Cocrystals of lamotrigine based on coformers involving carbonyl group discovered by hot-stage microscopy and DSC screening

Article abstract of DOI:10.1021/cg201426z

Four novel lamotrigine cocrystals, namely, 1:1 lamotrigine:phthalimide (1), 1:1:1 lamotrigine:pyromellitic diimide:DMF (2), 2:1:0.64 lamotrigine:caffeine: 3-pentanone (3), and 1:1 lamotrigine:isophthaldehyde (4), were discovered using a combined hot-stage thermomicroscopy and differential-scanning calorimetry screening technique. The utilized cocrystal screening method is rapid, requires the use of small amounts of material, and is highly suitable for compounds that are prone to solvate formation. The structurally characterized cocrystals were prepared in an attempt to develop lamotrigine cocrystals based on cocrystal formers involving carbonyl and amide functional groups. The prepared cocrystals are sustained by N-H(amide)???N(pyridyl), N-H(amino) ???O(amide), and N-H(amino)???O(carbonyl) hydrogen bonds.

Full text of DOI:10.1021/cg201426z

Article
pubs.acs.org/crystal
Cocrystals of Lamotrigine Based on Coformers Involving
Carbonyl Group Discovered by Hot-Stage Microscopy and
DSC Screening
Edislav Leksic,*,† Gordana Pavlovic,‡ and Ernest Mestrovic†
̌
́
́
̌
́
†PLIVA Croatia, Ltd., Research and Development, Prilaz baruna Filipovica
‡Laboratory of General Chemistry, Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb,
Prilaz baruna Filipovica 28a, 10000 Zagreb, Croatia
́
29, 10000 Zagreb, Croatia
́
S
* Supporting Information
ABSTRACT: Four novel lamotrigine cocrystals, namely, 1:1 lamotrigine:phthalimide (1), 1:1:1 lamotrigine:pyromellitic
diimide:DMF (2), 2:1:0.64 lamotrigine:caffeine:3-pentanone (3), and 1:1 lamotrigine:isophthaldehyde (4), were discovered
using a combined hot-stage thermomicroscopy and differential-scanning calorimetry screening technique. The utilized cocrystal
screening method is rapid, requires the use of small amounts of material, and is highly suitable for compounds that are prone
to solvate formation. The structurally characterized cocrystals were prepared in an attempt to develop lamotrigine cocrystals
based on cocrystal formers involving carbonyl and amide functional groups. The prepared cocrystals are sustained by
N−H(amide)···N(pyridyl), N−H(amino)···O(amide), and N−H(amino)···O(carbonyl) hydrogen bonds.
The poor aqueous solubility of lam may be attributed to its
tendency to form an extensively hydrogen-bonded network in
the solid state.3 Within the network, the lam molecules are held
together by strong N−H(amino)···N(pyridyl) hydrogen bonds
that participate in the formation of both R22(8) and R32(8)
homosynthons (Figure 1). Numerous attempts have so far been
made to obtain crystalline lam phases wherein lam forms
crystalline architectures that are more soluble in aqueous media.
These attempts yielded, cited by reference codes or their working
titles, so far 8 solvates; (KADPAG,4 WUVLIJ,5 XUVLOP,6
WUVLOP,5 OVUNAV,7 YERTAR,8 IJAHOR,9 OVOMUO7),
17 salts (YUCRAQ,3 YUCREV,3 WUVKUU,5 WUVLAB,5
WUVLEF,5 OVUMOI,7 OVUMEY,7 GAVLEV,10 YEXFUD,11
FOXLUA,12 FUHVOU,12 FOXMEL,12 WUVKOO,12 lam:ace-
tate,13 lam:4-hydroxy benzoate,13 KUZMUO,14 QEJHUI15), 4
cocrystals (WUVKEE/WUVKEE01,5 WUVKII,5 lam:aceta-
mide13), and notably, no lam polymorphs.
1. INTRODUCTION
Lamotrigine (i.e., 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-dia-
mine, lam; Scheme 1) is an anticolvulsant1 that exhibits very
Scheme 1. Chemical diagrams of lam and four cocrystal
formers; ptl, pmd, caf and ipa
Crystal engineering and cocrystals have recently emerged
as viable means to design and fabricate APIs with enhanced
poor solubility in water. This active pharmaceutical ingredient
(API) was primarily developed for treatments of epilepsy and
bipolar disorders, but it has also been reported as beneficial in
the treatment of specific cluster headaches and migraines.2
Received: October 27, 2011
Revised: March 5, 2012
Published: March 6, 2012
© 2012 American Chemical Society
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method, also commonly called contact method by McCrone,27
is nowadays widely used for fast cocrystal screens of binary
system. On the basis of known melting points of the cocrystal
components, the Kofler contact method provides information
about the formation of new solid phases or eutectic mixtures
formation. DSC23 is also a powerful and rapid cocrystal screening
method, and is particularly useful if utilized in combination with
HSM as presented in this work. Both screening methods are
solvent free and, therefore, sustainable and require only very
small quantities of the cocrystal components.
It is of high importance to state that cocrystal screening
involving lam, based on liquid evaporation technique, could be
misleading because of lam’s tendency for solvates formation or
to its relatively low solubility in organic solvents. The results
of experiments obtained by combination of HSM and DSC
experiments indicated that cocrystal phase must exist and that
under suitable crystallization conditions cocrystal phase can be
isolated by solvent evaporation.
We herein reported the results of our cocrystal screen, as well
as four cocrystal structures of lamotrigine, namely the lam:ptl
cocrystal (1:1) (1), the lam:pmd:DMF solvate cocrystal (1:1:1)
(2), the lam:caf:3-pentanone solvate cocrystal (2:1:0.64) (3)
and the lam:ipa cocrystal (1:1) (4) (Scheme 1).
Figure 1. Hydrogen-bonding motifs observed in the crystal structure
of lam.3
physicochemical properties (e.g., solubility,16 stability,17 com-
pressibility,18 etc.). With this in mind, a study of supramolecular
synthons and understanding the hierarchy in lam multi-
component solids is required. Our working hypothesis is
based on the presumption that lam cocrystals with disrupted
aminopyridine homosynthons may exhibit better solubility
profiles in aqueous media. Because of the literature data, it has
been shown so far that carboxylic acids are suitable salt formers
with lam but not cocrystal formers.
Considering the relatively small number of carboxylic acids in
the GRAS and EAFUS lists,19 as well as the large abundance
of aldehydes, ketones and amides in these lists, we recognized
the need to develop lam cocrystals based on supramolecular
synthons involving carbonyl and amide groups. That ketones
are indeed worthwhile being considered as suitable cocrystal
formers for lam was shown in a Cambridge Structural Database
(CSD)20 survey (Supporting Information Table S1). Specifi-
cally, there are two polymorphs of lam cocrystals with
methylparaben; one with disrupted both motifs 1 and 2, and
the other with preserved motif 1.5 The crystal structure of lam:
nicotinamide cocrystal also disrupts motif 2,5 while acetamide
cocrystal preserves motif 1.13
We have, therefore, preformed a cocrystal screen involving
various carbonyls and amides shown in Scheme 1. Although
cocrystal formers used in this study are mainly not listed as
GRAS and EAFUS compounds, they still represent valuable
model compounds for the development of lam cocrystals
involving on coformers based on carbonyl and amide
functionalities. The cocrystal formers were selected based
on their presumed inability to form salts. Both phthalimide
and piromellitic diimide exhibit pKa values (i.e., 8.3 and 8.5,
respectively) that do not support salt formation with lam
(pKa(lam) = 5.7) since the cocrystal components exhibit a
negative ΔpKa value.21
To screen for lam cocrystal formation, we used hot-stage
microscopy (HSM)22 and differential scanning calorimetry
(DSC).23 Thermomicroscopy of organic compounds is one of
the oldest and simplest methods suitable for screening purposes.
This fast technique allows the fast identification of polymorphs,
solvates and hydrates, as well as the study of material
decomposition and phase transitions.24 The microscopic
observation of thermally treated binary systems was initially
described by Lehmann25 and later on refined by Kofler.26 This
2. MATERIALS AND METHODS
2.1. Materials. Lamotrigine was supplied from the in-house source
with purity of 99.9%. Pyromellitic diimide (97%) has been supplied
by Alfa Aeser. Anhydrous caffeine (99%) has been supplied by
Fluca while phthalimide (98%) and isophthaldehyde (97%) have been
supplied by Sigma-Aldrich. All chemicals were used without further
purification.
2.2. Synthesis of the 1:1 lam:ptl Cocrystal, 1. lam (0.064 g,
0.25 mmol) was dissolved in 5 mL of hot 3-pentanone. The hot
solution was subsequently filtered into a glass vial, and a 3-pentanone
solution (2 mL) of ptl (0.037 g (0.25 mmol) was added to the
lam solution. The obtained solution was filtered and left to evaporate
slowly at room temperature. The crystallization vial was covered with
perforated paraffin film. Colorless and hexagonal crystalline plates
suitable for single crystal X-ray diffraction emerged after 6 days.
2.3. Synthesis of the lam:pmd:DMF Solvate Cocrystal (1:1:1),
2. lam (0.128 g, 0.50 mmol) was dissolved in 2 mL of hot
dimethylformamide DMF, while pmd (0.108 g, 0.50 mmol) was
dissolved in 3 mL of hot DMF. The solutions were hot-filtered and
mixed in a glass vial. The obtained solution was left to evaporate at
room temperature. After 3 days, white crystals of pyromellitic diimide
appeared. Yellow prisms of 2 were isolated after 14 days as a second
fraction.
2.4. Synthesis of lam:caf:3-Pentanone Solvate Cocrystal
(2:1:0.64), 3. lam (0.128 g, 0.50 mmol) was dissolved in 15 mL of hot
3-penthanone, whereas caf (0.097 g, 0.50 mmol) was solubilized in
12 mL of the same solvent. The solutions were filtered while still hot
and subsequently combined in a glass vial that was covered by paraffin
in order to slow down the solvent evaporation. After 10 days of solvent
evaporation, colorless prisms were isolated from the crystallization
vial. The harvested crystals were small in size and were, thus, used as
seeds in other crystallization trials. To prepare a single crystal of 3, a
concentrated suspension of 3 was prepared. The suspension was hot-
filtered and cooled to room temperature and then filtered once more.
Several previously obtained small single crystals of 3 were added to
the filtrate to seed the formation of sizable single crystals. Slow
evaporation at room temperature was achieved by covering the glass
vial with a paraffin film with a small hole. Single crystals of 3 suitable
for single crystal X-ray diffraction were obtained after 7 days.
2.5. Synthesis of the lam:ipa Cocrystal (1:1), 4. lam (0.05 g,
0.20 mmol) was dissolved in 4 mL of methyl−ethyl ketone by heating.
The solution was filtered while hot and added to a glass vial containing
ipa (0.027 g, 0.20 mmol). The obtained suspension was mixed until all
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Table 1. Crystallographic Data for 1, 2, 3, and 4
1
2
3
4
chemical formula
stoichiometry
C17H12Cl2N6O2
1:1
C22H18Cl2N8O5
1:1:1
C29.20H29.40Cl4N14O2.64
2:1:0.64
C17H12Cl2N5O2
1:1
Mr
403.23
545.34
760.51
389.22
crystal system, color and habit
monoclinic, colorless hexagonal
plate
triclinic, yellow prism
monoclinic, colorless
prism
monoclinic, colorless
plate
crystal dimensions (mm3)
0.55 × 0.48 × 0.24
P21/c
0.52 × 0.44 × 0.39
P1
̅
2
0.58 × 0.34 × 0.22
P21/n
0.35 × 0.28 × 0.11
P21/c
space group
Z
4
4
4
a (Å)
15.4408(4)
7.9449(2)
14.8452(4)
8.5495(2)
10.9017(3)
13.8187(4)
91.066(2)
107.330(2)
94.090(2)
1225.29(6)
1.478
10.6828(3)
14.0628(3)
23.7907(5)
16.8971(10)
8.0443(4)
13.4064(7)
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å3)
ρ(calcd)/g cm−3
T (K)
105.774(3)
95.746(2)
97.556(5)
1752.56(8)
3556.12(15)
1.420
1806.45(17)
1.431
1.528
296(2)
296(2)
105(2)
296(2)
reflns collected, unique, Rint., observed
[I ≥ 2σ(I)]
4794 (0.1028) 2620, 1997
18987 (0.0206) 4376,
3706
22415 (0.0331) 6347,
5506
5145 (0.0278) 2697,
1578
R1 [I ≥ 2σ(I)]
R2 (all data)
0.0706
0.0447
0.0582
0.0463
0.1795
z0.1367
1.132
0.1722
0.1164
GOF on F2, S
0.973
1.029
0.831
max. and min. electron density (e Å−3
)
0.637, −0.52
0.411, −0.55
1.014, −0.54
0.33, −0.22
particles were dissolved. The solution was covered by a perforated
paraffin film and let to evaporate at room temperature. The solution
yielded colorless crystalline plates of 4 after 1 day. Noteworthy,
crystals of 4 were observed to form only on the walls of the vial, while
the bottom of the vial held a physical mixture of the starting materials.
2.6. Desolvatation of 3. The unsolvated lam:caf cocrystal was
obtained by either (a) heating the 3 to a temperature of 184 °C in the
DSC, and (b) by heating a milled 2:1 physical mixture of lam and caf.
The transformations of the two solids into the unsolvated lam:caf
cocrystal were monitored by XRPD.
2.7. Mechanochemical Experiments. Solid-state grinding
performed using binary mixtures containing lam and one of the
studied cocrystal formers. About 1 g of the physical mixture (1:1) was
ground in a Pulverisettte 7 planetary ball mill. Samples were grounded
in 12 mL SiN jars with 7 SiN balls (10 mm in diameter) with 600 rpm
for either 30 and 60 min. Solvent-drop grinding was performed under
the same conditions with the addition of about 3 drops of the same
solvent from which single crystals were isolated. All obtained solids
were characterized by XRPD.
2.8. Hot-Stage Optical Microscopy. Thermomicroscopic experi-
ments were performed with an optical polarizing microscope (Olympus
BX51) equipped with a Linkam hot-stage microscope THMS 600
being connected to a TMS 94 temperature controller. The micro-
graphs were recorded at 50× magnification using a JVS camera being
attached to the microscope. Samples were heated with constant heating
rate of 10 and 20 °C/min over a temperature range from 25 °C until
the melting of substance with higher melting point. The samples were
discontinued upon melting. The hot-stage was controlled by the
Lynksys 32 software package (version 1.96).28
2.8.1. Mixed Fusion (Contact) Method. Two components under
observation are brought in physical contact by melting them between a
glass microscope slide and a coverslip. Small quantity of powder of the
component with higher melting point is placed on one side of covered
glass slide and heated on Kofler bench. The liquid passes within the
slide and coverslip and fulfils one-half of the glass surface. After the
solidification of the component on the opposite glass side, component
with lower melting point is placed and heated until it is melted and
spread within the glass slide and a coverslip. When the second molten
component is being brought into the contact with the first component
it causes partial solubility of the first component. By solidification
mixing zone is created and it is observed during heating in hot-stage
experiments.
2.9. Thermal Analysis (DSC). DSC profiles were generated in the
range of 30−250 °C using a TA Instrument Q1000. About 3−5 mg of
the sample was encapsulated in a pierced Al pan. The same empty pan
was used as reference. A nitrogen purge at 50 mL/min was employed.
The resulting data were analyzed using the TA Instruments Universal
Analysis 2000 software (version 4.7A).29
2.10. Single Crystal X-ray Diffraction. Single-crystal analyses of
1−4 were performed on a Oxford Xcalibur Gemini diffracto-
meter equipped with a Sapphire CCD detector and graphite-mono-
chromated Cu Kα radiation (λ = 1.5418 Å). The diffraction data for
1, 2, and 4 were collected at 296(2) K, while the data for 3 was collected
at 105(2) K. All diffraction frames were collected using ω-scans
(Table 1).
The CrysAlis CCD and CrysAlis RED (Version 1.171.33.66)
programs were employed for data collection, cell refinement and
data reduction.30 The Lorentz-polarization effect was corrected and
the diffraction data have been scaled for absorption effects by the
multiscanning method. The structures were solved by direct methods
and refined on F2 by weighted full-matrix least-squares. SHELXS9731
and SHELXL9731 (being integrated in the WinGX version 1.80.05
software package) were used to solve and refine the structures. All
non-hydrogen atoms were refined anisotropically. Hydrogen atoms
belonging to C(sp2) and C(sp3) carbon atoms were placed in
geometrically idealized positions with isotropic displacement param-
eters fixed at 1.2 times Ueq (for C(sp2) carbon atoms) or 1.5 times Ueq
(for methyl groups) of the atoms to which they were attached and
they were constrained to ride on their parent atoms. Hydrogen atoms
of the lam amino groups (belonging to the N3 and N5 nitrogen
atoms) or of coformers ptl in 1 and pmd in 2 were located in
difference Fourier maps as small electron densities at final stages of
the refinement procedures. These H-atom coordinates were refined
freely with isotropic displacement parameters being set at 1.2 Ueq of
the corresponding nitrogen atoms. In the structure of 2, the DMF
molecule were found to exhibit positional disorder (53:47) with CO
distances restrained by DFIX instruction to 1.22(1) Å. The
occupancies of atoms belonging to 3-pentanone solvent molecule in
3 were refined as free variables and fixed at 0.64 at the end of the
refinement in order to shorten the molecular formula of 3. One of the
aldehyde groups in the ipa coformer molecule in 4 exhibits a stacking
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Table 2. Synthon Types (Denoted as A, B, C, D, or Their Combination) Established in lam Structures and Its Derivatives
disorder in the crystal structure. The disorder has been modeled into
two alternating positions in a 0.57:0.43 ratio, thus indicating differently
stacked ipa molecules within the crystal structure of 4. ORTEP views
(Supporting Information Figures S8−S11) of the molecular structures
show the major occupation site of the aldehyde group denoted as A,
and minor one as B. Molecular geometry calculations (including
H-bonding and noncovalent interactions) were performed using the
PLATON32 and PARST33 programs being integrated in the WinGX
software system.34 ORTEP-335 was used for molecular visualization.
Packing diagrams were generated using Mercury.36
2.11. Cambridge Structural Database Survey. The Cambridge
Structural Database (CSD)20 (version 5.32, update of Nov 2011) was
surveyed for structures containing 1,3-diaminotriazine (Scheme 1),
and was carried out using ConQuest37 (version 1.13) and performed
without the use of any filters (e.g., organic compounds, determined
3D-coordinates, etc.). CSD was in addition surveyed to examine the
number of cocrystals containing carbonyl group according to the
applied filters and by hand selection.38
with a 1,3-diaminotriazine moiety, whereof 30 related to a lam
structure and another 5 to a lam analogue (i.e., BEZGUI,
CIQLET, LINFOD, TEKWAH, and WINMIP). Including
the literature search a total of 38 structures containing a
1,3-diaminotriazine structure were found.13 Among the 38
multicomponent structures, we identified various structural
motifs, which we divided in five classes (i.e., A, B, C, D or their
combination (AB), Table 2) in contrast to motif 1 and motif 2
that relate to lamotrigine structure itself.
Structural motif A is a R42(16) synthon that can be regarded
as a combination of the aminopyiridine R22(8) homosynthon
(motif 1 in lam)3 that is based on N−H(amino)···N(pyridyl)
hydrogen bonds, and a R32(8) synthon based on
N−H(amino)···N(pyridyl) and N−H(amino)···O hydrogen
bonds, whereby the hydrogen-bond-accepting O-atom belongs
to either water,6 DMF,8 acetamide13 or an alcohol.4,5,7,9 Based on
this observation, we proposed that oxygen atoms belonging to
the carbonyl groups of aldehydes and ketones could potentially
participate in the formation of motif A. Such proposition is
additionally supported by the large number of crystal structures
deposited in the CSD that entail functional groups analogous
to amino-triazine ring being bound to carbonyl moieties via
3. RESULTS AND DISCUSSION
3.1. Synthon Analysis. A combined literature and CSD
survey were performed to evaluate the feasibility of using
ketones and amides as cocrystal formers for the synthesis of
lam cocrystals. The survey of CSD base revealed 35 entries
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N−H(amino)···O(carbonyl) hydrogen bonds (Supporting In-
formation Table S1).
Structural motif B is heterosynthon R22(8) based on charge
assisted N+-H(amino)···O−(carboxy) hydrogen bonds. This
structural motif was found in lam salts involving carboxylic
acids. It is presumed that other strong hydrogen-bonding
functionalities, such as amides, might be able to be bounded to
the 1,3-diaminotriazine lam ring.
Besides described motifs two other, motif C and motif D,
have been recognized among structures and could be utilized in
further crystal engineering approach in cocrystal design.
3.2. Screening and Characterization. Thermomicro-
scopy was employed to evaluate the potential ptl, caf, pmd
and ipa to form cocrystals with lam. Samples for the micro-
scopic examinations were prepared by the Kofler contact
method.22a Additional DSC measurements were performed for
each binary 1:1 homogenized mixture to gain a better
understanding of the thermal events revealed by HSM.
Visual investigations of samples containing lam and ptl
showed a solid phase of ptl and the amorphous lam phase
being divided by the mixing zone. The amorphous state of lam
was supported with a series of combined XRPD and DSC
measurements. The mixing zone is formed by melting ptl in
lam on a Kofler’s bench and is in a glassy state. It was observed
that the mixing zone turns into a liquid at 177 °C whereby at
the same time lam starts to crystallize. No other thermal events
were observed until the melting point of lam (217.1 °C). Once
the heating was stopped at about 190 °C and the sample was
allowed to cool down to room temperature, the liquid mixing
zone solidified with a different molar ratio (as compared to the
initial glass formation) and a new phase becomes visible on the
lam side of the glass slide. When a new cycle of heating is
applied, the new phase serves as a nucleus in a crystallization
event that starts at about 125 °C from the residual glassy phase
of the mixing zone. At about 200 °C the new phase completely
fulfils the gap between the lam and ptl phases. The melting
points of two eutectics were shown to be close to the melting
points of the new phase. At about 205 °C the liquid zone is
visible between the new phase and lam (Figure 2). The new
phase melts about 207 °C (Figure 3).
Figure 3. Contact area of lam:ptl system at 207 °C in second heating
cycle. Cocrystal phase (C) melting is ongoing and solid phase is placed
between two liquid zones, presenting eutectic melts (D). Lam (B) and
ptl (A) are in the solid state and melt at the end in accordance to their
melting point temperatures.
The process described above was shown to be reversible in
numerous heating/cooling cycles. The DSC profile of the
physical mixture of lam and ptl revealed an endothermic peak
at 177.0 °C that was attributed to the fusion of eutectic
mixtures (Figure 4).
Figure 4. DSC profiles of caf (1), lam (2), ipa (3), ptl (4), binary
mixture of lam and ptl (5), binary mixture of lam and caf (6), and
binary mixture of lam and ipa (7) (endothermic signal down).
The small exothermic peak at 178.9 °C suggests both the
clustering of molecules in the eutectic melt and a recrystalliza-
tion event indicating interaction between lam and ptl. The
DSC thermogram revealed three additional endothermic signals
at 198.2 °C, 202.6 °C (weak), and 206.7 °C (strong) that cor-
responds to the melting of the eutectic mixture (lam/ptl), the
melting of a mixture of the eutectic and the new phase, and the
melting of the new phase, respectively. Notably, the melting
point of the new phase (i.e., 206.7 °C) was found to be in good
agreement with the melting point of solid 1 (i.e., 205.5 °C) that
has been determined by DSC using a batch of single crystals
(Figure 5).
Figure 2. Contact area of lam-pht system at 205 °C in second heating
cycle. Cocrystal phase (C) is placed centric. Eutectic lam:cocrystal
starts to melt (D) on the board with solid lam (B). Ptl is in the solid
state (A).
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Figure 5. DSC profiles of cocrystals 1, 2, 3, and 4 (endothermic signal
down).
Figure 6. Contact area of lam−caf system at 190 °C. Eutectic
caf:cocrystal (D) is melted. Lam (B) still undergoes crystallization.
The new cocrystal phase (C), in the middle of lam (B) and eutectic
melt (D) is visible.
A physical mixture of lam and ptl 1:1 was melted on Kofler’s
bench and XRPD pattern was compared with the XRPD
pattern of batch of single crystals. Two examined patterns
proved the same crystalline cocrystal form. In addition,
mechanochemical experiments showed that the same poly-
morph form can be obtained by milling in a ball without using
any solvents to facilitate cocrystal formation. Noteworthy,
the reaction mixture undergoes a phase transformation after
30 min of grinding to result in the formation of an amorphous
solid. Further grinding resulted in partial cocrystal formation, as
evidenced by PXRD (Supporting Information Figure S1).
A DSC curve of the milled sample revealed only the
crystallization of the amorphous lam phase and the melting
of 1: no signs of fusion of the eutectic mixture were observed.
Solvent drop grinding with 3-penthanone, on the other hand,
significantly enhanced the mechanochemical reaction yields.
The increase of the reaction yield was attributed to the
increased molecular mobility of lam through the presence of
3-pentanone, a fairly good solvent for lam.
Figure 7. Contact area of lam-caf system at 200 °C. Lam (B) and caf
(A) exist in solid state, while the cocrystal phase is completely melted.
In the case of lam and caf, the sample prepared by the Kofler
contact method clearly shows the formation of a mixing zone
between the solid caf phase and the amorphous lam phase.
Heating of the initially prepared sample allows the observation
of two thermal events occurring at the same time. Specifically, a
strong strip in the range of the mixing zone appears at about
130 °C, indicating the formation of a new phase. Second event
relates to the crystallization of amorphous lam influenced by
heat. The first eutectic (caf/cocrystal) melts at about 190 °C
(Figure 6).
At about 196 °C, the new phase is completely melted (Figure 7).
DSC experiment on the physical mixture shows a broad
endothermic peak at 175.8 °C (Figure 4). This peak cor-
responds to the melting of the eutectic (lam/caf). This was
evidenced by XRPD experiments on a sample obtained by
heating the physical mixture of lam and caf (2:1) up to 168 °C
in the calorimeter. Besides physical mixture, XRPD evidenced
traces of new crystalline phase crystallized from melt (the
solid is described below as unsolvated form of 3, Supporting
Information Figures S2 and S3). Single crystals of 3 were
isolated from 3-pentanone in the form of solvate. The DSC
profile shows three thermal events (Figure 5). The first
endothermic peak was observed at 177.6 °C and was attributed
the desolvatation process (Figure 8), as demonstrated
by a mass loss in related TGA measurements (Supporting
Information Figure S4).
The desolvation is followed by a small exothermic peak
indicating the recrystallization of initial solvated phase and
a new phase formation. The new unsolvated form melts at
194.9 °C. The reversible transformation to 3 was proved by
slurring the unsolvated form in 3-pentanone. The preparation
of 3 was also attempted mechanochemically. In particular, lam
and caf 2:1 was ground in a ball mill and the resulting solid was
shown to be amorphous, as revealed by XRPD. Solvent drop
grinding was shown to enhance cocrystal formation (Support-
ing Information Figure S5), and the observed reaction yields
were proportional to the amounts of solvent (i.e., 3-pentanone)
added to reaction mixture. The dependence of reaction yields
on the amount of solvent is not surprising considering that
3-pentanone is built into the lam:caf crystal lattice.
Microscopic observations of lam and ipa physical mixtures
revealed no interaction between the two compounds prior to
heating. The mixing zone does not even appear when the pre-
pared sample is isothermally treated at 60 °C on Kofler’s bench.
We also note that heating at lower rates (i.e., 1−10 °C/min)
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Figure 8. Desolvatation of 3. Crystals 3 at room temperature (A), losing the transparency at about 182 °C (B), and crystal melting at 188 °C (C).
allows to observe melting of ipa, which is being followed by the
melting of lam. We found that the DSC trace of the physical
mixture (ground for 1 min) consists of two close endothermic
peaks, one corresponding to the melting of ipa at 87.4 °C and the
another one relating to the formation of the new solid form at
115.0 °C (Figure 4). The same HSM experiment were also
performed using increased heating rate, that is, 20 °C/min and
lead to the observation of two eutectic melting points, as well as
the formation of a new phase. We found that the first eutectic
(ipa/cocrystal) melts at a temperature close to the melting point
of ipa (i.e., ∼86 °C) (Figure 9).
Figure 10. Contact area of lam−ipa at about 100 °C. Eutectic (D) is
completely melted making cocrysatlline phase (C) separated from lam
solid (B). ipa is present in liquid state (A).
grinding involving DMF as solvent. The reaction yields were
also found to be proportional with the amounts of DMF used,
as DMF is built into the crystal lattice during cocrystal forma-
tion (Figure S7). Single crystals of 2 were also isolated from
DMF. DSC thermogram exhibits a broad endothermic peak at
188.0 °C that corresponds to the desolvation of DMF (Figure 5).
3.3.1. Crystal Structure Analysis. Lam:Ptl (1:1) Cocrys-
tal, 1. The asymmetric unit of 1 comprises one lam and ptl
Figure 9. Contact area of lam−ipa system at 86 °C. Cocrystal phase
molecule (Supporting Information Figure S8). The basic
(C) is visible attached to the solid lam phase (B). ipa (A) is almost
supramolecular unit is built up of lam−lam homosynthon via
melted.
N−H···N hydrogen bond between N5 amino group of one lam
and the triazine N4 atom of the other lam molecule
The second eutectic (lam/cocrystal) melted completely at
about 100 °C, as shown in Figure 10.
The melting of the new solid phase was completed at about
(Supporting Information Table S2, Figure 11a).
Therefore, R22(8) ring motif is formed (aminopyridine dimer
or motif 1 in lam structure itself,3 Figure 1). The lam dimers are
115 °C. We have also preformed mechanochemical screens
further conjugated by both sides via noncentrosymmetric R32(8)
that demonstrated cocrystal formation in traces when dry- and
heterosynthon formed between the other disposable N5 amino
solvent-drop grinding conditions were applied (Supporting
hydrogen atom and the ptl keto O2 atom and between the
Information Figure S6). Anhydrous single crystals of 4 were,
amino N3 group of another lam and the ptl keto O2 atom
leading to the O2 atom acting as double proton acceptor. The
combination of these two supramolecular units produces a
R42(16) motif. Contrary to O2, the other ptl keto O1 atom
participates in hydrogen bond formation as a single proton
acceptor shaping R22(8) noncentrosymmetric heterosynthon with
the N3 amino group and via N6−H1N6···N2 hydrogen bond
between the ptl N6−H1N6 group and triazine N2 atom as a
proton acceptor. Therefore, hydrogen-bonded zig−zag ribbons
are formed spreading along c axis in alternating ABA fashion
(A = ptl coformer molecule, B = lam molecule) (Figure 11b).
The ptl N6−H1N6 group forms at the same time N−H···N
hydrogen bond with the triazine N1 atom, but comparably
however, isolated from MEK. DSC experiments involving these
single crystals revealed an endothermic at 127.2 °C (Figure 5).
Pyrommelitic diimine has a high melting point (i.e., > 350 °C
as determined by DSC) and exhibits low solubility in most
solvents. For that reason, we found the Kofler contact method
as unsuitable for screening experiments. DSC thermogram of
the physical mixture did not show any thermal events but the
lamotrigine melting. In spite of that fact and due to fragment
molecular similarity with ptl, we expected existence of cocrystals
with pmd. Dry grinding experiments did not yield the cocrystal,
as the mechanochemical treatment of the lam:pmd mixtures
results in the formation of an amorphous phase. Nevertheless,
we were able to form compound 2 after 30 min of solvent drop
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Figure 11. (a) Partial packing diagram of 1 showing supramolecular synthons with applied graph-set analysis. (b) Packing diagram of 1 viewed in ac
plane. Hydrogen-bonded zig−zag ribbons are formed spreading along c axis in alternating ABA fashion (A = ptl coformer molecule, B = lam
molecule).
Figure 12. Packing diagram of 2 showing chains of rings with the alternating R42(16) synthon and R22(8) heterosynthons in ABC fashion along a axis
(A = R22(8) heterosynthon between two pmd molecules, B = R22(8) heterosynthon between pmd and lam molecules, C = R42(16) synthon between
pmd and lam molecules).
Figure 13. Packing diagram of 3 showing chains of rings established by R42(16) and R22(8) N−H···N homosynthons with inserted layers which
contains AAB array of dichlorophenyl lam rings and caf molecules. The chains of rings and non-hydrogen bonded layers spread along c axis in an
alternating fashion.
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Article
weaker than N6−H1N6···N2 hydrogen bond. The lam and ptl
coformer molecule are further interlinked via C4−H4···O2 and
C14−H14···Cl2 hydrogen bonds (Supporting Information
Table S2). The lam molecules are mutually joined via C5−
H5···Cl1 and C6−H6···Cl1 intermolecular hydrogen bonds.39
3.3.2. Lam:Pmd:DMF Solvate Cocrystal (1:1:1), 2. The
asymmetric unit of 2 consists of lam molecule, pmd coformer
molecule and DMF solvent molecule (Supporting Information
Figure S9). The disorder of DMF keto and methyl group is
described in section 2.10. Both conjugated structural motifs
R22(8) homosynthon (formed via N5−H2N5···N4 hydrogen
bond, Supporting Information Table S2) and noncentrosym-
metric R22(8) heterosynthon (formed via N3−H2N3···O5 and
N5−H1N5···O5 hydrogen bonds, Supporting Information
Table S2) forming R42(16) basic supramolecular unit are
preserved in 2. But, unlike in 1, the heterosynthon in 2
originates from the keto oxygen double acceptor O5 atom of
the solvent DMF molecule via N5−H1N5···O5 (Supporting
Information Table S2). The R42(16) synthon alternates with
R22(8) synthon (formed via N3−H1N3···O2 and N7−
H1N7···N2 hydrogen bonds between lam and pmd molecules)
and R22(8) synthon (formed via N6−H1N6···O3 bond) between
two pmd molecules in ABC fashion into ribbons spanning along
a axis (Figure 12).
The ribbons are interlinked along c axis by C20A-H20A···O3
hydrogen bond between aldehyde C−H group and the diimide
keto oxygen atom O3 as well as by C4−H4···O4 hydrogen
bond formed between dichlorophenyl C−H group of lam
molecule and diimide keto O4 atom (Supporting Information
Table S2). It is interesting that diimide keto O1 atom does not
participate in the hydrogen bond formation with lam molecule.
It only forms hydrogen bonds with methyl and methylene
groups of DMF molecule (with both major A and minor B
component). By a careful inspection of Supporting Information
Table S2, one can observe that the assembling of DMF
molecule with pmd molecule is not the same for the A and B
components (C20A−H20A···O3, C22A−H22A···O1, and
C22A−H22B···N1 bonds versus C21B−H21F···O1, C22B−
H22F···O3, and C21B−H21D···Cl2 bonds). The latter hydro-
gen bond is at the same time the only hydrogen bond with the
lam chlorine atom acting as a proton acceptor.
3.3.3. Lam:Caf:3-Pentanone Solvate Cocrystal (2:1:0.64),
3. The asymmetric unit of 3 contains two crystallographically
independent lam molecules (denoted as A and B), one caf
coformer molecule and 3-pentanone solvent molecule
(Supporting Information Figure S10). Hydrogen bonding
architecture is the most complex in 3 in comparison with
other three cocyrstal structures. This cocrystal structure
imitates the basic supramolecular unit R42(16) like in 1 formed
between two lam molecules mutually and their assemblies with
caf molecule. That includes both supramolecular units: R22(8)
homosynthon and R32(8) heterosynthon (Figure 13 and
Supporting Information Table S2).
Figure 14. (a) Packing diagram of 4 showing supramolecular unit
spreading along c axis. (b) Packing diagram of 4 viewed in ac plane.
The chain of triazine lam rings parallel to c axis interchanges with the
layer of hydrogen bonded dichlorophenyl rings and ipa molecules
along a axis. ipa and dichlorophenyl rings are almost perpendicularly
oriented in relation to triazine rings.
axis are formed by an alternated array of supramolecular
assembly denoted as R42(16) and noncentrosymmetric R22(8)
homosynthon shaped between A and B lam molecules (via
N3B−H3B2···N2A and N3A−H3A1···N2B hydrogen bonds).
Since the caffeine keto atoms O1 and O2 act as a double proton
acceptor in the R32(8) heterosynthon formation they simulta-
neously act as a span between ribbons. Thus, caf coformer
molecules are sandwiched between dichlorophenyl lam rings
in a AAB fashion (A = dichlorophenyl ring, B = caf molecule).
Final supramolecular assembling can be described as a chains of
rings established by R42(16) and R22(8) synthons with inserted
layers which contains AAB array of dichlorophenyl lam rings
and caf molecule. Such formed 3D hydrogen pattern propagates
along c axis in an alternating fashion (Figure 12). Hydrogen
bonding patterns that include 3-pentanone solvent molecule
includes keto O3 atom acting as a the double proton acceptor
in two hydrogen bonds C7−H7A···O3 and C8−H8C···O3
(Supporting Information Table S2) with caf methyl groups, and
The additional feature of homosynthon is that does not shape
the centrosymmetric dimer, since it occurs between conforma-
tionally different lam molecules A and B (N5A−H5A1···N4B
and N5B−H5B2···N4A hydrogen bonds). The heterosynthon
R32(8) (N3B−H3B2···O1 and N5A−H5A2···O1, as well as
N3A-H3B1···O2 and N5B−H5B1···O2 hydrogen bonds) is
formed like in 1 and unlike in 2 with caf coformer molecule
and not with 3-pentanone solvent molecule. The feasible reason
for that is owing to steric demands of 3-pentanone solvent
molecule. The ribbons (or chains of rings) spreading along a
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Scheme 2. Supramolecular Synthons Found in lam Cocrystals (1−4) and Their Correlation with A, B, C, and D Motif Notation
several hydrogen bonds of C−H···N type between methyl C9
and methylene C12 groups of lower Lewis acidity and triazine
nitrogen atoms of both lamotrigine molecules A and B
(C9−H9B···N1A, C9−H9B···N2A, C12−H12B···N2A, C9−
H9C···N4B; Supporting Information Table S2). Thus,
3-pentanone molecule is not included in hydrogen bonded
lam:caf 3D network. Two chlorine atoms are involved in
C−H···Cl hydrogen bonds generating C6B−H6B···Cl1B and
C8−H8A···Cl2A hydrogen bonds with the caf C6 and C8
methyl group (Supporting Infromation Table S2).
3.3.4. Lam:Ipa Cocrystal (1:1), 4. Asymmetric unit of 4
involves one lam molecule and one ipa molecule (Supporting
Information Figure S11). The orientational disorder of one of
the aldehyde groups (possible positions are denoted as A and B)
is described in section 2.10. This different spatial orientation of
the aldehyde group within the crystal structure can result in
different hydrogen bonding patterns with A and B aldehyde
positions i.e. their supramolecular assembling is different. Basic
supramolecular R22(8) homosynthon designed by the N4 triazine
acceptor atom and the N3 amino group of centrosymmetrically
related lam molecule presenting in all 1 − 3 structures (in 1 − 3
between amino N5 group and the N4 triazine atom) is found
in 4, too (via hydrogen bond N3−H2N3···N4; Supporting
Information Table S2 and Figure 14a).
molecule is clasped to this 2D chain of rings by the N5−
H2N5···O1, C17A−H17A···Cl2, C13−H13···Cl2, and C11−
H11···N1 hydrogen bonds (Supporting Information Table S2).
Two different orientations of the aldehyde group denoted as
A and B form different types of hydrogen bonds: O2A acts
as a proton acceptor, forming interaction with lam aromatic
C4−H4 group, while O2B participates into C15−H15···O2B
acting between two ipa molecules. There is another hydrogen
bond between two ipa molecules C17B−H17B···O1. Thus, the
chain of the triazines lam rings parallel to c axis interchanges
along a axis with the layer of hydrogen bonded dichlorophenyl
rings and ipa molecules almost perpendicularly oriented in
relation to the triazine rings (Figure 14b).
Correlating (Scheme 2) synthons found in 1−4 with motifs
1 and 2 in lam structure itself, as well as with established
synthons by CSD survey, in all four cocrystal structures (1−4)
robust amino pyrimidine lam dimer retains showing that
breaking the robust dimer synthon is not a demand for the lam
cocrystals design and their formation.
The role of carbonyl group in supramolecular synthons forma-
tion in structures 1−4 is different. While it is demonstrated that
carbonyl group participates in formation of motif A (in structure 3),
motif B (in structure 2) and motif AB (in structure 1), structure 4
preserves motif D which does not include participation of carbonyl
group. In addition, the N−H group of the coformers participates in
the formation of strong hydrogen bond establishing robust synthon
described as the N−H(amino)···O(carbonyl) (denoted as motif B)
which is analogous to the N+−H(amino)···O−(carboxy) found in
salts. Regarding synthon hierarchy in lam multicomponent solids
we conclude that motif B is dominant in comparison to motif A.
The presumption for motif AB formation is first generation of motif
B containing strong N−H(amino)···O(carbonyl) hydrogen bond
following by motif A emergence (Scheme 2).
On the contrary to 1−3 structures, the supramolecular R32(8)
homosynthon in 4 which is abutted on the R22(8) both sides,
is built up via N5−H1N5···N2 and N3−H1N3···N2 hydro-
gen bonds. Therefore, the motif D in Table 2, which is
characteristic for crystal structure of lam molecule itself, is
accomplished in 4. The H1N3 atom of the N3 amino group
takes part in bifurcated hydrogen bond with N2, but also with
the N1 triazine atom. Taking into account N3−H1N3···N1
hydrogen bond the synthon R32(8) can be described as R32(9)
one. The combination of R22(8) and R32(8) synthons results in
R42(16) supramolecular unit spreading along c axis. The ipa
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4. CONCLUSION
Article
email: deposit@ccdc.cam.ac.uk]. Tables of structure factors
are available from the authors by request.
Lam is a relevant API, and its poor aqueous solubility stressed
the need for the development of lam-based salts and cocrystals
with enhanced solubility. In this context, lam has been previously
subjected to cocrystal formation using carboxylic acids as
cocrystal formers. Considering the relatively low number of
pharmaceutically acceptable carboxylic acids, as well as the high
number of amides, aldehydes and ketones listed in the GRAS
and EAFUS lists, we turned to explore the utility of later classes
of compounds in the preparation of lam cocrystal. Our efforts
resulted in the formation of four novel lam cocrystals based on
amides and aldehydes, namely lam:ptl cocrystal (1:1) 1,
lam:pmd:DMF solvate cocrystal (1:1:1) 2, lam:caf:3-pentanone
solvate cocrystal (2:1:0.64) 3 and lam:ipa cocrystal (1:1) 4.
The cocrystals were discovered using a screening method
based on HSM and DSC. The results obtained using the
combined HSM/DSC screening methods were also compared
to those obtained during mechanochemical cocrystal screens.
Notably, the HSM/DSC screening method was shown to be as
sufficient as neat and solvent-drop grinding: two mechano-
chemical screening methods being generally regarded as highly
efficient and suitable for cocrystal screening. Considering the
small amounts of material required for HSM/DSC cocrystal
screens, it appears reasonable to suggest the use of this method
as standard when only small amounts of material are available
for screening purposes, or when safety considerations do not
allow the use of larger quantities.
Screening of lam cocrystals based on solvent evaporation
technique from water and common organic solvents resulted in
numerous solved lam crystalline structures (solvates) and not the
cocrystals. This negative result in cocrystal formation emphasizes
the valuable screening results based on HSM and DSC showing
that under specific crystallization conditions cocrystals can be
isolated.
Structural studies of the cocrystals revealed that carbonyl and
amide functionalities participate in the formation of supra-
molecular motifs that have so far been observed in lam
multicomponent solids. In all four cocrystal structures robust
amino pyrimidine lam dimer retain showing that breaking the
robust dimer synthon is not a demand for lam cocrystals design
and their formation.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: edislav.leksic@pliva.com. Phone: +385-1-372-2719.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
G.P. gratefully acknowledges support by grant 09-1191344-
2943 by the Ministry of Science, Education and Sports of the
Republic of Croatia.
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* Supporting Information
Details relating to the CSD survey, table of hydrogen bonds
and interactions geometry, TGA thermogram of the lam:caf:3-
pentanone solvate, FT-IR of desolvated form of lam:caf
cocrystal and its XRPD, XRPDs of ground physical mixtures,
ORTEP views for all cocrystal structures 1−4. This material is
available free of charge via the Internet at http://pubs.acs.org.
The CIFs of compounds 1-4 (CCDC deposition numbers
844580 − 844583) can be obtained free of charge at www.ccdc.
cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(0)1223−336033;
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