Novel solid forms of the anti-tuberculosis drug, Isoniazid: Ternary and polymorphic cocrystals

Article abstract of DOI:10.1039/c3ce40729b

Novel cocrystals of an anti-tuberculosis drug, Isoniazid (INH), with pharmaceutically acceptable coformers such as nicotinamide (NA), 4-hydroxybenzoic acid (HBA), fumaric acid (FA), and succinic acid (SA) are reported. Cocrystallization experiments involving INH and HBA produced two polymorphs of a novel hydrate of the INH·HBA cocrystal. Similarly, cocrystallization of INH and FA produced a novel polymorph of the reported INH·FA cocrystal. We have successfully explored the idea of designing ternary cocrystals involving INH with NA and FA or SA. All the novel solids were thoroughly characterized and their crystal structures determined. All the crystal structures feature an acid-pyridine heterosynthon involving INH and the carboxylic acid. Stability of the novel cocrystals was evaluated by slurry experiments and dynamic vapor sorption studies. In addition, stability of the cocrystals at accelerated test conditions (40°C, 75% RH) was also tested. Anhydrous INH·HBA cocrystal and Form I of INH·HBA cocrystal hydrate were found to convert to Form II of the INH·HBA hydrate, and Form II of INH·FA cocrystal converted to Form I of the INH·FA cocrystal. Ternary cocrystals remain stable at all test conditions. Solubility and dissolution experiments revealed a greater solubility of the INH·NA·SA cocrystal and its dissolution rate is comparable to the dissolution rate of the native INH. All other cocrystals showed lower solubility and dissolution rate compared to INH.

Full text of DOI:10.1039/c3ce40729b

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Novel solid forms of the anti-tuberculosis drug,
Isoniazid: ternary and polymorphic cocrystals3
Cite this: CrystEngComm, 2013, 15,
5877
Srinivasulu Aitipamula,*a Annie B. H. Wong,a Pui Shan Chowa and Reginald B.
H. Tan*ab
Novel cocrystals of an anti-tuberculosis drug, Isoniazid (INH), with pharmaceutically acceptable coformers
such as nicotinamide (NA), 4-hydroxybenzoic acid (HBA), fumaric acid (FA), and succinic acid (SA) are
reported. Cocrystallization experiments involving INH and HBA produced two polymorphs of a novel
hydrate of the INH?HBA cocrystal. Similarly, cocrystallization of INH and FA produced a novel polymorph of
the reported INH?FA cocrystal. We have successfully explored the idea of designing ternary cocrystals
involving INH with NA and FA or SA. All the novel solids were thoroughly characterized and their crystal
structures determined. All the crystal structures feature an acid–pyridine heterosynthon involving INH and
the carboxylic acid. Stability of the novel cocrystals was evaluated by slurry experiments and dynamic vapor
sorption studies. In addition, stability of the cocrystals at accelerated test conditions (40 uC, 75% RH) was
also tested. Anhydrous INH?HBA cocrystal and Form I of INH?HBA cocrystal hydrate were found to convert
to Form II of the INH?HBA hydrate, and Form II of INH?FA cocrystal converted to Form I of the INH?FA
cocrystal. Ternary cocrystals remain stable at all test conditions. Solubility and dissolution experiments
revealed a greater solubility of the INH?NA?SA cocrystal and its dissolution rate is comparable to the
dissolution rate of the native INH. All other cocrystals showed lower solubility and dissolution rate
compared to INH.
Received 26th April 2013,
Accepted 21st May 2013
DOI: 10.1039/c3ce40729b
www.rsc.org/crystengcomm
of existing drugs by developing novel formulations is currently
a prime research area.5
Introduction
Isoniazid (INH) is one of the key active pharmaceutical
ingredients (APIs) used in combination with rifampicin,
pyrazinamide (PZA), and ethambutol for the treatment of
tuberculosis.1 According to the World Health Organization,
tuberculosis is a worldwide pandemic that in 2010 infected 8.8
million people and killed 1.4 million of them.2 Strikingly,
tuberculosis is well-known to be resistant to first-line drugs,
and preventive therapy for tuberculosis usually consists of a
combination therapy involving high doses of INH and
rifampicin for 6–9 months.3 Therefore, there is an intense
activity towards the development of novel drugs that can
advance tuberculosis treatment. While the discovery and
development of new chemical entities for tuberculosis treat-
ment have been in progress,4 attempts to enhance the efficacy
Cocrystallization offers practical applications of crystal
engineering towards the development of novel pharmaceutical
formulations through cocrystallization of APIs with pharma-
ceutically acceptable compounds.6 Judicious selection of
coformers helps to fine tune pharmaceutical properties such
as physical stability, mechanical strength, color, half-life,
bioavailability, solubility and dissolution rate, etc.7 The ease
of preparation, availability of a wide variety of coformers, and
pharmaceutical relevance of cocrystals make them suitable for
pharmaceutical development.
From a crystal engineering viewpoint, INH represents an
interesting compound for cocrystal design. As shown in Fig. 1,
it possesses a pyridine–N, which is well known to form
pyridine–carboxylic acid heterosynthons with carboxylic acids,
and a carbohydrazide group which can form a range of homo
and heterosynthons with other functional groups. The ability
of INH to form various hydrogen bond synthons with
carboxylic acid, carboxamide, and pyridine functionalities
has recently been demonstrated.8 For example, Lemmerer
et al. reported a series of cocrystals with aliphatic dicarboxylic
acid and aromatic carboxylic acids.8c–e In addition, INH has
been used as a supramolecular reagent to demonstrate in situ
modification of hydrogen bonding functionality by reacting
with simple ketones.8c–e More recently, INH cocrystals with a
aInstitute of Chemical and Engineering Sciences, A*STAR (Agency for Science,
Technology and Research), 1, Pesek Road, Jurong Island, 627833, Singapore.
E-mail: srinivasulu_aitipamula@ices.a-star.edu.sg
bDepartment of Chemical & Biomolecular Engineering, National University of
Singapore, 4 Engineering Drive 4, 117576, Singapore. E-mail: reginald_tan@ices.a-
star.edu.sg
Electronic supplementary information (ESI) available: Crystallographic
3
information files (CIFs), PXRD patterns of the samples obtained in grinding,
dehydration, and stability experiments, and DSC thermograms of the ternary
cocrystals. CCDC 935247–935252. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3ce40729b
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Results and discussion
Isoniazid has not yet been shown to exhibit polymorphism and
until now has no reported solvates or hydrates. Crystallization
of INH from common organic solvents resulted in long needle-
shaped crystals that correspond to the reported orthorhombic
crystal structure of INH.12 All the solid forms reported in this
paper were obtained from solvent evaporative crystallization
experiments (see Experimental section for details).
Alternatively, some of these solids can also be prepared in
quantitative amounts via solid-state grinding methods (ESI ).
3
Crystal structure analysis
INH?HBA cocrystal hydrate (Form I and II). Cocrystallization
of INH and HBA in 1 : 1 molar ratio from alcoholic solutions
resulted in two polymorphs of a monohydrate of the 1 : 1
cocrystal of INH?HBA as blocks (Form I) and needles (Form II)
concomitantly. Interestingly, whereas neat grinding of INH
and HBA in 1 : 1 molar ratio produces the reported anhydrous
INH?HBA cocrystal,8e solvent-drop grinding with the aid of a
few drops of water selectively produces Form II of the
INH?HBA hydrate.
Fig. 1 Chemical diagram of INH and cocrystal formers used in this study.
series of carboxylic acids have been reported.8f Attempts have
also been made to find multi-drug cocrystals of INH with other
anti-tuberculosis drugs, such that these cocrystals may be
promising candidates for combination drug therapy which is a
common method of treatment for resistant strains of
tuberculosis. For example, Desiraju and co-workers reported
a multi-drug cocrystal involving INH and another anti-
tuberculosis drug, 4-aminosalicylic acid, that features pure
Crystal structure analysis of the polymorphs revealed
significant packing differences. Form
I belongs to the
monoclinic space group P21/n with one molecule each of
INH, HBA and water in the asymmetric unit (Table 1). In the
crystal structure, the INH molecules form a head-to-head
…
hydrogen bonded and partially ionic carboxylic acid nitrogen
base dimers in the same crystal structure.8b Cherukuvada and
Nangia reported binary and ternary eutectic compositions
involving INH and another anti-tuberculosis drug, PZA, and
pharmaceutically acceptable dicarboxylic acids.8a
…
…
hydrazide hydrazide homosynthon via N–H O hydrogen
bonds (Fig. 2b, Table 2). The carboxylic acid group of HBA
…
forms an O–H N hydrogen bond to the pyridine nitrogen
atom of the INH to result in an acid–pyridine heterosynthon.
The water molecule, on the other hand, is involved in the
formation of three hydrogen bonds with phenolic and
INH is a highly soluble API,9 but it has been reported that
INH in tablet formulations undergoes chemical degradation
upon storage for long time periods and also at accelerated
conditions.10 The presence of other anti-tuberculosis drugs,
such as PZA and ethambutol which are generally formulated as
fixed dose combinations with INH, were further found to
…
carbonyl oxygens of HBA via O–H O hydrogen bonds as a
accelerate the degradation of INH.11 Therefore, from
a
pharmaceutical perspective, there is a need to develop novel
formulations which can enhance the stability of INH.
We report here novel crystalline forms of INH with
coformers 4-hydroxybenzoic acid (HBA), fumaric acid (FA),
succinic acid (SA), and nicotinamide (NA). Whereas our
cocrystallization experiments with HBA revealed the existence
of dimorphs of a novel hydrate of the cocrystal involving INH
and HBA, cocrystallization experiments with FA resulted in a
novel polymorph of the reported INH?FA cocrystal. We also
report ternary cocrystals of INH, INH?NA?SA and INH?NA?FA.
All the solid forms are thoroughly characterized by spectro-
scopic, X-ray diffraction and thermal techniques. In addition,
pharmaceutically relevant properties such as stability, hygro-
scopicity, solubility and dissolution rate of the novel solids are
evaluated.
Fig. 2 Crystal structure of INH?HBA hydrate Form I, (a) showing the hydrogen
…
bonds of water molecule, (b) sheet structure mediated by hydrazide hydrazide
…
homosynthon, acid pyridine heterosynthon and water molecules.
5878 | CrystEngComm, 2013, 15, 5877–5887
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Table 1 Crystallographic data for the INH cocrystals
INH?HBA
hydrate Form I
INH?HBA
hydrate Form II
INH?FA
Form I
INH?FA
Form II
Compound reference
INH?NA?FA
INH?NA?SA
Chemical formula
Formula mass
Crystal system
a/Å
b/Å
c/Å
C13H15N3O5
293.28
Monoclinic
7.0070(14)
11.224(2)
16.950(3)
90.00
91.95(3)
90.00
1332.3(5)
110(2)
C13H15N3O5
293.28
Monoclinic
6.8143(14)
22.419(5)
8.8759(18)
90.00
101.85(3)
90.00
1327.1(5)
110(2)
C16H18N6O6
390.36
Monoclinic
7.8906(16)
8.7030(17)
12.517(3)
90.00
97.84(3)
90.00
851.5(3)
110(2)
C16H18N6O6
390.36
Monoclinic
3.7036(7)
7.8401(16)
29.573(6)
90.00
90.63(3)
90.00
858.6(3)
110(2)
C16H17N5O6
375.35
Monoclinic
5.0595(10)
17.246(3)
19.056(4)
90.00
97.25(3)
90.00
1649.5(6)
110(2)
C16H19N5O6
377.36
Monoclinic
5.1175(10)
17.467(4)
18.763(4)
90.00
96.71(3)
90.00
1665.7(6)
110(2)
a/u
b/u
c/u
Unit cell volume/Å3
Temperature/K
Space group
P21/n
4
P21
4
P21/n
2
6538
2113
0.0201
0.0502
0.1207
0.0526
0.1229
P21/n
2
6384
2095
0.0346
0.0671
0.1879
0.0749
0.2067
P21/n
4
P21/n
4
No. of formula units per unit cell, Z
No. of reflections measured
No. of independent reflections
Rint
Final R1 values (I . 2s(I))
Final wR(F2) values (I . 2s(I))
Final R1 values (all data)
Final wR(F2) values (all data)
10 544
3307
0.0363
0.0773
0.1908
0.0877
0.1996
10 379
5747
0.0369
0.0528
0.1351
0.0563
0.1394
22 825
4045
0.0285
0.0586
0.1539
0.0599
0.1587
11 614
4027
0.0190
0.0461
0.1217
0.0474
0.1231
donor, and with a hydrogen atom of the secondary amine of
the hydrazide fragment of INH via an N–H O hydrogen bond
as an acceptor (Fig. 2a). The phenolic O–H of the HBA interacts
hydrazide and acid–pyridine synthons along the crystallo-
…
graphic c-axis. These hydrogen bonded chains are intercon-
…
nected to each other through water molecules via O–H O and
…
N–H O hydrogen bonds, generating a 2-dimensional sheet
with the terminal nitrogen atom of the hydrazide via an O–
…
structure (Fig. 2b). Notably, the second H atom on the terminal
N atom of the hydrazide, which is not involved in the
H
N hydrogen bond. The overall crystal structure is com-
…
posed of chains of molecules connected via hydrazide
…
hydrazide hydrazide homosynthon, is not involved in any
strong hydrogen bond.
The crystal structure of Form II of the INH?HBA hydrate was
solved in the monoclinic P21 space group with two molecules
each of INH, HBA and water in the asymmetric unit. All our
attempts to solve the crystal structure in a higher symmetry
space group failed to yield a suitable solution. Evaluation of
the crystal data using ADDSYM/PLATON13 did not suggest any
higher metric space group. In the crystal structure, the water
molecule forms three hydrogen bonds that involve carbonyl
and terminal amine N of INH, and hydroxyl group of HBA
(Fig. 3a). The crystal structure is composed of symmetry
independent supramolecular chains that are mediated by
acid–pyridine heterosynthon involving the carboxylic acid
group of HBA and pyridine group of INH (Fig. 3b).
Interestingly, the crystal structure does not feature the head-
…
to-head hydrazide hydrazide homosynthon that is observed
in Form I.
INH?FA cocrystal (form I and II). Cocrystallization of INH
and FA in 1 : 0.5 molar ratio from common organic solvents
resulted in crystals of two different morphologies (block and
needle) concomitantly (Fig. 4). Single crystal X-ray analysis of
the block-shaped crystal (Form I) revealed that it belongs to
the reported INH?FA (1 : 0.5) cocrystal.8a However, the needle-
shaped crystals (Form II) were found to correspond to a new
polymorph of the INH?FA (1 : 0.5) cocrystal. In both the crystal
structures, INH and FA molecules interact via strong acid–
pyridine heterosynthons. The FA molecule resides on an
inversion centre and each FA molecule is hydrogen bonded to
two INH molecules via acid–pyridine heterosynthons. The
Fig. 3 Crystal structure of INH?HBA hydrate Form II, (a) showing the hydrogen
bonds of the water molecule, (b) a 3-dimensional structure composed of
supramolecular chains mediated by acid–pyridine heterosynthon and water
molecules. Symmetry independent molecules are shaded with different colors.
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Table 2 The geometric parameters for the intermolecular interactions in the INH cocrystals (neutron normalized)
a
…
…
…
…
Cocrystal
D–H
A
H
A/Å
D
A/Å
D–H A/u
Symmetry code
…
INH?HBA Form I
N2–H1 O5
1.81
2.11
1.62
1.77
1.87
1.96
2.84
2.78
2.83
2.34
2.28
1.84
1.83
2.47
2.42
2.36
2.44
1.6
2.800(3)
2.984(3)
2.606(2)
2.741(3)
2.834(3)
2.912(3)
3.196(3)
3.400(3)
3.332(3)
3.298(3)
3.264(3)
2.809(3)
2.782(3)
2.829(3)
2.804(3)
2.829(3)
2.804(3)
2.579(3)
2.608(3)
2.588(3)
2.609(3)
2.851(3)
2.863(3)
2.855(3)
2.836(3)
3.324(3)
3.357(3)
3.147(3)
3.186(3)
3.388(3)
3.399(3)
3.268(3)
2.830(2)
2.993(2)
3.018(2)
2.520(2)
3.338(2)
3.371(2)
3.365(2)
2.852(2)
3.090(2)
2.541(2)
3.400(3)
3.224(3)
3.383(2)
3.148(2)
3.404(2)
3.119(2)
3.104(2)
2.891(2)
2.582(2)
2.554(2)
3.385(2)
3.398(2)
3.078(2)
3.147(2)
3.372(2)
3.372(2)
3.230(2)
3.171(2)
3.181(2)
2.905(2)
2.609(2)
2.584(2)
3.295(2)
3.179(2)
3.232(2)
3.175(2)
166
143
180
169
165
163
102
116
108
147
150
160
155
100
102
107
100
177
173
157
163
176
167
175
163
121
121
134
125
110
163
115
161
144
148
174
139
109
119
161
159
175
155
119
146
115
104
161
154
175
169
171
151
152
101
160
119
145
117
123
156
179
167
171
103
161
117
123
…
N3–H6 O1
2x, 2y, 1 2 z
x, y, 1 + z
…
O3–H10 N1
…
O4–H13 N3
…
O5–H14 O2
1/2 2 x, 1/2 + y, 3/2 2 z
2x, 1 2 y, 1 2 z
2x, 1 2 y, 1 2 z
x, y, 21 + z
1/2 2 x, 21/2 + y, 1/2 2 z
1/2 2 x, 1/2 + y, 1/2 2 z
…
O5–H15 O4
…
O5–H15 O5
…
C3–H3 O2
…
C3–H3 O5
…
C4–H4 O1
…
C5–H5 O5
…
INH?HBA Form II
N2–H1 O2A
1 2 x, 1/2 + y, 2z
x, y, 1 + z
21 + x, y, 21 + z
1 + x, y, z
21 + x, y, 21 + z
1 + x, y, z
x, y, 21 + z
1 + x, y, 21 + z
1 + x, y, z
21 + x, y, z
21 + x, y, z
1 2 x, 21/2 + y, 2z
x, y, 1 + z
…
N2A–H1A O2
…
N3–H6 O4
…
N3A–H6A O4A
…
N3–H7 O4
…
N3A–H7A O4A
…
O3–H10 N1
…
O3A–H10A N1A
1.63
1.65
1.65
1.87
1.90
1.87
1.88
2.64
2.66
2.29
2.44
2.86
2.35
2.66
1.86
2.11
2.11
1.54
2.44
2.86
2.70
1.88
2.13
1.56
2.39
2.56
2.43
2.53
2.97
2.15
2.16
1.88
1.61
1.58
2.40
2.40
2.68
2.11
2.71
2.43
2.59
2.45
2.23
1.90
1.64
1.61
2.88
2.14
2.59
2.46
…
O4–H13 O5
…
O4A–H13A O5A
…
O5–H14 N3A
…
O5A–H14A N3
…
O5–H15 O1
…
O5A–H15A O1A
…
C3–H3 O2
x, y, 1 + z
…
C3A–H3A O2A
21 + x, y, 1 + z
1 2 x, 1/2 + y, 1 2 z
x, y, 1 + z
1 2 x, 1/2 + y, 1 2 z
1 2 x, 1/2 + y, 2z
x, y, 1 + z
x, 1 + y, z
1/2 + x, 3/2 2 y, 21/2 + z
3/2 2 x, 1/2 + y, 3/2 2 z
…
C4–H4 O1A
…
C4A–H4A O1
…
C5–H5 O1A
…
C5–H5 O2A
…
C5A–H5A O1
…
INH?FA Form I
INH?FA Form II
N2–H1 O2
…
N3–H6 O3
…
N3–H7 O1
…
O3–H9 N1
…
C2–H2 O2
x, 1 + y, z
2x, 1 2 y, 2 2 z
…
C3–H3 O3
…
C4–H4 O2
…
N2–H1 O2
21 + x, 1 + y, z
3/2 2 x, 1/2 + y, 1/2 2 z
…
N3–H6 O1
…
O3–H9 N1
…
C2–H2 O1
3/2 2 x, 21/2 + y, 1/2 2 z
…
C3–H3 O2
…
C5–H5 O2
21 + x, 1 + y, z
x, 1 + y, z
2 2 x, 2y, 2z
…
C5–H5 O2
…
C8–H8 O3
…
INH?NA?FA
N2–H1 O5
x, 21 + y, z
…
N3–H6 O3
1/2 2 x, 21/2 + y, 1/2 2 z
21 2 x, 1 2 y, 2z
21 2 x, 1 2 y, 2z
3/2 2 x, 1/2 + y, 1/2 2 z
x, 21 + y, z
x, 21 + y, z
21 + x, 21 + y, z
…
N5–H13 O2
…
O4–H16 N1
…
O6–H17 N4
…
C2–H2 O5
…
C3–H3 O4
…
C3–H3 O5
…
C8–H8 O1
…
C9–H9 O5
3/2 2 x, 21/2 + y, 1/2 2 z
3/2 2 x, 1/2 + y, 1/2 2 z
…
C9–H9 N3
…
…
C10–H10 O3
C11–H11 O3
…
INH?NA?SA
N3–H6 O3
1/2 2 x, 1/2 + y, 1/2 2 z
21 2 x, 1 2 y, 2z
21 2 x, 1 2 y, 2z
3/2 2 x, 21/2 + y, 1/2 2 z
21 + x, 1 + y, z
…
N5–H13 O2
…
O4–H16 N1
…
O6–H17 N4
…
C4–H4 O5
…
C8–H8 O1
…
…
C10–H10 O3
C11–H11 O3
a
D = donor, A = acceptor.
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resulting three-component supramolecular units are con-
…
nected to each other via N–H (secondary amine of INH)
O
(carbonyl of FA) hydrogen bonds to produce hydrogen bonded
ladders along the crystallographic b-axis (Fig. 5) in Form I. The
ladder networks that are related by a glide plane are connected
…
to each other via N–H (terminal amine of INH) O (carbonyl of
INH) hydrogen bonds, generating 2-dimensional sheets that
are interconnected to each other via N–H (terminal amine of
…
INH) O (oxygen of the hydroxyl of FA) (not shown in Fig. 5)
hydrogen bonds.
The ladder network that features the supramolecular three-
component units persists in Form II (Fig. 6). However, the
…
Fig. 5 A 2-dimensional sheet structure in the crystal structure of Form I of
INH?FA cocrystal.
terminal amine of INH, which participates in N–H
O
hydrogen bonds with the carbonyl of INH and hydroxyl group
…
of FA in Form I, now participates in N–H O hydrogen bonds
with carbonyl groups of two adjacent INH molecules. The
overall crystal structure is composed of ladder networks which
are interconnected via N–H O hydrogen bonds.
Notably, one of the eutectic compositions (INH-SA-PZA) has
been found to offer faster dissolution rate for INH compared
to its native form.
…
In both the crystal structures, there is a partial proton
transfer from the carboxylic acid of FA to the pyridine group of
INH. In general, the nature of a molecular complex, whether it
is a salt or cocrystal, can be predicted based on the DpKa rule.
A DpKa . 3 will be expected to form a salt, while a DpKa , 0
We set our goals to explore the idea of designing ternary
cocrystals involving INH and turned our attention to pharma-
ceutically acceptable NA which is structurally related to PZA.
Cocrystallization of INH, NA and dicarboxylic acids such as SA
and FA in 1 : 1 : 1 molar ratio readily resulted in ternary
cocrystals of the desired stoichiometry. Crystal structures of
the ternary cocrystals are isostructural with minor differences
in the unit cell parameters and also the way in which the
cocrystal components pack in the crystal structure. Both the
crystal structures contain one molecule each of INH, NA and
dicarboxylic acid. As expected, carboxylic acid molecules act as
results in a neutral cocrystal. In the DpKa range of 0 to 3, the
+
…
…
¯
O
intermolecular contact has an intermediate O–H N/N –H
character.14 The pKa difference between INH (pKa of the
pyridine N: 3.5) and FA (pKa 3.03) is 0.47. Therefore, the
observed partial proton transfer in INH?FA cocrystal is in
agreement with the DpKa rule. Cherukuvada and Nangia have
recently found that the partial proton transfer in the INH?FA
cocrystal (Form I) is temperature dependent.8a The proton lies
closer to the pyridine N atom at 100 K, but it lies closer to the
carboxyl O at room temperature. A similar observation has also
been made in the case of a cocrystal involving INH and
4-aminosalicylic acid.8b
…-
non-covalent linkers to form ternary cocrystals via acid
pyridine heterosynthons involving carboxylic acid groups and
pyridine groups of INH and NA (Fig. 7 and 8). In both the
cocrystals, the amide group of the NA forms an amide–amide
homosynthon. In addition, both the crystal structures feature
…
a C–H O interaction between p-C–H of the NA and terminal
INH?NA?FA and INH?NA?SA ternary cocrystals. Cherukuvada
and Nangia have recently attempted to prepare ternary
cocrystals involving INH, PZA and dicarboxylic acids such as,
SA and FA.8a In this study, the acid–pyridine heterosynthon
has been chosen as a design element such that the SA and FA
act as non-covalent linkers for INH and PZA to form ternary
cocrystals via the acid–pyridine synthon. However, all these
attempts instead produced ternary eutectics that were com-
amine N of the INH. The overall crystal structures can be best
represented as a 2-dimensional sheet structure in the (2105)
…
plane, which are interconnected via weak N–H O hydrogen
bonds involving the terminal amine of INH and carbonyl O of
the carboxylic acid.
posed of the cocrystals INH-diacid(0.5) and PZA-diacid(0.5)
.
Fig. 4 Concomitant crystallization of INH?FA cocrystal polymorphs from metha-
Fig. 6 Supramolecular ladders in the crystal structure of Form II of the INH?FA
nol, blocks (Form I) and needles (Form II).
cocrystal. All three ladders shaded with different colors are symmetry related.
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Fig. 7 A 2-dimensional sheet structure in the crystal structure of INH?NA?FA
ternary cocrystal.
Fig. 9 Comparison of FT-IR spectra of INH and its cocrystals.
Spectroscopic analysis
Changes in vibrational frequencies due to cocrystal formation
can be easily monitored by Fourier-Transform Infrared (FT-IR)
spectroscopy. In the case of polymorphic structures, differ-
ences in the hydrogen bonding lead to changes in the
vibrational frequencies. Change in the CLO stretching
frequency of INH, which appears as a strong band at 1666
cm21 in the FT-IR spectrum of INH, was considered to identify
the cocrystal formation. There was a significant shift in the
vibrational frequency upon cocrystal formation (Fig. 9). For
example, the CLO stretching frequency was observed at 1660
cm21 for INH?NA?SA, and at 1657 cm21 for INH?NA?FA.
INH?FA polymorphs showed an identical CLO stretching
frequency at 1659 cm21 due to the similar hydrogen bonding
and crystal packing. In the case of INH?HBA hydrate
polymorphs, the CLO stretching frequency of Form I appeared
at 1652 cm21, but at 1656 cm21 for Form II. This could be
because of the differences in hydrogen bonding in the crystal
structures, where as the CLO of the INH involved in an N–
Thermal analysis
All the solids were analyzed by differential scanning calori-
metry (DSC) and thermogravimetric analysis (TGA). In the DSC
analysis, all the cocrystals showed a different melting point
compared to their constituents and thus confirmed the
cocrystal identity. The DSC thermogram of Form
I of
INH?HBA hydrate showed a broad endotherm for water loss
in the temperature range of 115–130 uC, followed by melting at
162.8 uC (Fig. 10). The water loss from the crystals was
reflected as weight loss step in the TGA profile (Fig. 10), and
partial opaqueness of the crystal in hot-stage microscopy
(HSM) experiment (Fig. 11). The DSC of Form II showed a
sharp endotherm at 123 uC for water release followed by
melting and decomposition in the temperature range of 140–
165 uC. It is difficult to identify possible polymorphic
transformations due to the fact that the dehydration resulted
…
…
O
H
O hydrogen bond in Form I, but it is involved in an O–H
in an anhydrous cocrystal (ESI ) and subsequent heating
provided the melting point of the anhydrous cocrystal. The
3
(with water) hydrogen bond in Form II.
DSC thermograms of INH?FA cocrystal polymorphs showed a
Fig. 8 A 2-dimensional sheet structure in the crystal structure of INH?NA?SA
ternary cocrystal. Notice that the crystal structure is isostructural to the crystal
structure of the INH?NA?FA cocrystal (Fig. 7).
Fig. 10 DSC and TGA profiles of INH?HBA hydrate polymorphs, black (Form I)
and red (Form II).
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Fig. 11 Photomicrographs of INH?HBA hydrate polymorphs at various stages of
Fig. 13 Photomicrographs of INH?FA polymorphs at various stages of the HSM
the HSM experiment.
experiment.
single sharp endotherm for melting at 169.4 uC for Form I and
173.1 uC for Form II (Fig. 12). The fact that the higher melting
Form II has the lower heat of fusion (122.3 J g21), and lower
et al.8e was also included in the stability studies for
comparison with its hydrate.
Thermodynamic stability of the cocrystals was first evalu-
ated by slurry experiments at 37 uC. In these experiments,
excess solids of the cocrystal powders were stirred in deionized
water for 24 h. Filtered and air-dried samples were analyzed by
PXRD for their phase purity. It was noted that while both the
ternary cocrystals were stable upon slurrying, Form II of
INH?FA completely converted to Form I, anhydrous INH?HBA
cocrystal and Form I of the INH?HBA hydrate completely
converted to Form II of the INH?HBA hydrate (Fig. 14). These
observations suggest that Form I of the INH?FA cocrystal and
Form II of INH?HBA cocrystal hydrate are thermodynamically
melting Form I has the higher heat of fusion (127.7 J g21
)
suggests that these polymorphs are related enantiotropically.15
There was no visible change in the morphology of the crystals
of Form I and II of INH?FA in HSM images in Fig. 13. Melting
point of the ternary cocrystals was observed in between the
melting points of INH and NA (ESI ).
3
Stability of cocrystals
In view of the chemical degradation of INH at accelerated
stability conditions,8f,10,11 stability of the cocrystals was
studied in this work by performing slurry experiments at 37
uC, storage of the cocrystals at accelerated conditions, and
using the dynamic vapour sorption (DVS) technique. The
INH?HBA anhydrous cocrystal reported recently by Lemmerer
Fig. 14 Comparison of the PXRD patterns of powder samples obtained in slurry
experiments with PXRD patterns of the corresponding crystal structures of the
cocrystals. The small shift in the 2h values between the observed and simulated
patterns is due to the PXRD being recorded at room temperature but the X-ray
crystal structures were determined at 110 K.
Fig. 12 DSC profiles of INH?FA polymorphs.
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Table 3 Solubility and IDR of INH and its cocrystals in pH 7.5 buffer
Solid form
Equilibrium solubility IDR (mg cm22
(in pH 7.5 buffer,
min21
)
mg ml21
)
INHa
183
0.16027
0.02565
0.04063
0.07134
0.11197
0.14621
INH?HBA hydrate (Form II) 17.9
b
INH?HBA anhydrous
INH?FA (Form I)
INH?NA?FA
—
66.5
131
285
INH?NA?SA
a
Experimental solubility of INH in water at 37 uC is 141 mg ml21
INH?HBA anhydrous cocrystal converts to hydrate in slurry
.
b
experiment.
Fig. 15 DVS profiles of INH and its cocrystals discussed in this paper. Profiles
designated with solid and open legends correspond to sorption and desorption
profiles, respectively.
impacting the bioavailability. Among the various INH cocrys-
tals reported, cocrystals with malonic, succinic, glutaric,
suberic and benzoic acids have been showed to have higher
solubility than the solubility of INH.8f In another study,
solubility of INH has been improved by preparing an eutectic
composition involving INH, PZA, and SA.8a Solubility of the
newly prepared cocrystals were measured in pH 7.5 buffer
solutions by slurrying the excess amounts of solids in buffer at
37 uC. In the case of cocrystal polymorphs, solubility of only
the thermodynamic forms of INH?HBA hydrate (Form II) and
INH?FA (Form I) was measured (Fig. 14). Solubility of the
anhydrous INH?HBA cocrystal was also not measured due to
the conversion to its hydrate. The INH concentration was
quantified by high performance liquid chromatography
(HPLC) (see Experimental section for details). Interestingly,
all the cocrystals showed lower solubility than INH, except that
the solubility of INH?NA?SA cocrystal is approximately 1.5
times the solubility of INH (Table 3). The cocrystal solubility
follows the solubility of the respective coformers in the
cocrystals. For example, among the different coformers used
in this study, HBA is the least soluble coformer and hence the
solubility of INH?HBA hydrate is the lowest among all other
cocrystals. INH?NA?FA cocrystal shows higher solubility than
the INH?FA cocrystal because of the presence of more soluble
NA in the cocrystal. The presence of more soluble NA and SA
facilitates improved solubility of INH in INH?NA?SA cocrystal
compared to all other cocrystals.
Intrinsic dissolution rate (IDR) provides a quantitative
measure of dissolution behavior. In these experiments, solid
samples are compressed into a die to get a specific surface area
which is then exposed to the dissolution media. The amount
dissolved in a particular time period per unit area can be
represented as IDR. All the cocrystals of the present study were
evaluated for their IDR. Fig. 16 shows the dissolution profiles
and the calculated IDR values are listed in Table 3. The IDR
values supplement the equilibrium solubility values in Table 3,
except that the highly soluble INH?NA?SA cocrystal now shows
a comparable dissolution rate to that of the dissolution rate of
INH. It is also important to highlight here that the anhydrous
INH?HBA cocrystal shows higher dissolution rate than the
INH?HBA cocrystal hydrate, which is consistent with the
general trend that the anhydrous materials are more soluble
than their respective hydrates.16
stable at 37 uC. These stable forms were chosen for further
stability experiments.
In the accelerated stability tests, the powder samples of the
cocrystals were stored at 40 uC and 75% RH. Results of the
stability tests suggest that ternary cocrystals, INH?FA (Form I),
and INH?HBA hydrate (Form II) remained the same after
storage for 13 weeks, but the anhydrous INH?HBA cocrystal
converted to INH?HBA hydrate (Form II) within 2 days of
storage (ESI ). The stability of the cocrystals at accelerated test
3
conditions is consistent with the thermodynamic stability
observed in the slurry experiments.
Stability of the cocrystals with respect to changes in relative
humidity was evaluated by DVS experiments. Fig. 15 shows a
comparison of the DVS results. Samples of INH, INH?NA?SA,
INH?NA?FA, and INH?HBA hydrate exhibit low absorption
(,1%) over a broad humidity range. In addition, their
absorption and desorption profiles essentially overlap suggest-
ing that the absorption and desorption profiles are reversible.
INH?FA was found to absorb y3.5% of the water at higher RH
(.80%), and its desorption profile overlaps with the sorption
profile. On the other hand, INH?HBA anhydrate exhibits
significant moisture absorption with increasing humidity and
also differences in its absorption and desorption profiles. The
large moisture uptake (y6.2%) during the sorption profile
indicates formation of INH?HBA hydrate. The total weight gain
agrees very well with that expected for the monohydrate
(6.15%). Interestingly, no weight loss was observed during the
desorption suggesting that moisture uptake during the
sorption is not adsorbed onto the surface of the material,
but facilitates the formation of the monohydrate by forming
hydrogen bonds with INH and HBA. It is also interesting to
note that once the INH?HBA hydrate is formed, it no longer
adsorbs moisture as it is evidenced by the sorption profile of
INH?HBA hydrate which does not show any moisture uptake
upon increasing the RH.
Solubility and dissolution studies
Solubility and dissolution rate are two critical parameters that
can influence the performance of drug products by directly
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cocrystals and suggest that for highly soluble APIs, cocrystals
may not always offer solubility advantages. However, these
cocrystals may be helpful to fine tune other pharmaceutical
properties such as stability, hygroscopicity, half-life, etc.7b
Experimental section
INH and all other coformers were purchased from Alfa-
Aesar1, Singapore. Analytical grade solvents were used for
the crystallization experiments.
Solution based cocrystallization. Pure cocrystal samples
were prepared by solvent-evaporative crystallization experi-
ments at ambient conditions.
INH?HBA hydrate polymorphs. INH (100 mg, 0.73 mmol)
and HBA (100.7 mg, 0.73 mmol) were dissolved in 5 mL of
acetonitrile at 50 uC and left for evaporation of the solvent at
ambient conditions. Single crystals of the anhydrous INH?HBA
cocrystal in 1 : 1 stoichiometry were obtained as colorless
blocks after 3 days. Cocrystallization conducted in methanol
or 50% methanol in water resulted in the concomitant
formation of INH?HBA hydrate polymorphs.
Fig. 16 IDR profiles of INH and cocrystals reported in this paper. The straighten-
ing of dissolution profiles of INH and INH?NA?SA after 80 min represents the
complete dissolution of the samples used for dissolution experiment.
INH?FA cocrystal polymorphs. INH (100 mg, 0.73 mmol) and
FA (42.37 mg, 0.365 mmol) were dissolved in 5 mL of methanol
at 50 uC and left for evaporation of the solvent at ambient
conditions. Block- and needle-shaped crystals that belonged to
INH?FA cocrystal polymorphs were obtained in approximately
3 days.
INH?NA?FA cocrystal. INH (100 mg, 0.73 mmol), NA (89.15
mg, 0.73 mmol), and FA (84.73 mg, 0.73 mmol) were dissolved
in 5 mL of methanol at 50 uC and left for evaporation of the
solvent at ambient conditions. Single crystals of the ternary
cocrystal in 1 : 1 : 1 stoichiometry were obtained as colorless
needles after 3 days.
INH?NA?SA cocrystal. INH (100 mg, 0.73 mmol), NA (89.15
mg, 0.73 mmol), and SA (86.21 mg, 0.73 mmol) were dissolved
in 5 mL of methanol at 50 uC and left for evaporation of the
solvent at ambient conditions. Single crystals of the ternary
cocrystal in 1 : 1 : 1 stoichiometry were obtained as colorless
needles after 3 days.
Conclusions
We have reported novel cocrystal forms of INH with
pharmaceutically acceptable coformers. Our experiments to
reproduce the recently reported cocrystals of INH with HBA
and FA unravelled polymorphs of a novel hydrate of INH?HBA
cocrystal, and a new polymorph of INH?FA cocrystal. In
addition, we have successfully prepared ternary cocrystals of
INH with NA and dicarboxylic acids such as FA and SA. INH
contains multiple hydrogen bonding sites (pyridine and
hydrazide), however, only the pyridine group can be effectively
used to design the cocrystals which form acid–pyridine
heterosynthons in the cocrystals. On the other hand, the
hydrazide group has been shown to form different hydrogen
bonds depending on the functional groups present on the
coformers. In the present study, while it participates in a
hydrazide–hydrazide homosynthon in Form I of the INH?HBA
hydrate, it forms a number of different synthons in other
crystal structures. Metastable polymorphs of INH?HBA hydrate
and INH?FA were found to convert to the stable polymorphs in
slurry experiments. Anhydrous INH?HBA cocrystal was found
to convert to its hydrate form in slurry and at accelerated
conditions. Ternary cocrystals are stable in slurry and at
accelerated test conditions. Solubility and dissolution experi-
ments revealed that the solubility of INH?NA?SA cocrystal is
higher than the solubility of INH and its dissolution rate is
comparable to the dissolution rate of INH. All other cocrystals
dissolve slower and their equilibrium solubility is lower than
the solubility of INH.
Grinding experiments
Grinding was performed using a Retsch Mixer Mill model
MM301 with 10 mL stainless steel grinding jars with one 7 mm
stainless steel grinding ball at a rate of 20 Hz for 30 min.
Experiments were carried out with 200 mg (0.567 mmol) of
INH and an equivalent stoichiometric amount of coformers.
SDG experiments were conducted by adding 2 drops of water
or methanol prior to the grinding.
Single crystal X-ray diffraction
A good quality single crystal grown from the solution crystal-
lization was chosen under a Leica microscope and placed on a
fibre needle which was then mounted on to the goniometer of
the X-ray diffractometer. X-ray reflections were collected on a
Rigaku Saturn CCD area detector with graphite monochro-
mated Mo Ka radiation (l = 0.71073 Å). Data were collected
and processed using CrystalClear (Rigaku) software. Structure
was solved by direct methods and SHELX-TL19 was used for
structure solution and least-squares refinement. The non-
While a number of cocrystals that demonstrate improve-
ment in solubility/dissolution rate of APIs have been
reported,7,17 cocrystals that show lower solubility than the
native drug have also been reported recently.18 For example,
Higuchi and Pitman reported 1 : 1 and 1 : 2 cocrystals of
caffeine with gentisic acid, which were claimed to be useful for
developing slow releasing tablets such as chewable tablets.18c
The INH cocrystals of this study belong to this category of
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hydrogen atoms were refined anisotropically. H atoms bonded
to N and O atoms were located in a difference map and
allowed to ride on their parent atoms in the refinement cycles,
with the exception that the H atoms bonded to O of the
carboxyl group in INH?FA polymorphs and INH?NA?FA were
constrained using DFIX command in SHELX because they
were found to be long in the normal refinement cycles. All
other H atoms were positioned geometrically and refined
using a riding model. All O–H, N–H and C–H distances are
neutron normalized to 0.983, 1.009 and 1.083 Å, respectively.
X-Seed and Mercury 3.0 were used to prepare the packing
diagrams. CCDC 935247–935252 contains the supplementary
Solubility and dissolution experiments
INH concentration from the solutions obtained in solubility
and dissolution experiments was measured by HPLC (Agilent
1100 series). Individual methods were developed to make sure
that the cocrystal components were observed at different
retention time. In all the experiments, the HPLC instrument
was equipped with an Agilent Eclipse XDB-C18 column (4.6 6
250 mm, 8 nm pore size, 5 mm). An injection volume of 10 mL
was used with an eluant flow rate of 1 mL min21. Detection
wavelength in the UV-visible range was set at 262 nm. The
samples were eluted with a mobile phase containing a mixture
of methanol and ultrapure water in a ratio (v/v) of 20 : 80 for
INH?FA and INH?NA?FA cocrystals, 60 : 40 for INH?HBA
cocrystal, and 5 : 95 for INH?NA?SA cocrystal. A table listing
the observed retention times for each of the cocrystal
crystallographic data for this paper.
3
Powder X-ray diffraction (PXRD)
The powder materials were identified by a D8 Advance powder
X-ray diffractometer (Bruker AXS GmbH, Germany) with Cu Ka
radiation (l = 1.54056 Å). The voltage and current applied were
35 kV and 40 mA, respectively. Samples were placed on the
sample holder which has 1 mm thickness and 1.5 cm
diameter. The sample was scanned within the scan range of
components was provided as ESI. Prior to the solubility and
3
dissolution experiments, a calibration plot for both INH and
cocrystals was constructed at a concentration range of 0.05–50
mg mL21 and with R2 of 0.99 (n = 3).
Equilibrium solubility values were determined using the
shake-flask method by stirring an excess amount of each of the
sample in 5 mL of pH 7.5 buffer at 37 uC for 24 h. The
solutions were filtered through a 0.2 mm syringe filter, and the
concentration of the solutions was determined using HPLC.
IDR experiments were conducted using a Varian VK7010
dissolution apparatus equipped with a VK750D heater/circu-
lator. In each experiment, approximately 500 mg of sample
was compressed to a 0.5 cm2 disk in a rotating disk intrinsic
dissolution die using a hydraulic press at a pressure of 5 ton
for 5 min. Only one side of the disk is exposed to the
dissolution medium and surface of the disk is constant
throughout the experiment. The intrinsic attachment was
placed in a jar of 900 mL of phosphate buffer (pH 7.5)
preheated at 37 uC and stirring at 50 rpm. At regular time
intervals, 2 mL of the samples were withdrawn manually. The
collected samples were filtered through 0.2 mm nylon filters,
and assayed for INH concentration using HPLC from the
respective calibration plots.
2h = 5u to 50u continuous scan, with a scan rate of 2u min21
.
The PXRD patterns were plotted using OriginPro 7.5.
Thermal analysis
DSC was performed with a Perkin Elmer Diamond DSC with an
Autosampler. Crystals taken from the mother liquor were
blotted dry with a filter paper and manually ground. The
samples were placed in crimped but vented aluminum sample
pans. The sample size was 2–5 mg and the temperature range
was typically 25–200 uC at a heating rate of 5 uC min21. The
samples were purged with a stream of flowing nitrogen (20 mL
min21). The calculated enthalpy values are the averages of
three independent experiments. The instrument was cali-
brated using indium as the reference material.
TGA was performed on a TA instruments TGA Q500
thermogravimetric analyzer. Approximately 15 mg of the
sample was added to an alumina crucible. The samples were
heated over the temperature range of 25 to 300 uC at a constant
heating rate of 5 uC min21. The samples were purged with a
stream of flowing nitrogen throughout the experiment at 40
Stress stability experiments
Stability of all the cocrystals (except the Form II of INH?FA and
Form I of INH?HBA hydrate) was investigated over a 13 week
period at 40 uC and 75% RH. Sample holders containing
approximately 100 mg of the cocrystal powder were stored at
this test condition and the stability of the cocrystal was
periodically monitored by determining the sample identity by
PXRD.
mL min21
.
Hot-stage microscopy (HSM)
Thermomicroscopic investigations were performed with an
optical polarizing microscope (Olympus, BX51) equipped with
a Linkam hot-stage THMS 600 connected to a TMS 94
temperature controller and a LNP 94/2 liquid nitrogen pump
(Linkam Scientific Instruments Ltd., Tadworth, Surrey, UK).
The microscopic images were recorded with a CCD camera
attached to the Olympus BX-51 microscope (Olympus Optical
GmbH, Vienna, A) at every 12 s time interval using Soft
Imaging System’s Analysis image capture software. Samples
were heated over a temperature range of 30–200 uC at a
constant heating rate of 5 uC min21. The hot-stage was
calibrated using USP melting point standards.
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