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The solvates and salt of antibiotic agent, nitrofurantoin:

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structural, thermochemical and desolvation studies3

Cite this: CrystEngComm, 2013, 15,
878
Venu R. Vangala,*a Pui Shan Chowa and Reginald B. H. Tan*ab

Received 28th September 2012,
Accepted 8th November 2012
DOI: 10.1039/c2ce26575c
www.rsc.org/crystengcomm
The ability of an antibacterial agent, nitrofurantoin (NF), to form molecular complexes with various pyridyl
bases and 4-aminobenzamide are investigated. Five solvates with the solvents pyridine (PYR, 1 : 1), 2/3/4-
picolines (2/3/4PIC, 1 : 1), 3-picoline + water (3PIC, H2O, 1 : 1 : 1), two co-crystal solvates involving
2-pyridone (2PYR) or 4-aminobenzamide (4ABM) with a solvent acetonitrile (ACN) and a salt with
4-dimethylaminopyridine (DMAP) were identified and characterized. Crystal structure analysis revealed
that the N–H…N heterosynthon between imide N–H and pyridyl–N are predominantly observed in the
solvates involving NF, whereas in a salt (NF-4DMAP), the +N–H…N2 heterosynthon is noted. Thermal
analysis established the stability and confirmed molar ratios of the reported solvates. Desolvation of NF
solvates, NF-PYR, NF-2PIC, NF-3PIC-H2O, NF-3PIC, NF-4PIC, yielded the anhydrous NF (b-form). Interestingly,
co-crystal solvates (NF-2PYR-ACN and NF-4ABM-ACN) upon desolvation produced novel anhydrous co-
crystals. The results suggest that co-crystal solvates could be an alternative route to prepare anhydrous co-
crystals that offer further avenues for expanding the new solid forms involving APIs.

Introduction solvates/hydrates are frequently observed.1–3,8 Hence, the

Solid forms such as polymorphs,1 hydrates,2 solvates,3 salts,4
co-crystals5 and amorphous forms6 of active pharmaceutical
ingredients (APIs) are often explored during drug develop-
ment. Polymorphs are crystalline forms that exist in at least
two different crystal structures for the same molecular
composition whereas all other solid forms are multi-compo-
nent crystals except the amorphous forms, which are non-
crystalline and high energy solid forms that lack long range
order.1 Solvates are crystalline solids that incorporate one or
more solvent molecules in the crystal lattice.3,7 These have
received great significance as the presence of a particular
solvent in the crystal lattice can impart characteristic
physicochemical properties to the APIs. If the incorporated
solvent is water the resulting solids are referred to as
hydrates.2 When APIs with multiple hydrogen bonding
functionalities are exposed to solvents during various manu-
facturing processes and formulation stages, the formation of
a
Crystallisation and Particle Science, Institute of Chemical and Engineering Sciences,
A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island,
627833, Singapore. E-mail: venugopal_vangala@ices.a-star.edu.sg;
Fax: +65 6316 6183; Tel: +65 6796 3862
b
Department of Chemical and Biomolecular Engineering, National University of
Singapore, 4 Engineering Drive 4, 117576, Singapore.
E-mail: reginald_tan@ices.a-star.edu.sg
3 Electronic supplementary information (ESI) available: Crystallographic
information files (CIFs), ORTEP diagrams, and 1H NMR results for the
desolvated samples. CCDC 847324–847330 and 861182. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2ce26575c
discovery and characterization of solvates are essential in the
screening of solid forms of APIs. It is to be mentioned that
desolvation of a solvate provides more insight on the
formation of the solvent free modification.9 The desolvation
outcome depends on several factors such as the kinetics of
desolvation, the thermodynamic stabilities between non-
solvated forms and the nature of the solvate, or the actual
condition for the removal of the solvent. Accordingly, different
phase transformations to stable or metastable forms can be
obtained. Studies concerning polymorphic modifications
under different experimental and storage conditions provide
fundamental information to establish the suitable conditions
at which a particular polymorph is stable.
Nitrofurantoin (NF), (E)-1-[(5-nitro-2-furyl)methylideneami-
no]imidazolidine-2,4-dione, is a widely prescribed antibacter-
ial drug for the treatment of urinary tract infections.10 NF is
marketed under the brand names of Furadantin, Macrodantin,
Macrobid, Furabid, Niftran, Urantoin, etc. Despite being on
the market for close to 60 years, there is continuous interest in
this drug because no known cases of drug resistance have been
reported for NF when drug resistance has become a major
problem with other newer, more potent antibiotics.11 NF is
also considered as a safe antibiotic for use in pregnant
patients.12 Various crystalline forms of NF have been reported
in the literature. These include polymorphic forms in both
anhydrate (a- and b-forms) and hydrate (Forms I and II)
phases;13 pseudopolymorphs with dimethylformamide
(DMF),14 dimethylacetamide (DMA),15 dimethylsulfoxide

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(DMSO),14,16 and methanol (MeOH),17 co-crystals,18 and
salts.18c An amorphous phase of NF was also traced.19
With our interest in exploring the solid form diversity and
to evaluate the molecular recognition between imide and
pyridyl–N and imide and amide in the presence of other
competing functionalities such as methyl groups at 2,3,4-
positions in an aromatic ring,20 amine and aryl groups, we
report a series of solvates of NF with pyridine (PYR), regio-
isomeric picolines (2PIC, 3PIC, 4PIC) and co-crystal acetoni-
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trile solvates of NF with 2-pyridone (2PYR) and 4-aminobenza-
mide (4ABM). A salt of NF with 4-dimethylaminopyridine
(DMAP) is also reported. The chemical structures of NF and all
the solvents and co-crystal forms used in this work are shown
in Scheme 1. For the molecular complexes discussed in this
study, plausible supramolecular synthons21 and their graph
set analysis22 are illustrated in Scheme 2. All the crystalline
materials were analyzed by differential scanning calorimetry
(DSC), thermogravimetric analysis (TGA), hot-stage microscopy
(HSM) and their crystal structures were determined by single-
crystal X-ray diffraction. We successfully prepared two anhy-
drous co-crystals during desolvation of NF-2PYR-ACN and NF-
4ABM-ACN. The propensity of imide functionality to interact
with pyridyl–N was analyzed using the crystal structures
deposited in the Cambridge structural database (CSD).
Results and discussion
Crystal structure analysis
Single crystal X-ray diffraction23 analyses were performed for
eight multi-component crystals. Crystallographic data and
Scheme 1 Chemical structures and pKa values of NF and pyridine based
compounds reported in this paper.
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hydrogen bonding geometries are provided in Tables 1 and 2.
Crystallographic asymmetric units with ORTEP diagrams for
these multi-component crystals are provided in the ESI.3
NF-PYR (2 : 2 or 1 : 1) crystallizes in the triclinic, P1̄ space
group with two molecules each of NF and PYR in the
asymmetric unit. These NF and PYR molecules adopt a nearly
planar conformation. The crystal structure is primarily
stabilized by the N–H…N heterosynthon (d/Å, h/u: 1.73 Å,
173u) formed between the N–H(imide) of NF and the N(pyridyl)
of PYR and it is supported by a weak C–H…O (2.70 Å, 173u)
(synthon I, ring motif R22 (7), Scheme 2, Fig. 1). These building
blocks are further connected via auxiliary C–H…O interactions
to form hydrogen bonded chains. A symmetrically indepen-
dent pair of NF and PYR molecules is arranged in an
orthogonal direction to the other pair of NF and PYR
molecules. The overall crystal packing is supported by several
C–H…O interactions between the perpendicular chains.
NF-2PIC (1 : 1) crystallizes in the monoclinic, P21/c space
group. It consists of one molecule each of NF and 2PIC in the
asymmetric unit. Herein the NF molecule adopts a molecular
conformation distinctive to that of NF in NF-PYR but such a
conformation was reported previously for some multi-compo-
nent crystals.18b The methyl substitution at the ortho position
of 2PIC molecules does not obstruct the most notable imide-
pyridyl heterosynthon of N–H…N interactions (synthon II,
finite motif D, 1.79 Å, 162u) between NF and 2PIC molecules
(Fig. 2). The adjacent molecules are supported by various C–
H…O hydrogen bonds to form a zig-zag sheet structure.
NF-3PIC crystallizes in the triclinic, P1̄ space group. It
consists of one molecule each of NF and 3PIC in the
asymmetric unit. Herein the NF molecule adopts a molecular
conformation similar to NF in NF-2PIC. The methyl substitu-
tion at the meta position of 3PIC has no counter influence on
the formation of the recurring key synthon of (imide)N–
H…N(pyridyl) interactions (synthon II, finite pattern D, 1.75 Å,
179u) between NF and 3PIC molecules (Fig. 3). The adjacent
molecules are connected by C–H…O hydrogen bonds to form
one dimensional tapes. These tapes are in turn linked through
nitro furyl dimer synthons (synthon IV, ring motif R22 (10),C–
H…O) and NF dimer synthons with C–H…O interactions (ring
motif R22 (14), synthon V) between the (azine)C–H and carbonyl
O atom to form a sheet-like structure.
NF-3PIC-H2O (1 : 1 : 1) was produced during a solution
crystallization of NF from 3PIC and water. It crystallizes in the
monoclinic, Pc space group with one molecule each of NF,
3PIC and water. Molecular conformations of NF, 3PIC were
nearly planar. In this crystal structure water was incorporated
in the lattice where imide–pyridyl interactions are mediated by
the water molecules (Fig. 4). The imide N–H of NF bonds to the
O atom of water (N–H…O, 1.71 Å, 164u) and the water
molecules (O–Hs) in turn connect with the pyridyl–N of 3PIC
(O–H…N, 1.78 Å, 173u) and the adjacent NF’s imide carbonyl
(O–H…O, 1.86 Å, 171u). The crystal structure is primarily
stabilized by synthon III (imide–pyridyl mediated by water,
chain motif C22 (6)). This motif is further supported by strong
C–H…O hydrogen bonds to form a sheet-like structure. A
detailed structure analysis reveals that the crystal structure is
close to a co-crystal hydrate involving NF, 1,2-bis(4-pyridy-
l)ethane and water (NF-BIPE-H2O, 1 : 0.5 : 1).18b The arrange-
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Scheme 2 Some plausible/observed supramolecular synthons with graph set notations in the crystal structures of NF solvates and a salt reported in this paper.
ments of NF, water and pyridyl molecules are similar in both
NF-BIPE-H2O and NF-3PIC-H2O.
NF-4PIC crystallizes in the monoclinic, P21/c space group. It
consists of one molecule each of NF and 4PIC. Molecular
conformations of NF and 4PIC are nearly planar. The methyl
substitution at the para position does not disrupt the key
heterosynthon formation between imide the N–H of NF and
the pyridyl–N (N–H…N, 1.72 Å, 176u) of 4PIC (Fig. 5a and 5b).
This synthon is assisted by the C–H…O hydrogen bond
(synthon I, ring motif R22 (7) ). These motifs were connected
via an auxiliary C–H…O interactions to form one dimensional
zig-zag chains. Solid-state packing showed that these one
dimensional chains extend in the opposite direction along the
a-axis (Fig. 5b). A three dimensional network consisting of
hydrogen bonded chains and supported by C–H…O interac-
tions along the b-axis to complete the close packing.
A co-crystal solvate, NF-2PYR-ACN (1 : 1 : 1), was obtained
during a co-crystallization attempt of NF and 2-hydroxypyr-
idine from acetonitrile. It crystallizes in the triclinic, P1̄ space
880 | CrystEngComm, 2013, 15, 878–889
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group. NF adopts the commonly observed (nearly planar)
molecular conformation whereas 2-hydroxypyridine undergoes
lactam lactim tautomerism (Scheme 3)24 to become a
2-pyridone form in the solid-state. The crystal structure
consists of 2-pyridone imide dimer homosynthons (synthon
VI, ring motif R22 (8), N–H…O: 1.76 Å, 175u) and heterosynthons
between the N–H(imide) of NF and CLO of 2-pyridone
(synthon VII, ring motif R22 (8), N–H…O, 1.78 Å, 173u) and it
was assisted by C–H…O (synthon VII, Fig. 6) interactions. The
adjacent NF molecules, along the c-axis, in the sheet-like
structure are connected by a notable C–H…O dimer synthon
(synthon IV). The nearby NF molecules, along the a-axis, self
assemble by an interesting C–H…O dimer synthon (ring motif
R22 (18), synthon VIII) between furyl C–H and carbonyl O atom.
In the crystalline lattice, acetonitrile molecules are incorpo-
rated and form weak C–H…N bonds.
In an attempt to co-crystallize NF and 4-aminobenzamide
using acetonitrile by evaporative crystallization, the co-crystal
solvate of NF-4ABM-ACN was obtained. NF molecules adopt a
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Table 1 Crystallographic data for nitrofurantoin solvates and a salt

NF-PYR NF-2PIC NF-3PIC NF-3PIC-H2O NF-4PIC NF-2PYR-ACN NF-4ABM-ACN NF-DMAP

Empirical (C8H6N4O5)? (C8H6N4O5)? (C8H6N4O5)? (C8H6N4O5)? (C8H6N4O5)? (C8H6N4O5)? (C8H6N4O5)? (C8H5N4O5)?

formula (C5H5N) (C6H7N) (C6H7N) (C6H7N)?(H2O) (C6H7N) (C5H5NO)? (C7H8N2O)? (C7H11N2)
(C2H3N) (C2H3N)
Formula weight 317.27 331.29 331.29 349.31 331.29 374.32 415.38 360.34
Crystal system Triclinic Monoclinic Triclinic Monoclinic Monoclinic Triclinic Monoclinic Monoclinic
Space group P1̄ P21/c P1̄ Pc P21/c P1̄ P21/c P21/c
T [K] 110(2) 110(2) 110(2) 110(2) 110(2) 110(2) 110(2) 110(2)
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a [Å] 8.3012(17) 7.0324(14) 6.1489(12) 15.268(6) 14.840(3) 8.1736(16) 7.2712(15) 8.616(4)

b [Å] 12.940(3) 22.647(4) 7.4328(15) 6.4161(19) 8.0152(16) 9.3544(19) 18.918(4) 26.655(11)
c [Å] 14.208(3) 10.031(4) 16.446(3) 8.461(3) 12.951(3) 11.894(2) 15.451(4) 7.029(3)
a [u] 111.01(3) 90 85.35(3) 90 90 103.46(3) 90 90
b [u] 96.22(3) 112.38(2) 85.97(3) 105.286(5) 91.12(3) 109.31(3) 117.41(2) 100.722(9)
c [u] 91.11(3) 90 83.67(3) 90 90 90.14(3) 90 90
Z 4 4 2 2 4 2 4 4
V [Å3] 1413.6(5) 1477.2(7) 743.2(3) 799.5(5) 1540.2(5) 831.5(3) 1886.8(7) 1586.1(12)
Dcalc [g cm23] 1.491 1.490 1.481 1.451 1.429 1.495 1.462 1.509
m [mm21] 0.118 0.116 0.116 0.116 0.112 0.119 0.114 0.117
Reflections 16 779 9055 7951 4817 8809 9022 10 631 16 954
used
Unique 5029 2594 2439 2644 2513 3033 3303 2524
reflections
Observed 4614 2324 2337 2549 2060 2881 3154 2260
reflections
Parameters 503 222 221 228 221 300 272 237
R1[I . 2s(I)] 0.0721 0.0603 0.0607 0.0333 0.0847 0.0622 0.0382 0.0996
wR2 [all] 0.1831 0.1595 0.1606 0.0833 0.2019 0.1744 0.0980 0.1857
GOF 1.209 1.174 1.157 1.074 1.183 1.147 1.118 1.247
Packing 70.7 72 71.3 70.2 69 72.3 71.2 73.5
fraction [%]
Crystal shape Yellow Yellow Yellow Yellow Yellow Yellow Orange Orange
hexagon platelet block block platelet block red block yellow block

frequently observed conformation (conformer I, ESI3). The
crystal structure is primarily stabilized by an imide–amide
hydrogen bonded motif (synthon IX, ring motif R22 (8))
constructed with N–H…O interactions (1.71 Å, 170u; 2.06 Å,
163u) between NF and 4ABM molecules (Fig. 7). Next, the NH2
group of 4ABM participates in the bifurcated hydrogen
bonding with the O/N acceptors of NF (synthon X, ring motifs
with bifurcated interactions R21 (5)). A two dimensional
corrugated sheet network is assisted by (azine)C–H…O(nitro)
between NF molecules. Acetonitrile is incorporated into the
crystal lattice by forming an N–H…N bond with the free amide
N–H of 4ABM (N–H…N, 2.18 Å, 163u; 2.42 Å, 131u). Solvent
molecules also form weak C–H…O interactions with adjacent
NF acceptors.
Single crystal X-ray diffraction of NF-DMAP reveals that it
crystallizes in the monoclinic space group P21/c with one
molecule each of NF and DMAP present in their ionic forms in
the asymmetric unit (Fig. 8). Again NF molecule adopts a
commonly observed molecular conformation (conformer I,
ESI3) here. A proton transfer occurred from the imide N–H of
NF to the pyridyl–N of DMAP. The crystal structure is mainly
stabilized by +N–H…N2 synthons (1.76 Å, 170u) between the
pyridinium +N–H of DMAP and (N2) the imide anion of NF
(synthon XI, finite motif D). The solid-state packing is
extended with the reliable nitro furyl dimer (synthon IV)
consisting of C–H…O hydrogen bonds between the adjacent
molecules. NF molecules also self assemble to form C–H…O
dimers (synthon VIII, ring motif R22 (18)) in the two dimen-
sional tape structures. The close packed three dimensional
network is assisted by p–p stacking between DMAP molecules
and within nitro furyl moieties of NF molecules.
In general, the reaction of an acid and a base affords a salt if
the DpKa [pKa (base) 2 pKa (acid)] is greater than 2 or 3, and
this criterion is frequently used to guide selection of counter-
ions during salt selection of pharmaceutical compounds.4 The
DpKa for NF-DMAP was found to be 2.33 (Scheme 1) and the
proton transfer from imide N–H to pyridyl–N was observed in
its crystal structure. The other molecular complexes discussed
in this study display a DpKa of less than 2. Consequently, no
salt formation was observed. In the case of NF-2PYR, lactam
lactim tautomerism occurred, so, DpKa rules do not apply.
Thus, DpKa values are consistent with the structural results
herein.
Thermal analysis
Thermal behavior of multi-component crystals were deter-
mined by simultaneous DSC and TGA. The TGA–DSC traces for
all the molecular complexes are shown in Fig. 9 and 10 and in
Table 3. Weight loss measurements in the TGA analysis are in
good agreement with the quantity of the solvent present in the
crystal lattice of all the solvates. The DSC thermograms reveal
that the endothermic peaks for the guest release and melting
of the solids are well separated for all the solvates. Based on

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Table 2 Hydrogen bond geometriesa for solvates and a salt of nitrofurantoin Table 2 (Continued)

Solvate/Salt D–H…Ab d(H…A)/Å d(D…A)/Å /(D–H…A)/u Solvate/Salt D–H…Ab d(H…A)/Å d(D…A)/Å /(D–H…A)/u
NF-PYR N–H…N 1.73 2.735(4) 173 C–H…O 2.33 3.324(6) 151
N–H…N 1.74 2.747(4) 174 C–H…O 2.40 3.358(6) 146
C–H…O 2.16 3.238(4) 175 C–H…N 2.59 3.517(7) 143
C–H…O 2.70 3.777(4) 173 C–H…O 2.11 3.177(6) 169
C–H…O 2.15 3.222(4) 172 C–H…O 2.41 3.188(6) 127
C–H…O 2.60 3.652(4) 164 C–H…O 2.53 3.518(6) 151
C–H…O 2.49 3.190(4) 121 C–H…O 2.46 3.269(6) 130
C–H…O
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2.66 3.454(4) 130 C–H…O 2.66 3.413(6) 126

C–H…O 2.60 3.294(4) 122
C–H…O 2.56 3.332(4) 128 a
N–H, O–H and C–H geometries are neutron normalized to 1.009,
C–H…O 2.44 3.517(5) 172 0.983 and 1.083 Å. b D = donor, A = acceptor.
C–H…O 2.57 3.410(5) 134
NF-2PIC N–H…N 1.79 2.770(3) 162
C–H…O 2.56 3.574(4) 156
C–H…O 2.42 3.383(4) 147
C–H…O 2.56 3.319(4) 126
C–H…O 2.69 3.668(4) 150
NF-3PIC N–H…N 1.75 2.759(3) 179
C–H…O 2.34 3.131(3) 129
C–H…O 2.41 3.483(3) 170
C–H…O 2.40 3.429(3) 158
C–H…O 2.37 3.310(2) 144
C–H…O 2.35 3.259(3) 140
NF-3PIC-H2O N–H…O 1.71 2.696(3) 164
O–H…O 1.86 2.836(2) 171
O–H…N 1.78 2.763(3) 173
C–H…O 2.29 3.060(3) 126
C–H…O 2.16 3.210(3) 164
C–H…O 2.37 3.414(3) 163
C–H…O 2.69 3.517(3) 132
C–H…O 2.42 3.460(3) 161
C–H…O 2.40 3.421(3) 156
NF-4PIC N–H…N 1.72 2.726(4) 176
C–H…O 2.15 3.220(5) 169
C–H…O 2.49 3.257(5) 127 Fig. 1 Crystal packing of NF-PYR viewed down the a-axis. While a pair of
C–H…O 2.42 3.491(5) 171 symmetrically independent NF and PYR form N–H…N heterosynthon chains
C–H…O 2.54 3.383(5) 134 (cyan color coding), the other pair form similar chains shown with default color
C–H…O 2.43 3.499(5) 171 coding extended in an orthogonal direction.
C–H…O 2.65 3.451(5) 130
C–H…N 2.58 3.535(5) 146
NF-2PYR-ACN N–H…O 1.76 2.771(2) 175
N–H…O 1.78 2.785(2) 173
C–H…O 2.38 3.3039(3) 142 the TGA and DSC curves it can be assessed that desolvation
C–H…O 2.19 3.187(3) 152
C–H…N 2.43 3.394(3) 147 occurs in a single step.
C–H…O 2.48 3.244(3) 126 The TGA trace of NF-PYR showed a weight loss of 24.6%,
C–H…O 2.38 3.446(3) 168 which is consistent with a calculated value of 24.93% for the
C–H…O 2.41 3.424(3) 155
C–H…N 2.65 3.407(3) 126 loss of one mole of pyridine per mole of drug (Fig. 9). The DSC
C–H…O 2.40 3.459(3) 164 trace of NF-PYR revealed that a desolvation endotherm was
C–H…N 2.65 3.718(3) 167 observed at an onset temperature of y115 uC, which is close to
C–H…O 2.50 3.310(3) 130
C–H…N 2.53 3.561(3) 159 the boiling point of pyridine (Table 3). It was followed by a
NF-4ABM-ACN N–H…O 1.71 2.7074(19) 170 sharp endotherm at y264 uC, which can be attributed to a
N–H…O 2.06 3.0335(18) 163
N–H…O 2.25 3.1800(19) 153
N–H…O 2.34 3.306(2) 161
N–H…O 2.35 3.0905(18) 130
N–H…N 2.18 3.160(2) 163
N–H…N 2.42 3.173(2) 131
C–H…O 2.32 3.285(2) 147
C–H…O 2.35 3.303(2) 146
C–H…O 2.35 3.318(3) 148
C–H…O 2.39 3.312(2) 142
C–H…O 2.47 3.455(2) 151
C–H…O 2.62 3.351(2) 124
NF-DMAP N+–H…N2 1.76 2.759(5) 170
C–H…O 2.30 3.226(6) 142
C–H…O 2.22 3.291(6) 171
Fig. 2 Crystal packing of NF-2PIC viewed down the a-axis. Notice the recurring
imide-pyridine heterosynthon (synthon I).

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Fig. 3 Crystal packing of NF-3PIC viewed down the b-axis. Notice the reliable
heterosynthon (N–H…N, synthon II) between the imide–pyridyl ring. The solid-
state structure is supported by various C–H…O dimer synthons (synthons IV and
V).
melting of desolvated NF-PYR (Fig. 10). This desolvated phase,
which could be a known anhydrous phase of NF (a-form or
b-form) or a novel phase of NF, needs to be analyzed further.
TGA traces of NF-2PIC, NF-3PIC, NF-4PIC all showed a
weight loss of 27.7%, which is consistent with a calculated
value of 28.11% for the loss of one mole of isomeric picoline
per mole of NF. DSC traces of these solvates show that NF-3PIC
desolvates at a relatively lower temperature (93.1 uC) as
compared to that of NF-2PIC (121.5 uC) and NF-4PIC (129.8
uC) and the desolvated materials melted at the similar onset
temperatures (y268 uC). TGA and DSC traces of NF-3PIC-H2O
established that there was one mole each of 3PIC and H2O per
mole of NF in the lattice and desolvation occurred with the
onset temperature of 68.6 uC.
In the case of co-crystal solvates (NF-2PYR-ACN and NF-
4ABM-ACN), a TGA profiles confirmed that there was one mole
of acetonitrile per mole of NF and the co-former was
incorporated. DSC traces showed that desolvations were
observed at 117.4 and 101.1 uC, respectively, which are higher
than the boiling point of acetonitrile (82 uC), indicating the
stabilization of solvate in the lattice through the weak C–H…N
and C–H…O hydrogen bonding with host molecules. The
desolvations were followed by melting with the unique onset
Fig. 4 Crystal packing of NF-3PIC-H2O viewed down the c-axis. Water mediated
the hydrogen bonding interactions between NF and 3PIC molecules.
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Fig. 5 (a) Crystal packing of NF-4PIC viewed down the b-axis. Notice the
positional change of the methyl group on isomeric picolines does not influence
the key heterosynthon of the imide–pyridyl N–H…N bond. (b) Extended solid-
state packing of NF-4PIC shows that imide-pyridyl building blocks extend in
opposite directions.
temperatures (213.9 and 168.3 uC). The TGA thermogram of
the NF-DMAP salt showed a major weight loss at y199 uC and
its DSC trace displayed an exotherm that can be attributed to
decomposition. It is to be mentioned that the NF-DMAP salt
did not show a melting event but decomposed at elevated
temperatures (Fig. 9 and 10).
Hot-stage microscopy (HSM)18b
The thermal events observed in the DSC–TGA experiments on
all the NF solvates were visualized using HSM. The photo-
micrographs in Fig. 11–13 show the snapshot images of the
crystals at various temperatures during the experiments. All
solvated crystalline materials were heated from 25 to 300 uC.
There was no visible change in the crystal of NF-PYR over the
temperature range of 25–114 uC. From Fig. 11, desolvation is
seen to occur from 115 uC, which is in agreement with DSC–
TGA results. A desolvated phase was subsequently melted at
275 uC. Similarly, photomicrographs of NF-2PIC, NF-3PIC-H2O,
NF-3PIC and NF-4PIC showed that desolvation appears to
occur from 121, 69, 96 and 132 uC, respectively and the
desolvated phases melted at y275 uC (ESI3). In the case of NF-
2PYR-ACN and NF-4ABM-ACN, as shown in Fig. 12 and 13,
desolvation is seen to occur from 116 and 102 uC, respectively
Scheme 3 Prototropic tautomerism of 2-hydroxypyridine to 2-pyridone.
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Fig. 6 Crystal packing of NF-PYR-ACN viewed down the b-axis. A hetero-
synthon between the imide N–H of NF and the CLO of 2-pyridone was observed.
In addition, there was also an imide dimer homosynthon between 2-pyridone
molecules.
Fig. 7 (a) A key building block in a crystal structure of NF-4ABM. (b) Crystal
packing of NF-4ABM-ACN viewed down the c-axis. Notice the imide–amide
synthon stabilizes the solid-state structure. While the NH2 group of 4ABM
participates in the bifurcated hydrogen bonding with O/N acceptors of NF,
acetonitrile forms a hydrogen bond with the amide N–H of 4ABM.
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Fig. 8 Crystal packing of NF-DMAP viewed along the a-axis. Notice a proton
transfer from the imide N–H of NF to pyridyl–N of DMAP.
and crystals became completely opaque by 124 and 116 uC and
these desolvated phases melted at 215 and 175 uC, respectively.
Desolvation experiments – preparation of anhydrous co-
crystals from co-crystal solvates
Desolvation experiments on the solvated crystals were con-
ducted to identify the solids remaining after desolvation.
Crystals obtained from the crystallization experiments were
dehydrated at 90 uC in a vacuum oven (y10 mbar pressure) for
two days. The resulting desolvated samples were analyzed by
PXRD, DSC–TGA and 1H NMR (Table 4, Fig. 14–17 and ESI3).
The desolvation can be easily realized by the loss of solvent
from the crystals, which was assessed by the loss of complete
opaqueness of the crystals. It was noted that the outward
shape of the crystals was unchanged even after complete
desolvation. Desolvation of NF-PYR, NF-2PIC, NF-3PIC-H2O,
NF-3PIC and NF-4PIC yielded the anhydrous phases that
match perfectly with the most stable anhydrous NF poly-
morph, NF (b-form) (Table 4, ESI3). Interestingly, desolvations
of NF-2PYR-ACN and NF-4ABM-ACN produced novel anhy-
drous co-crystals. This was demonstrated by unique PXRD
patterns for the desolvated phases to that of NF (b-form),
corresponding co-former and solvated phases (Fig. 14 and 16).
Fig. 9 TGA plots of NF solvates and a salt.
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Table 3 Thermal data (DSC and TGA) for NF solvates structures and flanked by weak interactions. As such these
solvated crystal structures are stabilized primarily by synthons
Calcd Obsvd Tonset for BP of VI and VII in NF-2PYR-ACN and synthons IX and X in NF-
NF solvate wt loss [%] wt loss [%] desolv [uC] solvent [uC] 4ABM-ACN. These heterosynthons could be retained in the
NF-PYR 24.93 24.6 115.1 115 novel anhydrous co-crystals and subtle structural re-arrange-
NF-2PIC 28.11 27.7 121.5 128 ment may take place. In our recent study, we noted that co-
NF-3PIC-H2O 31.81 30.3 58.3 100, 144a crystal hydrates upon dehydration can provide novel anhy-
NF-3PIC 28.11 27.7 93.1 144
NF-4PIC 28.11 27.7 129.8 145 drous co-crystals. The results suggest that co-crystal solvates or
NF-2PYR-ACN 10.97 10.9 117.4 82 hydrates3a,18b could be an alternative route to prepare novel co-
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NF-4ABM-ACN 9.88 9.5 101.1 82 crystals that would offer further avenues for expanding the
a
Boiling point of water and 3PIC, respectively. new solid forms of APIs.

Cambridge structural database (CSD)25

Thermal profiles (DSC–TGA) of each of the novel phase show
that there is one major endotherm and corresponding weight
loss, which can be attributed to their melting events (Fig. 15
and 17). These thermal profiles are compared with the thermal
events of the respective solvated forms (Fig. 11). Herein it is
noted that there is no endotherm/weight loss at the desolva-
tion temperature but a perfect matching with only the melting
event was observed meaning that all solvents were removed
during dehydration. It was further confirmed by 1H NMR that
these are 1 : 1 stoichiometric co-crystals (ESI3).
Structural rearrangement with concomitant loss of crystal-
linity is usually observed upon desolvation under reduced
pressure or by thermal treatment.7a,b In the case of co-crystal
solvates, the possible outcomes of desolvation are: (i) the co-
crystal may dissociate into its components and exist as a
physical mixture, (ii) the crystal lattice may remain essentially
unchanged compared to the solvate, and (iii) the desolvated
form may have a lattice structure that is different from the
original material. Organic/pharmaceutical solids are held
together by intermolecular interactions, removal of guest
molecules would likely induce complete collapse of the
structure. Hence, we anticipate that first of the three
possibilities mentioned above could be the most probable
outcome in the desolvation of a cocrystal solvate. In the case of
NF-2PYR-ACN and NF-4ABM-ACN, surprisingly, the desolva-
tion produced anhydrous co-crystals. It can be envisioned that
during the desolvation, significant structural changes are not
expected to occur as acetonitrile is incorporated in the channel
A CSD analysis was conducted in order to evaluate the ability
of formation of supramolecular heterosynthons that involve
two of the relevant functional groups in the context of active
pharmaceutical ingredients, imide N–H and pyridyl–N in
competitive environments. We retrieved compounds that
contain both imide and pyridyl groups in single and multi-
component crystals. 224 entries were found with imide and
pyridyl groups, of which 84 entries (37.5%)18b form a N–H…N
heterosynthon (SI) in four solvates (NF-PYR, NF-2PIC, NF-3PIC,
NF-4PIC) out of the seven multi-component crystals, except for
NF-4ABM-ACN. It indicates that this heterosynthon is one of
the favourable motifs in organic/pharmaceutical solids that
contain imide and pyridyl groups in either single or multi-
component crystals.
Conclusions
Seven solvates and a salt of NF with pyridine bases and
4-aminobenzamide compounds were identified and structu-
rally characterized. The heterosynthons between imide N–H
and pyridyl–N (N–H…N synthon, NF-PYR, NF-2PIC, NF-3PIC,
NF-4PIC), imide N–H and 2-pyridone CLO (N–H…O), imide
and amide dimer; pyridinium and imide anion (N+–H…N2) are
predominantly observed in the crystal structures. Thermal
analysis established the stability and confirmed molar ratios
of the reported solvates. Desolvation experiments suggest that
the desolvation of pyridine of isomeric picoline solvates
produced a thermodynamically stable anhydrous NF (b-form).
Interestingly, anhydrous co-crystals were obtained upon
desolvation of co-crystal solvates, NF-2PYR-ACN and NF-
4ABM-ACN. The results suggest that co-crystal solvates could
be an alternative route like co-crystal hydrates,3a,18b which
offer further avenues for expanding the new solid forms
involving APIs.

Fig. 10 DSC traces of NF solvates and a salt.
Experimental
Materials
Nitrofurantoin (b-form), 2-hydroxypyridine, 4-aminobenza-
mide, 4-dimethylaminopyridine were obtained from Sigma-
Aldrich and used as received. The solvents, acetonitrile,
pyridine and 2/3/4-picolines, were of analytical grade.

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Fig. 11 Hot-stage microscopy images obtained with a crystal of NF-PYR at 25, 115, 129, and 275 uC.
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Fig. 12 Hot-stage microscopy images obtained with a crystal of NF-2PYR-ACN at 26, 116, 124 and 215 uC.
Preparation
All the solvates and multi-component crystals of the present
paper were prepared by slow evaporation of a saturated
solution of NF (b-form) at ambient conditions using the
solvents in Scheme 1. Crystals of NF-3PIC-H2O were obtained
when NF (b-form) was crystallized from a solvent mixture of
3PIC and water. The multi-component crystals NF-2PYR-ACN,
NF-4ABM-ACN, and NF-DMAP were obtained from NF (b-form)
with 2-hydroxypyridine, 4-aminobenzamide, and 4-dimethyla-
minopyridine, respectively, using acetonitrile as the solvent.
Single crystal X-ray diffraction
Single crystals of suitable quality were placed on a fibre needle
which was then mounted on the goniometer of the X-ray
diffractometer. The crystal was purged with a cooled nitrogen
gas stream at 110 K during the data collection. X-ray
reflections were collected on a Rigaku Saturn CCD area
detector with graphite monochromated Mo Ka radiation (l =
0.71073 Å). Data were collected and processed using
CrystalClear–Rigaku software. All crystal structures were solved
by direct methods and SHELX-TL was used for structure
solution and least-squares refinement. Non-hydrogen atoms
were refined anisotropically. All hydrogen atoms were fixed at
Fig. 13 Hot-stage microscopy images obtained with a crystal of NF-4ABM-ACN at 26, 102, 116 and 172 uC.
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idealized positions except for the N–H hydrogens, which were
located from the difference Fourier map and allowed to ride
on their parent atoms in the refinement cycles. All N–H and C–
H distances are neutron normalized to 1.009 and 1.083 Å,
respectively. X-Seed was used to prepare the packing diagrams.
Data collection and refinement details are given in Table 1,
and relevant hydrogen bonding interactions and their geome-
tries are listed in Table 2.
Powder X-ray diffraction (PXRD)
PXRD data were collected in Bragg-Brentano geometry with a
Bruker D8 Advance (Bruker AXS GmbH, Germany) X-ray
powder diffractometer equipped with a Cu Ka radiation (l =
1.54056 Å) source, a Nickel-filter, 0.3u divergence slit and a
linear position sensitive detector (Vantec-1). The diffract-
ometer was operated at 35 kV and 40 mA. The sample was
loaded onto a glass circular sample holder that has 1 mm
thickness and 1.5 cm diameter. The sample was scanned
within the scan range of 2h = 5u to 50u continuous scan, at a
scan rate of 2u min21.
Thermal analysis
Simultaneous differential scanning calorimetry and thermo-
gravimetric analysis (DSC–TGA) were performed with SDT
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Table 4 Results of desolvation experiments on NF solvates

NF solvate Desolvation outcomea

NF-PYR NF (b-form)
NF-2PIC
NF-3PIC-H2O
NF-3PIC
NF-4PIC

NF-2PYR-ACN Anhydrous Co-crystals

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NF-4ABM-ACN
a
Performed at 90 uC, 10 mbar pressure for one day.

Fig. 16 Comparison of the PXRD patterns of NF, 4ABM, NF-4ABM-ACN and a

product obtained from the desolvation experiment at 90 uC under vacuum
(y10 mbar pressure) for two days.

added to a crucible. The samples were heated over the

temperature range of 25 to 310 uC at a heating rate of 10 uC
min21. The samples were purged with a stream of flowing
nitrogen throughout the experiment at 200 mL min21.

Hot-stage microscopy (HSM)

Fig. 14 Comparison of the PXRD patterns of NF, 2-hydroxypyridine, NF-2PYR-
ACN and a product obtained from the desolvation experiment at 90 uC under
vacuum (y10 mbar pressure) for two days.
2960, TA instruments. Crystals taken from the mother liquor
were blotted dry on a filter paper and manually ground to
obtain fine powder. Approximately, 5 mg of the sample was
Thermomicroscopic investigations were performed with an
optical polarizing microscope (Olympus, BX51) equipped with
a Linkam hot-stage THMS 600 connected to a TMS 94
temperature controller and a LNP 94/2 liquid nitrogen pump
(Linkam Scientific Instruments Ltd, Tadworth, Surrey, UK).
The microscopic images were recorded with a CCD camera
attached to the Olympus BX-51 microscope at 12 s time
intervals using Soft Imaging System’s Analysis image capture
software. Crystalline solvates were heated over the temperature
range of 25–300 uC at a constant heating rate of 10 uC min21.

Fig. 17 DSC and TGA traces of dehydrated NF-4ABM-ACN at 90 uC in a vacuum

oven (y10 mbar pressure) for 2 days. Notice an endotherm corresponding to
Fig. 15 DSC and TGA traces of dehydrated NF-2PYR-ACN at 90 uC in a vacuum
the melting of a new phase, which is an anhydrous co-crystal of NF-4ABM
oven (y10 mbar pressure) for two days. Notice an endotherm corresponding to
(1 : 1).
a melting of a new phase, which is an anhydrous co-crystal of NF-2PYR (1 : 1).

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The hot-stage was calibrated using USP melting point
standards.
Cambridge structural database (CSD)
A CSD search was conducted to understand the generality of
imide interactions with pyridine bases. Both imide (cyclic –
NH–CLO–) and pyridyl–N containing molecules were retrieved
from ConQuest 1.14 (CSD version 5.33, Feb 2012 update). For
the searches, the structures with 3D coordinates determined
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and ‘‘no errors’’, ‘‘no polymeric’’, ‘‘no ions’’ and ‘‘only
organics’’ were considered. A 3D search on synthon II was
performed using the accepted range for N–H…N (1.6–2.8 Å,
120–180u) hydrogen bonding interactions in a synthon.
Acknowledgements
This work was supported by Science and Engineering Research
Council of A*STAR (Agency for Science, Technology and
Research), Singapore. We thank Chia Sze Chen and Grace
Lau for their technical assistance.
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