:1:1:1
316.15
296
330.17
736.44
736.44
120
296
150
0.71073
triclinic
0.71073
tetragonal
I41/a (No. 88)
18.6293(4)
18.6293(4)
17.6086(5)
90.000(0)
90.000(0)
90.000(0)
16
0.71073
monoclinic
P21/c (No.14)
9.308(2)
11.356(3)
32.107(8)
90.000 (0)
96.093(4)
90.000(0)
4
0.71073
monoclinic
P21/c (No. 14)
8.8620(6)
16.8932(11)
22.8226(12)
90.000(0)
90.170(11)
90.000(0)
4
P1 (No. 2)
̅
9.5973(6)
11.9400(6)
12.7279(6)
99.038(4)
95.005(4)
90.240(4)
4
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
Z
vol (Å3)
1434.67(13)
1.464
6111.1(3)
1.436
3374.59(13)
1.450
3416.7(4)
1.432
density (g·cm−3
)
μ(mm−1
F(000)
)
0.461
0.436
0.403
0.402
648
2720
1520
1528
θ (deg) range for data coll.
reflns coll.
1.63−25.21
10 735
2.70−24.99
16 898
1.28−25.10
22 805
1.78−25.07
19 092
independent reflns
reflns with I >2σ(I))
Rint
5129
2686
5996
5148
2675
1887
3388
2782
0.0397
0.065
0.081
0.0855
no. of params refined
GOF on F2
372
195
442
397
0.976
1.171
1.044
0.918
a
b
final R1 /wR2 (I >2σ(I))
weighted R1/wR2 (all data)
largest diff. peak and hole (e·Å−3
0.0555/0.1393
0.1223/0.1774
0.0508/0.1374
0.0786/0.1521
0.0683/0.1626
0.1324/0.1987
1.20 and −0.46
0.0695/0.1844
0.1213/0.2042
)
b
0.390 and −0.428
0.531 and −0.366
1.168 and −0.55
a
R1 = ∑∥Fo| − |Fc∥/∑|Fo|. wR2 = [∑w(Fo − Fc2)2/∑w(Fo )2]1/2, where w = 1/[σ2(Fo ) + (aP)2 + bP], P = (Fo + 2Fc2)/3.
2
2
2
2
present in the ab and bc planes, respectively, but instead of
motif 1 in pure LTG, motif 4 is involved in the formation of
both of these dimeric units (Figure 6). In the dimer formed in
Figure 6. The presence of motif 4 and charge-assisted hydrogen
bonding N+H···O− and N−H···O in basic supramolecular unit of
compound 6.
the ab plane, one LTG molecule is linked to one acetate
molecule via N+H···O− charge-assisted hydrogen bonding
(N9+H9A···O2) and N−H···O interactions (N8−H8A···O1),
while the other LTG molecule is linked to one acetate molecule
via N−H···O interactions (N6−H6B···O3). Proton transfer is
evidenced by the C−O bond distances of the carboxylate group
(with ΔDC−O = 0.017 Å; see Table 3) and the geometry of the
Figure 5. Asymmetric unit of 6, showing the atom-labeling scheme.
Displacement ellipsoids are drawn at 50% probability level.
called a 1:1 salt of LTG and AA. In the crystal lattice of
complex 6, two different LTG dimer homosynthons formed by
N−H···N interactions (N6−H6A···N7 and N1−H1B···N2) are
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Table 3. Distribution of C−O Bond Lengths for Compounds
6−9 Formed with Carboxylic Acids
complex coformer
DC−O (Å)
ΔDC−O (Å)
6
AA
1.249(6), 1.266(6) (DC11−O1, DC11−O2
)
)
0.017
0.005
0.006
0.097
0.013
0.016
0.029
1.252(5), 1.247(5) (DC22−O3, DC22−O4
7
8
PA
SA
1.264(3), 1.258(3) (DC10−O1, DC10−O2)
1.211(6), 1.308(6) (DC10−O1, DC10−O2
1.266(6), 1.253(5) (DC25−O3, DC25−O4
1.248(6), 1.264(6) (DC19−O1, DC19−O2
1.244(6), 1.273(6) (DC23−O3, DC23−O4
)
)
)
)
9
GA
LTG triazine ring. The C20−N9−N10 angle of the triazine ring
in the crystal structure of 6 is 121.2(3)°, which correlates well
with the previously reported higher values of protonated
LTG.20,41 Similarly, in the dimer formed in the bc plane, each
LTG molecule is linked to two acetate molecules via N+H···O−
charge-assisted hydrogen bonding (N4+H4A···O4) and N−
H···O interactions (N3−H3A···O3 and N1−H1A···O2). Here
also, a proton transfer has occurred, from O4 to N4, as
evidenced by the C−O bond distances of the carboxylate group
(with ΔDC−O = 0.005 Å) (Table 3) and the C9−N4−N5 angle
of the triazine ring (121.3(3)°). Thus, each discrete unit
consisting of four LTG molecules and four acetate molecules is
linked to four such neighboring units through N−H···N
interactions, resulting in formation of a ladder-type network
(Figure 7). This structural information correlates well the DSC
and TGA results of 6.
Figure 8. Asymmetric unit of 7, showing the atom-labeling scheme.
Displacement ellipsoids are drawn at 50% probability level.
LTG-PA Salt, 7 (1:1). Complex 7 crystallizes in the tetragonal
crystal system in the centrosymmetric space group I41/a. Figure
8 shows the asymmetric unit and the atomic numbering
scheme. The asymmetric unit consists of one LTG cation and
one propionate anion, resulting in a 1:1 salt of LTG and
propionic acid. An LTG aminopyridine dimer homosynthon is
present in the salt structure (N1−H1A···N2), but instead of N2
and N3 in LTG, N1 and N2 are involved in the formation of
the dimeric unit (motif 4). The dimers are further connected to
acids through N+H···O− charge-assisted hydrogen bonding
(N4+H4A···O2) apart from several other N−H···O interactions
(N3−H3A···O1, N3−H3B···O1) (Figure 9a). Proton transfer is
evidenced by the C−O bond distances of the carboxylate group
Figure 9. (a) Basic supramolecular unit of 7. (b) Interactions involving
chlorine atoms in compound 7.
(with ΔDC−O = 0.006 Å) (Table 3) and the angle C9−N4−N5
of the triazine ring (122.8(2)°) of LTG in 7. The crystal
packing is further supported by C−H···Cl hydrogen bonds
(C12−H12B···Cl1, C12···Cl1 3.765(4) Å, H12B···Cl1 2.903(1)
Å, C12−H12B···Cl1 150.0(2)°) (Figure 9b). Four LTG
molecules and four propionic acid molecules altogether form
octameric units connected through N−H···O interactions that
are responsible for the 41 screw symmetry (Figure 10a,b). Thus,
Figure 7. Packing diagram of salt 6 showing the formation of a ladder-type network.
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Figure 10. (a) Octameric unit of compound 7 connected through N−H···O hydrogen bonds. (b) The arrangement of molecules around 41 screw
axis in compound 7 (the white color scheme is used for hydrogen for the packing diagrams for a clear view).
the unusual higher symmetry space group I41/a arises for this
complex.
LTG-SA Salt-Cocrystal, 8 (2:2). Complex 8 crystallizes in the
monoclinic space group P21/c with an asymmetric unit
consisting of a lamotrigine cation and a sorbate anion, along
with a neutral LTG and SA molecule (Figure 11). The
Figure 12. Charge-assisted and neutral hydrogen bonds involved in
acid-LTG heterosynthon formation in the basic supramolecular unit of
compound 8.
Figure 11. ORTEP diagram of the asymmetric unit of compound 8
with 50% thermal ellipsoid probability.
and O−H···N hydrogen bonds (O2−H2···N4) parallel to the a
axis (Figure 13b). A ΔDC−O = 0.097 Å for these SA molecules
molecular packing in 8 involves supramolecular heterosynthons
formed between the aminopyridinium and carboxylate moieties,
through N+H···O− charge-assisted hydrogen bonding
(N9+H9···O4) and a N−H···O hydrogen bond ((N6−
H6B···O3) and between amino and carboxyl moieties through
a N−H···O hydrogen bond ((N8−H8B···O4) (Figure 12).
This results in forming a supramolecular zigzag-type chain that
extends along the b axis (Figure 13a). The proton transfer from
the carboxylic group (atom O4) to the triazine (atom N9) ring
is evidenced by the difference between the C−O bond
distances of the carboxylate group (with ΔDC−O = 0.013 Å)
(Table 3) and the C18−N9−N10 angle of the triazine ring
(122.8(4)°). Another dominant supramolecular synthon
present in the crystal lattice of 8 is the LTG dimer, sustained
by N−H···N hydrogen bonds (motif 4) (N1−H1B···N2). Both
LTG molecules of this dimer are connected to neutral SA
molecules through N−H···O hydrogen bonds (N3−H3B···O1)
proves them to be present as neutral carboxylic acids (ΔDC−O >
0.08 suggests that carboxylic acid is not ionized, but present in
the neutral state), and the C9−N4−N5 angle of 116.4(4)° in
the triazine ring of LTG correlates well with that observed for
the neutral LTG molecule. This suggests that the LTG
molecules involved in the dimer homosynthon (motif 4) are
neutral and are hydrogen-bonded to SA molecules, resulting in
a 1:1 cocrystal. Each such discrete unit, comprising an LTG
dimer hydrogen-bonded to two neutral SA molecules, interacts
with four neighboring supramolecular chains of lamotriginium
sorbate units running along the b axis via N−H···N hydrogen
bonds (motif 2) (N6−H6A···N5) and N−H···O hydrogen
bonds (N3−H3A···O3), thereby generating a 3D structure.
Thus, the overall packing in 8 involves chains formed by
lamotriginium sorbate units running along the b axis, which are
connected by the discrete units of the LTG-SA cocrystal
formed along the a axis. The structure of 8 thus confirms the
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Figure 13. (a) The supramolecular zigzag chains formed by lamotriginium sorbate units running along the b axis. (b) LTG dimer sustained by N−
H···N hydrogen bonds (motif 4) connected to neutral SA molecules through N−H···O hydrogen bonds and O−H···N hydrogen bonds parallel to
the a axis (LTG cations, blue; SA anions, yellow; LTG neutral molecules, green; SA neutral molecules, red).
Figure 14. Asymmetric unit of 9, showing the atom-labeling scheme. Displacement ellipsoids are drawn at 50% probability level.
findings of the FT-IR technique, which suggested the presence
of both the salt and cocrystal peaks in the IR spectrum of 8.
LTG-GA Salt Isobutanolate Monohydrate, 9 (2:1:1:1).
Complex 9 crystallizes in the space group P21/c with the
asymmetric unit consisting of two LTG cations, one glutarate
dianion, and one molecule each of isobutanol and water (Figure
14). In the crystal lattice of 9, the LTG molecules form
aminopyridine dimers sustained by N−H···N hydrogen bonds
(N6−H6C···N7). Interestingly, this dimeric unit involves motif
4, instead of motif 1 found in pure LTG. The homodimers are
connected through the GA molecule, thus forming chains
extending along the c axis. In the chain, one homodimer is
connected to the neighboring GA molecules through N+H···O−
charge-assisted hydrogen bonding (N9+H9···O4) and N−H···O
hydrogen bonding (N8H8B···O3), while the next homodimer
in the chain is connected to neighboring GA molecules via two-
point N−H···O interactions (N6H6D···O2 and N8H8A···O2).
The proton transfer from the carboxylic group (atom O4) to
the triazine (atom N9) ring is evidenced by the C−O bond
distances of the carboxylate group (with ΔDC−O = 0.029 Å)
(Table 4) and the C18−N9−N10 angle of the triazine ring in
the crystal structure of 9 (122.6(4)°), which correlates with the
angle of protonated LTG rather than its neutral form. Further,
each LTG homodimer-GA chain is connected to the adjacent
chain through GA molecules extending via N+H···O− and N−
H···O hydrogen bonds. Thus, these drug homodimer-GA
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Table 4. Geometrical Parameters of Hydrogen Bonds in Compounds 6−9
D−H···A
symmetry
r (H···A) (Å)
compound 6
r (D···A) (Å)
r (D−H) (Å)
∠D−H···A (deg)
N6−H6A···N7
N1−H1B···N2
N9+H9A···O2
N8−H8A···O1
N6−H6B···O3
N4+H4A···O4
N3−H3A···O3
N1−H1A···O2
1 − x, 1 − y, 2 − z
2.09
2.12
2.952(5)
2.974(5)
2.546(5)
2.860(5)
2.798(4)
2.564(5)
2.869(4)
2.999(4)
0.86
175(5)
174
2 − x, 1 − y, 1 − z
−x, 1 − y, 1 − z
−x, 1 − y, 1 − z
0.86
1.57(6)
2.02
1.00(6)
0.86
166(5)
166
2.07
0.86
141
1.60(5)
2.02
0.97(5)
0.86
175(5)
168
1 + x, y, z
2.28
0.86
141
compound 7
1.61(3)
1.918(2)
2.074(2)
N4−H4A···O2
N3−H3A···O1
N1−H1A···N2
N1−H1B···O1
N3−H3B···O1
x + 1, +y, +z
2.634(3)
2.769(3)
2.927(3)
2.790(0.003)
2.963(3)
1.03(3)
170(3)
x + 1, +y, +z
0.860(2)
0.860(2)
0.860(2)
0.860(2)
170.1(2)
171.1(2)
135.7(2)
167.8(1)
−x + 1/2 + 1, −y + 1/2, −z + 1/2 + 1
y + 1/4, −x + 1/4, +z + 1/4
−y + 1/4 + 1, +x + 1/4, −z + 1/4 + 1
2.109(0.002)
2.117(2)
compound 8
1.79
N9+H9···O4
−x, 1/2 + y, 1/2 − z
−x, 1/2 + y, 1/2 − z
1 + x, y, −z
2 − x, 1 − y, −z
−1 + x, y, z
2.641(6)
2.782(6)
2.716(6)
2.924(6)
2.831(6)
2.665(5)
3.021
0.86
0.86
0.86
0.77(6)
0.86
0.82
0.86
0.86
168
173
N6−H6B···O3
N8−H8B···O4
N1−H1B···N2
N3−H3B···O1
O2−H2···N4
N6−H6A···N5
N3−H3A···O3
1.93
1.97
145
2.16(6)
1.98
176(2)
172
1 + x, y, −z
1.88
161
2.26
148
1 + x, 1/2 − y, −1/2 + z
2.20
3.048
169
compound 9
2.07
N6−H6C···N7
N9+H9···O4
N8H8B···O3
N6H6D···O2
N8H8A···O2
O5H5A···O1
N4+H4A···O2
N3H3B···O1
N1H1B···O3
−x, −y, −z
−1 + x, 1/2 − y, −1/2 + z
−1 + x, 1/2 − y, −1/2 + z
2.931(6)
2.632(5)
2.750(5)
2.813(6)
3.006(5)
2.874(8)
2.720(5)
2.798(6)
2.744(6)
0.86
0.86
0.86
0.86
0.86
0.86
0.86
0.86
0.86
179
170
173
133
152
132
163
168
157
1.78
1.89
2.16
−x, −y, −z
2.22
1 − x, 1/2 + y, 1/2 − z
−x, 1/2 + y, 1/2 − z
−x, 1/2 + y, 1/2 − z
2.26
1.89
1.95
1.93
chains result in formation of sheets diagonal to the ac plane
(Figure 15). Each GA molecule is also connected to an
isobutanol molecule via an O−H···O hydrogen bond
(O5H5A···O1) at one carboxyl end and to a water molecule
at another carboxyl end with the isobutanol molecules
extending out from the plane of sheets.
carboxyl moieties of each GA molecule, this complex can be
called a lamotriginium glutarate isobutanolate monohydrate.
The crystal structure of 9 further explains the weight loss step
observed in TGA.
Solubility and Powder Dissolution Studies. Equilibrium
solubility studies of LTG in its free base sample and all the four
multicomponent forms were performed in pure water at 25 °C.
Table 5 shows the maximum concentration of drug achieved in
the free base sample of LTG and its multicomponent forms.
Complexes 6 and 7 have been found to improve the water
solubility of LTG by 16 and 14 times, respectively, whereas 8
and 9 improved it up to 7 times that of the free base sample.
Interestingly, this increase in water solubility corresponds with
decrease in the pH of their solutions in water (which varied due
to the presence of acidic coformers in their crystal lattice), as is
shown in Table 5. This inverse correlation between solubility
and pH in pure water is thus significant in understanding the
solubility behavior of complexes reported in this study. The
DSC and PXRD analyses (Figures S2 and S3 given in the
Supporting Information) of solid residues remaining after the
solubility experiment showed that the pure LTG converted to
LTG hydrate and the salts 6 and 7 and salt-cocrystal 8
remained almost stable under the aqueous conditions, whereas
salt isobutanolate monohydrate 9 transformed to its desolvated
salt form.
The molecular packing in 9 also involves another dominant
set of supramolecular heterosynthons between the amino-
pyridinium of LTG and one carboxylate moiety of GA via
N+H···O− charge-assisted hydrogen bonding (N4+H4A···O2)
and N−H···O hydrogen bonding ((N3−H3B···O1). The
proton transfer from the carboxylic group (atom O2) to the
triazine (atom N4) ring is evidenced by the C−O bond
distances of the carboxylate group (with ΔDC−O = 0.016 Å)
(Table 4) and the C9−N4−N5 angle of the triazine ring
(123.4(4)°). The other carboxylate moiety of this GA molecule
is connected to the next LTG molecule through a N−H···O
hydrogen bond (N3−H3B···O4), thereby forming chains that
run down the a axis. These LTG-GA chains are connected to
the adjacent chains through a N−H···O hydrogen bond (N1−
H1B···O3), thus forming corrugated sheets that extend along
the b axis in the ab plane (Figure 16). These LTG-GA-LTG
sheets intersect homodimer-GA-homodimer sheets, thus
forming an interwoven three-dimensional network (Figure
17). As a proton transfer is clearly evidenced in both the
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Figure 15. LTG dimer-GA-LTG dimer chains in 9 forming sheets diagonal to the ac plane.
Figure 16. Corrugated sheets formed by LTG-GA chains in 9, extending along the b axis in the ab plane.
Figure 17. (a) LTG-GA-LTG sheets intersecting LTG dimer-GA-LTG dimer sheets in compound 9. (b) An interwoven three-dimensional network
of compound 9 (LTG cations involved in dimer-GA-dimer sheets, blue; LTG cations involved in LTG-GA-LTG corrugated sheets, green; GA
dianions, red; isobutanol molecules, pink; water molecules, yellow).
The dissolution profiles for all the new phases at various time
points in 0.1 N HCl at 37 °C are shown in Figure 18 in a
comparison to the LTG free base. In the free base sample, LTG
reached a maximum concentration of 4.05 mg/mL after a time
interval of 25 min, whereas 6, 7, 8, and 9 reached a maximum
concentration of 3.12, 3.28, 3.76, and 4.2 mg/mL, respectively,
at a time interval of 5 min. After reaching the maximum
concentration, the solubility declined slightly before a plateau is
achieved. The concentration of the drug achieved in all the salts
after 6 h of dissolution study in acidic medium was found to be
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motif 2 can increase the solubility in acidic medium, the
presence of motif 4 lowers the solubility of LTG multi-
component forms in acidic medium. Thus, disruption of motif
1 and formation of motif 4 in compounds 6−9 explains their
higher solubility in water, but lower solubility in acidic medium,
respectively, in comparison with LTG free base.
Stability Studies. The physical stability of LTG free base
and its multicomponent forms was investigated at 40 °C/75%
RH for 1 month. The DSC and PXRD results showed the total
conversion of LTG to LTG hydrate while sample 9 was
partially transformed to its desolvated salt form. The PXRD of
6, 7, and 8 showed no apparent form change, indicating these
to be stable under humid conditions (the post-storage DSC and
PXRD results for sample 9 are available as Figures S4 and S5 in
theSupporting Information).
Table 5. Solubility (mg/mL), pH of Slurry, and Potential
Conversion of Multicomponent Forms during Solubility
Studies in Water after 24 h at 25 °C
pH of the
solubility in water at
slurry
conversion during
a
compound 25 °C after 24 h (mg/mL) after 24 h
experiment
LTG
0.154
2.547
2.166
1.119
1.103
6.81
4.91
5.01
5.06
5.15
yes (LTG hydrate)
6
7
8
9
no
no
no
yes (LTG·glutarate)
a
Conversion assessed by DSC and PXRD analyses.
lower than that of the free base LTG sample. This can be
explained by the fact that, in the case of LTG salts, LTG is
already protonated; therefore, lowering the pH of the medium
results in decreased solubility of these salts due to the common
ion effect. However, among the four multicomponent forms,
the salt-cocrystal 8 exhibited the highest stable concentration of
LTG during the dissolution studies in acidic medium. The FT-
IR analysis of solid residues remaining after the experiment
showed that all the samples converted to LTG hydrochloride
salt in the HCl medium. The pH of all the solutions resulting
after the slurry experiment was also measured, but no
significant pH change was observed, suggesting that dissolution
profiles in the acidic medium were not affected by the pH.
According to the crystal packing−solubility relationship
observed in LTG and its multicomponent forms by Cheney
et al,20 the breaking of motif 2 but retention of motif 1 resulted
in improved concentrations of LTG in acidic medium, whereas
the breaking of motif 1 increased the concentration in water.
The solubility results obtained in the present study are in good
agreement with the observations made by Cheney et al.20 In all
the four complexes 6−9, motif 1 is broken, which accounts for
their higher solubility in water than the free base LTG.
However, the solubility of all of these compounds in acidic
medium is lower than that of pure LTG despite the breaking of
motif 2 (except 8, where motif 2 is retained). This can be
accounted for by the formation of motif 4 in compounds 6−9.
This correlates well with that found in the case of LTG-4-
hydroxybenzoate by Chadha et al.,33 where this compound,
possessing motif 4, exhibited lower solubility than pure LTG at
pH 2. Thus, it can be inferred that, although the breaking of
CONCLUSION
■
The work described herein illustrates the complete structural
characterization of four new multicomponent forms of LTG
that have been identified to be a salt/salt-cocrystal of LTG. The
formation of new solid phases in each case was indicated by
DSC/TGA and PXRD, whereas the confirmation of the salt/
salt cocrystal was performed by FT-IR analysis and single-
crystal X-ray diffraction studies. All compounds in this study
exhibited the breaking of motifs 1 and 2 that are present in the
crystal structure of LTG, but displayed a different motif of the
aminopyridine dimer homosynthon (motif 4), except in the
case of salt-cocrystal 8, which involved both motifs 2 and 4.
This arrangement of packing motifs resulted in a significant
improvement in water solubility of complexes 6−9, but lowered
their solubility in acidic medium as compared to that of free
base LTG. The analysis of solids remaining after the solubility
experiment in water and stability studies under high humidity
conditions showed that LTG free base converted to its hydrate
form and salt isobutanolate hydrate 9 transformed to its
desolvated salt form, whereas 6, 7, and 8 remained stable even
under 100% aqueous conditions. Thus, the work details an
effort to prepare and characterize new multicomponent forms
of LTG, having better solubility and stability in water than free
base LTG.
Figure 18. Powder dissolution studies of LTG free base and its multicomponent forms 6−9 at various time points in 0.1 N HCl at 37 °C.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Comparison of experimental PXRD patterns with the simulated
patterns, postdissolution DSC and PXRD data, post-storage
data for compound 9, and crystallographic CIF files. This
material is available free of charge via the Internet at http://
pubs.acs.org. CCDC reference numbers for compounds 6−9
are 904852, 821041, 904853, and 904854, respectively.
AUTHOR INFORMATION
Corresponding Author
*E-mail: renuchadha@pu.ac.in (R.C.), sanjaymandal@
iisermohali.ac.in (S.K.M.). Tel: +91-9316015096 (R.C.), +91-
9779932606 (S.K.M.).
■
(30) Janes, R. W.; Lisgarten, J. N.; Palmer, R. A. Acta Crystallogr.
1989, C45, 129−132.
Notes
The authors declare no competing financial interests.
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(32) Sridhar, B.; Ravikumar, K. Mol. Cryst. Liq. Cryst. 2007, 461,
131−141.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the funding provided by the UGC
(Research Fellowship for Meritorious Students), New Delhi,
India. A.S. and S.K. are grateful to UGC and CSIR, respectively,
for research fellowships. The X-ray facility at IISER, Mohali, is
gratefully acknowledged.
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