Modification of the Supramolecular Hydrogen-Bonding Patterns of

Article pubs.acs.org/crystal

Modification of the Supramolecular Hydrogen-Bonding Patterns of Acetazolamide in the Presence of Different Cocrystal Formers: 3:1, 2:1, 1:1, and 1:2 Cocrystals from Screening with the Structural Isomers of Hydroxybenzoic Acids, Aminobenzoic Acids, Hydroxybenzamides, Aminobenzamides, Nicotinic Acids, Nicotinamides, and 2,3-Dihydroxybenzoic Acids Jenniffer I. Arenas-García,† Dea Herrera-Ruiz,*,† Karina Mondragón-Vásquez,† Hugo Morales-Rojas,‡ and Herbert Höpf l*,‡ †

Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, C.P. 62209 Cuernavaca, México Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, C.P. 62209 Cuernavaca, México

‡

S Supporting Information *

ABSTRACT: Acetazolamide (ACZ) has been combined via liquid-assisted grinding in water with a library of cocrystal formers derived from benzoic and nicotinic acid, which provided novel cocrystals with 2-hydroxybenzamide, 2aminobenzamide, picolinamide, and 2,3-dihydroxybenzoic acid. The cocrystalline phases were identified first by XRPD analysis and then structurally characterized by IR spectroscopy and single-crystal X-ray diffraction analysis. These cocrystals and the previously reported cocrystalline phases obtained from 4-hydroxybenzoic acid and nicotinamide constitute a series of six cocrystals of varied stoichiometric ratios (3:1, 2:1, 1:1, and 1:2), which allowed for a profound analysis of the structural and chemical factors that govern their formation. The structural analysis has shown that the ACZ molecules participate in the dominant hydrogen-bonding patterns within the crystal structures: three cocrystal structures exhibit extended supramolecular aggregates of ACZ having channels, pores, or semispherical voids, in which the cocrystal formers are included as guest molecules, and can, therefore, be described as inclusion or clathrate complexes. One cocrystal can be considered as a pillared or intercalation compound, and the remaining two cocrystals are true two-component 2D or 3D networks. In addition, a variety of alternative preparative methods (liquidassisted grinding, neat grinding, reaction crystallization, solution-mediated phase transformation, and solution crystallization) have been employed, showing that four of the six cocrystals required the presence of water for successful cocrystal formation. overcome problems in formulation and manufacturing.1,2 An important advantage of pharmaceutical cocrystals is that there is a large number of reagents available for the exploration of cocrystal formation, e.g., the GRAS list approved by the FDA,6 which is particularly relevant for APIs lacking functional groups that enable salt formation. In this context, we have become interested in the preparation and examination of new solid-state phases of acetazolamide (ACZ), 5-acetamido-1,3,4-thiadiazole-2-sulfonamide. This drug is an inhibitor of carbonic anhydrase and is used for the treatment of glaucoma. Further, it has antiepileptic and diuretic properties, and has been evaluated as a remedy for respiratory diseases and the prevention of adverse effects of drugs in the

1. INTRODUCTION Variations in the structural organization of a chemical compound in the solid state influence the physical and chemical properties on the macroscopic level, which can have important implications in diverse fields such as materials and pharmaceutical sciences. In the case of active pharmaceutical ingredients (APIs), biopharmaceutical properties such as solubility, dissolution rate, chemical stability, and hygroscopicity are modified by changes of the solid-state structures. For this reason, generally different solid-state forms of a given API are explored systematically, i.e., amorphous forms, polymorphs, solvates, salts, and, more recently, cocrystals.1−4 At present, cocrystals of APIs are receiving increased attention from the scientific communities in public institutions, industry, and regulatory agencies, and diverse studies have revealed promising results concerning the improvement of the biopharmaceutical properties.5 Moreover, such new solid phases may help also to © 2011 American Chemical Society

Received: August 31, 2011 Revised: November 10, 2011 Published: November 17, 2011 811

dx.doi.org/10.1021/cg201140g | Cryst. Growth Des. 2012, 12, 811−824

Crystal Growth & Design

Article

experiments. The systematic study of different solid forms for a given compound enables the evaluation of competition effects for hydrogen bond formation between different functional groups, which is relevant for supramolecular synthesis and crystal engineering as well as for understanding phenomena such as polymorphism and structure−property relationships.12 The library is constituted of a complete series of structural isomers for seven different types of chemical compounds, all of which have one or two of the above-mentioned functional groups: (i) hydroxybenzoic acids, (ii) aminobenzoic acids, (iii) hydroxybenzamides, (iv) aminobenzamides, (v) nicotinic acids, (vi) nicotinamides, and (vii) 2,3-dihydroxybenzoic acids (Scheme 1). Therefore, an important aspect is that the possible cocrystal formers have similar size and molecular shape but different numbers and spatial distribution of hydrogen bond donor and acceptor atoms. Our screening experiments lead to four cocrystals of ACZ, which have been characterized in a comparative manner together with the previously prepared compounds ACZ-4HBA and ACZ-NAM-H2O.11 Recent reports have documented that the preparative method can be crucial for generating the desired cocrystal.13 Therefore, a variety of previously established preparative methods (liquidassisted grinding, neat grinding, reaction crystallization, and solution-mediated phase transformation) have been employed for the preparation of the six cocrystals of ACZ, in order to evaluate the influence of the experimental setup for cocrystal formation.

treatment of influenza. ACZ has low solubility (0.72 mg/mL in water at 25 °C) and poor permeability, which makes the discovery and identification of new solid forms of ACZ relevant to improve its physical and/or chemical properties.7−10 In a previous study, we have combined ACZ with a total of 20 cocrystal formers via liquid-assisted grinding (LAG) in acetone, acetonitrile, and water, which led to the discovery of cocrystals ACZ-4HBA and ACZ-NAM-H2O (4HBA = 4-hydroxybenzoic acid; NAM = nicotinamide). The structural analysis of these cocrystals has shown that oxygen- and nitrogen-containing functions, i.e., hydroxyl, pyridine, carboxyl, and carboxamide groups, are promising candidates for the interaction with the three sites capable of forming hydrogen-bonding interactions in ACZ: (i) the acetamide group, (ii) the sulfonamide group, and (iii) the thiadiazole ring (Chart 1).11 In contrast to Chart 1

acetamide and sulfonamide functions, thiadiazole heterocycles are unusual in drugs and have, as far as we know, not been explored previously for cocrystallization experiments with APIs. In order to provide a more profound insight into the structural and chemical factors that govern the formation of cocrystals with ACZ, we set up a library of cocrystal formers structurally related to 4HBA and NAM and employed them for screening

2. EXPERIMENTAL SECTION 2.1. Materials. Acetazolamide (form A), cocrystal formers, and solvents were commercially available and have been used as received without further purification. 2.2. Cocrystal Preparation. Liquid-assisted grinding (LAG) experiments were performed by mechanical grinding in a Retsch MM400 mixer

Scheme 1. a

a

Screening experiments with these cocrystal formers gave six pharmaceutical cocrystals with ACZ of varied stoichiometric compositions. Note: the cocrystal formers that provided cocrystals are highlighted in red and the compositions are given below the corresponding chemical drawing. 812



Article

Table 1. Experimental Conditions for the Successful Preparation of Cocrystals with Acetazolamide by Exploring Different Methods

a

The stoichiometry of ACZ and the cocrystal former used for the preparation of the saturated solution is indicated. bOnly starting materials were detected. cSmall quantities of solid cocrystalline material were added (seeding). dA solid phase different from that found by solution crystallization had formed. eA mixture of the dehydrated cocrystal ACZ-2ABAM, the phase found by LAG in water, and starting materials had formed. fTraces of an unidentified lateral byproduct were detected. gApparently, the sample absorbed water from the atmosphere. hTraces of ACZ were detected. solution, refinement, and data output were carried out with the SHELXTL-NT program package.14c,d Nonhydrogen atoms were refined anisotropically. C−H hydrogen atoms were placed in geometrically calculated positions using the riding model. O−H and N−H hydrogen atoms have been located from iterative examination of difference Fourier maps following least-squares refinements of the previous models with dO−H = 0.84 Å, dN−H = 0.86 Å, and Uiso(H) = 1.5Ueq(O,N). Simulated PXRD patterns were calculated with the WINGX program package.15 DIAMOND was used for the creation of figures and analysis of hydrogen-bonding interactions in the crystal lattice.16 Crystallographic data for the five crystal structures have been deposited with the Cambridge Crystallographic Data Centre as supplementary publications no. CCDC-841869−841872. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax, (+44)1223-336-033; e-mail, [email protected]; http://www.ccdc.cam.ac.uk).

mill (30 min at 25 Hz). Before starting, the corresponding mixtures of ACZ and the cocrystal former were placed into stainless steel grinding jars (1.5 mL), and one drop of water, acetonitrile, or acetone was added. Neat grinding (NG) was performed with the same equipment in an analogous manner but without solvent and extending the mechanical grinding to 60 min. For the reaction crystallization (RC) experiments, a saturated solution of the corresponding cocrystal former was prepared either in acetonitrile or a 1:1 solvent mixture between acetonitrile and water. Upon heating, small quantities of ACZ were added until a precipitate was observed. After precipitation was initiated, the solutions were allowed to cool down to room temperature under stirring. Finally, the precipitates were filtered and characterized by XRPD. For the solution-mediated phase transformation (SMPT, slurry technique), ACZ and the corresponding cocrystal former were combined under stirring in the presence of a few drops of acetonitrile, water, or a 1:1 mixture of these solvents (Table 1). After a period of 3−4 h, a paste had formed, which was distributed on a filter paper for drying. The solids obtained from LAG, NG, RC, and SMPT were examined by PXRD in order to establish if a new solid phase had formed. For the solution crystallization (SC) experiments, the starting materials were dissolved in 2:1, 1:1, 1:2, 1:3, 1:4, and 1:5 stoichiometric ratios in hot acetonitrile, water, acetone, or a 1:1 (v/v) acetonitrile−water mixture. After filtration, the solutions were stored at room temperature and allowed to slowly evaporate the solvent. In a parallel series of experiments small quantities of solid cocrystalline material were added (seeding). The specific experimental conditions, from which crystals suitable for singlecrystal X-ray diffraction could be grown, are listed in Table 1. 2.3. Instrumental. IR spectra have been 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 was placed in alumina crucibles and analyzed in the temperature range of 50−350 °C with a heating rate of 10 °C/min, using a current of 50 mL/min of nitrogen as inert gas purge. 2.4. X-ray Diffraction Analysis. X-ray powder diffraction (XRPD) analyses were carried out in the transmission mode on a Bruker D8-Advance diffractometer equipped with a LynxEye detector (λCu−Kα1 = 1.5406 Å; monochromator, germanium). The equipment was operated at 40 kV and 40 mA, and data were collected at room temperature in the range of 2θ = 5−40°. Single-crystal X-ray diffraction studies were performed on a Bruker-APEX diffractometer with a CCD area detector (λMοKα = 0.71073 Å; monochromator, graphite). Frames were collected at T = 293 K via ω/ϕ-rotation at 10 s per frame (SMART).14a The measured intensities were reduced to F2 and corrected for absorption with SADABS (SAINT-NT).14b Corrections were made for Lorentz and polarization effects. Structure

3. RESULTS AND DISCUSSION 3.1. Screening Experiments. Screening experiments were carried out with all of the reagents outlined in Scheme 1 except for 3-hydroxybenzamide (3HBA), which was commercially not available, and those which have been examined already in the foregoing project (benzoic acid, salicylic acid, 4-hydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 4-hydroxybenzamide, picolinic acid, nicotinic acid, isonicotinic acid, nicotinamide, and isonicotinamide).11 On the basis of the previous results, which gave cocrystals with 4HBA and NAM,11 the liquid-assisted grinding (LAG) method17 using water as solvent was also employed herein. Novel solid phases were identified by XRPD, and to discriminate cocrystals from polymorphs or solvates, parallel grinding experiments using only ACZ or the corresponding cocrystal former were performed. This procedure allowed us to establish that 2-hydroxybenzamide (2HBAM), 2-aminobenzamide (2ABAM), picolinamide (PAM), and 2,3dihydroxybenzoic acid (23DHBA) gave XRPD patterns, which differed significantly from known polymorphs of the starting materials and could not be attributed either to hydrates of the corresponding cocrystal former, as it occurred for 4-hydroxybenzamide as well as 2,4-, 2,6-, 3,4-, and 3,5-dihydroxybenzoic acid. The solids formed with 2HBAM, 2ABAM, PAM, and 23DHBA were then further characterized by IR spectroscopy and single-crystal X-ray diffraction analysis, showing that cocrystals of varied stoichiometric composition had formed 813



Article

(vide infra). As outlined in Scheme 1, 2HBAM, PAM, and 23DHBA generated 2:1, 1:2, and 3:1 cocrystals, respectively, while 2ABAM gave a 4:2:3 cocrystal trihydrate. The composition of this hydrate was also confirmed by thermogravimetric analysis (Figure S1, Supporting Information). Together with the previously reported 1:1 cocrystal ACZ4HBA and the 1:1:1 cocrystal hydrate ACZ-NAM-H2O,11 we have now a library of six cocrystals with ACZ. 3.2. Evaluation of Different Preparative Methods. The six cocrystals formed by LAG in water comprise a collection large enough for systematically exploring how diverse factors such as

solvents and preparative techniques might influence the formation of cocrystalline phases. For that reason, different alternative preparative methods were employed for the combination of ACZ with 4HBA, 2HBAM, 2ABAM, PAM, NAM, and 23DHBA: (i) neat grinding (NG),3e (ii) solution-mediated phase transformation (SMPT, slurry technique),18 (iii) reaction crystallization (RC),19 and (iv) crystallization from solution (SC). Additionally, the LAG technique was performed also with the less polar solvents acetonitrile and acetone, in which ACZ is significantly more soluble than in water. Comparative surveys of the XRPD patterns resulting from the different experimental methods used for the preparation of cocrystals ACZ-2HBAM, ACZ-2ABAM-H2O, ACZ-PAM, and ACZ-23DHBA are given in Figures 1−4.

Figure 1. XRPD patterns of the following samples and experiments: (a) ACZ form A, (b) ACZ form B, (c) 2HBAM, (d) LAG with H2O, (e) NG, (f) SMPT in CH3CN-H2O (50/50 vv), (g) RC in CH3CNH2O (50/50 vv), and (h) pattern simulated from the single-crystal X-ray diffraction analysis. All XRPD patterns of cocrystals given in this figure correspond to 2:1 stoichiometric combinations of ACZ and 2HBAM.

Figure 3. XRPD patterns of the following samples and experiments: (a) ACZ form A, (b) ACZ form B, (c) PAM, (d) LAG with H2O, (e) NG, (f) SMPT in CH3CN, (g) RC in CH3CN, and (h) pattern simulated from the single-crystal X-ray diffraction analysis. All XRPD patterns of cocrystals given in this figure correspond to 1:2 stoichiometric combinations of ACZ and PAM.

Figure 2. XRPD patterns of the following samples and experiments: (a) ACZ form A, (b) ACZ form B, (c) 2ABAM, (d) LAG with H2O, (e) NG, (f) SMPT in H2O, (g) RC in CH3CN-H2O (50/50 vv), (h) sample crystallized from water, (i) thermal treatment of ACZ2ABAM-H2O at 100 °C for 15 min, (j) stirring of ACZ-2ABAM in H2O for 16 h, and (k) pattern of ACZ-2ABAM-H2O simulated from the single-crystal X-ray diffraction analysis. All XRPD patterns of cocrystals given in this figure correspond to 2:1 stoichiometric combinations of ACZ and 2ABAM.

Figure 4. XRPD patterns of the following samples and experiments: (a) ACZ form A, (b) ACZ form B, (c) 23DHBA, (d) LAG with H2O, (e) NG, (f) SMPT in CH3CN-H2O (50/50 vv), (g) RC in CH3CNH2O (50/50 vv), and (h) pattern simulated from the single-crystal X-ray diffraction analysis. All XRPD patterns of cocrystals given in this figure correspond to 3:1 stoichiometric combinations of ACZ and 23DHBA. 814



Article

Table 2. Relevant Bands (in cm−1) in the IR Spectra of ACZ, 2HBAM, 2ABAM, PAM, 23DHBA, and the Cocrystals Examined Herein (ACZ-2HBAM, ACZ-2ABAM-H2O, ACZ-2ABAM-1/2H2O, ACZ-2ABAM, ACZ-PAM, and ACZ-23DHBA) API ACZ

cocrystal formers 2HBAM 2ABAM

cocrystals

PAM

23DHBA

ν CO

1680

1676

1660

1663

1678

ν O−H, N−H

3302 3182

3397 3313 3190

3411 3323 3196

3418 3276 3181

3376 3245

ν N−HII

1551a b

1589 1629b ν SO2NH2 a

1368 1177

b

1585 1628b

b

1588 1608b

ACZ2HBAM

ACZ- 2ABAMH2O

ACZ- 2ABAM-1/2 H2O

ACZ2ABAM

ACZPAM

ACZ23DHBA

1682 1654 3483 3369 3343 3306 3171

1674 1660 3625 3546 3472 3390 3335 3151

1662

1662

1680

1684

3505 3467 3386 3316 3162

3446 3413 3328 3250 3181

3454 3351 3281 3259 3142

1546a 1573b 1619b 1355 1178

1545a 1579b 1620b 1345 1173

3503 3469 3390 3333 3185 2902 2771 1543a 1578b

1539a 1578b

1564a 1589b

1546a

1372 1171

1368 1176

1363 1173

1375 1171

ν N−HII for ACZ. bν N−HII for 2HBAM, 2ABAM, and PAM, respectively.

3.3. Formation of Cocrystal ACZ-2ABAM (2:1). The crystal lattice water molecules in ACZ-2ABAM-H2O can be eliminated through thermal treatment. After heating the cocrystal trihydrate to 100 °C for a period of 15 min, a new solid phase was obtained as shown by a comparison of the XRPD patterns (Figure 2h and i). The same crystalline phase was present also in the sample obtained by the neat grinding method (Figure 2e). This new phase is a cocrystal as can be seen from a comparison of the IR data given in Table 2 and Figure 5,

Figures 1−4 and the results summarized in Table 1 show that only two of the six cocrystals identified from LAG in water could be prepared also by LAG in acetonitrile and acetone (ACZ-4HBA and ACZ-PAM). This is understandable for the cocrystal hydrates ACZ-2ABAM-H2O and ACZ-NAM-H2O, but ACZ-2HBAM and ACZ-23HDBA do not contain water molecules in the crystal structure. Two possible explanations might be given: the first is related to the low solubility of 2HBAM and 23DHBA in acetonitrile and acetone, and the second is that water might play an important role in the kinetics of crystal nucleation and growth. Cocrystal formation by NG was successful for all water-free cocrystals and additionally for ACZ-NAM-H2O, which has been attributed to the absorption of water from the atmosphere during the grinding process.11 In the case of 2ABAM, the resulting sample was a mixture of the dehydrated phase ACZ2ABAM, the cocrystalline phase already obtained from LAG with water, which is suggested to be the hemihydrate ACZ2ABAM-1/2H2O, and starting materials (vide infra). For the SMPT and RC techniques, acetonitrile was used preferably since ACZ is far more soluble in this solvent than in water. However, only 4HBA and PAM were sufficiently soluble in this solvent. Therefore, depending on the solubility of the cocrystal former, in the remaining cases either a 1:1 mixture of water and acetonitrile or pure water was employed. With the exception of 2ABAM, which gave a solid form different from that formed by LAG with water (vide infra), in all cases both methods lead to phases with PXRD patterns identical to those obtained from the samples prepared by LAG with water and neat grinding. However, for all samples prepared by the SMPT and RC techniques, the PXRD patterns were identical to those simulated from the structures determined by single-crystal X-ray diffraction analysis (see simulated patterns at the bottom in Figures 1−4). As already observed for ACZ-4HBA and ACZ-NAM-H2O and other cocrystals with APIs having low solubility, ACZ requires an excess of the cocrystal former for cocrystal growth from solution (solution crystallization).11,20 Moreover, in five of the six systems explored herein the addition of small quantities of solid cocrystalline material to the crystallizing solution (seeding) was required (Table 1).

Figure 5. Infrared spectra of (a) ACZ, (b) 2ABAM, (c) ACZ-2ABAMH2O, (d) ACZ-2ABAM-1/2H2O, and (e) ACZ-2ABAM.

which evidence the presence of both ACZ and 2ABAM. The TGA graph in Figure S2 (Supporting Information) shows that the cocrystal is water-free so that the composition ACZ-2ABAM (2:1) can be proposed. Comparison of the XRPD patterns in Figure 2i and j shows that the dehydrated phase is unstable when stirred in water for 16 h and transforms to a phase identical to that obtained by LAG in water (Figure 2d), which is different from that obtained by solvent evaporation from water (compare Figure 2j with 2d and h). This solid form is also one of the products formed by the neat grinding method (Figure 2e). The similarity between the PXRD patterns shown in Figures 2h−j and the observation that this phase is formed by LAG in water, but not obtained by LAG in acetone or 815



Article

acetonitrile, permits one to suggest that it is a second hydrated phase or a polymorph of ACZ-2ABAM-H2O. Thermogravimetric analysis indicates a weight loss of 0.70% (calculated: 0.78%) within the temperature range of 40 to 120 °C, indicating that the phase might be the hemihydrate ACZ-2ABAM-1/2H2O (Figure S3, Supporting Information). The IR spectra of dehydrated ACZ-2ABAM and hemihydrate ACZ-2ABAM-1/ 2H2O are very similar (Figure 5d and e, and Table 2), suggesting a strong structural relationship. This is reasonable considering that the ACZ/2ABAM/H2O ratio in this phase would be 8:4:1. 3.4. IR Spectroscopy. As already shown in our previous report for ACZ-4HBA and ACZ-NA-H2O, a comparison of the solid-state IR spectra of ACZ, the cocrystal former, and the corresponding cocrystal allows us to establish whether a new solid form has been generated.11 This is illustrated for compounds ACZ-2ABAM-H2O and ACZ-23DHBA in Figures 5 and 6, showing that the IR spectrum of the cocrystal does not

Among the most important evidence for cocrystal formation is the observation that all spectra show broad bands in the region of 2500−3500 cm−1, which are typical for crystal structures with extended hydrogen-bonding interactions.21 The presence of ACZ in the solid phases is indicated mainly by two characteristic bands for vibrations of the sulfonamide group in the region of 1345−1375 and 1171−1178 cm−1, and the amide II vibration νN−H in the range of 1539−1564 cm−1 (Table 2). The shifts in comparison to the values found for ACZ (1368 and 1177 cm−1 for νsulfonamide; 1551 cm−1 for νN−H) reflect variations in the hydrogen-bonding patterns within the crystal structures of the resulting cocrystals. A further relevant observation is that the IR spectrum of the cocrystal hydrate ACZ-2ABAM-H2O shows a band centered at 3625 cm−1, which can be attributed to the νO−H stretching frequency of crystal lattice water.22 As expected, this band is absent in the spectrum of ACZ-2ABAM (Figure 5). Of the cocrystal formers which could be incorporated in the new solid phases of ACZ described herein, 23DHBA has a pKa value (pKa = 2.9) that might enable proton transfer to ACZ (pKa = 7.2) and, thus, give a salt.23 Examination of the IR spectrum shown in Figure 6 indicates that such a proton transfer from the cocrystal former to ACZ did not occur because the CO stretching band at 1677 cm−1 did not suffer a significant shift to lower wavenumbers. There is no strong band in the region for the asymmetric νCOO vibration in the range of 1610−1550 cm−1, in which arylcarboxylate salts typically have a strong absorption.21 3.5. Single-Crystal Diffraction Analysis. Single cocrystals of ACZ-2HBAM, ACZ-2ABAM-H2O, ACZ-PAM, and ACZ-23DHBA have characteristic morphologies, which allow one to distinguish them from ACZ under a microscope (Figure 7). The most relevant crystallographic data for these cocrystals are listed in Table 3. Hydrogen bond parameters are summarized in Table 4. 3.6. Hydrogen-Bonding Characteristics of ACZ. The previous structural reports on the polymorphs of ACZ (forms A and B)9 and cocrystals ACZ-4HBA and ACZ-NAM-H2O11 have shown that ACZ has a relatively rigid molecular conformation with only one site of certain conformational flexibility. As shown in Scheme 2, the molecular structure can be divided into three fragments: (i) the acetamide group, (ii) the central thiadiazole ring, and (iii) the sulfonamide group.

Figure 6. Infrared spectra of (a) ACZ, (b) 23DHBA, and (c) ACZ23DHBA.

correspond to a superposition of the IR spectra of the individual components (ACZ and cocrystal former). The analogous graphs for the remaining cocrystals examined herein are available in Supporting Information (Figures S4−S5). Listings of the most characteristic IR bands are given in Table 2, together with the data for ACZ and the corresponding cocrystal formers.

Table 3. Crystallographic Data for Compounds ACZ-2HBAM, ACZ-2ABAM-H2O, ACZ-PAM, and ACZ-23DHBA

a

crystal dataa

ACZ-2HBAM (2:1)

ACZ-2ABAM-H2O(4:2:3)

ACZ-PAM (1:2)

ACZ-23DHBA (3:1)

formula MW (g mol−1) space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z μ (mm−1) ρcalcd (g cm−3) Rb,c Rwd,e

2C4H6N4O3S2·C7H7NO2 581.63 P1̅ 8.8200(8) 9.1977(8) 14.8854(14) 95.872(2) 100.119(2) 102.197(2) 1149.68(18) 2 0.478 1.680 0.068 0.142

4C4H6N4O3S2·2C7H8N2O·3H2O 1215.35 P21/n 11.2462(17) 26.971(4) 17.230(3) 90 103.151(2) 90 5089.1(13) 4 0.438 1.586 0.051 0.126

C4H6N4O3S2·2C6H6N2O 466.50 P1̅ 8.6156(12) 10.4253(14) 11.6675(16) 79.910(2) 86.334(2) 88.606(2) 1029.6(2) 2 0.307 1.505 0.068 0.148

3C4H6N4O3S2·C7H6O4 820.86 P21/c 9.763(3) 14.434(4) 22.839(7) 90 94.942(6) 90 3206.2(16) 4 0.509 1.701 0.063 0.137

λMoKα = 0.71073 Å. bFo > 4σ(Fo). cR = Σ∥Fo| − |Fc∥/Σ|Fo|. dAll data. eRw = [Σw(Fo2 − Fc2)2/Σw(Fo2)2]1/2. 816



Article

Scheme 2. The Molecular Structure of ACZ Can Be Divided into Three Sections, Each of Which Contains Sites for Intermolecular Interactions

torsion angles with values ranging from −78.2 to −137.7° and +78.2 to +137.7° for the above-mentioned series of compounds.24 These structural characteristics of ACZ generate three sites for relatively strong hydrogen bonds that can give rise to motifs I, IIa, IIb, IIIa, IIIb, IVa, and IVb (Scheme 3). Of these, motif I occurs at the carboxamidine fragment in ACZ and represents the homodimeric C(N)NH···HN(N)C synthon that is structurally related to the homodimer formed by 2-aminopyridines.25 Motifs IIa and IIb are the cyclic and catemer patterns resulting from the N−H···OC hydrogen-bonding interaction formed between the aminogroup of the sulfonamide function and the carbonyl group of the acetamide moiety. Motifs IIIa/IIIb and IVa/IVb are well known from assemblies of molecules containing sulfonamide and carboxamide groups, respectively.25 In the case of ACZ, the intramolecular O···S contact in ACZ inhibits the

Figure 7. Crystals of acetazolamide (ACZ) and the corresponding cocrystals with 2HBAM, 2ABAM, PAM, and 23DHBA can be distinguished by their different shapes.

Because of an intramolecular O···S interaction and delocalization of the Namide lone pair, the thiadiazole acetamide fragment is quite rigid and has Z-configuration.9d Comparing the conformation of the ACZ molecules in the crystal structures of the known polymorphs of ACZ and the six cocrystals characterized herein, we see that there are only small variations in the dihedral angles formed between the mean planes of these moieties. This can be seen from the S1−C2−N3−C3 torsion angles ranging from −0.1 to −4.5° and +0.1 to +4.5°.24 The sulfonamide group is more flexible, and rotation around the N4−S2 and C1−S2 bonds allows for a large variety of rotational conformers. This is illustrated by the N4−S2−C1−S1

Table 4. Hydrogen-Bonding Geometries for Compounds ACZ-2HBAM, ACZ-2ABAM-H2O, ACZ-PAM, and ACZ-23DHBA compd

motif

H-bond

D−H [Å]

H···A [Å]

D···A [Å]

∠DHA [deg]

symmetry code

ACZ-2HBAM

I I IIa IIa IIIa IIIa V V I I I I IIc IIc IIa VII VII IX IX X X I I I IIa IIe IIe IIe IIIa VI VI

N3−H1···N22 N23−H21···N2 N4−H3···O1 N24−H23···O21 N4−H2···O2 N24−H22···O22 N5−H12···O3 S1···O4 N3−H1···N22 N23−H21···N2 N43−H41···N62 N63−H61···N42 N4−H2···O5w O5w-H5A···O1 N4−H3···O1 N3−H1···O4 N6−H11···N2 N4−H2···O5 N8−H17···O3 N6−H12···N7 N8−H18···N5 N3−H1···N22 N23−H21···N2 N43−H41···N42 N44−H43···O41 N4−H3···O42 N24−H22···O1 N44−H42···O21 N24−H23···O23 O7−H13···O3 S1···O6

0.86 0.86 0.86 0.86 0.86 0.86 0.86

2.06 2.01 2.15 2.02 2.18 2.27 2.24

175 176 165 163 168 157 156

0.86 0.86 0.86 0.86 0.86 0.84 0.86 0.86 0.86 0.86 0.86 0.86 0.86 0.86 0.86 0.86 0.86 0.86 0.86 0.86 0.86 0.84

2.10 2.00 1.99 2.04 1.99 1.91 2.16 1.92 2.11 1.95 2.12 2.42 2.62 2.01 2.09 2.05 2.27 2.16 2.18 2.07 2.27 2.06

2.921(5) 2.870(5) 2.991(5) 2.850(3) 3.029(6) 3.076(6) 3.049(6) 2.978(4) 2.963(3) 2.860(3) 2.843(3) 2.891(3) 2.837(4) 2.754(4) 2.982(4) 2.779(3) 2.961(4) 2.802(4) 2.970(4) 3.108(4) 3.349(4) 2.861(6) 2.944(6) 2.897(6) 3.042(6) 2.991(6) 2.949(6) 2.923(6) 3.087(6) 2.754(5) 3.254(4)

+x,+y,+z +x,+y,+z −x+1,−y+1,−z+2 −x+1,−y,−z −x+2,−y+2,−z+2 −x+1,−y,−z+1 +x,+y,+z−1 +x,+y,+z−1 +x,+y,+z +x,+y,+z +x−1/2,−y+1/2,+z+1/2 +x+1/2,−y+1/2,+z−1/2 −x+1,−y,−z+1 +x,+y,+z −x+1,−y+1,−z+1 −x,−y+2,−z −x,−y+2,−z −x+1,−y+2,−z +x,+y+1,+z −x+1,−y+2,−z+1 −x+1,−y+2,−z+1 +x,+y,+z +x,+y,+z −x+1,−y+2,−z+1 −x+2,−y+2,−z+1 +x-1,+y,+z +x+1,+y,+z +x,+y,+z −x+1,−y+2,−z +x+1,− y+1/2 + 1,+z+1/2 +x+1,−y+1/2 + 1,+z+1/2

ACZ-2ABAM -H2O

ACZ-PAM

ACZ-23DHBA

817

179 177 175 173 170 179 161 178 171 170 169 137 144 170 174 167 149 162 149 174 158 140



Article

Scheme 3. Possible Cyclic and Polymeric Hydrogen-Bonding Patterns for ACZ

syn-orientation of the N−H and CO groups; therefore, the homodimeric synthon IVa might be less favored in this case. 3.7. Acetazolamide-2-hydroxybenzamide (2:1). The asymmetric unit of ACZ-2HBAM comprises two ACZ and one 2HBAM molecule, showing that the API−cocrystal former stoichiometry of the cocrystal is 2:1. Within the crystal lattice, the ACZ molecules are connected through hydrogen bonds based on motifs I, IIa, and IIIa (Scheme 3) to give 2D layers running parallel to (11̅1) (Figure 8a). The conformation of these layers can be described as rectangular undulated, thus providing cavities located alternately above and below the mean plane of the layer (Figure 8b). In the cavities, discrete entities of the 2HBAM cocrystal former molecules are embedded (Figure 8c), which interact with one of the independent ACZ molecules through Ocarboxamide···Sthiadiazole and Ncarboxamide-H···Osulfonamide bonds (Table 4) to form the heterodimeric motif V (Scheme 4 and Figure 8d). So far, there are relatively few reports on O···S interactions.26 The distance of the intermolecular O···S bond, 2.978(4) Å, is significantly less than the sum of the van der Waals radii of oxygen and sulfur (3.30 Å), but longer than the intramolecular O···S contacts in the thiadiazole carboxamide fragments, 2.730(3) and 2.737(3) Å. The host−guest interactions are completed by Ncarboxamide-H···Osulfonamide and C2HBAM-H···Osulfonamide contacts between the guest and surrounding ACZ molecules (Table S1, Supporting Information). A further interesting observation is that the ACZ homodimer (motif I) forming the

bottom of the cavity is significantly distorted from planarity, although there are no short π···π contacts between the participating entities. This is shown by the dihedral angle formed between the mean planes of the thiadiazole rings: 19.5°. The O−H function in 2HBAM is involved in an intramolecular O−H···O hydrogen bond with the neighboring carboxyl group and only participates in an additional weak C−H···O contact. In the third dimension, the 2D layers are translation stacked and held together by dipole···dipole and van der Waals forces. 3.8. Acetazolamide-2-aminobenzamide Trihydrate (4:2:3). The asymmetric unit of ACZ-2ABAM-H2O is composed of four ACZ, two 2ABAM, and three water molecules. Thus, as for the case of ACZ-2HBAM, the API− cocrystal former stoichiometry of the cocrystal is 2:1. In the crystal structure, the four independent ACZ molecules form homodimers with hydrogen bonds based on motif I. Further connection through Nsulfonamide-H···Ocarboxamide and NsulfonamideH···Osulfonamide gives 2D hydrogen layers propagating parallel to the ac plane (Figure 9a). In the third dimension, the 2D double-layers are cross-linked via Ow-H···Ocarboxamide, Ow-H···Osulfonamide, and Nsulfonamide-H···Ow hydrogen bonds with all three independent crystal lattice water molecules (O5, O6, and O7). Thus, in contrast to the crystal structure of ACZ-2HBAM, an overall 3D hydrogen-bonded network has formed (Figure 9b). Although the homodimeric cyclic motifs IIa and IIIa which are common for ACZ are not observed in this 818



Article

structures has been documented recently by comparative structural analyses of different series of cocrystals.27 As for ACZ-2HBAM, the arrangement of the ACZ molecules generates cavities, in which discrete 2ABAM molecules are embedded through N amine -H···O sulfonamide , N carboxamide H···O sulfonamide , and C−H 2ABAM ···O carboxamide interactions (Table 4 and Figure 9c). In contrast to ACZ-2HBAM, in this case no heterodimeric motif is formed. A possible reason might be that the carboxamide function of 2ABAM is compromised in strong CO···H−Ow and N−H···Ow hydrogen bonds with water molecules. Similar to ACZ-2HBAM, the NH2 function is involved in an intramolecular N−H···O hydrogen bond with the neighboring carboxamide group. The inclusion of the cocrystal former generates two crystallographically independent 2D layers of the composition [(ACZ)2(2ABAM)]n, each of which is formed by two independent ACZ and one independent 2ABAM (Figure 9d). 3.9. Acetazolamide-picolinamide (1:2). The asymmetric unit of ACZ-PAM consists of one crystallographically independent ACZ molecule and two cocrystal former entities, now giving a 1:2 API−cocrystal former stoichiometry of the cocrystal. Within the crystal lattice, the ACZ molecules form dimeric units based on motif IIa, and each ACZ molecule binds one of the two independent PAM molecules, giving the heterodimeric motif VII (Scheme 4 and Figure 10a,b). This pattern is similar to motif VIII (Scheme 4), which had formed between ACZ and 4HBA in the 1:1 cocrystal ACZ-4HBA11 and is known also from a series of cocrystals derived from sulfathiazole and related sulfadrugs.3d,5d,e,28 The so-formed [2 + 2] aggregates are involved in additional hydrogen bonds (motif IX, Scheme 4 and Figure 10c) with the second group of independent PAM molecules to give 1D chains running along axis c. Motif IX can be considered as an expanded pattern of

Figure 8. In the crystal structure of ACZ-2HBAM, rectangular undulated layers of ACZ (a,b) generate cavities, in which the 2HBAM molecules are included (c,d).

case, the 3D framework exhibits a water-expanded pattern of motif IIa (motif IIc, Scheme 4). That water molecules play an important role for the stabilization and organizing of crystal

Scheme 4. Hydrogen-Bonding Patterns Relevant for the Discussion of the Supramolecular Organization in the Crystal Structures of ACZ-2HBAM, ACZ-2ABAM-H2O, ACZ-PAM, and ACZ-23DHBAa

a

(a) motifs formed between ACZ molecules, (b) motifs formed between ACZ and the cocrystal former, and (c) motifs for PAM. 819



Article

Figure 9. In the crystal structure of ACZ-2ABAM-H2O, hydrogen-bonding interactions between the ACZ molecules generate 2D hydrogen bonded layers (a), which are cross-linked further by water molecules to a 3D hydrogen bonded network (b). The 2ABAM molecules are included within cavities (c), whereby the connectivity between ACZ and 2ABAM generates 2D layers (d). Note: Only one of the crystallographically independent 2D layers (d) is shown.

The channels of the 3D skeleton are occupied by 1D chains of the third independent ACZ molecule (S41) and discrete 23DHBA molecules. The chains are sustained by homodimeric units based on motifs I and IIa (Figure 11c), and connected to the 2D layers via Nsulfonamide-H···Ocarboxamide and NsulfonamideH···Osulfonamide hydrogen bonds, which generate an expanded pattern of motif IIa (motif IIe, Scheme 4) and strengthen the 3D hydrogen bonded framework. The 23DHBA molecules are connected to all three independent ACZ molecules via O 23D HBA -H···O s u l fo n ami de , C 23DHBA -H···O s ulf on ami d e , and Sthiadiazole···O23DHBA contacts (Figure 11d). Of these, the interaction with ACZ (S1) occurs via the heterodimeric motif VI (Figure 11e), which is structurally related to motif V (Scheme 4). Nevertheless, in this case the O···S interaction is significantly longer than that in ACZ-2HBAM, 2.978(4) Å versus 3.254(4) Å, and has a value close to the sum of the van der Waals radii of oxygen and sulfur (3.30 Å). The X-ray diffraction study also confirms the observations from the IR spectra that ACZ-23DHBA is a cocrystal and not a salt. Examination of the Fourier difference maps revealed that there is a hydrogen atom in close proximity to one of the oxygen atoms belonging to the COOH group. In addition, the C−O and CO bond lengths for the carboxyl groups in the 23DHBA molecules are in the expected range for COOH groups when compared to the COO− moieties (1.335(6) and 1.228(6) Å, respectively). In deprotonated benzoic acids with delocalized carboxylate functions, the C−O distance is approximately 1.25 Å; otherwise, the average C−O and CO distances are 1.31 Å and 1.21 Å, respectively.23

motif IIIa (Scheme 3). At the same time, the two independent PAM molecules form the homodimeric motif X (Figure 10b), which is unusual for molecules containing carboxamide groups. Typically, amide functions are linked based on motif XI (Scheme 4), as is the case for the crystal structure of the cocrystal former.29 The hydrogen-bonding patterns based on the abovementioned motifs (IIa, VII, IX, and X) generate 2D doublelayers parallel to (110) (Figure 10d). In the third dimension, the double layers are stacked and held together by CcarboxamideH···Osulfonamide, dipole···dipole and van der Waals forces. Of these, the C−H···O interactions are sustained between neighboring ACZ molecules, forming the so far unknown homodimeric motif IId (Scheme 4). 3.10. Acetazolamide-2,3-dihydroxybenzoic Acid (3:1). The asymmetric unit of ACZ-23DHBA contains three ACZ and one 23DHBA molecule, showing that the API− cocrystal former stoichiometry of the cocrystal is 3:1. The crystal lattice consists of a complex 3D hydrogen-bonded skeleton setup by ACZ molecules. Two of the three independent ACZ molecules (S1 and S21) form homodimeric units based on motif I, which are further connected by Nsulfonamide-H···Osulfonamide and Nsulfonamide-H···Ocarboxamide bonds to a 3D framework having channels in the direction of axis a (Figure 11a). A more profound analysis reveals that this skeleton contains 2D wave-like layers running parallel to the ab plane (Figure 11b), which are linked in the third dimension by homodimeric Nsulfonamide-H···Osulfonamide bonds based on motif IIIa. 820



Article

molecule uses all three possible N−H donor sites for hydrogenbonding interactions. ACZ has five oxygen and nitrogen acceptor atoms, and additionally, the sulfur atom of the thiadiazole ring can form intra- and intermolecular O···S interactions. However, in all cases a maximum of four acceptor atoms is involved in the formation of the hydrogen bonded networks. Under these circumstances, it can be expected that possible cocrystal formers must have several donor and acceptor atoms for being able to penetrate into the supramolecular structure of ACZ. Indeed, the results show that the reagents which were able to form a cocrystal with ACZ contain at least two hydrogen bond donor and acceptor atoms. A further interesting observation from Table 5 (column 7) is that none of the cocrystal formers retained a hydrogen-bonded fragment from its proper solid-state organization within the crystal structure of the cocrystal. In four cocrystals, the cocrystal formers were included in the form of discrete molecules, and in the remaining two samples in the form of hydrogen-bonded dimeric aggregates, whereby one consisted of a water-expanded homodimeric pattern (NAM). This indicates that ACZ is the dominant building block for hydrogen bonding in at least four of the six cocrystals. In all crystal structures listed in Table 5, the ACZ molecules are connected with each other by hydrogen bonds, with a clear dominance of the cyclic homodimeric motifs I and IIa. Motif I appears in both polymorphs of ACZ and three cocrystals, while motif IIa is only found in ACZ form A but in five of the six cocrystals. Interestingly, motif I is only found in the ACZ-rich cocrystals ACZ-23DHBA (3:1), ACZ-2HBAM (2:1), and ACZ-2ABAM (2:1), in which part of the ACZ molecules interact with the cocrystal former. The remaining ACZ molecules exhibit heterodimeric synthons (motifs V, VI, VII, and VIII) or other strong hydrogen-bonding interactions with the cocrystal former at the thiadiazole acetamide or thiadiazole sulfonamide site. Particularly interesting is the finding that the conformational flexibility of the sulfonamide groups allows for the formation of extended 2D and 3D hydrogen-bonded aggregates of varying topology. In the crystal structures of ACZ-2HBAM, ACZ-2ABAM-H2O, and ACZ-4HBA, the ACZ molecules form 2D layers having either planar or undulated topology. Of these, the layers in ACZ-2HBAM and ACZ-2ABAM-H2O have semispherical and spherical cavities, respectively, in which the cocrystal formers are located. In ACZ-4HBA, the cocrystal former crosslinks the 2D layers, giving the crystal structure the appearance of an intercalation or pillared compound. The 2D layers in the crystal structures of ACZ-2HBAM, ACZ-2ABAM-H2O, and ACZ4HBA show moderate to strong similarity with the structural organization of the 2D layers found in ACZ form A (Figure S6, Supporting Information). Thus, the conformational flexibility of the sulfonamide group enables ACZ to adapt its extended supramolecular structure by topological variations to the presence of varied guest molecules. In ACZ-23DHBA, the linkage of ACZ molecules generates a 3D porous framework, in which the channels are filled by additional ACZ molecules and the cocrystal former. The inclusion of the cocrystal former within cavities or channels in ACZ-2HBAM, ACZ-2ABAM-H2O, and ACZ-23DHBA resembles the corresponding networks to inclusion complexes or clathrates. Under this angle of view, only ACZ-NAM-H2O and ACZ-PAM seem to be true two-component networks because in this case, discrete homodimeric entities of each ACZ and the cocrystal former are hydrogen bonded to each other to form the overall 2D and 3D networks.

Figure 10. In the crystal structure of ACZ-PAM, 1D chains (a) are formed by a series of hydrogen-bonding interactions between ACZ and PAM including the heterodimeric motif VII (b,c). Further connection through motif X generates 2D double layers (d). Note: arrows indicate sites for cross-linkage of the 1D chains through motif X.

3.11. Comparative Analysis of the Hydrogen-Bonding Interactions. In order to detect the similarities and differences between the supramolecular arrangements of the ACZ molecules in the different structures and to gain a more profound insight into the factors that govern the formation of crystals between two chemical compounds, we have systematically analyzed the hydrogen-bonding patterns found in the polymorphs and cocrystals of ACZ. For this purpose, we arranged a series of parameters suitable for the characterization of hydrogen bonded supramolecular aggregates in Table 5. They include (i) the number of donor and acceptor atoms that participate in hydrogen bonds for each component and the corresponding sum for the entire cocrystal, (ii) the dimensions of the hydrogen-bonding patterns for ACZ, the cocrystal former, and the corresponding overall cocrystal structure, and (iii) the type of particular homo- and heterodimeric motifs exhibited in the different crystal structures. For better comparison, the cocrystals have been ordered according to decreasing molar content of ACZ (3:1, 2:1, 1:1, and 1:2). At this point, it is important to mention that a series of cocrystals with varying composition of stoichiometry are rare and that there is probably no precedent for a cocrystal series comprising the above-indicated range of molar ratios. Column 3 in Table 5 summarizes the number of donor and acceptor atoms that participate in hydrogen bonds within the crystal structures of the polymorphs and the cocrystals known for ACZ. In all solid phases included in this table, each ACZ 821



Article

Figure 11. In the crystal structure of ACZ-23DHBA, two of the three independent ACZ molecules form a porous 3D hydrogen bonded framework (a), which contains 2D wave-like layers (b). The channels are occupied by additional ACZ molecules forming 1D chains (c) and discrete 23DHBA molecules. The 23DHBA guests are connected to all three independent ACZ molecules (d), forming with one of them the heterodimeric motif VI (e).

Table 5. Comparative Analysis of the Hydrogen-Bonding Interactions and the Resulting Networks in the Polymorphs and Cocrystals of ACZ donor and acceptor atoms with H-bonds (D/A)a cocrystal former ACZ form A ACZ form B ACZ-23DHBA ACZ-2HBAM ACZ-2ABAM-H, ACZ2ABAM-1/2H2O ACZ-4HBA ACZ-NAM-H2O ACZ-PAM

ACZ/cocrystal former ratio

ACZ

dimension of hydrogen bondingb coformerc

type of homo- and heterodimeric hydrogenbonding motifs

coformer

sum

ACZc

sumd

ACZc

3:1 2:1 2:1

3/3 3/4 9/10 6/8 12/16

1/0 3/1 6/2

3/3 3/4 10/10 9/9 18/18

2D 3D 3D 2D 2D

0D 0D 0D

3D 2D 3D

I, I I, I, I,

1:1 1:1 1:2

3/4 3/3 3/3

2/2 2/2 4/4

5/6 5/5 7/7

2D 0D 0D

0D 0D 0D

3D 3D 2D

IIa IIa IIa, IId

coformerc

ACZcoformerd

IIa, IIIa IIa, IIe, IIIa IIa, IIIa IIc

VI V

VIII X

VII, IX

a

Only intermolecular hydrogen bonds are considered. ACZ-2ABAM-H2O and ACZ-NAM-H2O contain additional donor and acceptor atoms at the water molecules. Bifurcated hydrogen bonds were counted as single interactions. bOnly O−H···O, O−H···N, N−H···O, and N−H···N hydrogen bonds were considered. cAnalysis considers interactions only for ACZ or the cocrystal former, respectively. dAnalysis considers all O−H···O, O−H···N, N−H···O, and N−H···N hydrogen bonds present in the crystal structure.

ACZ forms cocrystals with carboxylic acids and carboxamides via two types of double-bridged heterodimeric synthons. In ACZ-4HBA and ACZ-PAM, the thiadiazole-carboxamide fragment is involved in synthons of the composition C(N)NH··· HOOC and C(N)NH···amide (motifs VII and VIII in Scheme 4). In ACZ-2HBAM and ACZ-23DHBA, the connectivity occurs at the thiadiazole-sulfonamide site, giving C(S)SO···HO(O)C2 and

C(S)SO···amide patterns (motifs V and VI in Scheme 4), in which, interestingly, the functional groups are connected by two different kinds of interactions, a hydrogen bond and a S···O contact. In contrast, the cocrystal hydrates ACZ-2ABAM-H2O and ACZNAM-H2O do not present a heterodimeric motif, and in these samples, ACZ and the cocrystal former are linked by single N−H···O, N−H···N, and C−H···O interactions. 822



Article

268−273. (b) Habgood, M.; Deij, M. A.; Mazurek, J.; Price., S. L.; ter Horst, J. H. Cryst. Growth Des. 2010, 10, 903−912. (c) Urbanus, J.; Roelands, C. P. M; Verdoes, D.; Jansens, P. J.; ter Horst, J. H. Cryst. Growth Des. 2010, 10, 1171−1179. (d) Stevens, J. S.; Byard, S. J.; Schroeder, S. L. M. Cryst. Growth Des. 2010, 10, 1419−1434. (e) Lee, T.; Wang, P. Y. Cryst. Growth Des. 2010, 10, 1435−1442. (f) Schultheiss, N.; Lorimer, K.; Wolfe, S.; Desper, J. CrystEngComm 2010, 12, 742−749. (g) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. Cryst.Growth Des. 2010, 10, 2229−2238. (h) Rager, T.; Hilfiker, R. Cryst.Growth Des. 2010, 10, 3237−3241. (i) Kastelic, J.; Hodnik, Ž .; Šket, P.; Plavec, J.; Lah, N.; Leban, I.; Pajk, M.; Planinšek, O.; Kikelj, D. Cryst.Growth Des. 2010, 10, 4943−4953. (j) Khan, M.; Enkelmann, V.; Brunklaus, G. J. Am. Chem. Soc. 2010, 132, 5254−5263. (k) Báthori, N. B.; Lemmerer, A.; Venter, G. A.; Bourne, S. A.; Caira, M. R. Cryst.Growth Des. 2011, 11, 75−87. (l) Das, B.; Baruah, J. B. Cryst.Growth Des. 2011, 11, 278−286. (m) Zheng, S.-L.; Chen, J.-M.; Zhang, W.-X.; Lu, T.-B. Cryst.Growth Des. 2011, 11, 466−471. (5) (a) McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; O’Donnell, E.; Park, A. Pharm. Res. 2006, 23, 1888−1897. (b) Variankaval, N.; Wenslow, R.; Murry, J.; Hartman, R.; Helmy, R.; Kwong, E.; Clas, S.-D.; Dalton, C.; Santos, I. Cryst. Growth Des. 2006, 6, 690−700. (c) Hickey, M. B.; Peterson, M. L.; Scoppettuolo, L. A.; Morrisette, S. L.; Vetter, A.; Guzmán, H.; Remenar, J. F.; Zhang, Z.; Tawa, M. D.; Haley, S.; Zaworotko, M. J.; Almarsson, Ö . Eur. J. Pharm. Biopharm. 2007, 67, 112−119. (d) Stanton, M. K.; Bak, A. Cryst.Growth Des. 2008, 8, 3856−3862. (e) Shiraki, K.; Takata, N.; Takano, R.; Hayashi, Y.; Terada, K. Pharm. Res. 2008, 25, 2581−2592. (f) Stanton, M. K.; Tufekcic, S.; Morgan, C.; Bak, A. Cryst.Growth Des. 2009, 9, 1344−1352. (g) Takata, N.; Takano, R.; Uekusa, H.; Hayashi, Y.; Terada, K. Cryst. Growth Des. 2010, 10, 2116−2122. (h) Cheney, M. L.; Weyna, D. R.; Shan, N.; Hanna, M.; Wojtas, L.; Zawarotko, M. J. J. Pharm. Sci. 2011, 100, 2172−2181. (i) Stanton, M. K.; Kelly, R. C.; Colletti, A.; Langley, M.; Munson, E. J.; Peterson, M. L.; Roberts, J.; Wells, M. J. Pharm. Sci. 2011, 100, 2734−2743. (j) Rahman, Z.; Samy, R.; Sayeed, V. A.; Khan, M. A. Pharm. Dev. Technol. 2011, doi: 10.3109/10837450.2010. 546412. (6) GRAS = Generally Regarded As Safe. This list is published by the U.S. Food and Drug Administration (FDA). (7) (a) Chakravarty, S.; Kannan, K. K. J. Mol. Biol. 1994, 243, 298− 309. (b) Nair, S. K.; Krebs, J. F.; Christianson, D. W.; Fierke, C. A. Biochemistry 1995, 34, 3981−3989. (8) (a) Kasim, N. A.; Whitehouse, M.; Ramachandran, C.; Bermejo, M.; Lennernäs, H.; Hussain, A. S.; Junginger, H. E.; Stavchansky, S. A.; Midha, K. K.; Shah, V. P.; Amidon, G. L. Mol. Pharmaceutics 2004, 1, 85−96. (b) Ono N.; Ushijima I. Patent JP2009269856(A), 2009. (c) Swenson E. R. Patent US2009131490(A1), 2009. (9) (a) Mathew, M.; Palenik, G. J. J. Chem. Soc., Perkin Trans. 2 1974, 532−536. (b) Umeda, T.; Ohnishi, N.; Yokoyama, T.; Kuroda, T.; Kita, Y.; Kuroda, K.; Tatsumi, E.; Matsuda, Y. Chem. Pharm. Bull. 1985, 33, 3422−3428. (c) Griesser, U. J.; Burger, A.; Mereiter, K. J. Pharm. Sci. 1997, 86, 352−358. (d) Nagao, Y.; Honjo, T.; Iimori, H.; Goto, S.; Sano, S.; Shiro, M.; Yamaguchi, K.; Sei, Y. Tetrahedron Lett. 2004, 45, 8757−8761. (e) Baraldi, C.; Gamberini, M. C.; Tinti, A.; Palazzoli, F.; Ferioli, V. J. Mol. Struct. 2009, 918, 88−96. (10) (a) Duffel, M. W.; Ing, I. S.; Segarra, T. M.; Dixson, J. A.; Barfknecht, C. F.; Schoenwald, R. D. J. Med. Chem. 1986, 29, 1488− 1494. (b) Parasrampuria, J.; Gupta, V. D. J. Pharm. Sci. 1990, 79, 835− 836. (c) El-Gazayerly, O. N.; Hikal, A. H. Int. J. Pharm. 1997, 158, 121−127. (d) Haznedar, S.; Dortunç, B. Int. J. Pharm. 2004, 269, 131− 140. (e) Pudipeddi, M.; Serajuddin, A. T. M. J. Pharm. Sci. 2005, 94, 929−939. (f) Granero, G. E.; Longhi, M. R.; Becker, C.; Junginger, H. E.; Kopp, S.; Midha, K. K.; Shah, V. P.; Stavchansky, S.; Dressman, J. B.; Barends, D. M. J. Pharm. Sci. 2008, 97, 3691−3699. (11) Arenas-Garcia, J. I.; Herrera-Ruiz, D.; Mondragon-Vasquez, K.; Morales-Rojas, H.; Höpfl, H. Cryst. Growth Des. 2010, 10, 3732−3742. (12) For previous analyses in this direction see: (a) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des. 2005, 5, 1013− 1021. (b) Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J.

4. CONCLUSIONS The above-described structural analyses have shown that ACZ is a strong self-complementary building block capable of generating extended 2D and 3D hydrogen bonded networks of varied topology. This is probably the reason why only two of the six cocrystals known so far for this API are true twocomponent networks, while the majority of the cocrystals resemble inclusion or clathrate complexes of ACZ, in which the cocrystal formers are located in channels, voids, or semispherical cavities. Because of the differences in the topology, it can be proposed that the cocrystal formers exercise a template effect during the self-assembly process. The research described herein is part of an ongoing study. We are currently carrying out cocrystal phase stability experiments in water and dry/humid atmospheres at varying temperatures, and examining changes in intrinsic solubility and dissolution rates, in order to reveal to what extent the structural variations within the cocrystals of ACZ influence the biopharmaceutical properties of this API.

■

ASSOCIATED CONTENT * Supporting Information TG analysis of ACZ-2ABAM-H2O, ACZ-2ABAM-1/2H2O, and ACZ-2ABAM; IR spectra for ACZ-2HBAM and ACZPAM; topology and hydrogen-bonding connectivities of ACZ in 2D hydrogen bonded layers present in the cocrystal structures; listing of all hydrogen-bonding interactions; X-ray crystallographic information files (CIF) for compounds ACZ2HBAM, ACZ-2ABAM-H2O, ACZ-PAM, and ACZ-23DHBA. This material is available free of charge via the Internet at http://pubs.acs.org. S

■

AUTHOR INFORMATION Corresponding Author *(D.H.-R.) E-mail: [email protected]. (H.H.) Fax: (+52) 7773-29-79-97. E-mail: [email protected].

■

ACKNOWLEDGMENTS This work received support from Consejo Nacional de Ciencia y Tecnologia (CONACyT) in form of a postgraduate fellowship for JIAG and through project No. CB2007-83440.

■

REFERENCES

(1) (a) Morissette, S. L.; Almarsson, Ö .; Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R. Adv. Drug Delivery Rev. 2004, 56, 275−300. (b) Blagden, N.; de Matas, M.; Gavan, P. T.; York, P. Adv. Drug Delivery Rev. 2007, 59, 617−630. (c) Chow, K.; Tong, H. H. Y.; Lum, S.; Chow, A. H. L. J. Pharm. Sci. 2008, 97, 2855−2877. (d) Shan, N.; Zaworotko, M. J. Drug Discovery Today 2008, 13, 440−446. (2) (a) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid State Chemistry of Drugs, 2nd ed.; SSCI Inc: West Lafayette, IN, 1999. (b) Datta, S.; Grant, D. J. W. Nat. Rev. Drug Discovery 2004, 3, 42−57. (3) For feature articles and reviews of pharmaceutical cocrystals see: (a) Almarsson, Ö .; Zawarotko, M. J. Chem. Commun. 2004, 1889−1896. (b) Bernstein, J. Chem. Commun. 2005, 5007−5012. (c) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499−516. (d) Caira, M. R. Mol. Pharmaceutics 2007, 4, 310−316. (e) Frišcǐ ć, T.; Jones, W. Cryst. Growth Des. 2009, 9, 1621−1637. (f) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950−2967. (g) Childs, S. L.; Zaworotko, M. J. Cryst. Growth Des. 2009, 9, 4208− 4211. (h) Stahly, G. P. Cryst. Growth Des. 2009, 9, 4212−4229. (4) For recent reports on pharmaceutical cocrystals see: (a) Guo, K.; Sadiq, G.; Seaton, C.; Davey, R.; Yin, Q. Cryst. Growth Des. 2010, 10, 823



Article

Mol. Pharmaceutics 2007, 4, 401−416. (c) Babu, N. J.; Reddy, L. S.; Nangia, A. Mol. Pharmaceutics 2007, 4, 417−434. (d) Childs, S. L.; Hardcastle, K. I. Cryst. Growth Des. 2007, 7, 1291−1304. (e) Bučar, D.-K.; Henry, R. F.; Lou, X.; Duerst, R. W.; MacGillivray, L. R.; Zhang, G. G. Z. Cryst.Growth Des. 2008, 8, 3032−3037. (f) Reddy, L. S.; Bethune, S. J.; Kampf, J. W.; Rodríguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 378−385. (g) Childs, S. L.; Wood, P. A.; RodríguezHornedo, N.; Reddy, L. S.; Hardcastle, K. I. Cryst. Growth Des. 2009, 9, 1869−1888. (h) Bučar, D.-K.; Henry, R. F.; Lou, X.; Duerst, R. W.; MacGillivray, L. R.; Zhang, G. G. Z. Cryst.Growth Des. 2009, 9, 1932− 1943. (i) Weyna, D. R.; Shattock, T.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2009, 9, 1106−1123. (j) Liao, X.; Gautam, M.; Grill, A.; Zhu, H. J. J. Pharm. Sci. 2010, 99, 246−254. (k) Kavuru, P.; Aboarayes, D.; Arora, K. K.; Clarke, H. D.; Kennedy, A.; Marshall, L.; Ong, T. T.; Perman, J.; Pujari, T.; Wojtas, L.; Zaworotko, M. J. Cryst. Growth Des. 2010, 10, 3568−3584. (l) Cheney, M. L.; Weyna, D. R.; Shan, N.; Hanna, M.; Wojtas, L.; Zaworotko, M. J. Cryst. Growth Des. 2010, 10, 4401−4413. (13) (a) Blagden, N.; Berry, D. J.; Parkin, A.; Javed, H.; Ibrahim, A.; Gavan, P. T.; De Matos, L. L.; Seaton, C. C. New J. Chem. 2008, 32, 1659−1672. (b) Childs, S. L.; Rodríguez-Hornedo, N.; Reddy, L. S.; Jayasankar, A.; Maheshwari, C.; McCausland, L.; Shipplett, R.; Stahly, B. C. CrystEngComm 2008, 10, 856−864. (c) Karki, S.; Frišcǐ ć, T.; Jones, W. CrystEngComm 2009, 10, 470−481. (14) (a) Bruker Analytical X-ray Systems. SMART: Bruker Molecular Analysis Research Tool, versions 5.057 and 5.618; Bruker AXS Inc.,: Madison, Wisconsin, U.S.A., 1997 and 2000. (b) Bruker Analytical X-ray Systems. SAINT + NT, versions 6.01 and 6.04; Bruker AXS Inc.,: Madison, Wisconsin, U.S.A., 1999 and 2001. (c) Sheldrick, G. M. SHELX86, Program for Crystal Structure Solution; University of Göttingen: Germany, 1986. (d) Bruker Analytical X-ray Systems. SHELXTL-NT, versions 5.10 and 6.10; Bruker AXS Inc.,: Madison, Wisconsin, U.S.A., 1999 and 2000. (15) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837−838. (16) Brandenburg, K. Diamond, version 3.1c, Crystal Impact: Bonn, Germany, 1997. (17) (a) Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 2372− 2373. (b) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem. Commun. 2004, 890−891. (18) (a) Zhang, G. G. Z.; Henry, R. F.; Borchardt, T. B.; Lou, X. J. Pharm. Sci. 2007, 96, 990−995. (b) Takata, N.; Shiraki, K.; Takano, R.; Hayashi, Y.; Terada, K. Cryst. Growth Des. 2008, 8, 3032−3037. (19) Rodríguez-Hornedo, N.; Nehm, S. J.; Seefeldt, K. F.; PagánTorres, Y.; Falkiewicz, C. J. Mol. Pharmaceutics 2006, 3, 362−367. (20) (a) Chiarella, R. A.; Davey, R. J.; Peterson, M. L. Cryst. Growth Des. 2007, 7, 1223−1226. (b) ter Horst, J. H.; Cains, P. W. Cryst. Growth Des. 2008, 8, 2537−2542. (c) Jayasankar, A.; Reddy, L. S.; Bethune, S. J.; Rodríguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 889−897. (21) (a) Brittain, H. G. Cryst Growth Des. 2009, 9, 2492−2499. (b) Brittain, H. G. Cryst Growth Des. 2009, 9, 3497−3503. (c) Brittain, H. G. Cryst Growth Des. 2010, 10, 1990−2003. (22) (a) Buck, U.; Huisken, F. Chem. Rev. 2000, 100, 3863−3890. (b) Köddermann, T.; Schulte, F.; Huelsekopf, M.; Ludwig, R. Angew. Chem., Int. Ed. 2003, 42, 4904−4908. (23) (a) Bis, J. A.; Zaworotko, M. J. Cryst. Growth Des. 2005, 5, 1169− 1179. (b) Bhogala, B. R.; Basavoju, S.; Nangia, A. CrystEngComm 2005, 7, 551−562. (c) Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharmaceutics 2007, 4, 323−338. (24) The ACZ molecules in the crystal lattices of the substances considered in this section are related by inversion centers. Therefore, each crystal lattice contains ACZ molecules, in which the S1-C2-N3C3 and N4-S2-C1-S1 torsion angles have opposite signs. (25) (a) Allen, F. H.; Motherwell, W. D. S.; Raithby, P. R.; Shields, G. P.; Taylor, R. New. J. Chem. 1999, 25−34. (b) Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. J. Am. Chem. Soc. 2002, 124, 14425−14432. (c) Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A.; Nieuwenhuyzen, M. Cryst. Growth Des. 2003, 3, 159−165. (d) Aakeröy, C. B.; Desper, J.; Helfrich, B. A. CrystEngComm 2004, 6, 19−24. (e) McMahon, J. A.; Bis, J. A.;

Vishweshwar, P.; Shattock, T. R.; McLaughlin, O. L.; Zawarotko, M. J. Z. Kristallogr. 2005, 220, 340−350. (f) Bhatt, P. M.; Azim, Y.; Thakur, T. S.; Desiraju, G. R. Cryst. Growth Des. 2009, 9, 951−957. (g) Sanphui, P.; Sarma, B.; Nangia, A. Cryst. Growth Des. 2010, 10, 4550−4564. (26) (a) Á ngyán, J. G.; Poirier, R. A.; Kucsman, A.; Csizmadia, I. G. J. Am. Chem. Soc. 1987, 109, 2237−2245. (b) Pandya, N.; Basile, A. J.; Gupta, A. K.; Hand, P.; MacLaurin, C. I.; Mohammad, T.; Ratemi, E. S.; Gibson, M. S.; Richardson, M. F. Can. J. Chem. 1993, 71, 561− 571. (c) Minkin, V. I.; Minyaev, R. M. Chem. Rev. 2001, 101, 1247− 1265. (27) (a) Rodriguez-Cuamatzi, Luna-García, R.; Torres-Huerta, A.; Bernal-Uruchurtu, M. I.; Barba, V.; Höpfl, H. Cryst. Growth Des. 2009, 9, 1575−1583. (b) Clarke, H. D.; Arora, K. K.; Bass, H.; Kavuru, P.; Ong, T. T.; Pujari, T.; Wojtas, L.; Zaworotko, M. J. Cryst. Growth Des. 2010, 10, 2152−2167. (c) Varughese, S.; Desiraju, G. R. Cryst. Growth Des. 2010, 10, 4184−4196. (28) (a) Bingham, A. L.; Hughes, D. S.; Hursthouse, M. B.; Lancaster, R. W.; Tavener, S.; Threlfall, T. L. Chem. Commun. 2001, 603−604. (b) Adsmond, D. A.; Grant, D. J. W. J. Pharm. Sci. 2002, 90, 2058−2077. (29) Takano, T.; Sasada, Y.; Kakudo, M. Acta Crystallogr. 1966, 21, 514.

824


Modification of the Supramolecular Hydrogen-Bonding Patterns of

Recommend Documents