Solvates and a monohydrate of N4-acetylsulfamerazine: Structural, thermochemical, and computational analysis

Article abstract of DOI:10.1016/j.molstruc.2011.08.038

A monohydrate, and three solvates of a metabolite of an antibacterial agent, sulfamerazine, N⁴-acetylsulfamerazine (NSMZ), were identified and characterized by nuclear magnetic resonance spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and single crystal X-ray diffraction. The solvates were obtained with the solvents: acetic acid, methanol, and 1,4-dioxane. All the crystal structures belong to the triclinic, P1? space group. Analysis of hydrogen bonding in the crystal structures revealed that the NSMZ molecules form a dimer via a pair of intermolecular N-H?N hydrogen bonds. These dimers are interconnected to each other via the solvent molecules forming extended hydrogen bonded networks. The conformations of the NSMZ in the hydrate/solvates are found to be significantly different. Thermal analysis established the stability and confirmed molar ratios of the reported hydrate/solvates, whereas crystal lattice energies and competitive crystallization experiments confirmed the stability of methanol solvate over the hydrate and other solvates.

Full text of DOI:10.1016/j.molstruc.2011.08.038

Journal of Molecular Structure 1005 (2011) 134–140
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Solvates and a monohydrate of N4-acetylsulfamerazine: Structural,
thermochemical, and computational analysis
a
a,b,
Srinivasulu Aitipamula a, , Pui Shan Chow , Reginald B.H. Tan
⇑
⇑
a Institute of Chemical and Engineering Sciences, AÃSTAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833, Singapore
b Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576, Singapore
a r t i c l e i n f o
a b s t r a c t
A monohydrate, and three solvates of a metabolite of an antibacterial agent, sulfamerazine, N4-acetylsul-
famerazine (NSMZ), were identified and characterized by nuclear magnetic resonance spectroscopy, dif-
ferential scanning calorimetry, thermogravimetric analysis, and single crystal X-ray diffraction. The
solvates were obtained with the solvents: acetic acid, methanol, and 1,4-dioxane. All the crystal struc-
Article history:
Received 13 May 2011
Received in revised form 19 August 2011
Accepted 23 August 2011
Available online 30 August 2011
ꢀ
tures belong to the triclinic, P1 space group. Analysis of hydrogen bonding in the crystal structures
revealed that the NSMZ molecules form a dimer via a pair of intermolecular N–HÁ Á ÁN hydrogen bonds.
These dimers are interconnected to each other via the solvent molecules forming extended hydrogen
bonded networks. The conformations of the NSMZ in the hydrate/solvates are found to be significantly
different. Thermal analysis established the stability and confirmed molar ratios of the reported
hydrate/solvates, whereas crystal lattice energies and competitive crystallization experiments confirmed
the stability of methanol solvate over the hydrate and other solvates.
Keywords:
N4-Acetylsulfamerazine
Hydrate
Solvate
Conformational analysis
Hydrogen bond
Thermal analysis
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
sulfonamide drugs such as, sulfadiazine and sulfathiazole, have
been claimed for its wider usage [8,9]. N4-acetylsulfamerazine
Solvates are referred to as crystalline solids that incorporate one
or more solvent molecules in the crystal lattice [1]. If the included
solvent is water the resulting solids are termed hydrates. In general,
active pharmaceutical ingredients are predisposed with multiple
hydrogen bonding functionalities and the fact that they are exposed
to solvents during various processes and manufacturing, there is a
strong possibility that these compounds will form hydrates/sol-
vates. The importance of hydrates/solvates in the pharmaceuticals
is enormous because the presence of a particular solvent in the crys-
tal lattice can impart specific properties to the drug substance [2].
Furthermore, an added advantage with the solvates is that they offer
an alternative route to control polymorphism through desolvation
[3–5]. Thus, identification and a thorough characterization of phar-
maceutical hydrates/solvates are very important.
(NSMZ, Fig. 1) is an acetylation metabolite of SMZ [10,11], which
is also a synthetic precursor of SMZ [12]. In contrast to SMZ, which
is reabsorbed by the renal tubules and binds to the plasma pro-
teins, NSMZ is secreted from the renal tubules [8]. More recently,
the importance of NSMZ in the stabilization of a metastable poly-
morph of SMZ has received particular attention [13]. The structural
similarity and its ability to disrupt the hydrogen bonding interac-
tions present in the crystal structure of SMZ are responsible for this
inhibitory effect. In this paper, we report a monohydrate (hereaf-
ter, NSMZ-Hydrate) and an acetic acid, methanol, and 1,4-dioxane
solvates of NSMZ (NSMZ-AA, NSMZ-MeOH, and NSMZ-Dioxane,
respectively). These solids were analyzed by nuclear magnetic res-
onance spectroscopy, differential scanning calorimetry (DSC), ther-
mogravimetric analysis (TGA), and single crystal X-ray diffraction.
Furthermore, lattice and conformational energies were computed
using Forcite module in Materials Studio and compared with the
experimental observations made in the competition crystallization
experiments to find out which of the solvents has more affinity to
form a solvate with the NSMZ.
Sulfamerazine (4-amino-N-[4-methyl-2-pyrimidinyl]benzene-
sulfonamide, SMZ, Fig. 1)) is one of the widely used sulfonamide
antibacterial drugs to treat susceptible microbial infections [6,7].
Faster absorption, low overall excretion rate by the kidneys, and
an equal therapeutic and toxic effects of SMZ compared to other
2. Experimental
⇑
Corresponding author at: Institute of Chemical and Engineering Sciences,
AÃSTAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island,
Singapore 627833, Singapore (S. Aitipamula). Tel.: +65 6796 3858; fax: 65 6316
6183.
2.1. Preparation
NSMZ was obtained during the recrystallization experiments of
SMZ from acetic anhydride. In a typical experiment, 10 g of SMZ
E-mail addresses: srinivasulu_aitipamula@ices.a-star.edu.sg (S. Aitipamula),
reginald_tan@ices.a-star.edu.sg (R.B.H. Tan).
0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2011.08.038

S. Aitipamula et al. / Journal of Molecular Structure 1005 (2011) 134–140
135
Fig. 1. The molecular structures of SMZ, NSMZ and the solvents that produced the solvates with NSMZ. Carbon and heteroatoms in NSMZ are numbered.
was dissolved in 15 mL of acetic anhydride. The resulting slurry
was stirred in a beaker at 70 °C for 30 min and was kept aside in
a fume hood. Block shaped crystals were obtained in 3–5 days.
The crystals were filtered and dried in vacuum at 40 °C before they
were used for further analysis. 1H NMR analysis of these crystals
confirmed that they belonged to NSMZ. Crystals of NSMZ-Hydrate
were obtained when NSMZ was crystallized from a tetrahydrofu-
ran and water solvent mixture. Crystallization of NSMZ from acetic
acid, methanol, and 1,4-dioxane solvents afforded solvates of the
respective solvents.
with a stream of flowing nitrogen (20 ml minÀ1). The instrument
was calibrated using indium as the reference material.
Thermogravimetric analysis (TGA) was performed on a TA
instruments, TGA Q500 thermogravimetric analyzer. Approxi-
mately 15 mg of the sample was added to an alumina crucible.
The samples were heated over the temperature range of 25–
275 °C at a constant heating rate of 5 °C minÀ1. The samples were
purged with a stream of flowing nitrogen throughout the experi-
ment at 40 ml minÀ1
.
2.5. Energy calculations
2.2. Nuclear magnetic resonance (NMR) spectroscopy
The conformer and lattice energies were computed using the
Forcite module in Materials Studio. Drieding force field was used
and the charges were used as assigned by the force field. The Ewald
summation method was used to calculate the non-bonded interac-
tions including the van der Waals and electrostatic contributions.
Crystal lattice energies were calibrated for the number of mole-
cules in the unit cell (per molecule).
All the 1H NMR spectra were recorded at 400 MHz on a Bruker
instrument in DMSO-d6 at 25 °C. The samples obtained from the
crystallization experiments were air dried before the analysis.
The NMR spectra of all the solvates/hydrate were provided as
Supplementary data.
2.3. Single-crystal X-ray diffraction
3. Results and discussion
X-ray reflections were collected on a Rigaku Saturn CCD area
Crystal structure of NSMZ has been reported recently [15]. In
the crystal structure, the molecules of NSMZ form a dimer via a
pair of intermolecular N–HÁ Á ÁN hydrogen bonds. The self-assembly
of the dimeric motifs via N–HÁ Á ÁO hydrogen bonds generate a two
dimensional (2D) infinite sheet structure (Fig. 2).
detector with graphite monochromated Mo-K
a
radiation
(k = 0.71073 Å). Data were collected and processed using Crystal-
Clear (Rigaku) software. Structures were solved by direct methods
and SHELX-TL [14] was used for structure solution and least-
squares refinement. The non-hydrogen atoms were refined aniso-
tropically. All hydrogen atoms were fixed at idealized positions
except for the N–H and O–H hydrogen atoms which were located
from the difference Fourier map and allowed to ride on their parent
atoms in the refinement cycles. The O–H bond distances of the
water molecule in the NSMZ-Hydrate were found to be longer than
usual in the normal refinement cycles, and hence these distances
were fixed using DFIX command in the SHELX. For the calculation
of hydrogen bond metrices, all O–H, N–H, and C–H distances are
neutron normalized to 0.983, 1.009, and 1.083 Å, respectively. Data
collection and refinement details are listed in Table 1, and perti-
nent hydrogen bond distances are provided in Table 2.
ꢀ
Crystal structure of NSMZ-Hydrate belongs to triclinic, P1 space
group, with each one molecule of NSMZ and water in the asym-
metric unit (Table 1). Similar to the parent crystal structure, the
crystal structure of the hydrate also features a dimer motif involv-
ing two molecules of NSMZ via N–HÁ Á ÁN (HÁ Á ÁA distance, 1.88 Å;
and D–HÁ Á ÁA angle, 174°, Table 2) hydrogen bonds. The translation
related dimeric motifs are connected via two molecules of water
involving O–HÁ Á ÁO (1.79 Å, 157°; 1.97 Å, 162°) hydrogen bonds,
generating 1D chain along the [011] direction (Fig. 3a). The 1D
chain features hydrogen bonded tetrameric motifs involving two
molecules each of NSMZ and water. The carbonyl of the acetyl
group was found to accept two hydrogen bonds from two water
molecules and the inversion center resides in the center of the tet-
rameric motif. The N–H of the acetylamido group extends the
hydrogen bonded network to a 2D sheet structure in the (011)
plane via N–HÁ Á ÁOwater (1.87 Å, 156°) hydrogen bonds (Fig. 3b).
The overall crystal structure features several C–HÁ Á ÁO (2.26–
2.47 Å, 131–157°) interactions.
2.4. Thermal analysis
Differential scanning calorimetry (DSC) was performed with a
Perkin Elmer Diamond DSC with an autosampler. Crystals taken
from the mother liquor were blotted dry on a filter paper and
placed in crimped but vented aluminum sample pans. The sample
size was 2–5 mg and the temperature range was typically 30–
275 °C at a heating rate of 5 °C minÀ1. The samples were purged
Single-crystal X-ray diffraction analysis of the NSMZ-AA re-
ꢀ
vealed that it belongs to the triclinic system, space group P1.
Asymmetric unit contains two molecules of NSMZ and one

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S. Aitipamula et al. / Journal of Molecular Structure 1005 (2011) 134–140
Table 1
Crystal data for the NSMZ hydrate/solvates.
Compound reference
NSMZ-Hydrate
13H16N4O4S
NSMZ-Acetic acid
NSMZ-Methanol
NSMZ-Dioxane
Chemical formula
Formula mass
Crystal system
a (Å)
b (Å)
c (Å)
C
C28H32N8O8S2
672.74
Triclinic
8.9647(18)
12.362(3)
15.957(3)
110.05(3)
94.16(3)
C14H18N4O4S
338.38
Triclinic
C15H18N4O4S
350.40
Triclinic
324.37
Triclinic
6.9245(14)
8.4098(17)
14.089(3)
77.55(3)
77.92(3)
67.09(3)
730.8(3)
110(2)
6.8443(14)
8.3829(17)
15.172(3)
96.89(3)
92.22(3)
112.30(3)
796.2(3)
110(2)
7.5966(15)
9.5204(19)
11.813(2)
98.19(3)
98.90(3)
97.69(3)
824.8(3)
110(2)
a
(°)
b (°)
(°)
c
108.28(3)
1544.9(5)
110(2)
Unit cell volume (Å)3
Temperature (K)
ꢀ
ꢀ
ꢀ
ꢀ
Space group
P1
P1
P1
P1
No. of formula units per unit cell, Z
No. of reflections measured
No. of independent reflections
Rint
2
2
2
2
10,207
3589
21,832
7502
11,448
3905
12,034
4056
0.0394
0.0665
0.1768
0.0698
0.1809
0.0238
0.0519
0.1288
0.0592
0.1368
0.0308
0.0604
0.1327
0.0680
0.1396
0.0413
0.0724
0.1634
0.0863
0.1776
Final R1 values (I > 2r(I))
Final wR(F2) values (I > 2
Final R1 values (all data)
r(I))
Final wR(F2) values (all data)
Table 2
Hydrogen bond parameters of the intermolecular interactions in the hydrate/solvates of NSMZ (D–H distances were neutron normalized).
Solid form
D–HÁ Á ÁAa
HÁ Á ÁA (Å)
DÁ Á ÁA (Å)
D–HÁ Á ÁA (Å)
Symmetry code
NSMZ-Hydrate
N3–H1Á Á ÁN2
N4–H2Á Á ÁO4
O4–H6Á Á ÁO3
O4–H9Á Á ÁO3
C4–H4Á Á ÁO1
C5–H5AÁ Á ÁO4
C13–H13CÁ Á ÁO2
1.88
1.87
1.97
1.79
2.45
2.26
2.47
2.886(3)
2.820(3)
2.918(3)
2.729(3)
3.280(3)
3.288(3)
3.284(3)
174
156
162
157
132
157
131
1 À x, 1 À y, Àz
1Àx, Ày, 1Àz
2 À x, Ày, 1 À z
1 À x, 1 À y, Àz
À1 + x, y, z
Àx, 1 À y, 1 À z
NSMZ-AA
N3–H1Á Á ÁN2A
N3A–H1AÁ Á ÁN2
N4–H2Á Á ÁO3A
N4A–H2AÁ Á ÁO4
O5–H5Á Á ÁO3
1.86
1.90
1.96
1.82
1.69
2.48
2.32
2.48
2.49
2.39
2.41
2.871(3)
2.904(3)
2.921(3)
2.818(3)
2.663(2)
3.303(3)
3.164(3)
3.327(3)
3.527(3)
3.463(3)
3.229(3)
175
179
158
172
170
132
133
134
160
171
131
x, y, 1 + z
x, y, À1 + z
1 À x, 1 À y, 1 À z
Àx, 1 À y, 1 À z
x, 1 + y, z
C4A–H4AÁ Á ÁO1
C8–H8Á Á ÁO3A
C8A–H8AÁ Á ÁO4
C11–H11Á Á ÁO1A
C13–H13CÁ Á ÁO1
C15–H15CÁ Á ÁO2
x, y, À1 + z
1 À x, 1 À y, 1 À z
Àx, 1 À y, 1 À z
Àx, Ày, 1 À z
Àx, Ày, 1 À z
Àx, 1 À y, 1 À z
NSMZ-MeOH
N3–H1Á Á ÁN2
N4–H2Á Á ÁO4
O4–H6Á Á ÁO3
C4–H4Á Á ÁO1
1.87
1.86
1.78
2.46
2.48
2.44
2.880(3)
2.858(3)
2.759(3)
3.266(3)
3.324(4)
3.507(3)
179
171
171
131
133
170
Àx, 1 À y, 1 À z
x, y, À1 + z
1 + x, y, 1 + z
Àx, 1 À y, 1 À z
x, y, À1 + z
C13–H13BÁ Á ÁO4
C14–H14AÁ Á ÁO2
1 À x, 1 À y, 1 À z
NSMZ-Dioxane
N3–H1Á Á ÁN2
N4–H2Á Á ÁO4
C10–H10Á Á ÁO3
1.86
1.89
2.29
2.868(3)
2.882(3)
2.858(4)
175
166
111
1 À x, 2 À y, Àz
Àx, 1 À y, 1 À z
a
D = Donor, A = Acceptor.
molecule of acetic acid. Analysis of the crystal packing revealed
that the symmetry independent molecules of NSMZ form a di-
mer via a pair of intermolecular N–HÁ Á ÁN (1.86 Å, 175°; 1.90 Å,
179°) hydrogen bonds. These dimers are interconnected to each
other via an N–HÁ Á ÁN (1.96 Å, 158°) hydrogen bond to generate a
four-component supramolecular unit (Fig. 4) involving the acet-
ylamido groups. Translation related four-component units are
connected via acetic acid molecule involving O–HÁ Á ÁO (1.69 Å,
170°) and N–HÁ Á ÁO (1.82 Å, 172°) hydrogen bonds, generating a
1D ladder like network along the (À110) direction (Fig. 4). A
number of relatively short C–HÁ Á ÁO (2.20–2.49 Å, 102–171°)
interactions further stabilize the crystal structure.
Crystal structure of the NSMZ-MeOH belongs to the triclinic
system, space group P1. One molecule each of NSMZ and methanol
ꢀ
constitute the asymmetric unit. The crystal structure finds close
similarities with the acetic acid solvate, wherein the NSMZ mole-
cules form dimers via N–HÁ Á ÁN (1.87 Å, 179°; 1.86 Å, 171°) hydro-
gen bonds and they are interconnected to each other through the
solvent methanol molecule. The result is a one dimensional hydro-
gen bonded ladder network along the crystallographic a-axis
(Fig. 5). The overall crystal structure also features structure stabi-
lizing C–HÁ Á ÁO (2.20–2.48 Å, 118–170°) interactions. The main dif-
ference between the two crystal structures is the presence of two
symmetry independent molecules in the acetic acid solvate which

S. Aitipamula et al. / Journal of Molecular Structure 1005 (2011) 134–140
137
Fig. 2. Part of the 2D sheet structure in the crystal structure of NSMZ [15].
Fig. 3. Part of the crystal structure of NSMZ-Hydrate showing: (a) 1D hydrogen bonded chain that features dimers of NSMZ molecules connected through water molecules
and (b) a 2D sheet structure. Water molecules are shown as ball-and-stick model for clarity.
form a dimeric motif and self-assemble to form a four-component
supramolecular unit, on the contrary, there is only one molecule of
NSMZ in the asymmetric unit of NSMZ-MeOH that generates a lad-
der network with the methanol molecules.
175°) hydrogen bond. The N–H of the acetylamido group of the
NSMZ forms a N–HÁ Á ÁO (1.89 Å, 166°) hydrogen bond with the
dioxane molecule and generates a 1D chain (Fig. 6a). These 1D
chains are closely packed in the crystal structure (Fig. 6b).
Conformations of the NSMZ molecules in the crystal structures
of the hydrate/solvates are found to be different. An overlay dia-
gram comparing the different conformers of NSMZ in the solvates
and in the reported crystal structure of the parent NSMZ is shown
in Fig. 7. The torsion angles for various NSMZ conformers are
ꢀ
Crystal structure of NSMZ-Dioxane belongs to the triclinic, P1
space group. The asymmetric unit constitute one molecule of
NSMZ and half a molecule of 1,4-dioxane. Similar to the crystal
structures described before, this solvate also features hydrogen
bonded dimers of NSMZ molecules involving N–HÁ Á ÁN (1.86 Å,

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S. Aitipamula et al. / Journal of Molecular Structure 1005 (2011) 134–140
Fig. 4. A part of the one dimensional hydrogen bonded ladder network in the
crystal structure of NSMZ-AA.
Fig. 7. Overlay of conformers of NSMZ, red: taken from Ref. [15], yellow: conformer
in NSMZ-Hydrate, blue and green represent the symmetry independent molecules
of NSMZ in the crystal structure of NSMZ-AA, pink: conformer in NSMZ-MeOH, and
orange: conformer in NSMZ-Dioxane. (For interpretation of the references to color
in this figure legend, the reader is referred to the web version of this article.)
tabulated in Table 3. It is clear from Fig. 7 that the conformational
difference arises because of the free rotation of the 4-methyl-2-
pyrimidinyl group at the sulfonyl bridge. Interestingly, the two
symmetry independent conformers of NSMZ in the NSMZ-AA (blue
and green) have significantly different torsion angles. Furthermore,
whereas the conformer found in the NSMZ-Hydrate (yellow)
adopts a similar conformation as in NSMZ-MeOH (pink), one of
the symmetry independent conformer in NSMZ-AA closely
matches with the conformer in the parent crystal structure of
NSMZ (red). The conformer in the crystal structure of NSMZ-Diox-
ane did not match with any of the conformers found in the crystal
structures. To better understand the energetics associated with the
various conformations of the NSMZ in its hydrate/solvates, confor-
mation energies were computed. The data obtained from these cal-
culations is tabulated in Table 3. It is evident from the energy
Fig. 5. Part of the one dimensional hydrogen bonded ladder network in the crystal
structure of NSMZ-MeOH.
Fig. 6. Crystal structure of NSMZ-Dioxane: (a) a 1D hydrogen bonded chain in the crystal structure of NSMZ-Dioxane, and (b) packing of 1D chains. The 1,4-dioxane molecules
are shown in ball-and-stick model.

S. Aitipamula et al. / Journal of Molecular Structure 1005 (2011) 134–140
139
Table 3
The calculated torsional angles (selected) of various conformers of NSMZ in the crystal structures of its hydrate/solvates and parent crystal structure.
a
Torsion angle (°)
s1 (C11–C6–S1–N3)
s2 (C6–S1–N3–C1)
s3 (S1–N3–C1–N2)
Conformer energy (kcal molÀ1
)
NSMZ (red)
NSMZ-Hydrate (Yellow)
NSMZ-AA
69.4
84.3
67.7
57.0
66.8
57.7
À175.7
À174.3
179.3
5.62
2.75
2.30
4.35
0
Conformer 1 (Blue)
Conformer 2 (Green)
À73.8
À65.9
168.6
NSMZ-MeOH (Pink)
NSMZ-Dioxane (Orange)
83.5
71.0
À179.0
62.4
53.6
À168.6
0.82
a
The lowest energy conformer is arbitrarily set to 0. Refer to Fig. 7 for color codes.
yellow–pink, red–blue are comparable, significant differences were
found in the conformational energies of the individual conformers.
The presence of rich conformational flexibility in the NSMZ mole-
cule suggests that it can also crystallize in different polymorphic
forms [16].
Lattice energies of the solvates and the solvent free crystal
structure of the NSMZ were calculated using the Materials Studio
(Dreiding 2.21, Table 4). Comparison of the lattice energies suggest
that the crystal structure of the NSMZ-MeOH is energetically most
stable among the four crystal structures discussed in this paper.
Interestingly, despite the fact that the crystal structure of the
NSMZ-AA contains the relatively stable conformers compared to
the conformer in the parent NSMZ crystal structure, the presence
of the acetic acid molecule destabilizes the overall crystal structure
and it is the least stable among the four crystal structures. How-
ever, the fact that crystallization of NSMZ from acetic acid solvent
Table 4
The computed lattice energies of the five crystals of NSMZ.
Solid form
Lattice energy (kcal molÀ1
)
NSMZ-Hydrate
NSMZ-AA
NSMZ-MeOH
NSMZ-Dioxane
NSMZ
À37.19
À26.65
À37.76
À32.82
À29.55
values that the solvent free crystal structure contains a molecular
conformer which is ꢀ5.6 kcal molÀ1 higher in energy than the sta-
ble conformer found in the crystal structure of the NSMZ-MeOH.
The symmetry independent conformers of NSMZ in the NSMZ-AA
have conformational energies that differ by ꢀ2.1 kcal molÀ1. Inter-
estingly, though the torsion angles for pairs of conformers,
Fig. 8. DSC and TGA thermograms of: (a) NSMZ-Hydrate, (b) NSMZ-AA, (c) NSMZ-MeOH, and (d) NSMZ-Dioxane.

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S. Aitipamula et al. / Journal of Molecular Structure 1005 (2011) 134–140
Table 5
Thermal data (DSC and TGA) for NSMZ solvates.
Solid form
Calculated
weight loss (%)
Observed weight
loss in TGA (%)
D
H for guest
Guest loss temp
range in TGA (°C)
Boiling point
of guest (°C)
loss (JgÀ1
)
NSMZ-Hydrate
NSMZ-AA
NSMZ-MeOH
NSMZ-Dioxane
5.55
8.93
9.47
12.57
5.41
8.23
9.20
13.04
61.07
90.27
150.49
47.04
60–90
100–136
63–90
100
118.1
64.7
101
100–120
resulted in NSMZ-AA could mean that the entropic factors domi-
nate during nucleation. To further evaluate the lattice energy cal-
culations and to study the preferential crystallization of hydrate/
solvates, competitive crystallization experiments were carried
out by crystallizing NSMZ from a mixture of methanol, and the sol-
vents that produced the solvates in different ratios (1:1, 1:2, 2:1,
1:1:2, 1:2:1, 2:1:1, etc). The crystals thus obtained were analyzed
by 1H NMR spectroscopy. In all the experiments, NSMZ showed
strong preference for methanol even when one or more of the
other solvents were present in excess. The 1H NMR spectrum of
the crystals obtained from these experiments showed a doublet
at d = 3.16 for the methyl group and a quartet at d = 4.10 ppm for
the hydroxyl group of the methanol.
structures. Methanol solvate has been identified as energetically
most stable among the various solid forms of N4-acetylsulfamer-
azine by the crystal lattice energy calculations. These results are
also consistent with the observations made in the competitive
crystallization experiments. However, the thermal stability of the
acetic acid solvate is higher than the hydrate and methanol solvate.
Acknowledgement
This work was supported by Science and Engineering Research
Council of A⁄STAR (Agency for Science, Technology and Research),
Singapore.
All the solvates/hydrate are analyzed by DSC and TGA. The DSC
and TGA traces are shown in Fig. 8 and the thermal data are tabu-
lated in Table 5. The DSC thermograms show two distinct endo-
therms, whereas the first endotherm was ascribed to the solvent
loss from the crystal lattice, the second endotherm is due to melt-
ing of the desolvated material at 246 °C. The release of solvent from
the crystal lattice was observed at the boiling point of the respec-
tive solvent, except that the release of water that started at 60 °C.
Weight loss measurements in the TGA analysis are in good agree-
ment with the quantity of the solvent present in the crystal lattices
of the hydrate/solvates. Interestingly, the TGA profile of the NSMZ-
AA shows two steps for the release of acetic acid from the crystal
lattice. Upon release of the solvent molecules, the solids decom-
pose upon melting after 250 °C which was observed in the TGA
profile as a continuous weight loss step after this temperature.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2011.08.038. These
include ORTEP diagrams, 1H NMR analysis of the hydrate/solvates.
CCDC 824754–824757 contain the crystallographic data for the
crystal structure reported in this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via http://www.ccdc.cam.ac.uk/data_request/cif.
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4. Conclusions
We have reported three solvates and a monohydrate of N4-acet-
ylsulfamerazine. All the solvates/hydrate have been characterized
by 1H NMR spectroscopy, thermal analysis and their crystal struc-
tures have been determined by single crystal X-ray diffraction. All
the crystal structures feature NSMZ dimers connected via a pair of
intermolecular N–HÁ Á ÁN hydrogen bonds. However, the overall
crystal structures of the hydrate and dioxane solvate are different
from the other two solvates. The crystal structure of hydrate can
be represented as a 2D hydrogen bonded sheet structure, while
the methanol and acetic acid solvates contain hydrogen bonded
ladder networks, and the 1,4-dioxane solvate can be represented
as 1D hydrogen bonded chains involving the solvent molecules.
Conformational and computational analysis revealed that N4-acet-
ylsulfamerazine adopts different conformations in the crystal