Pharmaceutical Co-crystals with isonicotinamide-vitamin B3, clofibric acid, and diclofenac-and two isonicotinamide hydrates

Article abstract of DOI:10.1021/cg100670k

The co-crystals of three industrially important pharmaceutical molecules, the Vitamin B group member nicotinamide (1), the antihyperlipidemic drug clofibric acid (2), and the nonsteroidal anti-inflammatory drug diclofenac (3), are synthesized with the co-crystal former isonicotinamide and characterized by thermal analysis and single crystal X-ray diffraction. Two dimorphic hydrates of isonicotinamide were obtained during the course of these experiments: hydrate 4 (form I) has been reported recently, and hydrate 5 (form II) is new. Both are monohydrates but differ in the number of independent molecules in the asymmetric unit, Z′ = 2 and 8, respectively. Form II is metastable compared to I and converts to form I in the solid state. In all three pharmaceutical co-crystals, it is the pyridine N atom of either the nicotinamide molecule in 1 or the N atom of the isonicotinamide molecule in 2 and 3 that is used in connecting the different molecules together, as a hydrogen bond acceptor from the amine of the isonicotinamide in 1 and the carboxylic acid protons in 2 and 3. The carboxylic acid...pyridine hydrogen bond is an often used supramolecular synthon. A survey of relevant structures in the Cambridge Structural Database of isonicotinamide and nicotinamide co-crystals is given for completeness, and the co-crystal former ability of isonicotinamide and nicotinamide was investigated by performing density functional theory calculations.

Full text of DOI:10.1021/cg100670k

DOI: 10.1021/cg100670k
Pharmaceutical Co-crystals with Isonicotinamide;Vitamin B3, Clofibric
Acid, and Diclofenac;and Two Isonicotinamide Hydrates
2011, Vol. 11
75–87
Nikoletta B. Bathori,*,†,‡ Andreas Lemmerer,†, Gerhard A. Venter,§ Susan A. Bourne,*,†
ꢀ
and Mino R. Caira†
†Centre for Supramolecular Chemistry Research, Department of Chemistry, University of Cape Town,
Rondebosch 7701, South Africa, ‡Faculty of Applied Sciences, Department of Chemistry,
Cape Peninsula University of Technology, P.O. Box 652, Cape Town 8000, South Africa, and
§Scientific Computing Research Unit, Department of Chemistry, University of Cape Town,
Rondebosch 7701, South Africa
Received May 20, 2010; Revised Manuscript Received November 13, 2010
ABSTRACT: The co-crystals of three industrially important pharmaceutical molecules, the Vitamin B group member nicotinamide
(1), the antihyperlipidemic drug clofibric acid (2), and the nonsteroidal anti-inflammatory drug diclofenac (3), are synthesized with the
co-crystal former isonicotinamide and characterized by thermal analysis and single crystal X-ray diffraction. Two dimorphic hydrates
of isonicotinamide were obtained during the course of these experiments: hydrate 4 (form I) has been reported recently, and hydrate 5
(form II) is new. Both are monohydrates but differ in the number of independent molecules in the asymmetric unit, Z0 =2 and 8,
respectively. Form II is metastable compared to I and converts to form I in the solid state. In all three pharmaceutical co-crystals, it is
the pyridine N atom of either the nicotinamide molecule in 1 or the N atom of the isonicotinamide molecule in 2 and 3 that is used in
connecting the different molecules together, as a hydrogen bond acceptor from the amine of the isonicotinamide in 1and the carboxylic
acid protons in 2 and 3. The carboxylic acid pyridine hydrogen bond is an often used supramolecular synthon. A survey of relevant
3 3 3
structures in the Cambridge Structural Database of isonicotinamide and nicotinamide co-crystals is given for completeness, and the
co-crystal former ability of isonicotinamide and nicotinamide was investigated by performing density functional theory calculations.
1. Introduction
examples is the pharmaceutical co-crystal (triazole)2 (succinic
3
acid), whose dissolution properties are considerably improved
over those of the pure API7 (further examples can be found in
the recent papers of Childs et al.,8 Vishweshwar et al.,9 and
Khan et al.10). In the last 5 years,11 much research has been
devoted to understanding how to effectively combine two
or even three unique chemical moieties into a co-crystal,12
and the potential now exists to design co-crystals by using
co-crystallization reagent molecules.
The design and synthesis of stable solid-state structures based
on noncovalent interactions is encompassed in the field of
supramolecular chemistry.1 The construction of a variety of
organized frameworks, often with potentially useful chemical
and physical properties, is one of the tenets of crystal engi-
neering.2 Active pharmaceutical ingredients (APIs) represent
one group of materials to which this approach has been
applied.3 Considerable research time and funding are spent
ondeveloping adrug, fromscreeningtodevelopinga synthesis
of the final product.3 Once the desired API is made, this is not
necessarily the end of its product development. One problem
encountered is unsatisfactory bioavailability, limited by the
solubility of the final drug compound, and further develop-
ment is spent on improving its solubility without decreasing its
performance or stability. Recently, this challenge has been
met by crystallizing the API with other solid compounds.4
This multicomponent molecular complex, known more com-
monly as a pharmaceutical co-crystal, consists of the API and
any compoundthatisa solidunderambient conditions, linked
by intermolecular forces, where the hope is to improve the
chemical and physical properties of the API constituent by co-
crystallizing it with the co-crystal former.5 If the co-crystal
former is a molecule that is safe for human consumption, a
classification known as Generally Recognized As Safe (GRAS),
the pharmaceutical co-crystal would be safe to use in pharma-
ceutical formulations.6 For instance, among a number of recent
Isonicotinamide is one of the most effectively used co-
crystallizing compounds,13 as the pyridine N atom of the iso-
nicotinamide molecule readily acts as a hydrogen bond acceptor
when faced with good hydrogen bond donors such as carboxylic
acids and alcohols.14 In fact, the carboxylic acid pyridine
3 3 3
hydrogen bond has been identified as a robust yet versatile
hydrogen bond and persists even in the presence of other good
donors.15 Isonicotinamide is not classified as a GRAS sub-
stance but is structurally closely related to its isomer nicoti-
namide, which is part of the Vitamin B group and a GRAS
substance. Our attempts to co-crystallize nicotinamide with
the biological agents here were unsuccessful (see the Support-
ing Information), so we turned instead to the structurally
related isonicotinamide. To determine if the failure to obtain
co-crystals with nicotinamide is related to specific intermolec-
ular interactions between the APIs and either nicotinamide
or isonicotinamide, we performed several density functional
theory (DFT) calculations. Both the charge density and the
C(sp2)-C(sp2)-C(sp2)-N amide conformational profile of
nicotinamide and isonicotinamide were compared to deter-
mine if there are any a priori reasons to assume the occurrence
of significantly different interactions. Extending this, we also
compare the binding energy of important synthons expected
to be dominant in the hitherto undetermined crystal structure.
*To whom correspondence should be addressed. E-mail: nikoletta.bathori@
uct.ac.za (N.B.B.); susan.bourne@uct.ac.za (S.A.B.). Fax: þ27-21-685-4580.
Telephone: þ27-21-650-2562.
Present address: Molecular Sciences Institute, School of Chemistry, Uni-
versity of the Witwatersrand, Johannesburg, P.O. WITS 2050, South Africa.
r
2010 American Chemical Society
Published on Web 12/20/2010
pubs.acs.org/crystal

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Bathori et al.
76 Crystal Growth & Design, Vol. 11, No. 1, 2011
Chart 1. The Four Neutral Molecules Investigated in This
Report
Figure 1. The four hydrogen bonded synthons observed in isoni-
cotinamide co-crystals.
Finally, we also selected a co-crystal former (4-hydroxybenzoic
acid) whose structure with both nicotinamide and isonicoti-
namide have been determined, to compare binding energies.
From the large number of empirical data found on isonic-
otinamide co-crystals with carboxylic acid containing mole-
cules (which will be analyzed in detail below), it has been found
that there are three possibilities of aggregation between the
functional groups: first, a heteromeric interaction between the
carboxylic acid H and the lone pair of the N atom to form a dis-
crete D carboxylic acid pyridine hydrogen bond (synthon I)
3 3 3
together with a second homomeric amide amide R22(8)16
dimer (synthon II) (Figure 1a) or, third, a heteromeric car-
3 3 3
boxylic acid amide R22(8) dimer (synthon III) (Figure 1b).
3 3 3
The hydrogen bonding interactions of the first two aggrega-
tions are in accord with Etter’s rules,16-18 which state that
(i) all good proton donors and acceptors are used in hydrogen
bonding; (ii) six-membered ring intramolecular hydrogen bonds
form in preference to intermolecular hydrogen bonds; and (iii) the
best proton donors and acceptors remaining after intramolecular
hydrogen-bond formation form intermolecular hydrogen bonds.
The carboxylic acid proton, being the most acidic proton, is the
best hydrogen bonding donor and interacts with the best hy-
drogen bonding acceptor, the basic lone pair of the pyridine
N. The second best donor/acceptor pair is the syn-proton
and the carbonyl oxygen of the amide. It is possible for the
and used without further purification. All solvents used in the study
were of ACS (g99%) quality.
2.2. Preparation of Co-crystals.
2.2.1. (isonicotinamide) (nicotinamide) (1). A 1:1 stoichiometric
3
amount of isonicotinamide (30 mg, 0.27 mmol) and nicotinamide
(30 mg, 0.27 mmol) was dissolved in acetone. The experiment was re-
peated in methanol, ethanol, ethyl acetate, ethyl acetate/chloroform,
and isopropanol, all of which produced the same 1:1 co-crystal.
2.2.2. (isonicotinamide) (clofibric acid) (2). Thirty milligrams of
3
isonicotinamide (0.27 mmol) and 71 mg of clofibric acid (0.27 mmol)
was added into a sample vial. The solid was further dissolved in meth-
anol (30 mL) and left to evaporate at room temperature.
2.2.3. (isonicotinamide) (diclofenac) (3). Thirty milligrams of
3
isonicotinamide (0.27 mmol) and 58 mg of diclofenac (0.27 mmol)
was added into a sample vial. The solid was further dissolved in
methanol (15 mL) and left to evaporate at room temperature.
carboxylic acid pyridine hydrogen bond to be supported
3 3 3
by a weak C-H O hydrogen bond. The carboxylic acid
3 3 3
and pyridine ring are then coplanar and a new R22(7) ringlike
hydrogen bond motif is formed (synthon IV) (Figure 1c). The
hydrogen bonded isonicotinamide and carboxylic acid mole-
cule form a four-membered supermolecule. The anti H of the
amide is then employed to link up the supermolecules, usually
connecting to the carbonyl of the acid. The supermolecules
can either be coplanar or at right angles to each other, result-
ing in either a ribbon or a network type structure.19 These two
architectures are generally encountered with monocarboxylic
acids; if the molecule is a dicarboxylic acid, it is possible to
get a combination of all three synthons I-IV and different,
higher dimensional architectures.
2.2.4. (isonicotinamide) (H2O) I (4) and II (5). Thirty milligrams
3
of isonicotinamide (0.27 mmol) and 0.71 mg of clofibric acid
(0.27 mmol) was added into a sample vial with methanol (5 mL)
and left to evaporate at room temperature. The clofibric acid did not
dissolve as well as the isonicotinamide in the 5 mL of methanol, and
only crystals of the isonicotinamide hydrates were obtained from
these experiments. Crystals of 5 (form II) were observed first, which
then converted to 4 (form I) over 2 weeks. We attempted to grow
single crystals of 4 by recrystallizing isonicotinamide from water
and water/methanol mixtures under a variety of conditions. All such
attempts were unsuccessful, with 5 being the form crystallized in
most cases. Solvent drop grinding experiments using water and
several solvents and solvent mixtures produced 5.
2.3. Differential Scanning Calorimetry (DSC). All DSC measure-
ments were performed using a Perkin-Elmer DSC7, heating rate
In this work, the API ingredients chosen were diclofenac (2-
(2-(2,6-dichlorophenylamino)phenyl)acetic acid), a nonsteroidal
anti-inflammatory drug, and clofibric acid (2-(4-chloropheno-
xy)-2-methylpropanoic acid), an antihyperlipidemic drug,
and the GRAS molecule nicotinamide. In addition, during
co-crystallization experiments with clofibric acid, two poly-
morphs of the hydrate of isonicotinamide were discovered
(Chart 1).
10 K min-1, under an atmosphereof dry N2, flowing at 30 cm3 min-1
The calorimeter was calibrated with indium and zinc.
.
2.4. Thermal Gravimetric Analysis (TGA). TGA measurements
for 4 and 5 were run on a Mettler-Toledo TGA/SDTA 851e at a
heating rate of 10 K min-1 under an atmosphere of dry N2 flowing
at 30 cm3 min-1
.
2.5. Cambridge Structural Database Search. All searches were
done on the Version 5.31 Database with the February 2010 update.
The search for isonicotinamide co-crystals was done with the fol-
lowing search parameters: (search fragment) isonicotinamide mo-
lecule and carboxylic acid functional group; (filters) 3D coordinates
determined, notdisordered, no errors, no ions, no powderstructures,
only organics. This gave 42 hits, which were reduced to 40 after
2. Experimental Section
2.1. . Materials. Isonicotinamide, nicotinamide, clofibric acid,
and diclofenac were purchased from commercial sources (Aldrich)

Article
Crystal Growth & Design, Vol. 11, No. 1, 2011 77
Table 1. Crystallographic Data and Structure Refinement Parameters
1
2
3
4
5
moiety formula
Mr
C6H6N2O
122.12
785370
100(2)
C6H6N2O C10H11O3Cl C6H6N2O C14H11NO2Cl2 C6H6N2O H2O
C6H6N2O H2O
3
3
3
3
336.77
785371
173(2)
418.27
785372
173(2)
140.14
785373
173(2)
140.14
785374
173(2)
CCDC No.
temp (K)
crystal size (mm3)
crystal system
space group
0.30 ꢀ 0.20 ꢀ 0.20 0.40 ꢀ 0.40 ꢀ 0.30
0.44 ꢀ 0.18 ꢀ 0.17
triclinic
P1
0.20 ꢀ 0.05 ꢀ 0.05 0.32 ꢀ 0.31 ꢀ 0.20
triclinic
P1
triclinic
P1
monoclinic
P21/n
monoclinic
Pc
19.099(17)
7.4858(7)
22.7304(15)
90
123.792(5)
90
2700.8(4)
16
1.379
0.106
1.79-25.50
22724
4979 [0.0321]
3630
0.0350
˚
a (A)
7.9828(4)
10.9899(8)
14.7699(11)
68.583(3)
87.300(4)
79.219(4)
1184.70(14)
8
6.9843(2)
15.8948(5)
16.2722(5)
110.079(2)
99.792(2)
95.324(2)
1649.48(9)
4
1.356
0.253
2.60-25.50
27333
7.4641(3)
8.8223(2)
14.8006(6)
89.144(2)
87.628(2)
82.788(2)
966.04(6)
2
1.438
0.363
2.69-25.50
13154
7.418(2)
10.774(3)
16.608(5)
90
92.686(7)
90
1325.8(7)
4
1.404
0.108
2.25-25.50
8392
˚
b (A)
˚
c (A)
R (deg)
β (deg)
γ (deg)
3
˚
V (A )
Z
F(calcd) (Mg m-3
)
)
1.369
0.098
μ(Mo KR) (mm-1
θ range for data collection (deg) 1.48-25.50
reflections collected
no. unique data [R(int)]
no. data with I > 2σ(I)
final R (I > 2σ(I))
final wR2 (all data)
extinction coefficient
34480
4395 [0.0485]
3436
0.0366
0.0950
0.025(3)
6135 [0.0402]
5361
0.0323
3575 [0.0577]
3010
0.0456
2386 [0.0313]
2093
0.0362
0.1226
0.0891
0.1281
0.1108
removing duplicate entries. The search for nicotinamide co-crystals
was done with the following search parameters: (search fragment)
nicotinamide molecule and carboxylic acidfunctional group;(filters)
3D coordinates. This gave 14 hits, which were reduced to 11 after re-
moving duplicate entries.
angle 110ꢀ) and then refined as riding atoms on the water molecules.
Diagrams and publication material were generated using ORTEP-3,27
PLATON,28 and DIAMOND.29 Experimental details of the X-ray
analyses are provided in Table 1, and the atomic numbering scheme
and thermal ellipsoids (50% probability level) are shown in Figure 2.
2.8. Computational Details. Density functional theory (DFT)
calculations were done using Becke’s three-parameter hybrid func-
tional for exchange coupled with the correlation functional of Lee,
Yang, and Parr, B3LYP.30 A6-31þG(2df,p) basis set was used. Binding
energies were corrected for zero point vibrational energy (scaled by
a factor of 0.98531) and the basis set superposition error (using the
counterpoise scheme of Boys and Bernardi32) according to
2.6. Powder X-ray Diffraction. Room temperature X-ray powder
diffraction data were collected on a HUBER Guinier 670 Imaging
˚
Plate diffractometer with Cu KR1 radiation (λ=1.5405 A). The sam-
ple was ground, spread on Mylar film, and mounted on a vertical
stage. A diffractogram was acquired under ambient conditions at a
power setting of 40 kV and 20 mA in transmission mode while the
sample oscillated perpendicular to the beam. The data compared
very favorably with the calculated powder data obtained from single
crystal data (see the Supporting Information), thereby proving that
the single crystal structure is representative of the bulk compound.
Variable temperature X-ray powder diffraction data were deter-
mined on hydrate 4 placed in a 1 mm capillary tube. The sample was
heated in a HUBER furnace, whose calibrations show temperature
control to within 1 ꢀC of the set temperature.
A∪B
Ebind ¼ E
ðA BÞ - ðEAAðAÞ þ EBBðBÞÞ þ ΔECP
ð1Þ
AB
3
A∪B
where E
(A B) represents the energy of the pair at their opti-
AB
3
mized geometry using the basis functions centered on both A and B,
and EAA(A) is the energy of A at its optimized geometry with those
basis functions centered on only atoms of A. The counterpoise
correction is
2.7. Single Crystal X-ray Diffraction. Diffraction data for com-
pounds 1-3 were collected on a Nonius Kappa CCD diffractometer20
A∪B
A∪B
ΔECP ¼ ðE
ðAÞ þ E
ðBÞÞ - ðEAABðAÞ þ EABBðBÞÞ ð2Þ
AB
AB
˚
with graphite-monochromated Mo KR1 radiation (λ = 0.71073 A) at
173 K using an Oxford Cryostream 600. Data reduction and cell
refinement were performed using DENZO,21 and the space groups of
these crystals were determined from systematic absences by XPREP22
and further justified by the refinement results. Diffraction data for
compounds 4 and 5 were collected on a Bruker DUO APEX II dif-
fractometer23 with graphite-monochromated Mo KR1 radiation
where EAAB∪B(A) is the energy of A at the pair geometry with the basis
set also including those functions assigned to atoms of molecule B.
Atomic partial charges were determined using the Merz-Kollman-
Singh fit to electrostatic potentials.33 The GAUSSIAN 09 package
was used for all calculations.34
˚
(λ=0.71073 A) at 173 K using an Oxford Cryostream 700. Data
3. Results and Discussion
reduction and cell refinement were performed using SAINT-Plus,24 and
the space groups of these crystals were determined from systematic
absences by XPREP22 and further justified by the refinement results.
Face-indexed absorption corrections were made in 2 and 3. In all
cases, the structures were solved in the WinGX25 Suite by direct
methods using SHELXS-9726 and refined using full-matrix least-
squares/difference Fourier techniques using SHELXL-97.26 The hy-
drogen atoms bound to carbon atoms were placed at idealized posit-
ions and refined as riding atoms with Uiso(H) = 1.2Ueq(Ar-H, CH2)
or 1.5Ueq(CH3). H atoms bonded to the carboxylic acid and amide
group were located in the difference Fourier map and their coordi-
nates refined freely, but their isotropic displacement parameters were
fixed (Uiso(H) = 1.5Ueq(O) or Ueq(N)). H atoms on the water mole-
cules were located in the difference Fourier map, and their isotropic
displacement parameters were fixed (Uiso(H) = 1.5Ueq(O)). In 4 the
H atom coordinates were refined freely. In 5, the coordinates of the
H atoms were restrained using DFIX and DANG until reasonable
3.1. Crystal Structures. Co-crystal 1 contains a 1:1 ratio of
the isomers isonicotinamide and nicotinamide. It crystallizes
with Z0 =2 in the asymmetric unit. The four molecules are
divided into pair A, containing isonicotinamide O1 and nico-
tinamide O3, and pair B, containing isonicotinamide O2 and
nicotinamide O4. Each pair of isonicotinamide and nicotin-
amide molecules has the same hydrogen bond interaction.
In pair A, the isonicotinamide forms not a R22(8) dimer, but
instead a C(7) chain from the syn H to the pyridine N atom
along the a-axis. These C(7) chains are flanked on both sides
by nicotinamide molecules. The isonicotinamide chains con-
nect to the nicotinamide molecules, first as a donor through
its anti H to the pyridine N of the nicotinamide molecules,
and second as an acceptor through the carbonyl O atom from
the anti H of the nicotinamide (Figure 3a and b). Finally, the
˚
water geometries were obtained (O-H distance 0.85 A, H-O-H

ꢀ
Bathori et al.
78 Crystal Growth & Design, Vol. 11, No. 1, 2011
Figure 2. Asymmetric units and atomic numbering schemes of co-crystals 1-3 and hydrates 4 and 5, drawn with 50% displacement ellipsoids.
Only the symmetry independent hydrogen bonds are shown. For clarity, the H atoms not involved in hydrogen bonding are omitted in 5.
nicotinamide itself forms the R22(8) homodimer through its
syn H. The net effect is a bilayer, where two parallel C(7)
chains at z=0.873 and 1.126 are connected by the nicotin-
amide dimers, which are inclined at an angle of 26.67(1)ꢀ to
the chains (Figure 3c). Pair B has the same hydrogen bonded
interactions, with the C(7) chains at z=0.377 and 0.622 but
with the nicotinamide dimers inclined at 28.19(1)ꢀ to the
plane of the chains.
Co-crystal 2 has a 1:1 ratio of isonicotinamide and clofib-
ric acid. As for 1, Z0 = 2. The two isonicotinamide molecules
in the asymmetric unit (labeled O1 and O2) form a noncen-
trosymmetric R22(8) homodimer. The two clofibric acid mole-
cules, labeled Cl1 and Cl2, have different conformations.
The torsion angles C20-C19-O5-C13 (55.4(2)ꢀ in Cl1)
and C30-C29-O8-C23 (71.9(2)ꢀ in Cl2) describe the incli-
nation of the aromatic ring to the carboxylic acid group. The
two clofibric acid molecules hydrogen bond to the pyridine N
atom of the corresponding isonicotinamides through synthon
I to form a four-membered supermolecule (Figure 4a). The
two clofibric acid molecules that hydrogen bond to their
respective isonicotinamide molecules are arranged differ-
ently, with molecule Cl1 inclined considerably further out
of the plane of its isonicotinamide molecule (57.9(1)ꢀ; mea-
sured through the least-squares plane of the aromatic ring
given by C13-C18 and the least-squares plane of the O1
isonicotinamide molecule) than molecule Cl2 (16.1(1)ꢀ; mea-
sured through the least-squares plane of the aromatic ring
given by C23-C38 and the least-squares plane of the O2
isonicotinamide molecule). The supermolecules are linked by
the hydrogen bond from the anti H of the isonicotinamide to
the carbonyl O atoms of the acid group to form the ribbon
motif (Figure 4b).
Co-crystal 3 has a 1:1 ratio of isonicotinamide and diclo-
fenac molecules in the asymmetric unit, but with Z0 = 1. This

Article
Crystal Growth & Design, Vol. 11, No. 1, 2011 79
Figure 3. Detailed hydrogen bonded interactions of the two pairs A (a) and B (b) of (isonicotinamide) (nicotinamide) molecules, that alternate
along the c-axis in the packing diagram (c). The H atoms not involved in hydrogen bonding are omitted for clarity in part c.
3
Figure 5. The three independent intermolecular hydrogen bonded
interactions that connect the isonicotinamide and diclofenac mo-
lecules in co-crystal 3. Note the intramolecular N-H O hydro-
3 3 3
gen bond typical of diclofenac (a). The packing is again the ribbon
motif (b).
Figure 4. (a) Carboxylic acid pyridine hydrogen bond (synthon I)
3 3 3
together with the homomeric amide amide R22(8) dimer (synthon
II) in the supermolecule of co-crystal 2. (b) Ribbon packing of 2 (for
clarity, the H atoms not involved in hydrogen bonding are omitted).
Again, the ribbon motif is formed (Figure 5b). The diclofenac
molecule also features an intramolecular hydrogen bond from
the amine H to the O atom of the acid group.
3 3 3
The first polymorph of the isonicotinamide hydrate 4
(form I) has a 1:1 ratio of isonicotinamide to water mole-
cules, but with Z0 = 2 in the asymmetric unit. The isonico-
tinamide forms R22(8) homodimers through the syn H.
Dimers at right angles are connected by hydrogen bonds
results in a supermolecule that has a center of inversion cen-
tered on a nicotinamide dimer. The diclofenac molecule hy-
drogen bonds to the pyridine N (synthon I) and accepts the anti
H of the isonicotinamide to its carbonyl oxygen (Figure 5a).

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Bathori et al.
80 Crystal Growth & Design, Vol. 11, No. 1, 2011
Figure 6. Hydrogen bonding interactions of (isonicotinamide) (H2O) form I (a) and form II (c). In form I, the water molecules hydrogen bond
3
to the isonicotinamide dimers through the amide O atom, whereas, in II, the water molecules hydrogen bond to the pyridine N. Both forms have
the water molecules packing in channels in between the isonicotinamide dimers (b and d).
from the anti H to the pyridine of adjacent dimers. Dimers
arranged parallel are connected by a tetrameric water cluster
(Figure 6a). The net arrangement is of four dimers, joined to
form a rectangular tetramer that surrounds the water mole-
cules. The isonicotinamde tetramers are all in a plane to form
a 2-D sheet (Figure 6b). Adjacent sheets are connected by the
water tetramers (Figure 7). Analysis of the water hydrogen
bond environment35 shows that waters in form I have a DDA
environment.
The second polymorph, hydrate 5 (form II), has the same
1:1 ratio as hydrate 4, but with Z0 = 8 in the asymmetric unit.
The eight unique isonicotinamide molecules form four non-
centrosymmetric R22(8) homodimers and hydrogen bond to
the eight water molecules via their anti H. In the asymmetric
unit, each of the eight water molecules hydrogen bonds to the
pyridine N of the eight isonicotinamide molecules through
one of the H atoms on the water molecules. The second hy-
drogen on each water molecule then hydrogen bonds to another
water molecule. The water molecules themselves are 2-fold
acceptors, with each one using both lone pairs on the O atom
(Figure 6c). This corresponds to a DDAA water H-bond
Figure 7. Side-on view of the hydrate 4, showing the water mole-
cules hydrogen bonding between the sheets.
environment. The relative arrangement of the dimers is par-
allel within a 2-D sheet, but slightly offset, allowing space
for the water molecules in the centers (Figure 6d). This hy-
drate was found not to be stable and after a while turned into
the form I hydrate in the solid state.

Article
Crystal Growth & Design, Vol. 11, No. 1, 2011 81
Table 2. Hydrogen Bonded Synthons in Isonicotinamide Co-crystals in the CSD
synthon types
observed
ratio acid to
isonicotinamide molecules
CSD ref code
carboxylic acid
motif
network
network
ribbon
ribbon
network
network
ribbon
(1) AJAKAX
(2) AJAKEB
(3) AJAKIF
(4) ASAXOH
(5) ASAXUN
(6) BUDWEC
(7) BUDZUV
(8) BUFBIP
(9) BUFQAU
(10) HANBOO
(11) JAWWAG
(12) JAWWEK
(13) LUNMAI
(14) LUNMEM
(15) LUNMIQ
(16) LUNMOW
(17) LUNMUC
(18) LUNNAJ
(19) LUNNEN
(20) LUNNIR
(21) LUNNOX
(22) LUNNUD
(23) LUNPAL
(24) LUNPEP
(25) ULAWAF
hex-2-enoic acid
4-nitrobenzoic acid
I, II
1:1
1:1
1:1:1
1:1
1:1
1:1
1:1:1
1:1:1
1:1:1
2:1
1:1
1:2
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:2
1:2
1:2
1:1
1:2
1:2
1:2
1:2
1:2
1:2
1:1
1:1
1:1
1:1:1
1:1
1:1
1:1
1:1
1:1
1:1
2:1
II, IV
I, III
II, IV
II, IV
II, IV
I, III
I, III
III, IV
III, IV
II, IV
I, II, IV
II, IV
II, IV
I, II
3,5-dinitrobenzoic acid 4-methylbenzoic acid
3-nitrobenzoic acid
4-fluorobenzoic acid
benzoic acid
3,5-dinitrobenzoic acid 3-methylbenzoic acid
3,5-dinitrobenzoic acid 4-(N,N-dimethylamino)benzoic acid
3,5-dinitrobenzoic acid 4-hydroxy-3-methoxycinnamic acid
propionic acid
ribbon
2D sheet
network
ribbon
corrugated sheet
ribbon
network
network
ribbon
3D
network
ribbon
2D sheet
2D sheet
2D sheet
3D
ribbon
3D
2D sheet
network
network
network
network
network
3D
network
ribbons
ribbon
acetic acid
cis,cis-1,3,5-cyclohexanetricarboxylic acid
cinnamic acid
3-hydroxybenzoic acid
3-(N,N-dimethylamino)benzoic acid
3,5-bis(trifluoromethyl)benzoic acid
12-bromododecanoic acid
monochloroacetic acid
fumaric acid monoethyl ester
4-ketopimelic acid
fumaric acid
I, II
I, II
II, IV
II, IV
I, II, IV
II, IV
I, II
II, IV
II, IV
II, IV
II, I
II, IV
I, II, IV
I, II
I, III
I, III
III
succinic acid
D,L-mandelic acid
thioglycolic acid
oxalic acid
(26) ULAWAF02 oxalic acid
(27) ULAWEJ
(28) ULAWOT
(29) ULAWUZ
(30) ULAXAG
(31) ULAXEK
(32) VAKTOR
(33) XAQPOV
(34) XEQQEM
(35) ROLFUU
(36) RONDAA
(37) ROLFOO
(38) RONDEE
(39) RONDII
(40) MELYEI
malonic acid
glutaric acid
adipic acid
glutaric acid
adipic acid
4-hydroxybenzoic acid
3,5-dinitrobenzoic acid and 3,4-dimethoxycinnamic acid
2-hydroxybenzoic acid
(RS)-2-phenylbutyric acid
(R)-2-phenylpropionic acid
(RS)-2-phenylpropionic acid
(R)-2-phenylbutyric acid
(S)-2-phenylbutyric acid
benzoic acid
I, III
I, II
II, IV
II, IV
II, IV
II, IV
II, IV
III, IV
network
network
ribbon
ribbon
network
Table 3. Hydrogen Bonded Synthons in Nicotinamide Co-crystals in the CSD
CSD ref code
carboxylic acid
synthon types observed
ratio acid to nicotinamide molecules
(1) FIFLAI
heptadecanoic acid
II, IV
I, II
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1:1
1:1
(2) IACNCA
(3) JEMDIP
(4) JILZOU
(5) PEQBES
(6) SODDIZ
(7) SODDOF
(8) SOGLAC
(9) UCOTUC
(10) XAQPUB
(11) XAQQIQ
indole-30-acetic acid
hexadecanoic acid
D-mandelic acid
II, IV
I, II, IV
II, IV
I, II
octadecanoic acid
(RS)-ibuprofen
salicylic acid
(S)-ibuprofen
dodecanoic acid
3,5-dinitrobenzoic 3-(dimethylamino) benzoic acid
3-hydroxybenzoic acid
IVa
I, II
II, IV
III, IV
III
a No dimer II; amide forms C(4) chain.
3.2. CSD Analysis. The two molecules isonicotinamide and
nicotinamide were stated to be both model co-crystal formers,
with the latter being a GRAS substance in addition. However,
not many co-crystals, pharmaceutical or otherwise, have been
made with nicotinamide. Much more numerous are isonicoti-
namide co-crystals, with some 40 identified in the CSD com-
pared to 11 for nicotinamide (Tables 2 and 3). Seeing the greater
preponderance of isonicotinamide co-crystals, it is valid to con-
sider how isonicotinamide co-crystals can be used as a model
system for nicotinamide co-crystals. The hydrogen bonded
interactions that isonicotinamide undergoes with carboxylic
both of these two synthons are observed 39/40 times in those
co-crystals (the 40th is synthon III). The second most frequent
motif is the R22(8) heterosynthon (synthon III), seen in 10
co-crystals; the remaining 30 co-crystals all have the isonico-
tinamide featuring the R22(8) homosynthon II. These statistics
are compared to those of nicotinamide co-crystals in Table 3.
Synthon I or IV is observed 10/11 times, with a single occur-
rence of an alcohol group hydrogen bonding to the pyridine
instead of the carboxylic acid. The heterodimer synthon III is
seen twice. The nicotinamide forms the self-complementary
synthon II eight times, and a C(4) chain is observed once. In
summary, both isonicotinamde and nicotinamide prefer to
hydrogen bond with each other through the stable synthon II
acids are generally an O-H N hydrogen bond (synthons I
and IV) from the carboxylic acid H to the pyridine N. Either or
3 3 3

ꢀ
Bathori et al.
82 Crystal Growth & Design, Vol. 11, No. 1, 2011
Table 4. Geometrical Parameters for Hydrogen Bonds in Co-crystals 1-3
˚
˚
d(H A) (A)
˚
d(D A) (A)
compd
d(D-H) (A)
—(D-H A) (deg)
symmetry operator
3 3 3
3 3 3
3 3 3
1
N1-H1S N2
3 3 3
0.96(2)
0.96(2)
0.95(2)
0.93(2)
0.92(2)
0.88(2)
0.92(2)
0.89(2)
1.99(2)
2.08(2)
1.99(2)
2.12(2)
2.04(2)
2.09(2)
1.99(2)
2.04(2)
2.946(2)
3.007(2)
2.931(2)
3.010(2)
2.946(2)
2.967(2)
2.903(2)
2.927(2)
174(2)
161(2)
174(2)
160(2)
172(2)
172(2)
175(2)
172(2)
x - 1, y, z
x - 1, y, z
N1-H1A N6
3 3 3
N3-H3S N4
3 3 3
N3-H3A N8
3 3 3
N5-H5S O3
-x, -y þ 1, -z
x, y - 1, z
3 3 3
N5-H5A O1
3 3 3
N7-H7S O4
-x - 1, -y, -z þ 1
3 3 3
N7-H7A O2
x, y - 1, z
3 3 3
2
N1-H1S O2
0.88(2)
0.87(2)
0.87(2)
0.87(2)
0.84(2)
0.84(2)
2.08(2)
2.14(2)
2.02(2)
2.02
1.75(2)
1.78(2)
2.958(2)
2.967(2)
2.898(2)
2.869(2)
2.570(2)
2.588(2)
175(2)
159(2)
179(2)
163(2)
163(2)
161(2)
3 3 3
N1-H1A O7
-x þ 1, -y þ 1, -z þ 1
-x þ 2, -y þ 2, -z þ 2
3 3 3
N3-H3S O4
3 3 3
N3-H3A O1
3 3 3
O3-H3 N2
3 3 3
O6-H6 N4
3 3 3
3
N1-H1S O1
0.86(3)
0.87(3)
1.09(3)
0.88(2)
2.09(3)
2.07(3)
1.48(3)
2.13(2)
2.940(2)
2.925(2)
2.556(2)
2.878(2)
169(2)
168(2)
170(2)
142(2)
-x þ 3, -y þ 2, -z þ 1
x, y þ 1, z
3 3 3
N1-H1A O3
3 3 3
O2-H2 N2
3 3 3
N3-H3 O2
3 3 3
and act as hydrogen bond acceptors to the carboxylic acid
groups, generally through either I or IV.
norfloxacin.4b Co-crystals 2 and 3 are two further additions.
Both of the new co-crystals adopt the ribbon motif, which is
one of the two commonly encountered motifs in isonicotin-
amide co-crystals with carboxylic acids. The crystal struc-
ture of clofibric acid (BEFVAJ) forms hydrogen bonded
dimers through its carboxylic acid group.40 The melting
point of clofibric acid is 118-123 ꢀC, and that of isonicotin-
amide is 155-158 ꢀC. The melting point of the co-crystal is
lowered, compared to those of the two starting molecules, to
89.5 ꢀC (see the Supporting Information for the DSC trace).
The conformation of the two clofibric molecules in the co-
crystal is different from the conformation of the molecule by
itself. The torsion angle Ar-C-O-C(CH3)2COOH is 4.4(2)ꢀ
(C14-C13-O5-C19) and -19.1(2)ꢀ (C24-C23-O8-C29)
in 2 and 54.4(1)ꢀ (C6-C1-O1-C7) in BEFVAJ. Co-crystal 3
displays an even more significant conformational change
comparedtoitsparent API. Diclofenachas three polymorphs,
known as HD1 (space group P21/c, SIKLHI02),41 HD2
(C2/c, SIKLIH03),41 and HD3 (Pcan, SIKLIH04).42 In
HD1 and HD2, the carboxylic acid dimer connects the
molecules, while, in HD3, no intermolecular hydrogen bonds
are observed.42 In all three forms, the intramolecular hydrogen
bond is to the carbonyl O atom of the carboxylic acid; in the
co-crystal, the exact opposite occurs. Presumably, the new
carboxylic acid hydrogen bond to the pyridine stabilizes this
new conformation. The melting point of the co-crystal (164 ꢀC,
see the Supporting Information for the DSC trace) is lower
than that of diclofenac (283-285 ꢀC) but higher than that of
isonicotinamide. Table 4 lists the hydrogen bond geometries
for these co-crystals. The intermolecular hydrogen bonds are
generally linear in the range from 159(2)ꢀ to 175(2)ꢀ.
3.3. Discussion of Crystal Structures. The co-crystal be-
tween isonicotinamide and nicotinamide is a notable struc-
ture. Both molecules have been used on their own as model
co-crystal formers, as mentioned above. Nicotinamide, as a
GRAS member, is the more promising of the two, to be used
in future formulations of pharmaceutical co-crystals. Berry
et al. carried out a co-crystal screen with nicotinamide as a
co-crystallizing agent and seven candidate APIs.36 A new co-
crystal phase was successfully obtained for those five APIs
which contain a carboxylic acid functional group, and the
crystal structures of three of them were determined. Other
APIs used in pharmaceutical co-crystals with nicotinamide
include celecoxib5k and carbamazepine.12e Our attempts to
prepare co-crystals of nicotinamide with clofibric acid and
diclofenac, from solution or by solvent-assisted grinding,
were unsuccessful (see the Supporting Information). It is
intriguing to compare the hydrogen bonding observed in the
(isonicotinamide) (nicotinamide) co-crystal to the crystal
3
structures of the individual compounds. Isonicotinamide has
two reported polymorphs.13a The crystal structure of form
II, EHOWIH02, has two isonicotinamide molecules in the
asymmetric unit. The syn H hydrogen bonds to the pyridine
N atom to form a C(7) chain, while the anti H forms a C(4)
chain. This is similar to the hydrogen bonding of the iso-
nicotinamide in 1, which also forms a C(7) chain. Hence,
it retains some of its hydrogen bonding characteristics in the
co-crystal. Nicotinamide has been reported to have four
polymorphs,37 but only the structure of the stable form has
been reported (NICOAM01).38 This stable form has C(4)
chains through its anti H and a hydrogen bond to the
pyridine N through its syn H. In co-crystal 1, nicotinamide
forms a homodimer, a preference when forming co-crystals
with carboxylic acids. A hydrogen bond that is retained from
the stable form is that between the nicotinamide pyridine and
the anti H of the isonicotinamide. The melting point of this
co-crystal (121 ꢀC, see the Supporting Information for the
DSC trace) is lower than that of nicotinamide (128-131 ꢀC)
and isonicotinamide (155-158 ꢀC).
The two isonicotinamide hydrates 4 and 5 were obtained
serendipitously in the co-crystallization experiments with
clofibric acid. The first co-crystallization experiment with
clofibric and isonicotinamide failed due to the incomplete
dissolution of the clofibric acid in the 5 mL of methanol used
(co-crystal 2 was subsequently obtained by using six times the
volume of solvent). Hydrate 4 has been reported recently,43
but we will refer to our structure for simplicity. Form II of the
isonicotinamide hydrates (5) was observed to crystallize first
from the solution experiments, followed by form I (4). In
both polymorphs, the asymmetric unit has Z0 > 1. In 4, there
is one complete hydrogen bonded dimer and two waters of
Pharmaceutical co-crystals with isonicotinamide are much
less numerous than those with nicotinamide. Two pharma-
ceutical co-crystals are known, with carbamazepine39 and

Article
Crystal Growth & Design, Vol. 11, No. 1, 2011 83
Table 5. Torsion Angles (deg) of Isonicotinamide Molecules in Compounds 1-5
1
2
3
4
5
-14.2(2)
-22.3(2)
-10.3(3)
C2-C1-C6-N1
-35.3(2)
-28.7(9)
C2-C1-C6-N1
-14.3(2)
C2-C1-C6-N1
26.2(2)
C2-C1-C6-N1
35.3(2)
C2-C1-C6-N1
10.4(9)
C8-C7-C12-N3
C8-C7-C12-N3
C8-C7-C12-N3
C8-C7-C12-N3
32.2(9)
C14-C13-C18-N5
-17.9(9)
C20-C19-C24-N7
14.7(9)
C29-C25-C30-N9
-31.9(8)
C32-C31-C36-N11
33.0(8)
C38-C37-C42-N13
-14.7(9)
C44-C43-C48-N15
Table 6. Geometrical Parameters for Hydrogen Bonds in Hydrate 4
˚
˚
d(H A) (A)
˚
d(D A) (A)
compd
d(D-H) (A)
—(D-H A) (deg)
symmetry operator
3 3 3
3 3 3
3 3 3
4
N1-H1S O2
0.89(2)
0.86(2)
0.89(2)
0.87(2)
0.89(2)
0.86(2)
0.92(2)
0.83(2)
2.03(2)
2.16(2)
2.04(2)
2.12(2)
1.92(2)
2.01(2)
1.87(2)
2.06(2)
2.918(2)
3.002(2)
2.927(2)
2.977(2)
2.798(2)
2.862(2)
2.780(2)
2.881(2)
172(2)
168(2)
172(2)
169(2)
168(2)
170(2)
172(2)
170(2)
3 3 3
3
1
N1-H1A N4
x - 1/2, -y þ /2, z þ /2
3 3 3
N3-H3S O1
3 3 3
1
1
N3-H3A N2
x þ /2, -y þ /2, z - 1/2
3 3 3
O1W-H1W O1
3 3 3
O1W-H2W O2W
x, y - 1, z
3 3 3
O2W-H3W O2
3 3 3
O2W-H4W O1W
-x þ 1, -y þ 1, -z þ 1
3 3 3
hydration, whereas, in 5, there are four unique hydrogen
bonded dimers and eight waters of hydration. Stoichiome-
trically, the ratio of isonicotinamide to water is 1:1. In both
cases, the large asymmetric units give indications of missed
higher symmetry; for example, the two molecules of the
isonicotinamide dimer in 4 are related by a pseudo center of
inversion. The torsion angle of the amide to the aromatic ring
is -35.3(2)ꢀ and 35.3(2)ꢀ for the two molecules (Table 5).
However, the pseudo center of inversion is not reflected in the
water molecules, which have different relative orientations to
each other and the dimer as well as different hydrogen bonded
geometries (Table 6). In hydrate 5, with Z0 = 8, the torsion
angles of the individual isonicotinamide molecules in their
respective dimeric arrangement are different (cf. in Table 5:
N1 vs N3; N5 vs N7; N9 vs N11; N13 vs N15). Ultimately the
difference between the two polymorphs is not in the hydro-
gen bonded dimers but in the way the water molecules hydro-
gen bond to the dimers. In 4, the H atoms on the water molec-
ules hydrogen bond to each other and to the carbonyl O atom
of the dimers, and they accept a single hydrogen bond from
a water molecule (DDA). In 5, one H atom hydrogen bonds
to a water molecule (as in 4), but the second H atom hydro-
gen bonds to the pyridine N atom instead of the carbonyl
oxygen atom. Furthermore, the water molecules have satu-
rated hydrogen bonding (DDAA),44 where both lonepairs are
used as acceptors (4 only has three hydrogen bonded interac-
tions, two donating and one accepting). The saturated hydro-
gen bondingin 5 is unusual, as a study45 found thatmostwater
molecules have three contacts, as in 4. The hydrogen bonding
geometries of 5 are given in the Supporting Information in
Table S1. The crystal packing of the two polymorphs features
layers of hydrogen bonded isonicotinamide dimers, which are
connected by hydrogen bonds to adjacent layers through the
water molecules in both polymorphs.
DSC and TGA traces. Form I (4) goes through a two-step
water loss, the first occurring at about 60 ꢀC with a mass loss
percentage of 6%, and the second at 100 ꢀC, with a further
loss of 7%. Each of these percentages corresponds to the loss
of half a water molecule, which means that a hemihydrate is
formed after the first loss, leading to an anhydrous form on
the second mass loss. Variable temperature PXRD (Figure 8b)
shows the diffraction pattern of the hemihydrate and the an-
hydrous form. The resulting anhydrous form does not corre-
spond with the known structure of isonicotinamide, suggesting
a new polymorphic form.
The thermal behavior of form II (5) shows only a single
mass loss step on the TGA, of 13%, occurring at about 50 ꢀC
(Figure 9). No PXRD of this form was possible due to sample
decomposition.
3.4.1. DFT Calculations on Nicotinamide and Isonicotina-
mide. Atomic partial charges (shown in Figure 10) confirm
that structural changes in the two isomers have little effect on
the charge density of those heteroatoms involved in forming
synthons I to IV. These also confirm assignment of the pyridine
nitrogen as the most nucleophilic site (-0.693 and -0.671 e),
followed by the amide carbonyl oxygen (-0.548 and -0.519 e).
A significant change in charge density is seen, however, on the
carbons and hydrogen atoms in the ring system. With the shift
in location of the pyridine N atom para and meta to the amide
group, the alternating relative acidities of the ring protons shift.
Based on charges calculated here though, these protons are
significantly less acidic than those on the amide and this change
will only affect the formation of weaker π-CH hydrogen bonds
in the plane of the pyridine ring. Based on the crystal structures
determined here, interactions of this type have not been found
to play an important direct role in the co-crystal formation of
these species.
Mueller et al.46 determined the activation enthalpy (ΔH‡)
for the rotation around the amide (OC-NH2) bond in nico-
tinamide to be 1.0 kcal/mol lower than that of isonicotinamide,
3.4. Thermal Analysis of Hydrates 4 and 5. The thermal
behavior of the two hydrates is different. Figure 8a shows the

ꢀ
Bathori et al.
84 Crystal Growth & Design, Vol. 11, No. 1, 2011
Figure 10. Atomic partial charges of (a) nicotinamide and (b) iso-
nicotinamide.
that is observed in both crystal structures with clofibric acid
and diclofenac (i.e., ring and amide nitrogen atoms cis) being
favored. This is a very subtle difference between nicotina-
mide and isonictonamide in that a collection of supramole-
cular synthons that predisposes the conformation with the
amine cis to the pyridine nitrogen in nicotinamide could be
favored. However, this comes at an energetic cost of only
1 kcal/mol.
Figure 8. (a) TGA and DSC traces of the dehydration of hydrate 4.
(b) The dehydration process was monitored byPXRD. AtT = 25ꢀC,
the pattern of hydrate I is seen. At T = 50 ꢀC, the hemihydrate is
formed, and at 90 ꢀC, the anhydrous form is observed.
3.4.2. DFT Calculation of Synthon Binding Energies. We
next determined if binding energies between synthons could
explain the preference of isonicotinamide to co-crystallize
with the APIs used in this study. Binding energies for
synthons I-IV, involving both nicotinamide and isonicotin-
amide and the APIs, were calculated. These are given in
Table 7. Synthons I and IV differ through additional inter-
action between the carboxylic acid carbonyl oxygen and a
pyridine ring hydrogen; in the absence of the crystal environ-
ment, it is IV that occurs predominantly and is listed here.
Synthons II and III are “locked” in only one possible con-
figuration by the nature of the complementary interaction.
The carbonyl O-pyridine H interaction of IV can have two
configurations, and we found that which involves the hydro-
gen adjacent to the carboxamide to be most stable. From the
binding energies, III shows no preference, with values that are
identical across all pairs, whereas II, the complementary
homomeric synthon, is more favorable with isonicotinamide.
Synthon IV, on the other hand, shows a preference toward
nicotinamide. From the calculated binding energies, it is clear
that other factors are at play in the formation of the crystal. In
the gas phase, synthon IV is stronger with nicotinamide, and
whereas III appears to be a more favorable interaction, it is II
that is encountered in these API co-crystals.
Figure 9. TGA and DSC traces of the dehydration of hydrate 5.
Note the single-step loss compared to the two-step loss of 4.
experimentally using dynamic NMR. DFT calculations at the
B3LYP/6-311þþG (d,p) level performed by them were in
excellent agreement, giving 0.9 kcal/mol. Here, we determine
the difference in the ease of rotation around the C-C bond be-
tween the aromatic carbon and the carboxamide carbon. A
relaxed energy profile scan was constructed, shown in Figure 11.
As expected, the symmetry around 90ꢀ for isonicotinamide
disappears when the torsion is calculated for nicotinamide,
due to the unsymmetrical positioning of the pyridine nitro-
gen relative to the carboxamide. This difference, though, is
only significant when the amide nitrogen atom approaches
trans to the pyridine nitrogen in nicotinamide. According to
these gas phase calculations, this results in an ∼0.9 kcal/mol
difference in the barrier to rotation, with the conformation
Several hydrogen bonding motifs around the heteroatoms
were extracted from the crystal structures of nicotinamide47
and isonicotinamide with 4-hydroxybenzoic acid (VAKTOR)
for further analysis. These crystal structures were selected
because they show a similar hydrogen bonding network in
their crystal structure that can be exploited for comparison.
Shown in Figure 12, this includes the heteromeric amide
carboxylic acid interaction (II), the carboxylic acid amide

Article
Crystal Growth & Design, Vol. 11, No. 1, 2011 85
Figure 11. C(sp2)-C(sp2)-C(sp2)-N torsion angle profiles for nicotinamide and isonicotinamide.
Table 8. Binding Energies and Optimized Hydrogen Bond Distances of
Interacting Pairs (See Figure 12 for Definitions)a
˚
interaction
Ebind/(kcal/mol)
r(H-X)/A
A
A
A
B
B
B
A1
A2
A3
B1
B2
B3
-9.4
5.4
-1.7
-10.6
0.4
(-12.8)
(0.6)
(-7.3)
(-12.8)
(-4.5)
(-7.4)
1.621/1.910
1.920
1.761
1.588/1.967
2.314
1.783
(1.659/1.845)b
(2.055)
3 3 3
3 3 3
3 3 3
3 3 3
3 3 3
3 3 3
(1.814)
(1.666/1.839)b
(2.048)
(1.818)
-2.9
a Values were obtained with non-hydrogen atoms kept fixed to the
crystal structure coordinates and hydrogen atom positions optimized.
Results from unconstrained optimizations are shown in parentheses.
b O H-O/N H-O.
3 3 3
3 3 3
expected lower binding energies obtained for the fully relaxed
pairs. The total interaction energies (Table 8) summed over the
values for the isolated pairs give, on first inspection, a stronger
interaction in isonicotinamidecompared to nicotinamide, with
these values being -5.7 kcal/mol (A A1 þ A A2 þ
3 3 3
3 3 3
Figure 12. Crystal structure-derived clusters of the co-crystals of
4-hydroxybenzoic acid and (a) nicotinamide or (b) isonicotinamide
used in the DFT calculations. The identification of interacting pairs
is shown in bold.
A
A3) and -13.1 kcal/mol (B B1 þ B B2 þ B B3),
3 3 3 3 3 3 3 3 3
3 3 3
respectively. This difference is due to an intramolecular
change in the carboxylic acid;the intramolecular hydrogen
bond breaks, giving an O-C-O-H torsion angle of 180ꢀ,
instead of 0ꢀ as in the optimized monomer from which the
binding energies were calculated. This was further verified
by calculating the energy difference between the τ(O-C-
O-H) = 0ꢀ and τ(O-C-O-H) = 180ꢀ conformer, which is
∼6 kcal/mol. This effect is an artifact of using isolated pairs in
the calculation, as expected from Etter’s rules for all good
donors to be used;16-18 in the crystal structure, the torsion is
0ꢀ due to the proton being used in a heteromeric synthon with
an adjacent nicotinamide/isonicotinamide. With the excep-
tion of this interaction, which after correcting for the intra-
molecular changes is similar in order, the synthons I and II in
the isonicotinamide model system, based on crystal coordi-
nates for the non-hydrogen atoms, appear to be slightly more
favorable per pair, with differences on the order of ∼1.2 kcal/
mol. It is noteworthy that although the pairs in the crystal
show notable differences, when optimizations are fully re-
laxed however, binding energies are very close (see Table 8,
values in brackets).
Table 7. Binding Energies of Synthons IV, II, and III in Interacting Pairs
synthon
donor
acceptor
Ebind/(kcal/mol)
IV
clofibric acid
clofibric acid
diclofenac
nicotinamide
isonicotinamide
nicotinamide
isonicotinamide
nicotinamide
isonicotinamide
nicotinamide
isonicotinamide
nicotinamide
isonicotinamide
-12.0
-10.8
-11.0
-9.7
-10.8
-11.2
-11.2
-11.2
-17.0
-17.0
diclofenac
II
nicotinamide
isonicotinamide
clofibric acid
clofibric acid
diclofenac
III
diclofenac
anti H interaction, and the alcohol pyridine nitrogen interac-
tion (modification of I). Two sets of calculations were per-
formed: in the first, the non-hydrogen atoms were constrained
to their crystallographic positions, with only hydrogen atom
positions optimized, and in the second set, all positions were
allowed to optimize. Both sets show similar trends, with the

ꢀ
Bathori et al.
86 Crystal Growth & Design, Vol. 11, No. 1, 2011
4. Conclusion
Zimenkov, Y.; Hickey, M. B. Mol. Pharmaceutics 2007, 4, 386–400.
(k) Babu, N. J.; Reddy, L. S.; Nangia, A. Mol. Pharmaceutics 2007, 4,
417–434. (l) Vogt, F. G.; Clawson, J. S.; Strohmeier, M.; Edwards,
A. J.; Pham, T. N.; Watson, S. A. Cryst. Growth Des. 2009, 9, 921–937.
The two isomers isonicotinamide and nicotinamide are
among the most popular co-crystal formers in the rapidly
developing field of co-crystals, especially when trying to pre-
pare pharmaceutical co-crystals with nicotinamide, as the
latter is a GRAS substance. Both molecules co-crystallize well
with molecules containing carboxylic acids, as they make
€
(m) Aakeroy, C. B.; Salmon, D. J. CrystEngComm 2005, 7, 439–448.
(n) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.; Stahly,
G. P. J. Am. Chem. Soc. 2004, 126, 13335–13342.
(6) Chow, K.; Tong, H. H. Y.; Lum, S.; Chow, A. H. L. J. Pharm. Sci.
2008, 97, 2855–2877.
(7) Remenar, J. F.; Morisette, S. L.; Peterson, M. L.; Moulton, B.;
use of the robust O-H N hydrogen bond, as seen in the
3 3 3
€
MacPhee, J. M.; Guzman, H. R.; Almarsson, O. J. Am. Chem. Soc.
reported co-crystals with clofibric acid and diclofenac. In this
work, we also found that the two isomeric molecules can form
a co-crystal with each other. In the literature, there are many
more examples of co-crystals with isonicotinamide and car-
boxylic acids (40) than with nicotinamide and carboxylic acids
(11). In our hands too, attempts to co-crystallize nicotinamide
with these particular carboxylic acids returned only the start-
ing materials. Althoughthe structural similarityof the isomers
(differing only in the position of the pyridine N atom) and the
parallelism in their hydrogen bonding interactions may sug-
gest that co-crystals of isonicotinamide can act as a model for
co-crystals of nicotinamide with carboxylic acids, it appears
that other factors may play an inhibiting role. This conclusion
is supported by DFT gas phase calculations that show that the
heteroatoms in nicotinamide and isonicotinamide involved in
formation of the supramolecular synthons are similar in nature.
Also, relating synthon binding energies between co-crystal
formers is not sufficient to explain the preference.
2003, 125, 8456–8457.
(8) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.;
Stahly, B. C.; Stahly, G. P. J. Am. Chem. Soc. 2004, 126, 13335–
13342.
(9) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J.
J. Pharm. Sci. 2006, 95, 499–516.
(10) Khan, M.; Enkelmann, V.; Brunklaus, G. J. Am. Chem. Soc. 2010,
132, 5254–5263.
(11) Childs, S. L.; Zaworotko, M. J. Cryst. Growth Des. 2009, 9, 4208–
4211.
(12) (a) Bhatt, P. M.; Azim, Y.; Thakur, T. S.; Desiraju, G. R. Cryst.
€
Growth Des. 2009, 9, 951–957. (b) Aakeroy, C. B.; Beatty, A. M.;
Helfrich, B. A. Angew. Chem., Int. Ed. 2001, 40, 3240–3242. (c) He,
G.; Chow, P. S.; Tan, R. B. H. Cryst. Growth Des. 2010, 10 (8), 3763–
3769. (d) Anderson, K. M.; Probert, M. R.; Whiteley, C. N.; Rowland,
A. M.; Goeta, A. R.; Steed, J. W. Cryst. Growth Des. 2009, 9, 1082–
1087. (e) Weyna, D. R.; Shattock, T.; Vishweshwar, P.; Zaworotko,
M. J. Cryst. Growth Des. 2009, 9, 1106–1123. (f) Zaworotko, M. J.
Cryst. Gowth Des. 2007, 7, 4–9.
€
(13) (a) Aakeroy, C. B.; Beatty, A. M.; Helfrich, B. A. Cryst. Growth
ꢀ
Des. 2003, 3, 159–165. (b) Lemmerer, A.; Bathori, N. B.; Bourne, S. A.
Acta Crystallogr., Sect. B 2008, 64, 780–790. (c) Vishweshwar, P.;
Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2003, 3, 783–790.
(14) (a) Sarma, B.; Reddy, L. S.; Nangia, A. Cryst. Growth Des. 2008, 8,
4546. (b) Vishweshwar, P.; Nangia, A.; Lynch, V. M. CrystEngComm
2003, 5, 164–168. (c) Huang, K.-S.; Britton, D.; Etter, M. C.; Byrn, S. R.
J. Mater. Chem. 1997, 7, 713–720. (d) Bourne, S. A.; Nassimbeni,
L. R.; Toda, F. J. Chem. Soc., Perkin Trans. 2 1991, 1335–1341. (e) Lough,
A. J.; Gregson, R. M.; Ferguson, G.; Glidewell, C. Acta Crystallogr., Sect.
C 1999, 55, 1890–1892. (f) Bourne, S. A.; Corin, K. C.; Nassimbeni, L. R.;
Toda, F. Cryst. Growth Des. 2005, 5, 379–382. (g) Nassimbeni, L. R.; Su,
H.; Weber, E.; Skobridis, K. Cryst. Growth Des. 2004, 4, 85–88. (h) Olenik,
B.; Boese, R.; Sustmann, R. Cryst. Growth Des. 2003, 3, 175–181.
(i) Vishweshwar, P.; Nangia, A.; Lynch, V. M. CrystEngComm 2003,
5, 164–168. (j) Bhogala, B. R.; Basavoju, S.; Nangia, A. CrystEngComm
2005, 7, 551–562. (k) Oliveira, M. A.; Peterson, M. L.; Klein, D. Cryst.
Growth Des. 2008, 8, 4487–4493.
Acknowledgment. Financial support was received from the
South African National Research Foundation (NRF) (Grant
FA2006030100003). A.L. thanks the NRF for a postdoctoral
scholarship (SFP2006061500015). We thank the University of
Cape Town for financial assistance. G.A.V. thanks the Centre
for High Performance Computing (CHPC) for computing
time.
Supporting Information Available: Cif files for each structure
have been deposited withthe CambridgeStructural Database (CCDC
785370-785374). DSC and TG curves (1-3), PXRDs (1-4), and
grinding experiments with nicotinamide, clofibric acid, and diclofenac
are available free of charge via the Internet at http://pubs.acs.org.
(15) (a) Shattock, T. R.; Arora, K. K.; Vishweshwar, P.; Zaworotko,
M. J. Cryst. Growth Des. 2008, 8, 4533–4545. (b) Mohamed, S.;
Tocher, D. A.; Vickers, M.; Karamertzanis, P. G.; Price, S. L. Cryst.
Growth Des. 2009, 9, 2881–2889.
(16) Etter, M. C. Acc. Chem. Res. 1990, 23, 120–126.
(17) Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr.,
References
(1) (a) Lehn, J.-M. Angew. Chem., Int. Ed. 1990, 29, 1304–1319. (b) Lehn,
J.-M. J. Chem. Sci. 1994, 106, 915–922. (c) Lehn, J.-M. Chem. Soc.
Rev. 2007, 36, 151–160.
(2) (a) Burrows, A. D. Struct. Bonding (Berlin) 2004, 108, 55–96.
(b) Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 2–17.
(3) (a) Stahly, G. P. Cryst. Growth Des. 2009, 9, 4212–4229. (b) Stahly,
G. P. Cryst. Growth Des. 2007, 7, 1007–1026.
Sect. B 1990, 46, 256–262.
(18) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew.
Chem., Int. Ed. 1995, 34, 1555–1573.
€
(19) Aakeroy, C. B.; Beatty, A. M.; Helfrich, B. A. J. Am. Chem. Soc.
(4) (a) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950–
2002, 124, 14425–14432.
€
2967. (b) Basavoju, S.; Bostrom, D.; Velaga, S. P. Cryst. Growth Des.
(20) COLLECT; Nonius BV: Delft, The Netherlands, 1998.
(21) Otwinowski, Z.; Minor, W. In International Tables for Crystal-
lography; Rossman, M. G., Arnold, E., Ed.; Kluwer: Dordrecht, 2000;
Vol. F.
(22) Bruker 2003, XPREP2. Version 6.14. Bruker AXS Inc., Madison,
Wisconsin, USA.
(23) APEX2, Version 1.0-27; Bruker AXS Inc.: Madison, WI, 2005.
(24) SAINT-Plus (including XPREP), Version 7.12; Bruker AXS Inc.:
Madison, WI, 2004.
2006, 6, 2699–2708. (c) Stanton, M. K.; Tufekcic, S.; Morgan, C.; Bak,
A. Cryst. Growth Des. 2009, 9, 1344–1352. (d) ter Horst, J. H.; Deij,
M. A.; Cains, P. W. Cryst. Growth Des. 2009, 9, 1531–1537. (e) Childs,
S. L. Hardcastle, K. I. Cryst. Growth Des. 2007, 7, 1291-1304. A list
of these GRAS substances is available (http://www.fda.gov/Food/
FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/default.
htm).
€
(5) (a) Almarsson, O.; Zaworotko, M. J. Chem. Commun. 2004, 1889–
1896. (b) Trask, A. V. Mol. Pharmaceutics 2004, 4, 301–309. (c) Shan,
N.; Zaworotko, M. J. Drug Discovery Today 2008, 13, 440–446.
(d) Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharmaceutics 2007, 4,
323–338. (e) Caira, M. R. Mol. Pharmaceutics 2007, 4, 310–316.
(25) Farrugia, L. J. WinGX. J. Appl. Crystallogr. 1999, 32, 837–838.
(26) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112–122.
(27) Farrugia, L. J. WinGX. J. Appl. Crystallogr. 1997, 30, 565.
(28) Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7–13.
(29) Brandenburg, K. Diamond, Version 2.1e.; Crystal Impact GbR:
Bonn, Germany.
€
(f) Aakeroy, C. B.; Fasulo, M. E.; Desper, J. Mol. Pharmaceutics 2007, 4,
ꢁ
317–322. (g) Bucar, D.-K.; Henry, R. F.; Lou, X.; Borchardt, T. B.; Zhang,
€
G. Z. Chem. Commun. 2007, 525–527. (h) Aakeroy, C. B.; Fasulo, M. E.;
(30) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang, W.;
Parr, R. G. Phys. Rev. B 1988, 37, 785. (c) Stephens, P. J.; Devlin, F. J.;
Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623.
(d) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200.
Desper, J. Mol. Pharmaceutics 2007, 4, 317–322. (i) Banerjee, R.; Bhatt,
P. M.; Ravindra, N. V.; Desiraju, G. R. Cryst. Growth Des. 2005, 5, 2299–
2309. (j) Remenar, J. F.; Peterson, M. L.; Stephens, P. W.; Zhang, Z.;

Article
Crystal Growth & Design, Vol. 11, No. 1, 2011 87
(31) Merrick, J. P.; Moran, D.; Radom, L. J. Phys. Chem. A 2007, 111,
11683.
(36) Berry, D. J.; Seaton, C. C.; Clegg, W.; Harrington, R. W.; Coles,
S. J.; Horton, P. N.; Hursthouse, M. B.; Storey, R.; Jones, W.;
ꢁꢁ ꢀ
(32) Boys, S. F.; Bernardi, F. Mol. Phys. 1970, 19, 553.
(33) (a) Besler, B. H.; Merz, K. M.; Kollman, P. A. J. Comput. Chem.
1990, 11, 431. (b) Singh, U. C.; Kollman, P. A. J. Comput. Chem. 1984,
5, 129.
Friscic, T.; Blagden, N. Cryst. Growth Des. 2008, 8, 1697–1712.
(37) Hino, T.; Ford, J. L.; Powell, M. W. Thermochim. Acta 2001, 374,
85–92.
(38) Miwa, Y.; Mizuno, T.; Tsuchida, K.; Taga, T.; Iwata, Y. Acta
(34) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian,
H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov,
V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell,
A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin,
R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador,
Crystallogr., Sect. B 1999, 55, 78–84.
(39) ter Horst, J. H.; Cains, P. W. Cryst. Growth Des. 2008, 8, 2537–
2542.
(40) Kennard, C. H. L.; Smith, G.; White, A. H. Acta Crystallogr., Sect.
B 1982, 38, 868–875.
(41) Castellari, C.; Ottani, S. Acta Crystallogr., Sect. C 1997, 53, 794–
797.
(42) Jaiboon, N.; Yos-in, K.; Ruangchaithaweesuk, S.; Chaichit, N.;
Thutivoranath, R.; Siritaedmukul, K.; Hannongbua, S. Anal. Sci.
2001, 17, 1465–1466. The R-factor is 13% for the reported structure and
the validity of the result is questionable.
(43) Seaton, C. C.; Parkin, A.; Wilson, C. C.; Blagden, N. Cryst. Growth
Des. 2009, 9, 47–56.
(44) Loehlin, J. H.; Okasako, E. L. N. Acta Crystallogr., Sect. B 2007,
63, 132–141.
€
P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
Revision A.1; Gaussian, Inc.: Wallingford, CT, 2009.
(35) Clarke, H. D.; Arora, K. K.; Bass, H.; Kavuru, P.; Ong, T. T.;
Pujari, T.; Wojtas, L.; Zaworotko, M. J. Cryst. Growth Des. 2010,
10, 2153–2167.
(45) Infantes, L.; Motherwell, W. D. S. Chem.Commun. 2004, 1166–
1167.
(46) Leskowitz, G. M.; Ghaderi, N.; Olsen, R. A.; Pederson, P.; Hatcher,
M. E.; Mueller, L. J. J. Phys. Chem. A 2005, 109, 1152–1158.
(47) Lemmerer, A. Private communication.