Covalent assistance to supramolecular synthesis: Modifying the drug functionality of the antituberculosis API isoniazid in situ during co-crystallization with GRAS and API compounds

Article abstract of DOI:10.1039/c1ce06310c

The anti-tuberculosis molecule isonicotinic acid hydrazide (isoniazid) is a promising molecule in the supramolecular synthesis of multi-component molecular complexes and also allows for its biological activity to be improved and modified by a simple covalent reaction. The low temperature crystal structures of both isoniazid (1) and the related N′-(propan-2-ylidene) isonicotinohydrazide molecule (2), the latter known to be a more effective agent against Mycobacterium tuberculosis, are reported. In addition, these two molecules were then co-crystallized with the same three Generally Regarded As Safe (GRAS) molecules, succinic acid, 4-hydroxybenzoic acid and 2-hydroxybenzoic acid, to produce the following pharmaceutical co-crystals: (isonicotinic acid hydrazide)₂·(succinic acid) 3, (N′-(propan-2-ylidene) isonicotinohydrazide)₂·(succinic acid) 4, (isonicotinic acid hydrazide)·(4-hydroxybenzoic acid) 6, (N′-(propan-2-ylidene) isonicotinohydrazide)·(4-hydroxybenzoic acid) 7, (isonicotinic acid hydrazide)·(2-hydroxybenzoic acid) 8, and (N′-(propan-2-ylidene) isonicotinohydrazide)·(2-hydroxybenzoic acid) 9. In addition, a co-crystal using 2-butanone as a modifier is also reported, (N′-(butan-2- ylidene)isonicotinohydrazide)₂·(succinic acid) 5. Drug-drug co-crystals were also made with the anti-HIV compound 2-chloro-4-nitrobenzoic acid: (isonicotinic acid hydrazide)·(2-chloro-4-nitrobenzoic acid) 10, and (N′-(propan-2-ylidene)isonicotinohydrazide)·(2-chloro-4- nitrobenzoic acid) 11. All the co-crystals use the carboxylic acid...pyridine hydrogen bond to connect the GRAS or drug molecule to the pyridine ring. In general, the co-crystals with the modified isoniazid feature the C(4) homosynthon, and those with the original isoniazid a variety of homo- and heterosynthons. By comparing the melting points of the co-crystals that use isoniazid and those that use the modified isoniazid, a reduction in melting point is observed. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c1ce06310c

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PAPER
Covalent assistance to supramolecular synthesis: modifying the drug
functionality of the antituberculosis API isoniazid in situ during
co-crystallization with GRAS and API compounds†
*
Andreas Lemmerer
Received 2nd October 2011, Accepted 3rd November 2011
DOI: 10.1039/c1ce06310c
The anti-tuberculosis molecule isonicotinic acid hydrazide (isoniazid) is a promising molecule in the
supramolecular synthesis of multi-component molecular complexes and also allows for its biological
activity to be improved and modified by a simple covalent reaction. The low temperature crystal
structures of both isoniazid (1) and the related N0-(propan-2-ylidene)isonicotinohydrazide molecule (2),
the latter known to be a more effective agent against Mycobacterium tuberculosis, are reported. In
addition, these two molecules were then co-crystallized with the same three Generally Regarded As Safe
(GRAS) molecules, succinic acid, 4-hydroxybenzoic acid and 2-hydroxybenzoic acid, to produce the
following pharmaceutical co-crystals: (isonicotinic acid hydrazide)2$(succinic acid) 3, (N0-(propan-2-
ylidene)isonicotinohydrazide)2$(succinic acid) 4, (isonicotinic acid hydrazide)$(4-hydroxybenzoic acid)
6, (N0-(propan-2-ylidene)isonicotinohydrazide)$(4-hydroxybenzoic acid) 7, (isonicotinic acid
hydrazide)$(2-hydroxybenzoic acid) 8, and (N0-(propan-2-ylidene)isonicotinohydrazide)$(2-
hydroxybenzoic acid) 9. In addition, a co-crystal using 2-butanone as a modifier is also reported, (N0-
(butan-2-ylidene)isonicotinohydrazide)2$(succinic acid) 5. Drug–drug co-crystals were also made with
the anti-HIV compound 2-chloro-4-nitrobenzoic acid: (isonicotinic acid hydrazide)$(2-chloro-4-
nitrobenzoic acid) 10, and (N0-(propan-2-ylidene)isonicotinohydrazide)$(2-chloro-4-nitrobenzoic acid)
11. All the co-crystals use the carboxylic acid/pyridine hydrogen bond to connect the GRAS or drug
molecule to the pyridine ring. In general, the co-crystals with the modified isoniazid feature the C(4)
homosynthon, and those with the original isoniazid a variety of homo- and heterosynthons. By
comparing the melting points of the co-crystals that use isoniazid and those that use the modified
isoniazid, a reduction in melting point is observed.
Introduction
The active pharmaceutical ingredient (API) isonicotinic acid
hydrazide (isoniazid) has received renewed interest from the
crystal engineering community due to its robust interactions with
carboxylic acid containing molecules, as well as with other APIs.
Co-crystals formed with Generally Regarded As Safe (GRAS)
molecules have been especially successful, and hence it makes
isoniazid an ideal molecule to do studies in the rapidly expanding
field of pharmaceutical co-crystals.1 Additionally, isoniazid is not
only an ideal supramolecular reagent that forms co-crystals with
Molecular Sciences Institute, School of Chemistry, University of the
Witwatersrand, Johannesburg, 2050, South Africa. E-mail: Andreas.
Lemmerer@wits.ac.za; Fax: +27 11 717 6749; Tel: +27 11 717 6711
† Electronic supplementary information (ESI) available: PXRD patterns
for 2–11 and DSC traces for all compounds, as well as cif files for all
compounds. CCDC reference numbers 847197 (1), 847198 (2), 746445
(3), 847200 (4), 847201 (5), 746449 (6) and 847203–847207 (7–11,
Scheme 1 Observed structures before (a) and after (b) modification of
the hydrazide group.
respectively). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ce06310c
This journal is ª The Royal Society of Chemistry 2012
CrystEngComm, 2012, 14, 2465–2478 | 2465

a number of co-crystal formers, but also allows for its hydrogen
bonding functionality to be modified.2 By adding a ketone to the
crystallization solution, the hydrazide functional group on the
isoniazid reacts in a condensation reaction with the ketone, and
the two amine H atoms from the N atom are replaced by an inert
hydrogen bonding hydrocarbon substituent. As only the amide
group is now left intact, the hydrogen bonding interactions
become simpler and involve chains of N–H/O hydrogen bonds
to connect the isoniazid molecules together. The modification
does not end there. If suitably large ketones are used, for example
sterically bulky phenyl groups, the remaining amide H atom of
the amide group can be prevented from approaching acceptor
atoms, including the O atom of the amide, thus masking the
amide H atom from any further intermolecular interactions. The
modifying and masking fall under the concept of the covalent
assistance to supramolecular synthesis purview recently intro-
duced into crystal engineering (Scheme 1).3
The reaction of isoniazid with ketones has been used previ-
ously to modify, or improve, the efficacy of the molecule on
a biological level. The efficacy against bacteria has especially
been studied using a large number of ketones.4 For example, the
use of 2-propanone shows an increase in activity against
Table 1 Crystallographic data for 1–5 and 6–11
1
2
3a
4
5
Empirical formula
Molecular weight
Crystal size/mm
Crystal system
Space group
C6H7N3O
137.15
0.48 ꢀ 0.25 ꢀ 0.16
Orthorhombic
P212121
173
3.7828(1)
11.2948(4)
14.6870(6)
90
90
90
628.25(4)
4
1.450
0.105
288
C9H11N3O
177.21
0.40 ꢀ 0.40 ꢀ 0.40
Orthorhombic
Pccn
C8H10N3O3
196.19
0.44 ꢀ 0.42 ꢀ 0.40
Monoclinic
P21/n
C11H14N3O3
236.25
0.65 ꢀ 0.20 ꢀ 0.10
Monoclinic
P21/c
C12H16N3O3
250.28
0.50 ꢀ 0.20 ꢀ 0.08
Monoclinic
P21/c
T/K
ꢀ
173
173
173
173
a/A
ꢀ
12.9790(5)
17.6437(3)
7.9695(2)
90
90
90
1825.00(9)
8
1.290
0.719
752
6.9976(4)
19.5601(10)
7.1495(5)
90
114.892(8)
90
887.67(9)
4
1.468
18.0455(3)
8.2643(3)
7.7750(6)
90
94.445(2)
90
1156.02(10)
4
1.357
0.101
500
5.0602(3)
31.8299(17)
8.0552(5)
90
98.780(3)
90
1282.21(13)
4
1.296
0.095
532
b/A
ꢀ
c/A
a/ꢁ
b/ꢁ
g/ꢁ
V/A
Z
3
ꢀ
r(calc)/g cmꢂ3
m/mmꢂ1
F(000)
Scan range (q)/ꢁ
Total reflections
Unique reflections [R(int)]
No. data with I $ 2s(I)
Parameters
2.27 to 27.99
5027
916 [0.0298]
876
100
4.23 to 67.51
10 141
1642 [0.0448]
1408
123
2.26 to 28.00
20 671
2782 [0.0288]
2491
162
2.56 to 28.00
20 982
3092 [0.0438]
2520
198
R1 [I > 2s(I)]
wR2 (all data)
CCDC no.
0.0299
0.0805
847197
0.0435
0.1243
847198
0.0497
0.1421
847200
0.0559
0.1564
847201
746445
6a
7
8
9
10
11
Empirical formula
Molecular weight
Crystal size/mm
Crystal system
Space group
C13H13N3O4
275.26
C16H13N3O4
315.33
C13H13N3O4
275.26
C16H17N3O4
315.33
C13H11ClN4O5
338.71
C64H60Cl4N16O20
1515.08
0.40 ꢀ 0.40 ꢀ 0.40 0.35 ꢀ 0.25 ꢀ 0.10 0.50 ꢀ 0.08 ꢀ 0.05 0.55 ꢀ 0.46 ꢀ 0.44 0.32 ꢀ 0.26 ꢀ 0.15 0.55 ꢀ 0.45 ꢀ 0.35
Monoclinic
P21/c
173
12.9083(5)
4.9898(1)
20.3294(9)
90
91.850(4)
90
1308.73(8)
4
1.397
Monoclinic
P21/n
173
11.0130(4)
13.1213(4)
11.9425(4)
90
114.128(2)
90
1574.98(9)
4
1.330
0.097
664
2.12 to 27.99
24 789
3813 [0.0279]
3153
Monoclinic
P21/n
173
11.2793(5)
3.7452(2)
29.8282(15)
90
93.567(4)
90
1257.60(11)
4
1.454
0.110
576
1.37 to 27.99
8409
2987 [0.0403]
2208
196
Monoclinic
P21/n
173
7.3504(4)
29.8032(16)
7.6524(4)
90
112.787(3)
90
1545.54(14)
4
1.355
0.099
664
2.73 to 27.99
16 272
3721 [0.0257]
3278
Triclinic
ꢁ
P1
173
Monoclinic
P21
173
6.8490(2)
38.7853(12)
12.7324(4)
90
98.265(2)
90
3347.11(18)
2
1.503
T/K
ꢀ
a/A
ꢀ
9.1538(3)
11.0592(4)
15.0521(5)
89.085(2)
72.649(2)
89.906(2)
1454.25(9)
4
1.547
0.296
696
1.42 to 28.00
16 205
b/A
ꢀ
c/A
a/ꢁ
b/ꢁ
g/ꢁ
V/A
Z
3
ꢀ
r(calc)/g cmꢂ3
m/mmꢂ1
0.266
1568
F(000)
Scan range (q)/ꢁ
Total reflections
Unique reflections [R(int)]
No. data with I $ 2s(I)
Parameters
1.93 to 28.00
42 752
14216 [0.0298]
13 432
949
6699 [0.0306]
4861
439
219
219
R1 [I > 2s(I)]
wR2 (all data)
CCDC no.
0.0384
0.1125
847203
0.0443
0.1130
847204
0.0419
0.1120
847205
0.0697
0.2086
847206
0.0490
0.1189
847207
746449
a
Taken from ref. 1.
2466 | CrystEngComm, 2012, 14, 2465–2478
This journal is ª The Royal Society of Chemistry 2012

Mycobacterium tuberculosis. 2-Propanone is the most convenient
ketone to modify the hydrogen bonding functionality with as it
can also function as a crystallization solvent, but it has a limited
masking reach due to its sterically small methyl groups.
In this report, we ask the question: How are the structures and
hydrogen bonding patterns of pharmaceutical isoniazid co-
crystals altered in response to the modification of its hydrogen
bonding functionality and the introduction of different co-crystal
formers?
Experimental
All reagents were purchased from commercial sources and used
without further purification. All solvents are of AP-grade.
Isonicotinic acid hydrazide, 1
Crystals of isoniazid were grown by slow evaporation of a meth-
anol solution. Colourless needles were obtained after three days.
N0-(Propan-2-ylidene)isonicotinohydrazide, 2
0.200 g of isonicotinic acid hydrazide (1.46 mmol) was dissolved
in 2 ml acetone and kept below the boiling point of acetone for 2
hours. Needles of the product were obtained upon cooling to
room temperature.
Scheme 2 Diagrams of the molecules used to modify the isoniazid drug
molecule, as well as the co-crystal and drug formers used to prepare co-
crystals 3–11.
(Isonicotinic acid hydrazide)2$(succinic acid), 3
See ref. 1.
(N0-(Propan-2-ylidene)isonicotinohydrazide)2$(succinic acid), 4
0.200 g of isonicotinic acid hydrazide (1.46 mmol) and 0.086 g of
succinic acid (0.73 mmol) were added into a sample vial. The
solids were dissolved in hot ethanol (4 ml) and acetone (1 ml),
refluxed in a closed vial for six hours, and left to stand at room
temperature open to the atmosphere. Colourless crystals were
afforded after several days.
(N0-(Butan-2-ylidene)isonicotinohydrazide)2$(succinic acid), 5
0.100 g of isonicotinic acid hydrazide (0.730 mmol) and 0.043 g
of succinic acid (0.36 mmol) were added into a sample vial. The
solids were dissolved in hot ethanol (4 ml) and 4 drops of
2-butanone, refluxed in a closed vial for six hours, and left to
stand at room temperature open to the atmosphere. Colourless
crystals were afforded after several days.
(Isonicotinic acid hydrazide)$(4-hydroxybenzoic acid), 6
See ref. 1.
(N0-(Propan-2-ylidene)isonicotinohydrazide)$(4-hydroxybenzoic
acid), 7
0.100 g of isonicotinic acid hydrazide (0.730 mmol) and 0.100 g
of 4-hydroxybenzoic acid (0.73 mmol) were added into a sample
vial. The solids were dissolved in hot ethanol (4 ml) and acetone
(4 ml), refluxed in a closed vial for six hours, and left to stand at
room temperature open to the atmosphere. Colourless crystals
were afforded after several days.
Fig. 1 The contents of the asymmetric unit for original (1) and modified
(2) isoniazid, showing the atomic numbering scheme. Displacement
ellipsoids are shown at the 50% probability level.
This journal is ª The Royal Society of Chemistry 2012
CrystEngComm, 2012, 14, 2465–2478 | 2467

(Isonicotinic acid hydrazide)$(2-hydroxybenzoic acid), 8
(N0-(Propan-2-ylidene)isonicotinohydrazide)$(2-hydroxybenzoic
acid), 9
0.100 g of isonicotinic acid hydrazide (0.730 mmol) and 0.100 g
of 2-hydroxybenzoic acid (0.73 mmol) were added into a sample
vial. The solids were dissolved in hot ethanol (3 ml) and left to
stand at room temperature open to the atmosphere. Colourless
crystals were afforded after several days.
0.200 g of isonicotinic acid hydrazide (1.46 mmol) and 0.200 g of
2-hydroxybenzoic acid (1.46 mmol) were added into a sample
vial. The solids were dissolved in hot ethanol (3 ml) and acetone
(3 ml), refluxed in a closed vial for six hours, and left to stand at
Table 2 Geometrical parameters for hydrogen bonds in compounds 1–11
:(D–H/A)/ꢁ
Symmetry transformations
ꢀ
d(D–H)/A
ꢀ
ꢀ
D–H/A
d(H/A)/A
d(D/A)/A
1
N(1)–H(1)/N(3)
N(3)–H(3A)/N(2)
N(3)–H(3B)/N(2)
2
0.90(2)
0.92(2)
0.89(2)
2.05(2)
2.14(2)
2.58(2)
2.919(2)
3.046(2)
3.157(2)
163(2)
172(2)
123
x ꢂ 1/2, ꢂy + 3/2, ꢂz + 1
ꢂx + 1/2, ꢂy + 1, z ꢂ 1/2
ꢂx + 3/2, ꢂy + 1, z ꢂ 1/2
N(1)–H(1)/O(1)
3
0.88(2)
2.19(2)
3.000(2)
153(2)
ꢂx + 1/2, y, z + 1/2
N(1)–H(1)/N(3)
N(3)–H(3A)/O(1)
N(3)–H(3B)/O(2)
O(2)–H(2)/N(2)
C(3)–H(3)/O(3)
4
0.87(2)
0.89(2)
0.91(2)
0.98(2)
0.93
2.15(2)
2.24(2)
2.26(2)
1.65(2)
2.71
2.937(2)
3.006(2)
3.084(2)
2.617(1)
3.334(2)
151(1)
145(1)
151(1)
172(2)
125
ꢂx + 1, ꢂy + 1, ꢂz + 1
ꢂx + 2, ꢂy + 1, ꢂz + 1
ꢂx + 3/2, y + 1/2, ꢂz + 3/2
—
—
N(1)–H(1)/O(1)
O(2)–H(2)/N(2)
5
0.89(2)
0.89(3)
2.30(2)
1.84(3)
3.1805(19)
2.7244(19)
169(2)
173(3)
x, ꢂy + 1/2, z ꢂ 1/2
—
N(1)–H(1)/O(1)
O(2A)–H(2A)/N(2)
O(2B)–H(2B)/N(2)
6
0.89(2)
0.84
0.84
2.25(2)
1.82
1.90
3.127(2)
2.643(5)
2.732(5)
168(2)
165
171
x ꢂ 1, y, z
—
—
N(1)–H(1)/O(1)
N(3)–H(3A)/O(3)
N(3)–H(3B)/O(4)
O(2)–H(2)/N(2)
O(4)–H(4)/N(3)
O(4)–H(4)/N(1)
7
0.875(2)
0.932(2
0.925(2)
0.97(2)
0.876(2)
0.876(2)
1.98(2)
2.04(2)
2.24(2)
1.72(2)
1.88(2)
2.68(2)
2.849(1)
2.948(2)
3.126(2)
2.682(2)
2.754(1)
3.412(1)
172(1)
164(1)
160(1)
171(2)
172(2)
142(1)
x, y ꢂ 1, z
ꢂx + 1, ꢂy + 1, ꢂz + 1
x ꢂ 1, ꢂy + 3/2, z ꢂ 1/2
—
x + 1, ꢂy + 1/2, z + 1/2
x + 1, ꢂy + 1/2, z + 1/2
N(1)–H(1)/O(4)
O(2)–H(2)/N(2)
O(4)–H(4)/O(1)
C(4)–H(4A)/O(3)
8
0.85(2)
0.94(2)
0.89(2)
0.95
2.66(2)
1.74(2)
1.77(2)
2.61
3.274(1)
2.676(1)
2.624(1)
3.278(1)
131(1)
174(2)
161(2)
128
ꢂx + 1/2, y + 1/2, ꢂz + 1/2
—
x ꢂ 3/2, ꢂy + 1/2, z ꢂ 1/2
—
N(1)–H(1)/O(4)
N(3)–H(3A)/N(3)
N(3)–H(3B)/O(1)
O(2)–H(2)/N(2)
O(4)–H(4)/O(3)
9
0.91(2)
0.90(2)
0.92(2)
0.94(2)
0.92(2)
2.05(2)
2.87(2)
2.16(2)
1.65(2)
1.67(2)
2.961(2)
3.745(2)
3.023(2)
2.589(2)
2.556(2)
173(2)
166(2)
156(2)
172(2)
159(2)
ꢂx + 1, ꢂy, ꢂz + 1
x, y + 1, z
ꢂx + 3/2, y ꢂ 1/2, ꢂz + 3/2
—
—
N(1)–H(1)/O(1)
O(2)–H(2)/N(2)
O(4)–H(4)/O(3)
C(4)–H(4A)/O(3)
10
0.90(2)
0.89(2)
0.89(2)
0.95
2.03(2)
1.80(2)
1.79(2)
2.49
2.933(1)
2.687(1)
2.610(1)
3.200(2)
175(2)
174(2)
151(2)
131
x + 1/2, ꢂy + 1/2, z + 1/2
—
—
—
N(3A)–H(3A)/O(5B)
N(3A)–H(3B)/O(1A)
N(1B)–H(1B)/N(3A)
N(3B)–H(3C)/O(1B)
N(3B)–H(3D)/O(5A)
O(2A)–H(2A)/N(2A)
O(2B)–H(2B)/N(2B)
11
0.79(4)
0.87(4)
0.85(4)
0.77(4)
0.83(4)
0.92(4)
0.73(4)
3.03(4)
2.11(4)
2.11(4)
2.29(4)
2.53(4)
1.69(4)
1.92(4)
3.807(3)
2.946(3)
2.911(3)
3.050(3)
3.287(3)
2.602(3)
2.642(3)
168(3)
161(3)
157(3)
168(4)
152(3)
171(4)
167(4)
ꢂx + 2, ꢂy + 1, ꢂz
ꢂx + 1, ꢂy, ꢂz + 1
ꢂx, ꢂy + 1, ꢂz + 1
ꢂx ꢂ 1, ꢂy, ꢂz + 2
N(1A)–H(1A)/O(1B)
N(2B)–H(2B)/O(2B)
C(4B)–H(4B)/O(3B)
N(1B)–H(1B)/O(1C)
N(1C)–H(1C)/O(1D)
N(1D)–H(1D)/O(1A)
O(2A)–H(2A)/N(2A)
O(2C)–H(2C)/N(2C)
O(2D)–H(2D)/N(2D)
0.89(4)
0.88
0.95
0.88(4)
0.87(4)
0.95(4)
1.08(4)
0.86(5)
0.91(5)
2.31(4)
1.86
2.64
2.11(4)
2.30(4)
2.28(4)
1.52(4)
1.74(5)
1.72(5)
3.151(4)
2.718(4)
3.161(4)
2.979(3)
3.135(4)
3.145(4)
2.585(3)
2.605(3)
2.632(4)
156(4)
166
115
168(4)
160(4)
150(4)
166(4)
173(4)
171(4)
—
—
—
—
—
x ꢂ 2, y, z + 1
—
—
—
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room temperature open to the atmosphere. Colourless crystals
were afforded after several days.
The solution was left to stand at room temperature open to the
atmosphere. Colourless crystals were afforded after several days.
Single crystal X-ray diffraction. Intensity data for all
compounds except 2 were collected on a Bruker APEX II CCD
area detector diffractometer with graphite monochromated
MoKa1 radiation (50 kV, 30 mA) at 173 K using an Oxford
Cryostream 600 cooler. The collection method involved u-scans
(Isonicotinic acid hydrazide)$(2-chloro-4-nitrobenzoic acid), 10
0.200 g of isonicotinic acid hydrazide (1.46 mmol) and 0.294 g of
2-chloro-4-nitrobenzoic acid (1.46 mmol) were added into
a sample vial. The solids were dissolved in hot ethanol (6 ml) and
acetonitrile (5 ml), and left to stand at room temperature open to
the atmosphere. Colourless crystals were afforded after several
days.
(N0-(Propan-2-ylidene)isonicotinohydrazide)$(2-chloro-4-
nitrobenzoic acid), 11
0.200 g of isonicotinic acid hydrazide (1.46 mmol) and 0.290 g of
2-chloro-4-nitrobenzoic acid (1.46 mmol) were added into
a sample vial. The solids were dissolved in acetone (5 ml) and
methanol (1 ml), and stirred for 12 hours at room temperature.
Fig. 2 Views of the homosynthon C(3) chain (a) and heterosynthon
C12(4) chain (b) in the original isoniazid molecule (1). (c) Packing diagram
showing part of the 3-D network built up by the two chain motifs. Atoms
with superscript i, ii and iii are at the symmetry positions [ꢂx + 1/2 , y + 1,
Fig. 3 (a) Detailed view of the C(4) chain, which is the common
homosynthon observed in modified propan-isoniazid (2). (b) Packing
diagram showing the relative arrangement of the chains of propan-
isoniazid (2) running along [001]. Atoms with superscript i are at the
symmetry position [ꢂx + /2 , y, z +1/2 ]
1
3
1
1
3
z ꢂ /2 ], [ꢂx + /2 , ꢂy + 1, z ꢂ /2 ] and [x ꢂ /2 , ꢂy + /2 , ꢂz + 1],
1
respectively.
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of width 0.5ꢁ. Data reduction was carried out using the program
SAINT+, version 6.025 and empirical absorption corrections
were made using the program SADABS.6 Single crystal diffrac-
tion data for 2 were collected in u-scan mode on an Oxford
Diffraction Gemini R Ultra diffractometer equipped with
hydrogen atoms were placed at idealized positions and refined as
riding atoms with isotropic parameters 1.2 times those of the
‘heavy’ atoms to which they are attached.
In 5, the positional disorder around the oxygen atoms O(2)
and O(3), and the carbon atom C(12), was resolved by finding
alternate positions from the difference Fourier map for the
respective atoms. These atoms were then refined anisotropically
with site occupancies such that the sum of the occupancies for the
two alternate atom positions equalled one. The bond lengths
were restrained using the SADI instruction in SHELX.
Hydrogen atom positions were then calculated for the respective
atoms using a riding model.
ꢀ
a Ruby CCD-detector with CuKa1 (l ¼ 1.5418 A, multi-layer
optics) at 173 K using an Oxford Cryostream 700 cooler. Data
reduction, cell refinement and empirical absorption corrections
were carried out using CrysAlisPro.7 Space group assignments
were made using XPREP5 on all compounds.
In all cases, the structures were solved in the WinGX8 Suite of
programs by direct methods using SHELXS-979 and refined
using full-matrix least-squares/difference Fourier techniques on
F2 using SHELXL-97.9 All non-hydrogen atoms were refined
anisotropically. Thereafter, all hydrogen atoms attached to N
and O atoms were located in the difference Fourier map and their
coordinates refined freely with isotropic parameters 1.5 times
those of the ‘heavy’ atoms to which they are attached. All C–H
In 11, the positional disorder around the nitrogen atom N(2b)
and carbon atoms was not resolved, and the N atom refined
isotropically.
Diagrams and publication material were generated using
ORTEP-3,10 PLATON11 and DIAMOND.12 Experimental
details of the X-ray analyses are provided in Table 1.
Fig. 4 The contents of the asymmetric unit for co-crystals 3–10, showing the atomic numbering scheme. Displacement ellipsoids are shown at the 50%
probability level. Only one of the disordered components in 5 is shown. Atoms with superscript (i) and (ii) are at the symmetry positions [ꢂx, ꢂy, ꢂz + 1]
and [ꢂx, ꢂy, ꢂz] respectively.
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Crystallographic data for the co-crystals 3 and 6 were reported
previously.1
Results
The compounds used to obtain the eleven crystal structures are
presented in a coherent sequence in Scheme 2. The pure active
pharmaceutical ingredient (API) is presented in its original (or
unmodified) version, 1. Isoniazid was reacted with acetone to
prepare the modified and improved drug molecule, N0-(propan-
2-ylidene)isonicotinohydrazide, 2. Ethanol aided (original
isoniazid) or ethanol–acetone aided (modified isoniazid) co-
crystallizations were carried out with the GRAS molecules:
succinic acid (suc) (3 and 4), 4-hydroxybenzoic acid (pHBA) (6
and 7) and salicylic acid (SA) (8 and 9). Lastly, drug–drug co-
crystals were made with the anti-HIV compound 2-chloro-4-
nitrobenzoic acid (2c4n) (10 and 11). In addition, a second
modified isoniazid was made by reacting it with 2-butanone and
co-crystallizing with succinic acid (5).
Powder X-ray diffraction. Powder X-ray diffraction data for all
compounds were collected at 293 K on a Bruker D2 Phaser
diffractometer which employs a sealed tube Cu X-ray source (l ¼
ꢀ
1.5406 A), operating at 30 kV and 10 mA, and LynxEye PSD
detector in Bragg-Brentano geometry. Powder X-ray diffraction
confirmed that the single crystal structures were representative of
the bulk material (see the ESI†).
Differential scanning calorimetry. Differential Scanning Calo-
rimetry (DSC) data were collected on a Mettler Toledo 822e at
a scan rate of 10 K minꢂ1 in sealed aluminium pans under air.
The temperature and the energy calibration was performed with
pure indium (purity 99.999%, mp 156.6 ꢁC, heat of fusion 28.45 J
gꢂ1). Measurements of onset temperature and heat of fusion of
the melting points of 1–11 were done in duplicate or triplicate,
except for 6. Results are summarized in Table 3, and DSC traces
are given in the ESI†.
The distances and angles within the eleven compounds
reported are generally as expected.13 Seeing that the hydrogen
Scheme 3 The expected homosynthon for modified isoniazid in co-
crystals (a), as well as the two heterosynthon variants used to co-crys-
tallize the modified isoniazid with carboxylic acids (b and c).
Fig. 5 Detailed view of the two homomeric synthons R22(6) and R22(10)
found in isoniazid, and the heteromeric R22(7) hydrogen bonding of the
GRAS molecule succinic acid to isoniazid in co-crystal 3. Figure adapted
from ref. 1.
Fig. 6 (a) The sandwich-like packing of the GRAS molecule succinic
acid bordered by propan-isoniazid in 4. (b) The relative packing of the 2-
D sandwiched layers.
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Fig. 7 (a) View of the hydrogen bonding interactions from the succinic acid to the butan-isoniazid molecules in co-crystal 5, using the same synthons as
seen in 4. Here, ribbons are formed instead of 2-D layers. (b) The packing of adjacent ribbons.
bonded interactions are central to this study, the hydrogen atoms
on the isoniazid and its modified derivatives are all labelled
consistently in order to make comparisons of the eleven struc-
tures easier. H(1) is the hydrogen atom bonded to the amide
group, and is the hydrogen atom always present. The two
hydrogen atoms on the NH2 of the hydrazide are labelled H(3A)
and H(3B). If there are multiple molecules in the asymmetric unit
(ASU), then the letters A, B, etc. are added after H(1), and
similarly, A and B, C and D, etc. after H(3). The H atoms on the
carboxylic acid functional groups are labelled consistently H(2)
and on the phenol H(4), and if there are multiple molecules in the
ASU, appended again using letters.
The crystal structure of the modified isoniazid, N0-(propan-2-
ylidene)isonicotinohydrazide (2), hereafter shortened to propan-
isoniazid, shows a substantial change in hydrogen bonding
pattern and packing. The removal of the two hydrazide H atoms,
replaced now by the propylidene group, removes two thirds of
the hydrogen bonding functionality of the original isoniazid
Crystal structures of isoniazid and modified isoniazid
The crystal structure of isoniazid (1) has been reported in the
literature previously by Jensen in 1954,14 and by Bhat et al. in
1974.15 The temperature of the crystal structure determinations
was room temperature, respectively INICAC and INICAC01 in
the Cambridge Structural Database (CSD),16 and to provide for
consistent comparison throughout all 11 structures, rede-
termined in this study at 173 K. The unit cell and conformation
of the molecule are the same as before, and the atomic labelling
scheme and displacement ellipsoids of the isoniazid molecule in
the asymmetric unit (ASU) are shown in Fig. 1a.
The crystal structure of isoniazid (1) consists of a 3-D network
built up by three strong N–H/N hydrogen bonds (see Table 2).
The amide H(1) hydrogen bonds to N(3) to form a C(3)17
hydrogen bonded chain down the a-axis (Fig. 2a). The two
hydrazide H atoms H(3A) and H(3B) form a C12(4) chain by
hydrogen bonding both to the pyridine N atom N(2), also
running down the a-axis (Fig. 2b). By virtue of these hydrogen
bonding interactions having acceptor atoms on both ends of the
isoniazid molecule, a 3-D network is built up (Fig. 2c). Note that
the oxygen atom of the amide group is not used in any strong
hydrogen bonding interactions.
Fig. 8 (a) The heteromeric and homomeric synthons connecting the
isoniazid and pHBA molecules to each other in 6. (b) The 2-D layer
formed by the combination of all the hydrogen bonding interactions.
Figure adapted from ref. 1.
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Fig. 9 (a) The R22(7) ring is used to connect the pHBA molecules to the propan-isoniazid molecules in 7. The combination of the carboxylic acid/
pyridine and phenol/carbonyl hydrogen bond creates a C22(15) chain formed by the two molecules. (b) These chains are then connected by a fairly
oblique discrete hydrogen bond from the amide H(1) to the carbonyl of the acid molecule, shown in purple dashed lines.
molecule. The crystal structure of this modified isoniazid was
also reported previously, again only at room temperature
(RUGSIW),18 and redetermined here at 173 K (Fig. 1b). The
crystal structure consists of a 1-D network of C(4) chains formed
by homomeric hydrogen bonding of the amide group, i.e. H(1)
hydrogen bonds to O(1) to form chains along the c-axis (Fig. 3a).
The packing consists of stacking of these chains in a head to tail
fashion to form a checkerboard pattern (Fig. 3b).
Crystal structures of isoniazid and modified isoniazid in co-
crystals with the GRAS compound succinic acid using two
different modifiers, 2-propanone and 2-butanone
The crystal structure of the co-crystal (isoniazid)2$(succinic acid)
(3) has been reported previously in the literature.1 The contents
Fig. 10 (a) The two chain homosynthons used by isoniazid in co-crystal
8. (b) Edge-on view of the 2-D layer formed.
Fig. 11 The C(4) homosynthon and R22(7) heterosynthon used in co-
crystal 9.
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of the ASU, and labelled atomic numbering scheme, are shown in
Fig. 4. The crystal structure of 3 is typical of the other known co-
crystals and relates well to the ones reported later. In order to
form co-crystals with other compounds, use is made of the robust
heteromeric carboxylic acid/pyridine hydrogen bond. This
hydrogen bond exists in two geometric variants. The carboxylic
acid functional group can be co-planar with the pyridine ring,
and then features a supporting weak C–H/O hydrogen bond to
form a R22(7) ring. Alternatively, the two hydrogen bonding
functional groups are not co-planar, resulting in a discrete D
hydrogen bond only (Scheme 3).
Co-crystal 3 displays the R22(7) ring variant when forming
a hydrogen bond between the GRAS molecule succinic acid and
isoniazid. Adding succinic acid as a co-crystal former results in
a substantial change in the hydrogen bonding pattern observed in
the isoniazid co-crystal in contrast to the pure isoniazid structure
(see Table 2). The amide H(1) now forms a R22(6) ring instead of
a C(3) chain to N(3), and the hydrogen atoms on N(3) no longer
hydrogen bond to the pyridine. Instead, H(3A) hydrogen bonds to
O(1) to form a larger R22(10) ring, and H(3B) hydrogen bonds to
the carboxylic O(2) (Fig. 5). The overall packing of co-crystal 3
consists of a 3-D network, consisting of stacked layers of the
hydrogen bonded isoniazid and succinic acid.
using two GRAS molecules that have different hydrogen
bonding groups. The previous co-crystals were made using
a dicarboxylic acid molecule; here we use a single carboxylic acid
functional group together with a phenol group. The modifier 2-
propanone is kept constant.
The crystal structure of the co-crystal (isoniazid)$(4-hydrox-
ybenzoic acid) (6) was reported previously,1 and a labelled
atomic numbering scheme of the ASU is shown in Fig. 4. The
crystal structure is built up from repeating R33(10) rings using the
amide H(1), one of the amine H(3A) atoms and the phenol H(4)
atom (Fig. 8a). In fact, a C(4) homosynthon is present within the
larger R33(10) synthon. On the other end of the GRAS molecule
pHBA, the carboxylic acid group hydrogen bonds to the pyridine
ring using the D variant (Fig. 8a), whereas the second amine H
(3B) hydrogen bonds to the carbonyl of the acid group to form
a R44(24) ring. Together, these hydrogen bonds form a 2-D layer
in the ac-plane (Fig. 8b).
The crystal structure using the propan-isoniazid to form the
co-crystal 7 has a very different packing to 6. The co-crystal
forms the R22(7) variant to connect the propan-isoniazid with
pHBA. These two molecules are then joined via a hydrogen
By altering the crystallization procedure used to produce co-
crystal 3, in this case by adding 2-propanone (acetone) as the
crystallization solvent, the modification of the hydrazide func-
tional group occurs in situ during co-crystallization with succinic
acid to produce co-crystal (propan-isoniazid)2$(succinic acid) 4,
bringing further changes to the hydrogen bonding and packing.
The ASU and numbering scheme of 4 are shown in Fig. 4. Just as
was the case when comparing the crystal structures of isoniazid
and propan-isoniazid, the hydrogen bonding interactions of the
propan-isoniazid molecule adopts the C(4) homomeric chain and
the hydrogen bond of succinic acid to the propan-isoniazid
adopts the D variant. As such, there are only two strong
hydrogen bonding interactions, resulting in a different packing
arrangement (Fig. 6a). The packing consists of 2-D layers in the
bc-plane, where the layers are formed by propan-isoniazid C(4)
chains sandwiching the central succinic acid molecules (Fig. 6b).
For co-crystals with succinic acid, we decided to modify the
isoniazid again using a different modifying group, 2-butanone, to
makethestructurallyrelatedco-crystal(butan-isoniazid)2$(succinic
acid) (5). This co-crystal, whose ASU is shown in Fig. 4, has the
same two synthons as co-crystal 4, C(4) and D, but has a different
packing arrangement. The same sandwiches are formed, where
succinic acid molecules hydrogen bond on both ends to terminating
butan-isoniazid molecules, which then form ribbons through the C
(4) chains (Fig. 7a). These ribbons extend along the a-axis and pack
in layers next to each other, with adjacent layers offset from each
other (Fig. 7b). This shows that the addition of an extra C atom on
the modifying group can lead to a different packing arrangement,
but nonetheless uses the same hydrogen bonding interactions.
Crystal structures of isoniazid and propan-isoniazid in co-
crystals with two different GRAS compounds, 4-hydroxybenzoic
acid and 2-hydroxybenzoic acid
Fig. 12 (a) The alternating sequence of R22(6) and R22(10) rings found in
isoniazid, and the heteromeric D hydrogen bonding of the 2c4n molecule
to isoniazid in co-crystal 10. The same sequence of rings is seen in co-
crystal 3. (b) Part of the repeating 3-D network.
We now illustrate the concept of making pharmaceutical co-
crystals while modifying the functionality of the drug molecule
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bond from the phenol H(4) to the carbonyl O(1) of the amide
to form
C22(15) chain approximately along the a-axis
Crystal structures of isoniazid and propan-isoniazid in drug–drug
co-crystals with 2-chloro-4-nitrobenzoic acid
a
(Fig. 9a). These chains are connected by a hydrogen bond from
the amide H(1) to the phenol O(4) in a discrete hydrogen bond,
with a very oblique angle of 131(1)ꢁ. This hydrogen bond joins
the chains along the b-axis to form a 2-D layer in the ac-plane
that has the width of the b-axis cell parameter (Fig. 9b). In
other words, the C(4) homosynthon is not formed in this co-
crystal.
We prepared co-crystals with a second drug molecule instead of
a GRAS molecule. In previous studies, the potential anti-HIV
drug molecule 2-chloro-4-nitrobenzoic acid (2c4n) has been co-
crystallized with the GRAS molecule nicotinamide.19 Isoniazid
itself has been used in drug–drug co-crystals with other anti-
tuberculosis drugs.20 We combined 2c4n with both isoniazid (10)
and modified isoniazid (11).
The next pair of co-crystals alters the position of the phenol
group relative to the carboxylic acid by using the GRAS
compound 2-hydroxybenzoic acid, also known as salicylic acid
(SA). The crystal structure of the co-crystal (isoniazid)$(2-
hydroxybenzoic acid) (8) has one molecule of isoniazid and SA in
the ASU, shown in Fig. 4 with their atomic numbering scheme.
The isoniazid molecules are connected by two homosynthons,
a C(5) chain from H(3B) to O(1), and a C(2) chain from H(3A) to
N(3). These two chains run along the b-axis (Fig. 10a). The
isoniazid molecules are connected to the SA molecule by the D
variant of the carboxylic acid/pyridine hydrogen bond, as well
as a hydrogen bond from the amide H(1) to the phenol O(4)
atom. The combination of these two hydrogen bonds results in
a R44(26) ring (excluding the S(6) hydrogen bond of the H(4)
hydrogen bonding to O(3)). All these combine to form a 2-D
layer along the bc-plane (Fig. 10b).
The crystal structure of the co-crystal (isoniazid)$(2c4n) 10
crystallizes with two molecules of isoniazid and two molecules of
2c4n in the ASU (Fig. 4), Z0 ¼ 2. This is in contrast to the other
co-crystals 3–9 that had Z0 ¼ 1 each time. The two crystallo-
graphically independent moieties of the two molecules are
labelled using A and B. The isoniazid molecules are connected to
each other by alternating R22(6) and R22(10) rings along the [220]
direction using the H atoms H(1A) and H(1B), and H(3B) and H
(3C) respectively. Both 2c4n molecules hydrogen bond to the
isoniazid molecules using the D variant to form ribbons
(Fig. 12a). The remaining two H atoms on the amine group, H
(3A) and H(3D), hydrogen bond to the O atoms of the nitro
group on 2c4n to form a 3-D network (Fig. 12b).
The crystal structure of the co-crystal (propan-isoniazid)$
(2c4n) 11 crystallizes with four molecules of propan-isoniazid
and four molecules of 2c4n in the ASU (Fig. 13), giving a Z0 ¼ 4.
This is double to what is observed for the unmodified co-crystal
10. The four crystallographically independent moieties of each of
the molecules are labelled A to D such that they hydrogen bond
to each other forming ribbons. Note that the B pair of propan-
isoniazid and 2c4n are a cation/anion pair, with the remaining
three pairs being neutral molecules. The four isoniazid molecules
Co-crystal 9, (propan-isoniazid)$(2-hydroxybenzoic acid),
using the propan-isoniazid, shows the expected homosynthon. A
C(4) chain formed from the remaining amide hydrogen bonding
ꢁ
functional group forms along the [101] direction, with the SA
molecule pendant to the propan-isoniazid using the R22(7)
variant. The S(6) hydrogen bond is the only interaction retained
compared to 8 (Fig. 11).
Fig. 13 The contents of the asymmetric unit for co-crystal 11, showing the atomic numbering scheme. Displacement ellipsoids are shown at the 50%
probability level.
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form a four-molecule repeating unit, where A and B molecules
form a pair aligned in the same direction, followed by the C and
D molecule in a pair rotated by 180ꢁ (Fig. 14a). The C(4)
homosynthon is used to connect all the propan-isoniazid mole-
cules. The 2c4n drug molecules hydrogen bond to the pyridine of
the isoniazid to form ribbons. The hydrogen bonds seen in the A,
C and D pairs are of the D variant. The charge-assisted hydrogen
bond resulting from proton transfer from the B acid to the B
propan-isoniazid can be considered to be the ionic equivalent of
the neutral R22(7) hydrogen bond, where the H atom moves along
a vector from the donor to the acceptor. These ribbons are
connected by type I and II halogen bonds from the Cl atoms to
the O atoms of the nitro groups to form a 3-D network
(Fig. 14b).
Here, co-crystal 4 showed that the concept works for alkyldi-
carboxylic acid molecules, whereas co-crystals 7, 9 and 11 show
that benzoic acid derivatives remain a good co-crystal former
choice. In terms of the observed hydrogen bonding interactions,
the robustness of the carboxylic acid/pyridine hydrogen bond
has been illustrated again as it is the dominant heteromeric
interaction to make co-crystals between isoniazid and various
carboxylic acid molecules. Regardless of the type of hydrogen
bond, i.e. the geometric variant, all nine co-crystals feature this
hydrogen bond. An unexpected charged variant was observed in
one of the pairs of ‘molecules’ in co-crystal 11, where the B pair is
in fact a cation/anion pair. This is seen in the bond distances of
the COOꢂ moiety, which has a ratio of 1.008 for the two C–O
bond lengths. The three other pairs have values of 1.063, 1.077
and 1.096, which is indicative of a neutral acid group with no
proton transfer to a base molecule.21 As to why three pairs of
molecules remain neutral, and one charged, is unclear at this
stage. However, it is possible that this imbalance is one of the
reasons for having a Z0 ¼ 4 asymmetric unit, as all molecules
have similar hydrogen bonding interaction. What does differ
significantly however is the geometries of the four isoniazid
moieties, as seen in Table 3 for the C(2)–C(1)–C(6)–N(1), N(3)–
N(1)–C(6)–O(1) and C(6)–N(1)–N(3)–C(8) torsion angles. In
addition, crystals of this co-crystal (11) were harvested from
a rapid evaporation process, and hence could represent the
kinetic product of the crystallization process.
Discussion
The co-crystals reported in this study, namely 3–11, show that
the modification of isoniazid still allows for co-crystals to be
formed with carboxylic acid containing co-crystal former mole-
cules. A previous study of the modification and masking process
was carried out using a number of different ketones and keeping
the co-crystal former the same, namely 3-hydroxybenzoic acid.
In terms of the homomeric interactions between isoniazid and
the modified isoniazid, some trends can be observed. Isoniazid,
both in its original and modified form, seldom undergoes any
heteromeric interactions when co-crystallized, and those kinds of
interactions are only seen in co-crystals 6 and 7. Pure isoniazid
itself does undergo a heteromeric interaction in its unimolecular
structure, a heteromeric C12(4) interaction; but in co-crystals, this
interaction is not seen as the pyridine group is already bonding to
the various carboxylic acids. More prevalent are homomeric
interactions seen in all co-crystals reported here. Most common
is the C(4) homosynthon in isoniazid, especially when in its
modified form. This is expected as the amide chain formed by N–
H/O hydrogen bonded interactions is very robust.22 Even when
other modifiers are used, apart from 2-propanone and 2-buta-
none, this homosynthon is seen.2 Correlated with the presence of
a C(4) homosynthon is the torsion angle of the modified group
relative to the amide functional group. The absolute torsion
angle C(6)–N(1)–N(3)–C(8) is close to 180ꢁ when the C(4) is not
formed, and varies from about 148.8(3) to 166.20(14)ꢁ when C(4)
is present (Table 3). Similar correlations are seen in the rotation
of the amide group relative to the pyridine group, where the
absolute torsion angle C(2)–C(1)–C(6)–N(1) varies from 18.1(2)
to 37.09(17)ꢁ when the C(4) homosynthon is present, and is
considerably more linear when C(4) is not present (3.3(4) to 16.7
(3)ꢁ). The C(3) homosynthon in pure isoniazid is not seen in any
of the unmodified co-crystals; instead R22(6) and R22(10) rings are
observed. These are common for isoniazid co-crystals.1
A part of the structural study of preparing co-crystals with
both original and modified isoniazid is the effect on the melting
point of the co-crystals, and how the removal of hydrogen
bonding functionality in general could alter the melting points.
In Table 3, the melting points of all 11 compounds discussed in
this report are listed, as well as their enthalpies of fusion. The
Fig. 14 (a) The C(4) chain formed by four crystallographically inde-
pendent propan-isoniazid molecules, and the four 2c4n molecules
hydrogen bonding to them, labelled (a–d). (b) View of the ribbons con-
nected by the halogen bonding to make a 3-D network.
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Table 3 Comparative features of all compounds
1
2
3
4
5
6
7
8
9
10
11
Melting point/ꢁC 170.4(1) 160.0(2)
139.1(1)
39.3(4)
126.2(3) 109.3(2) 161.6
49.5
156.2(3) 145.8(1) 114.0(1) 116.3(5)
93.4(6)
33.4(7)
Heat of
fusion/kJ molꢂ1
NH2 modified
31.0(3) 29.9(7)
31.8(8)
39.5(3)
52.8(1)
49.3(6)
No
C(2)/C(5) C(4)
None
41.4(2)
Yes
40.3(5)
No
No
Homosynthons C(3)
Heterosynthons C12(4)
Yes
C(4)
None
—
No
Yes
Yes
C(4)
None
D
No
Yes
No
Yes
R22(6)/R22(10) C(4)
C(4)
R34(10)
D
R22(6)/R22(10) C(4)
None
R22(7)
None
D
D/C22(15) None
None
D/D
None
D/R22(7)a/D/D
Acid/pyridine
variant
—
R22(7)
D
R22(7)
Isoniazid and
modified
isoniazid:
C(2)–C(1)–
C(6)–N(1)/ꢁ
Isoniazid and
modified
ꢂ18.1(2) 50.90(19)
ꢂ19.48(18) 31.9(2)
34.8(2)
37.09(17) ꢂ8.66(17) 34.8(2)
36.50(16) 16.7(3) (A) 145.0(3) (A)
3.3(4) (B)
ꢂ22.7(4) (B)
29.8(4) (C)
23.6(4) (D)
ꢂ5.5(2) 5.0(2)
ꢂ8.0(2)
ꢂ5.0(2)
ꢂ9.2(2)
6.07(19) 0.91(18) ꢂ0.6(3) ꢂ7.21(17) 5.0(4) (A)
ꢂ3.3(5) (A)
ꢂ0.9(4) (B) 8.8(5) (B)
isoniazid:
4.8(5) (C)
ꢂ4.1(5) (D)
N(3)–N(1)–
C(6)–O(1)/ꢁ
Mod. isoniazid:
C(6)–N(1)–
N(3)–C(8)/ꢁ
—
ꢂ159.82(13) —
163.26(15) 166.20(14) —
173.21(11) —
153.02(11)
ꢂ167.9(3) (A)
ꢂ148.8(3) (B)
163.0(3) (C)
159.3(3) (D)
a
Charged, N+–H/Oꢂ.
highest melting point is seen for pure isoniazid 1, which then
decreases by 10 ꢁC for the pure modified isoniazid 2. Does
a similar trend occur in the four co-crystal pairs, namely 3–4–5,
6–7, 8–9 and 10–11? The answer is yes, but the question that
begets to be asked is if that can be correlated to the absence of the
two H bonding donors. Since hydrogen bonding is the strongest
of the intermolecular forces observed in molecular co-crystals,
decreasing the number of potential hydrogen bonds in the
isoniazid molecule by two thirds can be a factor, in addition to
the disruptive influence of the heteromeric interactions required
for co-crystallization in this study. The enthalpies of fusion show
a less clear trend, with the co-crystal pairs 3–5 and 6–7 showing
equal or increasing enthalpies of fusion, implying that the co-
crystal using a modified isoniazid is equal or more stable than the
co-crystal using the original isoniazid. The caveat is that all
intermolecular interactions and their contributions to the lattice
energy need to be considered, but further investigations showing
a similar trend in co-crystal stability might shed light on this.
Acknowledgements
The University of the Witwatersrand and the Molecular Sciences
Institute are thanked for providing the infrastructure and
financial support to do this work. Prof. David G. Billing is
thanked for X-ray infrastructure support and technical assis-
tance, Prof. Volker Kahlenberg of the University of Innsbruck
for data collection of compound 2, and Dr Gaelle Ramon of the
University of Cape Town for valuable comments during the
preparation of this manuscript.
Notes and references
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show that it is possible to prepare co-crystals of potential medical
relevance that are prepared by reacting the active pharmaceutical
ingredient with a ketone. The covalent and supramolecular
reactions that occur in solution must not be in a position to
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€
€
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