Co-crystals of active pharmaceutical ingredients-acetazolamide

Article abstract of DOI:10.1021/cg1005693

A total of 20 co-crystal formers have been combined with acetazolamide (ACZ) via solvent drop grinding in acetone, acetonitrile, and water. The screening experiments provided co-crystals with 4-hydroxybenzoic acid (4HBA) and nicotinamide (NA) (ACZ-4HBA and ACZ-NA-H₂O), which were identified by X-ray powder diffraction (XRPD) and further characterized by IR spectroscopy and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA). Both co-crystals could be prepared also by neat grinding (NG) and reaction crystallization (RC). Single-crystal X-ray diffraction analyses allowed for an examination of the dominant hydrogen bonding patterns in the co-crystals, showing that 4HBA binds to the thiadiazole acetamide fragment of ACZ via C(N)NH...HOOC and O-H...N interactions, while NA is linked through N-H...N and N-H...O contacts. In ACZ-NA-H₂O, the components are connected further by crystal lattice water molecules through N-H...O_w and O_w-H...N hydrogen bonds. Phase stability assays in water at physiological pH values ranging from 1.2 to 6.8 showed that for ACZ-4HBA the crystalline solid phase did not transform to ACZ within 72 h, while for ACZ-NA-H₂O a gradual transformation occurred. Thermal treatment of ACZ-NA-H₂O and reaction crystallization experiments in methanol and anhydrous ethanol gave the dehydrated crystalline phase ACZ-NA, which is stable at ambient conditions for at least four months but transforms to the corresponding co-crystal monohydrate when stirred with deionized water.

Full text of DOI:10.1021/cg1005693

DOI: 10.1021/cg1005693
Co-Crystals of Active Pharmaceutical Ingredients - Acetazolamide
2010, Vol. 10
3732–3742
‡
Jenniffer I. Arenas-Garcıa,† Dea Herrera-Ruiz,*,† Karina Mondragon-Vasquez,
ꢀ
ꢀ
‡
Hugo Morales-Rojas, and Herbert Hopfl*
,‡
€
†
ꢀ
Facultad de Farmacia, Universidad Autonoma del Estado de Morelos, Av. Universidad 1001,
C.P. 62209 Cuernavaca, Mexico, and Centro de Investigaciones Quımicas, Universidad Autonoma del
‡
ꢀ
´
ꢀ
Estado de Morelos, Av. Universidad 1001, C.P. 62209 Cuernavaca, Meꢀxico
Received April 28, 2010; Revised Manuscript Received June 13, 2010
ABSTRACT: A total of 20 co-crystal formers have been combined with acetazolamide (ACZ) via solvent drop grinding in
acetone, acetonitrile, and water. The screening experiments provided co-crystals with 4-hydroxybenzoic acid (4HBA) and
nicotinamide (NA) (ACZ-4HBA and ACZ-NA-H2O), which were identified by X-ray powder diffraction (XRPD) and further
characterized by IR spectroscopy and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA). Both
co-crystals could be prepared also by neat grinding (NG) and reaction crystallization (RC). Single-crystal X-ray diffraction
analyses allowed for an examination of the dominant hydrogen bonding patterns in the co-crystals, showing that 4HBA binds to
the thiadiazole acetamide fragment of ACZ via C(N)NH HOOC and O-H N interactions, while NA is linked through
3 3 3 3 3 3
N-H N and N-H O contacts. In ACZ-NA-H2O, the components are connected further by crystal lattice water molecules
3 3 3 3 3 3
through N-H Ow and Ow-H N hydrogen bonds. Phase stability assays in water at physiological pH values ranging from
3 3 3
3 3 3
1.2 to 6.8 showed that for ACZ-4HBA the crystalline solid phase did not transform to ACZ within 72 h, while for ACZ-NA-H2O
a gradual transformation occurred. Thermal treatment of ACZ-NA-H2O and reaction crystallization experiments in methanol
and anhydrous ethanol gave the dehydrated crystalline phase ACZ-NA, which is stable at ambient conditions for at least four
months but transforms to the corresponding co-crystal monohydrate when stirred with deionized water.
1. Introduction
ACZ are known (forms A and B), form A being the more stable
solid phase at room temperature.9,10
Most medicaments contain active pharmaceutical ingredi-
ents (APIs) in the solid form. For commercial purposes,
crystalline forms are strongly preferred because they tend to
be more stable, reproducible, and amenable to purification
than other types of solids.1
The arrangement of molecules in the crystalline state affects
physical and chemical properties on the macroscopic level, and
variations in the structural organization can influence the effi-
cacy and bioavailability of the drug.1,2 Most of the strategies to
improve the biopharmaceutical properties of a drug, such as
solubility, dissolution rate, chemical stability, and hygroscopi-
city, focus on the preparation of amorphous solids, polymorphs,
solvates, salts,1,2 and, more recently, co-crystals.1,3,4 According
to Zawarotko’s definition, a co-crystal is a compound made
from reagents that are solids at ambient temperature3a and can
be designed by crystal engineering5 with the intention to improve
the solid-state properties of an active pharmaceutical ingredient
(API) without affecting its intrinsic structure. Co-crystals are
endowed with particular scientific1,3,4 and regulatory advan-
tages6 which confer them great opportunities and challenges.
Acetazolamide (ACZ), 5-acetamido-1,3,4-thiadiazole-2-sulfo-
namide, is an inhibitor of carbonic anhydrase and is used mainly
for the treatment of glaucoma.7 It has been considered also as an
antiepileptic and diuretic agent, for treating acute high altitude
sickness, and most recently has been evaluated as a remedy
against respiratory diseases and to prevent adverse effects of
drugs in the treatment of influenza.8 ACZ has a pKa value of 7.2,
and so far, two structurally characterized polymorphic forms of
By virtue of the fact that acetazolamide has low solubility
(0.72 mg/mL in water at 25 °C) and permeability, the discovery
and identification of new solid forms of ACZ is relevant to
improve its physical and/or chemical properties.8a,10 Hence, in
this work we report on new solid-state phases of acetazolamide
in the form of co-crystals that potentially present advantages
over the medicament in its actual commercially available pre-
sentations. Additionally, four different methods of co-crystal
preparation have been examined and preliminary studies have
been carried out concerning thermal stability and co-crystal
phase stability in the presence of water.
2. Experimental Section
Materials. Acetazolamide (form A), co-crystal formers, and
solvents were commercially available and were used as received
without further purification.
*To whom correspondence should be addressed. (D.H.-R.) E-mail:
dherrera@uaem.mx. (H.H.) Fax: (þ52) 77-73-29-79-97. E-mail: hhopfl@
ciq.uaem.mx.
r
pubs.acs.org/crystal
Published on Web 06/29/2010
2010 American Chemical Society

Article
Co-Crystal Screening of Acetazolamide. Solvent drop grinding
Crystal Growth & Design, Vol. 10, No. 8, 2010 3733
Scheme 1. Homo- and Heterodimeric Synthons Formed
between Carboxylic Acids, Carboxamides, Carboxamidines,
and Sulfonamides
(SDG) experiments were performed by combining equimolar ratios
of ACZ and the corresponding co-crystal former. These mixtures
were then placed into stainless steel grinding jars (1.5 mL), and one
drop of acetone, acetonitrile, or water was added to the compound
mixture before starting mechanical grinding in a Retsch MM400
mixer mill for 30 min at 25 Hz, using one stainless steel grinding ball.
The solid phases were then characterized by X-ray powder diffrac-
tion (XRPD).
Neat Grinding and Reaction Crystallization Experiments. Neat
grinding (NG) experiments were performed with the same equip-
ment in an analogous manner, but without solvent and enhancing
the duration of the mechanical grinding to 60 min. For the reac-
tion crystallization (RC) experiment with 4-hydroxybenzoic acid
(4-HBA) as co-crystal former, a saturated solution of 4-HBA in
THF was heated to 50 °C, whereupon small quantities of ACZ
were added until a white powder was observed. For the preparation
of ACZ-NA-H2O, nicotinamide (NA) was dissolved in water or
solvent mixtures of acetonitrile, acetone, or methanol with water (in
each case, 75/25, 50/50, and 25/75 vv) to prepare a saturated
solution, which was heated to 90 °C. Then, small quantities of
ACZ were added until a white powder was observed. When using
methanol or anhydrous ethanol as solvent, water-free ACZ-NA was
obtained. In all cases, after precipitation was initiated the solutions
were cooled down slowly to room temperature and stirred for 8 h.
The precipitates formed were filtered and characterized by XRPD.
Single-Crystal Growth. Co-crystals were grown also by slow
evaporation experiments.
Acetazolamide-4-Hydroxybenzoic Acid 1:1 (ACZ-4HBA). 1:1, 1:3,
and 1:5 stoichiometric ratios of the starting materials were dissolved
in hot acetonitrile. A mixture of single crystals of ACZ and ACZ-
4HBA co-crystals were obtained after three days by slow solvent
evaporation at room temperature from the 1:3 mixture. The 1:1 and
1:5 mixtures provided only crystals of ACZ.
for Lorentz and polarization effects. Structure solution, refinement,
and data output were carried out with the SHELXTL-NT program
package.11c,d Non-hydrogen atoms were refined anisotropically.
C-H hydrogen atoms were placed in geometrically calculated
positions using a riding model. O-H and N-H hydrogen atoms were
localized by difference Fourier maps and refined fixing the bond
Acetazolamide-Nicotinamide-H2O 1:1:1 (ACZ-NA-H2O). 1:0.5,
1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, and 1:10 stoichiometric ratios of ACZ
and nicotinamide (NA) were employed to crystallize the sample
from hot water in the presence of small quantities of the compound
previously obtained by grinding (seeding). Large single-crystals of
ACZ-NA-H2O formed after three months by slow solvent evapora-
tion at room temperature from the 1:4 mixture.
˚
lengths to 0.84 and 0.86 A, respectively; the corresponding isotropic
temperature factors have been fixed to a value 1.5 times that of the
corresponding oxygen/nitrogen atoms. Figures were created with
SHELXTL-NT.11c,d Hydrogen-bonding interactions in the crystal
lattice were calculated with the WINGX program package.12 Crystal-
lographic data for the five crystal structures were deposited with the
Cambridge Crystallographic Data Centre as supplementary publica-
tions no. CCDC-773415-773419. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: (þ44) 1223-336-033; e-mail: deposit@ccdc.cam.
ac.uk, www: http://www.ccdc.cam.ac.uk).
Nicotinamide-4-Hydroxybenzoic Acid 1:1 (NA-4HBA). A 1:1
mixture of nicotinamide and 4-hydroxybenzoic acid was dissolved
in acetone. Single crystals were obtained in pure form by slow
evaporation of the solution.
Co-Crystal Phase Stability Tests. 100 μL of deionized water were
added to 25 mg of co-crystal. After the suspension was stirred for 16
or 72 h, the resulting solid was filtered under a vacuum and
characterized by XRPD. In a similar manner, experiments using
buffer solutions adjusted to pH values of 1.2 (hydrochloric acid
solution, 0.034 M), 4.5 (phosphate buffer solution, 0.1 M), and 6.8
(phosphate buffer solution, 0.05 M) were accomplished.
Instrumental. IR spectra were recorded on a Bruker Vector 22 FT
spectrophotometer and measured in the range of 4000-400 cm-1
using the KBr pellet technique. Differential scanning calorimetry
(DSC) and thermogravimetric analyses (TGA) were accomplished
with a TA SDT Q600 instrument. Approximately 3 mg of each solid
sample were placed in alumina crucibles and analyzed in the
temperature range of 50-400 °C with a 10 °C/min heating rate,
using a current of 50 mL/min of nitrogen as inert gas purge.
X-ray Diffraction Analysis. XRPD analyses were carried out in
the transmission mode on a BRUKER D8-ADVANCE diffract-
3. Results and Discussion
Screening Experiments. In the crystal structures of both
polymorphs reported so far for ACZ, the molecules are linked
through double-bridged homodimeric C(N)NH HN(N)C
3 3 3
synthons (motif C in Scheme 1) and N-H O interactions
3 3 3
between the sulfonamide groups. However, only one of the
two polymorphs (form A) contains the homodimeric sulfo-
namide sulfonamide synthon D (vide infra).9a,c,d Because
3 3 3
˚
of the structural relationship of these functions with carbox-
amide and carboxylic acid homodimers (motifs A and B), we
have chosen mainly carboxylic acids and carboxamides as co-
crystal formers for the experiments performed herein with the
hypothesis that the formation of dimeric heterosynthons E-H
(Scheme 1) might induce co-crystallization. Furthermore,
many of these derivatives are members of the GRAS list13
and have been employed previously for co-crystallization
experiments with APIs.3,4 Co-crystals of APIs with nicotina-
mide and 4-hydroxybenzoic acid as co-crystal formers have
ometer equipped with a LynxEye detector (λCu-KR1 = 1.5406 A,
monochromator: germanium). Data were collected at room tem-
perature in the range of 2θ = 5-40 or 5-50° (step size 0.011°, step
times 0.30 and 10 s). Single-crystal X-ray diffraction studies were
performed on a Bruker-APEX diffractometer with a CCD area
˚
detector (λΜoKR = 0.71073 A, monochromator: graphite). Frames
were collected at T=100 K (compounds ACZ-4HBA, ACZ-NA-
H2O, and NA-4HBA) and T = 293 K (compounds ACZ-4HBA and
ACZ-NA-H2O) via ω/φ-rotation at 10 s per frame (SMART).11a
The measured intensities were reduced to F2 and corrected for
absorption with SADABS (SAINT-NT).11b Corrections were made

3734 Crystal Growth & Design, Vol. 10, No. 8, 2010
Table 1. Results of the Screening Experiments for the Formation of Co-Crystals with Acetazolamide
Arenas-Garcıa et al.
a1:2 and 2:1 grinding experiments showed that only the 1:1 co-crystal is formed under these conditions, since additionally only peaks for the unreacted
reagent in excess were observed.
been reported for caffeine,14 carbamazepine,15 celecoxib,16
ethyl paraben,17 ibuprofen,15e,18 piracetam,3c piroxicam,15a,19
and theophylline.20
The formation of 1:1 co-crystals was confirmed also by
comparison with the XRPD patterns resulting from 1:2 and
2:1 grinding experiments, showing for all co-crystals de-
scribed herein in the first case peaks of unreacted co-crystal
former and in the second case peaks of unreacted ACZ. The
co-crystals were further characterized by DSC-TGA, IR
spectroscopy, and single-crystal X-ray diffraction analysis,
showing that 4HBA generated pharmaceutical 1:1 co-crys-
tals, while NA gave a 1:1:1 co-crystal hydrate. The results of
the screening experiments are summarized in Table 1.
XRPD Analysis. A comparison of the XRPD patterns
given for ACZ, 4HBA, and the solid obtainedfrom the solvent
drop grinding (SDG) experiment in acetonitrile indicates the
formationofasolid phasedifferentfromthe startingmaterials
(Figure 1a-d). The same phase was obtained using acetone
A total of 20 co-crystal formers were employed in the
screening experiments using the solvent drop grinding
(SDG) method.21 For this purpose, three solvents of differ-
ent polarity were chosen: acetone, acetonitrile, and water.
Novel solid phases were identified by XRPD, and to dis-
criminate co-crystals from polymorphs or solvates, parallel
grinding experiments were performed using only ACZ or the
corresponding co-crystal former with the respective solvent.
This procedure allowed us to establish that the solid phases
obtained with 4-hydroxybenzamide and isonicotinamide
contained only the monohydrate of the corresponding
co-crystal former22 and ACZ.

Article
Crystal Growth & Design, Vol. 10, No. 8, 2010 3735
Figure 1. XRPD patterns of (a) ACZ form A, (b) ACZ form B, (c)
4HBA, (d) co-crystals ACZ-4HBA obtained by SDG with acetoni-
trile, (e) co-crystals ACZ-4HBA obtained by NG, and (f) co-crystals
ACZ-4HBA obtained by RC in THF. (g) Pattern calculated from
the single-crystal X-ray diffraction analysis.
Figure 3. Infrared spectra of (a) ACZ, (b) 4HBA, and (c) ACZ-
4HBA.
Figure 4. TGA graphs of (a) ACZ, (b) ACZ-4HBA, (c) ACZ-NA-
H2O, and (d) ACZ-NA.
Figure 2. XRPD patterns of (a) ACZ form A, (b) ACZ form B,
(c) NA, (d) co-crystals ACZ-NA-H2O obtained by SDG with H2O,
(e) co-crystals ACZ-NA-H2O obtained by NG, and (f) co-crystals
ACZ-NA-H2O obtained by RC in a solvent mixture of acetonitrile
and water (50/50 vv). (g) Pattern calculated from the single-crystal
X-ray diffraction analysis.
atmosphere (Figure 2). For a successful performance of the RC
method, in this case a hot solvent mixture containing a
significant amount of water was required, that is, 75/25, 50/
50, or 25/75 vv mixtures of water with acetonitrile, acetone, or
methanol. The product also can be prepared from hot water
alone (90 °C); however, because of the low solubility of ACZ in
this solvent, only very small quantities were obtained.
IR Spectroscopy. IR spectroscopy is a valuable supple-
mentary tool for the identification of new solid forms. Figure 3
shows the IR spectra of ACZ,9b,e co-crystal former 4HBA, and
co-crystal ACZ-4HBA. The corresponding IR spectra for ACZ-
NA-H2O are shown in the Supporting Information (Figure S1).
A listing of the most characteristic IR bands of all co-crystals
examined herein is given in Table 2, together with the data for
ACZ and the corresponding co-crystal formers.
and water as solvents. In view of the formation of a new phase,
additionally neat grinding (NG)3f and reaction crystallization
(RC) experiments3f,15b were carried out, showing that the
same phase also can be formed in the absence of solvent and
via reaction precipitation in THF (Figure 1e,f). Comparison
of the corresponding diffraction patterns with that calculated
from the single-crystal data of ACZ-4HBA (Figure 1g) show
further that the crystalline compound obtained by slow
solvent evaporation is identical to the products formed by
the above-mentioned methods.
With NA a new solid phase was observed only for the SDG
experiment using water, thus indicating that a hydrate had
formed (ACZ-NA-H2O), which was further evidenced by TGA
and single-crystal X-ray diffraction analysis. Interestingly, the
co-crystal also could be prepared by the NG method, indi-
cating that the sample mixture incorporated water from the
For both co-crystals the resulting spectra are different from
superimposed spectra of the starting materials, and broad bands
in the region of 2500-3500 cm-1 are observed, which are typical
for crystal structures with extended hydrogen bonding interac-
tions.23 Furthermore, the presence of ACZ in the solid phases of

3736 Crystal Growth & Design, Vol. 10, No. 8, 2010
Table 2. Relevant Bands in the IR Spectra of ACZ, 4HBA, NA, and the Co-Crystals Examined Herein
Arenas-Garcıa et al.
ACZ
4HBA
NA
ACZ-4HBA
ACZ- NA-H2O
ACZ- NA
NA-4HBA
ν CdO
ν OH, N-H
1680
3302
3182
1677
3391
1679
3368
3162
1686
3303
3173
1680
3450
3305
3242
1562a
1609b
1355
1172
1681
3445
3161
1672
3436
3359
3194
ν N-HII
1551a
1567a
1553a
1619b
1594b
ν SO2NH2
1368
1177
1371
1174
1361
1167
a ν N-HII for ACZ. b ν N-HII for NA.
Table 3. DSC-TG Analyses of ACZ, 4HBA, NA, Co-Crystals
TGA mass
loss before
mp [°C] melting [%] evap. [°C]
TGA
solvent
compound
ACZ
4HBA
mp (rep.) [°C]a
258-259 (dec.)b 270 (dec.)b
0
0
0
0
4.8
0
213-217
128-131
212
131
NA
ACZ-4HBA
ACZ-NA-H2O
ACZ-NA
NA-4HBA
235 (dec.)
154
147
75
185 (dec.)
0
a Reported by Sigma-Aldrich. b The melting point of ACZ depends
among others on the temperature of initial heating and the heating rate,
mainly because ACZ starts to decompose above 255 °C. The reported
melting points of ACZ vary from 250 to 270 °C.9c
Figure 6. XRPD patterns of (a) ACZ and (b) co-crystal ACZ-NA-
H2O prepared by SDG with water, and after co-crystal phase stabi-
lity tests (c) in water for 16 h, (d) in water for 72 h and for 72 h: (e) at
pH 1.2, (f) at pH 4.5, (g) at pH 6.8.
Figure 7. Crystals of acetazolamide (ACZ) and the corresponding
co-crystal with 4-hydroxybenzoic acid (ACZ-4HBA) can be distin-
guished by their different shapes.
co-crystal rather than a salt was confirmed also by subse-
quent single-crystal X-ray diffraction analysis (vide infra).
DSC-TG Analysis. The TGA and DSC curves of ACZ and
co-crystals ACZ-4HBA and ACZ-NA-H2O are shown in
Figures 4a-c and S2-S4. Table 3 summarizes the most rele-
vant data of the DSC-TG analysis. The thermal profile of
ACZ-4HBA reveals an endothermic peak at 235 °C which can
be associated with starting decomposition. This value is
different from those observed in the DSC-TGA curves of
acetazolamide (270 °C) and 4-hydroxybenzoic acid (212 °C),
confirming the formation of a new solid phase. The thermal
curve of ACZ-NA-H2O indicates a mass loss of 4.8% starting
at 75 °C, which is in accordance with the presence of solvent
(water) in the sample (calc.: 4.97%). Fusion of the residual
solid occurs at 154 °C, a temperature lying between the melting
points of ACZ (270 °C) and NA (131 °C). After fusion, the
compound starts to decompose.
Figure 5. XRPD patterns of (a) ACZ form A, (b) ACZ form B,
(c) NA, (d) co-crystals ACZ-NA-H2O obtained by SDG with H2O,
(e) co-crystals ACZ-NA obtained after thermal treatment (75 °C for
a period of 30 min), (f) co-crystals ACZ-NA obtained by RC in
methanol, (g) co-crystals ACZ-NA after storage at ambient condi-
tions (capped vial) for four months, and (h) co-crystals ACZ-NA
after exposition to water for 16 h.
ACZ-4HBA and ACZ-NA-H2O can be deduced from two
characteristic bands for vibrations of the sulfonamide group in
the region of 1355-1371 and 1167-1177 cm-1 (Table 2).23
The IR spectra allow the differentiation also between salts
and co-crystals, which differ by the location of the proton
between the acid and the base.20,24 The infrared spectrum of
4HBA shows a CdO stretching band at 1677 cm-1. Since
there was no significant shift to lower wavenumbers for
ACZ-4HBA, a proton transfer from the coformer to ACZ
did not occur (Figure 3). Arylcarboxylate salts generally
show a strong band for the asymmetric νCOO vibration
Formation of Co-Crystal ACZ-NA. The TGA experiment of
ACZ-NA-H2O suggests that the crystal lattice water molecules
in the range of 1610-1550 cm-1 23
That ACZ-4HBA is a
.

Article
Crystal Growth & Design, Vol. 10, No. 8, 2010 3737
Table 4. Crystallographic Data for Compounds ACZ-4HBA, ACZ-NA-H2O, and NA-4HBA
ACZ-4HBA (100 K) ACZ-4HBA (293 K) ACZ-NA-H2O (100 K) ACZ-NA-H2O (293 K)
C4H6N4O3S2 C7H6O3 C4H6N4O3S2 C7H6O3 C4H6N4O3S2 C6H6N2O H2O C4H6N4O3S2 C6H6N2O H2O C6H6N2O C7H6O3
crystal dataa
formula
NA-4HBA (100 K)
3
3
3
3
3
3
3
MW (g mol-1
space group
temp (K)
)
360.37
P21/c
360.37
P21/c
362.39
P1
100(2)
362.39
P1h
293(2)
260.25
C2/c
100(2)
30.839(5)
7.2117(11)
11.1457(17)
90
107.561(2)
90
2363.3(6)
8
0.110
1.463
0.051
0.116
100(2)
9.8604(11)
17.317(2)
8.6148(10)
90
99.901(2)
90
1449.1(3)
4
0.406
293(2)
10.0472(15)
17.417(3)
8.6623(13)
90
100.733(3)
90
1489.3(4)
4
0.395
˚
a (A)
8.1739(13)
9.8875(16)
10.3940(17)
66.946(2)
84.672(3)
77.519(2)
754.7(2)
2
8.3077(14)
9.9633(17)
10.4596(18)
66.601(2)
83.567(3)
76.787(3)
773.3(2)
2
˚
b (A)
˚
c (A)
R (°)
β (°)
γ (°)
3
˚
V (A )
Z
μ (mm-1
)
0.389
1.595
0.380
1.556
Fcalcd (g cm-3
)
1.652
0.040
0.092
1.607
0.041
0.102
Rb,c
Rw
0.035
0.093
0.038
0.100
d,e
b
c
d
e
aλMoKR = 0.71073 A. Fo > 4σ(Fo). R = Σ||Fo| - |Fc||/Σ|Fo|. All data. Rw = [Σw(Fo2 - Fc2)2/Σw(Fo2)2]1/2
.
˚
Scheme 2. Hydrogen Bonding Motifs Identified in the Crystal Structures of Co-Crystals ACZ-4HBA (Motifs I-IV), ACZ-NA-H2O
(Motifs V-VIII), and NA-4HBA (Motifs IX-X)
canbeeliminatedthroughthermal treatment. Indeed, after heat-
ing the co-crystal monohydrate to either 75 °C for a period of
30 min or 100 °C for 10 min, a new solid phase was obtained as
shown by a comparison of the XRPD patterns (Figure 5). The
same crystalline phase could be obtained also with the RC
method using methanol or anhydrous ethanol as solvent,
whereas from THF, acetonitrile, and acetone only ACZ pre-
cipitated. That this new phase is a co-crystal can be seen from a
comparison of the IR data given in Table 2 and Figure S5, which
shows the presence of both ACZ and NA. The TGA graph
in Figure 4d shows that the co-crystal is water-free, so that
the composition ACZ-NA can be proposed, which is further

3738 Crystal Growth & Design, Vol. 10, No. 8, 2010
Arenas-Garcıa et al.
Figure 8. (a, b) In the crystal lattice of ACZ-4HBA alternating undulated layers of ACZ (layer A) and 4HBA molecules (layer B) are identified,
which are (c) linked between each other through motifs I and III to give a 3D hydrogen bonded network. Symmetry operator: (i) 2 - x, -y,
1 - z. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii.
supported by the integrated 1H NMR spectrum of the sample
prepared by the RC method (Figure S6). A comparison of
the XRPD patterns in Figure 5f,g shows that this new phase is
stable in a capped vial at ambient conditions at least for four
months; however, when stirred in water, the sample rehydrates
(Figure 5h).
ground mechanically in the presence of 1 drop of acetonitrile
and water, respectively. In both cases a new solid phase was
identified, which resulted in co-crystal NA-4HBA (1:1). This
phase has been prepared also by SDG and NG in the absence of
ACZ. Since this co-crystal has not been reported earlier, it has
been characterized by XRPD (Figure S8), IR spectroscopy
(Figure S9, Table 2), DSC-TGA (Figure S10, Table 3), and
single-crystal X-ray diffraction analysis. As for ACZ-4HBA, the
spectroscopic and structural data prove that also this phase is a
true solvent-free co-crystal and not a salt (vide infra).
Single-Crystal Diffraction Analysis. Single co-crystals of
ACZ-4HBA and ACZ-NA-H2O could be grown only from
solutions containing an excess of the co-crystal former (1:3
and 1:4, respectively); however, for ACZ-4HBA only crystal
mixtures of ACZ and the corresponding co-crystal were
obtained, which could be separated manually due to their
different shapes (Figure 7). This phenomenon is common for
solutions containing components with different solubilities
and has been explained by the corresponding phase solubility
diagram. For these cases, typically a rotation of the relatively
small region, in which the co-crystal is the stable phase,
toward the axis of the co-crystal former is found.15g,h,25
On the contrary, the generation of the NA-4HBA co-crystals
could be performed straightforward from the 1:1 mixture of the
components in acetone and they were isolated in pure form.
The most relevant crystallographic data of ACZ-4HBA,
ACZ-NA-H2O, and NA-4HBA are listed in Table 4.
Co-crystals with ACZ have been collected both at room and
at low temperature (293 and 100 K) in order to verify if a phase-
Co-Crystal Phase Stability Assays. In order to evaluate the
solid-phase stability of co-crystals ACZ-4HBA and ACZ-
NA-H2O, samples of each phase were exposed to water at
different physiological pH values, in order to examine if they
transform to ACZ. For this purpose 25 mg samples of the
co-crystals were stirred for 16 and 72 h in 100 μL of deionized
water, and buffer solutions were adjusted to physiological
pH values of 1.2, 4.5, and 6.8. Comparison of the XRPD
patterns given in Figures S7 and 6 with the previously
established patterns of the co-crystal (Figures 1 and 2) show
that only ACZ-4HBA is stable, at least for 72 h, over the
whole pH range examined. The XRPD pattern of ACZ-NA-
H2O recorded after exposition to water for 16 h indicated the
presence of small quantities of ACZ (Figure 6c). When the
experiment was prolonged to 72 h the transformation to
ACZ increased significantly. Furthermore, the degree of
transformation of ACZ-NA-H2O to ACZ was found to be
pH-dependent (Figure 6d-g). As already mentioned above,
the dehydrated sample of this co-crystal, ACZ-NA, is comple-
tely rehydrated when stirred in deionized water (Figure 5h).
Competition Experiment for ACZ. In an attempt to carry
out a competition experiment between 4HBA and NA for
ACZ, a 1:1:1 stoichiometric mixture of these reagents was

Article
Crystal Growth & Design, Vol. 10, No. 8, 2010 3739
former, but interestingly, there are no direct hydrogen bonding
interactions between the 4HBA units, which in neat 4HBA are
linked through homodimeric COOH HOOC and OH
3 3 3
3 3 3
OH interactions.26 This is because both the carboxyl and the
hydroxyl functions interact through O-H NandN-H
O
3 3 3
3 3 3
hydrogen bonds with the thiadiazole and acetamido groups
of ACZ molecules in neighboring A-layers (see motifs I, III,
and IV in Scheme 2), thus generating a 3D hydrogen bonded
network (Table S1, Figure 8). The double-bridged heterodimeric
synthon C(N)NH HOOC (III) substitutes the dominating
3 3 3
homodimeric C(N)NH HN(N)C synthon in forms A and B
3 3 3
of neat ACZ.9a,c,d The formation of the heterodimeric C(N)-
NH HOOC synthon instead of the C(N)NH HN(N)C
3 3 3
3 3 3
homodimeric motif has been observed also for a series of co-
crystals derived from sulfathiazole and related sulfadrugs.3d,27
Motifs I and III resemble two well-known synthons from
traditional crystal engineering. The O-H N motif I is
3 3 3
typically found in co-crystals formed between pyridine and
alcohols,28 and motif III is structurally related to the hetero-
synthons formed between 2-aminopyridine derivatives and
carboxylic acids.29 It is well-known that the formation of
double-bridged heterosynthons is frequently preferred over
the formation of the corresponding homosynthons.28 There-
fore, it is not surprising to find that 4HBA is an ideal
co-crystal former for ACZ.
The X-ray structural data confirm also the observations
from the IR spectra that ACZ-4HBA is indeed a co-crystal
and not a salt. In deprotonated benzoic acids with delocalized
carboxylate functions, the C-O distance in the carboxylate
˚
group is approximately 1.25 A; otherwise, the average C-O
15j,24
˚
and CdO distances are 1.31 A and 1.21 A, respectively.
˚
For ACZ-4HBA the C-O and CdO bond lengths at T = 293
K were 1.320(3) and 1.217(3) A, respectively, confirming the
formation of a true co-crystal.
˚
Figure 9. (a) In the crystal lattice of ACZ-NA-H2O dimeric units
containing ACZ and NA molecules are linked to 2D hydrogen bonded
layers, which are (b) further connected through Nsulfonamide-H Ow
Acetazolamide-Nicotinamide Monohydrate (1:1:1). The
asymmetric unit of ACZ-NA-H2O contains one molecule of
each ACZ and NA plus one molecule of water, confirming the
1:1:1 stoichiometry of the co-crystal monohydrate (Figure 9).
Similar to the crystal structures of ACZ-form A and ACZ-
4HBA the ACZ molecules are connected to dimeric units
3 3 3
interactions to give an overall 3D hydrogen bonded network. Sym-
metry operator: (i) -x, 1 - y, 1 - z. Displacement ellipsoids are drawn
at the 50% probability level and H atoms are shown as small spheres of
arbitrary radii.
transition occurred and to visualize the extent of variations in
the hydrogen-bonding geometries due to the temperature diffe-
rence of 173 K. Interestingly, in both cases only very slight
changes in the bonding parameters could be observed, indicat-
ing that the crystal structures are quite compact. Table S1
through Nsulfonamide-H Oacetamide interactions (motif II).
3 3 3
The NA molecules form a water-expanded homodimeric motif
through N-H Ow and Ow-H Ocarboxamide hydrogen
3 3 3 3 3 3
bonds (motif VIII). The ACZ and NA dimeric units are linked
to each other through NNA-H Osulfonamide, Ow-H
shows that, as expected, the D A distances diminish upon
3 3 3
3 3 3
3 3 3
lowering the data collection temperature; however, the values
Nthiadiazole, and NACZ-acetamide-H Npyr interactions (motifs
3 3 3
˚
˚
decrease less than 0.05 A for ACZ-4HBA and 0.03 A for ACZ-
NA-H2O. The corresponding maximum variations of the DHA
bond angles are 3 and 4°, respectively. Scheme 2 summarizes
the different hydrogen bonding motifs found in ACZ-4HBA
(motifsI-IV), ACZ-NA-H2O(motifsV-VIII), andNA-4HBA
(motifs IX-X, Scheme 2).
V and VI) to give the 2D hydrogen bonded layer shown in
Figure 9a. These 2D layers are further connected through
Nsulfonamide-H Ow interactions (motif VII) to give an overall
3 3 3
3D hydrogen bonded network (Table S1, Scheme 2). The latter
interactions generate hydrogen bonded chains of ACZ dimers
linked by water molecules running parallel to the ab diagonal
(Figure 9b). This connectivity indicates that each water mole-
cule participates in a total of four hydrogen bonds, thus playing
a key role in the stabilization of this crystal structure.
Acetazolamide-4-hydroxybenzoic Acid (1:1). The asym-
metric unit of ACZ-4HBA contains one molecule of each com-
ponent confirming the 1:1 stoichiometry of the co-crystal. When
viewed along axis c, two types of undulated layers can be
identified, which are organized in the ABABAB... sequence
typical for hcp structures. The A-layers contain only ACZ
molecules, which are linked via the sulfonamide and aceta-
Nicotinamide-4-hydroxybenzoic Acid (1:1). The asym-
metric unit of NA-4HBA contains one molecule of each com-
ponent confirming the 1:1 stoichiometry of the co-crystal. The
supramolecular organization of the NA and 4HBA molecules in
the crystal structure of NA-4HBA and the resulting hydrogen
bonding pattern can be seen from Figure 10. The two compo-
mide groups through Nsulfonamide-H Oacetamide and bifur-
3 3 3
cated Nsulfonamide-H Osulfonamide interactions (see motifs II
3 3 3
and IV in Scheme 2). Motif II is also found in the crystal
lattice of acetazolamide form A, and the bonding geometries
are very similar.9a,d The B layers are formed by the co-crystal
nents form the well-known COOH amide and O-H Npyr
3 3 3 3 3 3
heterosyntons IX29,30 and X28 to give 1D infinite double chains
running along the ac diagonal (Table S1, Scheme 2). The 3D

3740 Crystal Growth & Design, Vol. 10, No. 8, 2010
Arenas-Garcıa et al.
Figure 10. The components in the crystal lattice of co-crystal NA-4HBA are connected through motifs IX and X to 1D double chains, which are
further linked through two different C-H O contacts. The supramolecular organization of the individual NA and 4HBA molecules is also
3 3 3
indicated. Symmetry operator: (i) 2 - x, y, 1.5 - z. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as
small spheres of arbitrary radii.
arrangement is further stabilized by two different C-H
O
3 3 3
˚
˚
contacts (C3-H O1 = 2.57 A; C9-H O2 = 2.67 A).
3 3 3
3 3 3
Interestingly, while motifs IX and X are both observed also in
the INA-4HBA co-crystal,31 in NA-3HBA30d and NA-2HBA18b
only the O-H Npyr motif X is found.
3 3 3
Analysis of Hydrogen Bonding Sites in Acetazolamide. In
the molecular structure of ACZ, three sites capable of
forming hydrogen bonding interactions can be identified: (i)
the acetamide group, (ii) the sulfonamide group, and (iii) the
thiadiazole ring. The acetamide and sulfonamide moieties
contain at least one hydrogen bond donor and acceptor, while
the thiadiazole ring can act only as hydrogen bond acceptor.
Overall, ACZ contains three N-H donor sites, but three
oxygen and two nitrogen acceptors, which might indicate that
co-crystal formers with an excess of donor functions are good
candidates for co-crystal formation with this API.
Figure 11. Molecular conformations of ACZ in the crystal struc-
tures of ACZ form A,9a,d ACZ form B,9c ACZ-4HBA, and ACZ-
NA-H2O. N4-S2-C1-S1 torsion angles are indicated. Note: Only
molecules with negative torsion angles are shown.
co-crystals described herein. Interestingly, due to an in-
tramolecular O S interaction in all cases the acetamide
3 3 3
function has Z-configuration,9d which explains that dou-
ble-bridged COOH amide and amide amide syn-
3 3 3
3 3 3
thons with ACZ are absent in the co-crystals examined
herein, albeit these synthons are relatively robust.29,30
Further, in all four molecular structures the acetamide
moiety is almost coplanar with the thiadiazole ring, as
indicated by the small angles formed between the mean
planes of these units (1.8-4.9° at T = 293 K). This can be
attributed to delocalization of the Namide lone pair, thus
making the whole thiadiazole acetamide fragment rela-
tively rigid. On the contrary, the sulfonamide moiety is
Figure 11 shows the molecular conformations of ACZ
found in the crystal structures of forms A and B,9a,c,d and the

Article
Crystal Growth & Design, Vol. 10, No. 8, 2010 3741
more flexible and rotational conformers arise both
from rotation around the N4-S2 and C1-S2 bonds.
This is illustrated by the N4-S2-C1-S1 torsion angles
with values ranging from -78.2 to -118.2° and þ78.2
to þ118.2° (T = 293 K).32
material is available free of charge via the Internet at http://pubs.
acs.org.
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