Modification of the Supramolecular Hydrogen-Bonding Patterns of Acetazolamide in the Presence of...

Modification of the Supramolecular Hydrogen-Bonding Patterns ofAcetazolamide in the Presence of Different Cocrystal Formers: 3:1,2:1, 1:1, and 1:2 Cocrystals from Screening with the StructuralIsomers of Hydroxybenzoic Acids, Aminobenzoic Acids,Hydroxybenzamides, Aminobenzamides, Nicotinic Acids,Nicotinamides, and 2,3-Dihydroxybenzoic AcidsJenniffer I. Arenas-García,† Dea Herrera-Ruiz,*,† Karina Mondrago !n-Va !squez,† Hugo Morales-Rojas,‡

and Herbert Ho"pf l*,‡†Facultad de Farmacia, Universidad Auto !noma del Estado de Morelos, Av. Universidad 1001, C.P. 62209 Cuernavaca, Me !xico‡Centro de Investigaciones Químicas, Universidad Auto !noma del Estado de Morelos, Av. Universidad 1001, C.P. 62209 Cuernavaca,Me !xico

*S Supporting Information

ABSTRACT: Acetazolamide (ACZ) has been combined via liquid-assistedgrinding in water with a library of cocrystal formers derived from benzoic andnicotinic acid, which provided novel cocrystals with 2-hydroxybenzamide, 2-aminobenzamide, picolinamide, and 2,3-dihydroxybenzoic acid. The cocrystallinephases were identified first by XRPD analysis and then structurally characterizedby IR spectroscopy and single-crystal X-ray diffraction analysis. These cocrystalsand the previously reported cocrystalline phases obtained from 4-hydroxybenzoicacid and nicotinamide constitute a series of six cocrystals of varied stoichiometricratios (3:1, 2:1, 1:1, and 1:2), which allowed for a profound analysis of thestructural and chemical factors that govern their formation. The structural analysishas shown that the ACZ molecules participate in the dominant hydrogen-bondingpatterns within the crystal structures: three cocrystal structures exhibit extendedsupramolecular 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 theremaining two cocrystals are true two-component 2D or 3D networks. In addition, a variety of alternative preparative methods (liquid-assisted grinding, neat grinding, reaction crystallization, solution-mediated phase transformation, and solution crystallization) have beenemployed, showing that four of the six cocrystals required the presence of water for successful cocrystal formation.

1. INTRODUCTIONVariations in the structural organization of a chemicalcompound in the solid state influence the physical andchemical properties on the macroscopic level, which can haveimportant implications in diverse fields such as materials andpharmaceutical sciences. In the case of active pharmaceuticalingredients (APIs), biopharmaceutical properties such assolubility, dissolution rate, chemical stability, and hygrosco-picity are modified by changes of the solid-state structures. Forthis reason, generally different solid-state forms of a given APIare 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 thescientific communities in public institutions, industry, and reg-ulatory agencies, and diverse studies have revealed promisingresults concerning the improvement of the biopharmaceuticalproperties.5 Moreover, such new solid phases may help also to

overcome problems in formulation and manufacturing.1,2 Animportant advantage of pharmaceutical cocrystals is that there isa large number of reagents available for the exploration ofcocrystal formation, e.g., the GRAS list approved by the FDA,6

which is particularly relevant for APIs lacking functional groupsthat 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 drugis an inhibitor of carbonic anhydrase and is used for thetreatment of glaucoma. Further, it has antiepileptic and diureticproperties, and has been evaluated as a remedy for respiratorydiseases and the prevention of adverse effects of drugs in the

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

Article

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© 2011 American Chemical Society 811 dx.doi.org/10.1021/cg201140g | Cryst. Growth Des. 2012, 12, 811!824

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

acetamide and sulfonamide functions, thiadiazole heterocyclesare unusual in drugs and have, as far as we know, not beenexplored 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 cocrystalswith ACZ, we set up a library of cocrystal formers structurallyrelated to 4HBA and NAM and employed them for screening

experiments. The systematic study of different solid forms for agiven compound enables the evaluation of competition effectsfor hydrogen bond formation between different functionalgroups, which is relevant for supramolecular synthesis and crystalengineering as well as for understanding phenomena such aspolymorphism and structure!property relationships.12 Thelibrary is constituted of a complete series of structural isomersfor seven different types of chemical compounds, all of whichhave one or two of the above-mentioned functional groups: (i)hydroxybenzoic acids, (ii) aminobenzoic acids, (iii) hydroxy-benzamides, (iv) aminobenzamides, (v) nicotinic acids, (vi)nicotinamides, and (vii) 2,3-dihydroxybenzoic acids (Scheme 1).Therefore, an important aspect is that the possible cocrystalformers have similar size and molecular shape but differentnumbers and spatial distribution of hydrogen bond donor andacceptor atoms. Our screening experiments lead to four co-crystals of ACZ, which have been characterized in a comparativemanner together with the previously prepared compoundsACZ-4HBA and ACZ-NAM-H2O.

11

Recent reports have documented that the preparative methodcan be crucial for generating the desired cocrystal.13 Therefore, avariety of previously established preparative methods (liquid-assisted grinding, neat grinding, reaction crystallization, andsolution-mediated phase transformation) have been employed forthe preparation of the six cocrystals of ACZ, in order to evaluatethe influence of the experimental setup for cocrystal formation.

2. EXPERIMENTAL SECTION2.1. Materials. Acetazolamide (form A), cocrystal formers, and

solvents were commercially available and have been used as receivedwithout further purification.

2.2. Cocrystal Preparation. Liquid-assisted grinding (LAG) experi-ments were performed by mechanical grinding in a Retsch MM400 mixer

Chart 1

Scheme 1.a

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

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dx.doi.org/10.1021/cg201140g | Cryst. Growth Des. 2012, 12, 811!824812

mill (30 min at 25 Hz). Before starting, the corresponding mixtures ofACZ and the cocrystal former were placed into stainless steel grinding jars(1.5 mL), and one drop of water, acetonitrile, or acetone was added. Neatgrinding (NG) was performed with the same equipment in an analogousmanner but without solvent and extending the mechanical grinding to 60min. For the reaction crystallization (RC) experiments, a saturated solutionof the corresponding cocrystal former was prepared either in acetonitrile ora 1:1 solvent mixture between acetonitrile and water. Upon heating, smallquantities of ACZ were added until a precipitate was observed. Afterprecipitation was initiated, the solutions were allowed to cool down toroom temperature under stirring. Finally, the precipitates were filtered andcharacterized by XRPD. For the solution-mediated phase transformation(SMPT, slurry technique), ACZ and the corresponding cocrystal formerwere combined under stirring in the presence of a few drops ofacetonitrile, water, or a 1:1 mixture of these solvents (Table 1). After aperiod of 3!4 h, a paste had formed, which was distributed on a filterpaper for drying. The solids obtained from LAG, NG, RC, and SMPTwere examined by PXRD in order to establish if a new solid phase hadformed. For the solution crystallization (SC) experiments, the startingmaterials were dissolved in 2:1, 1:1, 1:2, 1:3, 1:4, and 1:5 stoichiometricratios in hot acetonitrile, water, acetone, or a 1:1 (v/v) acetonitrile!watermixture. After filtration, the solutions were stored at room temperature andallowed to slowly evaporate the solvent. In a parallel series of experimentssmall quantities of solid cocrystalline material were added (seeding). Thespecific experimental conditions, from which crystals suitable for single-crystal 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 scanningcalorimetry (DSC) and thermogravimetric analyses (TGA) wereaccomplished with a TA SDT Q600 instrument. Approximately 3 mgof each solid sample was placed in alumina crucibles and analyzed inthe 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 aBruker D8-Advance diffractometer equipped with a LynxEye detector(!Cu!K"1 = 1.5406 Å; monochromator, germanium). The equipmentwas operated at 40 kV and 40 mA, and data were collected at roomtemperature in the range of 2# = 5!40°. Single-crystal X-raydiffraction studies were performed on a Bruker-APEX diffractometerwith a CCD area detector (!M$K" = 0.71073 Å; monochromator,graphite). Frames were collected at T = 293 K via %/&-rotation at 10 sper 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

solution, refinement, and data output were carried out with theSHELXTL-NT program package.14c,d Nonhydrogen atoms wererefined anisotropically. C!H hydrogen atoms were placed ingeometrically calculated positions using the riding model. O!H andN!H hydrogen atoms have been located from iterative examination ofdifference Fourier maps following least-squares refinements of theprevious 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 theWINGX program package.15 DIAMOND was used for the creation offigures and analysis of hydrogen-bonding interactions in the crystallattice.16 Crystallographic data for the five crystal structures have beendeposited with the Cambridge Crystallographic Data Centre assupplementary publications no. CCDC-841869!841872. Copies ofthe 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).

3. RESULTS AND DISCUSSION3.1. Screening Experiments. Screening experiments were

carried out with all of the reagents outlined in Scheme 1 exceptfor 3-hydroxybenzamide (3HBA), which was commercially notavailable, and those which have been examined already in theforegoing project (benzoic acid, salicylic acid, 4-hydroxybenzoicacid, 2,5-dihydroxybenzoic acid, 4-hydroxybenzamide, picolinicacid, nicotinic acid, isonicotinic acid, nicotinamide, andisonicotinamide).11 On the basis of the previous results, whichgave cocrystals with 4HBA and NAM,11 the liquid-assistedgrinding (LAG) method17 using water as solvent was alsoemployed herein. Novel solid phases were identified by XRPD,and to discriminate cocrystals from polymorphs or solvates,parallel grinding experiments using only ACZ or thecorresponding cocrystal former were performed. This procedureallowed us to establish that 2-hydroxybenzamide (2HBAM),2-aminobenzamide (2ABAM), picolinamide (PAM), and 2,3-dihydroxybenzoic acid (23DHBA) gave XRPD patterns, whichdiffered significantly from known polymorphs of the startingmaterials and could not be attributed either to hydrates of thecorresponding cocrystal former, as it occurred for 4-hydrox-ybenzamide as well as 2,4-, 2,6-, 3,4-, and 3,5-dihydroxybenzoicacid. The solids formed with 2HBAM, 2ABAM, PAM, and23DHBA were then further characterized by IR spectroscopyand single-crystal X-ray diffraction analysis, showing thatcocrystals of varied stoichiometric composition had formed

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

aThe stoichiometry of ACZ and the cocrystal former used for the preparation of the saturated solution is indicated. bOnly starting materialswere detected. cSmall quantities of solid cocrystalline material were added (seeding). dA solid phase different from that found by solutioncrystallization had formed. eA mixture of the dehydrated cocrystal ACZ-2ABAM, the phase found by LAG in water, and starting materials hadformed. fTraces of an unidentified lateral byproduct were detected. gApparently, the sample absorbed water from the atmosphere. hTraces ofACZ were detected.



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(vide infra). As outlined in Scheme 1, 2HBAM, PAM, and23DHBA generated 2:1, 1:2, and 3:1 cocrystals, respectively,while 2ABAM gave a 4:2:3 cocrystal trihydrate. The compositionof this hydrate was also confirmed by thermogravimetric analysis(Figure S1, Supporting Information).Together with the previously reported 1:1 cocrystal ACZ-

4HBA and the 1:1:1 cocrystal hydrate ACZ-NAM-H2O,11 wehave 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 largeenough for systematically exploring how diverse factors such as

solvents and preparative techniques might influence the formationof cocrystalline phases. For that reason, different alternativepreparative methods were employed for the combination of ACZwith 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 LAGtechnique was performed also with the less polar solventsacetonitrile and acetone, in which ACZ is significantly more solublethan in water. Comparative surveys of the XRPD patterns resultingfrom the different experimental methods used for the preparation ofcocrystals ACZ-2HBAM, ACZ-2ABAM-H2O, ACZ-PAM, andACZ-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 CH3CN-H2O (50/50 vv), and (h) pattern simulated from the single-crystalX-ray diffraction analysis. All XRPD patterns of cocrystals given in thisfigure correspond to 2:1 stoichiometric combinations of ACZ and2HBAM.

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 ACZ-2ABAM-H2O at 100 °C for 15 min, (j) stirring of ACZ-2ABAM inH2O for 16 h, and (k) pattern of ACZ-2ABAM-H2O simulated fromthe single-crystal X-ray diffraction analysis. All XRPD patterns ofcocrystals given in this figure correspond to 2:1 stoichiometriccombinations of ACZ and 2ABAM.

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) patternsimulated from the single-crystal X-ray diffraction analysis. All XRPDpatterns of cocrystals given in this figure correspond to 1:2stoichiometric combinations of ACZ and PAM.

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 CH3CN-H2O (50/50 vv), and (h) pattern simulated from the single-crystalX-ray diffraction analysis. All XRPD patterns of cocrystals given in thisfigure correspond to 3:1 stoichiometric combinations of ACZ and23DHBA.



Figures 1!4 and the results summarized in Table 1 show thatonly two of the six cocrystals identified from LAG in watercould be prepared also by LAG in acetonitrile and acetone(ACZ-4HBA and ACZ-PAM). This is understandable for thecocrystal hydrates ACZ-2ABAM-H2O and ACZ-NAM-H2O,but ACZ-2HBAM and ACZ-23HDBA do not contain watermolecules in the crystal structure. Two possible explanationsmight be given: the first is related to the low solubility of2HBAM and 23DHBA in acetonitrile and acetone, and thesecond is that water might play an important role in the kineticsof crystal nucleation and growth.Cocrystal formation by NG was successful for all water-free

cocrystals and additionally for ACZ-NAM-H2O, which hasbeen attributed to the absorption of water from the atmosphereduring the grinding process.11 In the case of 2ABAM, theresulting sample was a mixture of the dehydrated phase ACZ-2ABAM, the cocrystalline phase already obtained from LAGwith water, which is suggested to be the hemihydrate ACZ-2ABAM-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 inwater. However, only 4HBA and PAM were sufficiently solublein this solvent. Therefore, depending on the solubility of thecocrystal former, in the remaining cases either a 1:1 mixture ofwater and acetonitrile or pure water was employed. With theexception of 2ABAM, which gave a solid form different fromthat formed by LAG with water (vide infra), in all cases bothmethods lead to phases with PXRD patterns identical to thoseobtained from the samples prepared by LAG with water andneat grinding. However, for all samples prepared by the SMPTand RC techniques, the PXRD patterns were identical to thosesimulated from the structures determined by single-crystalX-ray diffraction analysis (see simulated patterns at the bottomin Figures 1!4).As already observed for ACZ-4HBA and ACZ-NAM-H2O

and other cocrystals with APIs having low solubility, ACZrequires an excess of the cocrystal former for cocrystal growthfrom solution (solution crystallization).11,20 Moreover, in five ofthe six systems explored herein the addition of small quantitiesof solid cocrystalline material to the crystallizing solution(seeding) was required (Table 1).

3.3. Formation of Cocrystal ACZ-2ABAM (2:1). Thecrystal lattice water molecules in ACZ-2ABAM-H2O can beeliminated through thermal treatment. After heating thecocrystal trihydrate to 100 °C for a period of 15 min, a newsolid phase was obtained as shown by a comparison of theXRPD patterns (Figure 2h and i). The same crystalline phase waspresent also in the sample obtained by the neat grindingmethod (Figure 2e). This new phase is a cocrystal as can be seenfrom a comparison of the IR data given in Table 2 and Figure 5,

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

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

API cocrystal formers cocrystals

ACZ 2HBAM 2ABAM PAM 23DHBAACZ-

2HBAMACZ- 2ABAM-

H2OACZ- 2ABAM-1/2

H2OACZ-

2ABAMACZ-PAM

ACZ-23DHBA

' C!O 1680 1676 1660 1663 1678 1682 1674 1662 1662 1680 16841654 1660

' O!H, N!H 3302 3397 3411 3418 3376 3483 3625 3503 3505 3446 34543182 3313 3323 3276 3245 3369 3546 3469 3467 3413 3351

3190 3196 3181 3343 3472 3390 3386 3328 32813306 3390 3333 3316 3250 32593171 3335 3185 3162 3181 3142

3151 29022771

' N!HII 1551a 1546a 1545a 1543a 1539a 1564a 1546a

1589b 1585b 1588b 1573b 1579b 1578b 1578b 1589b

1629b 1628b 1608b 1619b 1620b

' SO2NH2 1368 1355 1345 1372 1368 1363 13751177 1178 1173 1171 1176 1173 1171

a' N!HII for ACZ.b' N!HII for 2HBAM, 2ABAM, and PAM, respectively.

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



acetonitrile, permits one to suggest that it is a second hydratedphase or a polymorph of ACZ-2ABAM-H2O. Thermogravi-metric analysis indicates a weight loss of 0.70% (calculated:0.78%) within the temperature range of 40 to 120 °C, indicatingthat the phase might be the hemihydrate ACZ-2ABAM-1/2H2O(Figure S3, Supporting Information). The IR spectra of de-hydrated ACZ-2ABAM and hemihydrate ACZ-2ABAM-1/2H2O are very similar (Figure 5d and e, and Table 2), suggestinga strong structural relationship. This is reasonable consider-ing that the ACZ/2ABAM/H2O ratio in this phase would be8:4:1.3.4. IR Spectroscopy. As already shown in our previous

report for ACZ-4HBA and ACZ-NA-H2O, a comparison of thesolid-state IR spectra of ACZ, the cocrystal former, and thecorresponding cocrystal allows us to establish whether a newsolid form has been generated.11 This is illustrated forcompounds ACZ-2ABAM-H2O and ACZ-23DHBA in Figures5 and 6, showing that the IR spectrum of the cocrystal does not

correspond to a superposition of the IR spectra of the individualcomponents (ACZ and cocrystal former). The analogous graphsfor the remaining cocrystals examined herein are available inSupporting Information (Figures S4!S5). Listings of the mostcharacteristic IR bands are given in Table 2, together with thedata for ACZ and the corresponding cocrystal formers.

Among the most important evidence for cocrystal formationis the observation that all spectra show broad bands in theregion of 2500!3500 cm!1, which are typical for crystalstructures with extended hydrogen-bonding interactions.21 Thepresence of ACZ in the solid phases is indicated mainly by twocharacteristic bands for vibrations of the sulfonamide group inthe region of 1345!1375 and 1171!1178 cm!1, and the amideII vibration 'N!H in the range of 1539!1564 cm!1 (Table 2).The shifts in comparison to the values found for ACZ (1368and 1177 cm!1 for 'sulfonamide; 1551 cm!1 for 'N!H) reflectvariations in the hydrogen-bonding patterns within the crystalstructures of the resulting cocrystals. A further relevantobservation is that the IR spectrum of the cocrystal hydrateACZ-2ABAM-H2O shows a band centered at 3625 cm!1,which can be attributed to the 'O!H stretching frequency ofcrystal lattice water.22 As expected, this band is absent in thespectrum 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 pKavalue (pKa = 2.9) that might enable proton transfer to ACZ(pKa = 7.2) and, thus, give a salt.23 Examination of the IRspectrum shown in Figure 6 indicates that such a protontransfer from the cocrystal former to ACZ did not occurbecause the C!O stretching band at 1677 cm!1 did not suffera significant shift to lower wavenumbers. There is no strongband in the region for the asymmetric 'COO vibration in therange of 1610!1550 cm!1, in which arylcarboxylate saltstypically have a strong absorption.21

3.5. Single-Crystal Diffraction Analysis. Single cocrys-tals of ACZ-2HBAM, ACZ-2ABAM-H2O, ACZ-PAM, andACZ-23DHBA have characteristic morphologies, which allowone to distinguish them from ACZ under a microscope (Figure 7).The most relevant crystallographic data for these cocrystals arelisted in Table 3. Hydrogen bond parameters are summarized inTable 4.

3.6. Hydrogen-Bonding Characteristics of ACZ. Theprevious structural reports on the polymorphs of ACZ (formsA and B)9 and cocrystals ACZ-4HBA and ACZ-NAM-H2O

11

have shown that ACZ has a relatively rigid molecularconformation with only one site of certain conformationalflexibility. As shown in Scheme 2, the molecular structure canbe 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) ACZ-23DHBA.

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

crystal dataa ACZ-2HBAM (2:1) ACZ-2ABAM-H2O(4:2:3) ACZ-PAM (1:2) ACZ-23DHBA (3:1)

formula 2C4H6N4O3S2·C7H7NO2 4C4H6N4O3S2·2C7H8N2O·3H2O C4H6N4O3S2·2C6H6N2O 3C4H6N4O3S2·C7H6O4

MW (g mol!1) 581.63 1215.35 466.50 820.86space group P1# P21/n P1# P21/ca (Å) 8.8200(8) 11.2462(17) 8.6156(12) 9.763(3)b (Å) 9.1977(8) 26.971(4) 10.4253(14) 14.434(4)c (Å) 14.8854(14) 17.230(3) 11.6675(16) 22.839(7)" (deg) 95.872(2) 90 79.910(2) 90( (deg) 100.119(2) 103.151(2) 86.334(2) 94.942(6)) (deg) 102.197(2) 90 88.606(2) 90V (Å3) 1149.68(18) 5089.1(13) 1029.6(2) 3206.2(16)Z 2 4 2 4* (mm!1) 0.478 0.438 0.307 0.509+calcd (g cm!3) 1.680 1.586 1.505 1.701Rb,c 0.068 0.051 0.068 0.063Rwd,e 0.142 0.126 0.148 0.137

a!MoK" = 0.71073 Å. bFo > 4,(Fo).cR = $"Fo| ! |Fc"/$|Fo|. dAll data. eRw = [$w(Fo2 ! Fc

2)2/$w(Fo2)2]1/2.



Because of an intramolecular O···S interaction and delocaliza-tion of the Namide lone pair, the thiadiazole acetamide frag-ment is quite rigid and has Z-configuration.9d Comparing theconformation of the ACZ molecules in the crystal structuresof the known polymorphs of ACZ and the six cocrystalscharacterized herein, we see that there are only small variationsin the dihedral angles formed between the mean planes of thesemoieties. This can be seen from the S1!C2!N3!C3 torsionangles ranging from !0.1 to !4.5° and +0.1 to +4.5°.24 Thesulfonamide group is more flexible, and rotation around theN4!S2 and C1!S2 bonds allows for a large variety of rota-tional conformers. This is illustrated by the N4!S2!C1!S1

torsion angles with values ranging from !78.2 to !137.7°and +78.2 to +137.7° for the above-mentioned series ofcompounds.24

These structural characteristics of ACZ generate three sitesfor relatively strong hydrogen bonds that can give rise to motifsI, IIa, IIb, IIIa, IIIb, IVa, and IVb (Scheme 3). Of these, motif Ioccurs at the carboxamidine fragment in ACZ and representsthe homodimeric C(N)NH···HN(N)C synthon that is structur-ally related to the homodimer formed by 2-aminopyridines.25

Motifs IIa and IIb are the cyclic and catemer patterns resultingfrom the N!H···O!C hydrogen-bonding interaction formedbetween the aminogroup of the sulfonamide function and thecarbonyl group of the acetamide moiety. Motifs IIIa/IIIb andIVa/IVb are well known from assemblies of molecules containingsulfonamide and carboxamide groups, respectively.25 In the caseof ACZ, the intramolecular O···S contact in ACZ inhibits the

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 N3!H1···N22 0.86 2.06 2.921(5) 175 +x,+y,+zI N23!H21···N2 0.86 2.01 2.870(5) 176 +x,+y,+zIIa N4!H3···O1 0.86 2.15 2.991(5) 165 !x+1,!y+1,!z+2IIa N24!H23···O21 0.86 2.02 2.850(3) 163 !x+1,!y,!zIIIa N4!H2···O2 0.86 2.18 3.029(6) 168 !x+2,!y+2,!z+2IIIa N24!H22···O22 0.86 2.27 3.076(6) 157 !x+1,!y,!z+1V N5!H12···O3 0.86 2.24 3.049(6) 156 +x,+y,+z!1V S1···O4 2.978(4) +x,+y,+z!1

ACZ-2ABAM I N3!H1···N22 0.86 2.10 2.963(3) 179 +x,+y,+z-H2O I N23!H21···N2 0.86 2.00 2.860(3) 177 +x,+y,+z

I N43!H41···N62 0.86 1.99 2.843(3) 175 +x!1/2,!y+1/2,+z+1/2I N63!H61···N42 0.86 2.04 2.891(3) 173 +x+1/2,!y+1/2,+z!1/2IIc N4!H2···O5w 0.86 1.99 2.837(4) 170 !x+1,!y,!z+1IIc O5w-H5A···O1 0.84 1.91 2.754(4) 179 +x,+y,+z

ACZ-PAM IIa N4!H3···O1 0.86 2.16 2.982(4) 161 !x+1,!y+1,!z+1VII N3!H1···O4 0.86 1.92 2.779(3) 178 !x,!y+2,!zVII N6!H11···N2 0.86 2.11 2.961(4) 171 !x,!y+2,!zIX N4!H2···O5 0.86 1.95 2.802(4) 170 !x+1,!y+2,!zIX N8!H17···O3 0.86 2.12 2.970(4) 169 +x,+y+1,+zX N6!H12···N7 0.86 2.42 3.108(4) 137 !x+1,!y+2,!z+1X N8!H18···N5 0.86 2.62 3.349(4) 144 !x+1,!y+2,!z+1

ACZ-23DHBA I N3!H1···N22 0.86 2.01 2.861(6) 170 +x,+y,+zI N23!H21···N2 0.86 2.09 2.944(6) 174 +x,+y,+zI N43!H41···N42 0.86 2.05 2.897(6) 167 !x+1,!y+2,!z+1IIa N44!H43···O41 0.86 2.27 3.042(6) 149 !x+2,!y+2,!z+1IIe N4!H3···O42 0.86 2.16 2.991(6) 162 +x-1,+y,+zIIe N24!H22···O1 0.86 2.18 2.949(6) 149 +x+1,+y,+zIIe N44!H42···O21 0.86 2.07 2.923(6) 174 +x,+y,+zIIIa N24!H23···O23 0.86 2.27 3.087(6) 158 !x+1,!y+2,!zVI O7!H13···O3 0.84 2.06 2.754(5) 140 +x+1,! y+1/2 + 1,+z+1/2VI S1···O6 3.254(4) +x+1,!y+1/2 + 1,+z+1/2

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

Scheme 2. The Molecular Structure of ACZ Can Be Dividedinto Three Sections, Each of Which Contains Sites forIntermolecular Interactions



syn-orientation of the N!H and C!O groups; therefore, thehomodimeric 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 andone 2HBAM molecule, showing that the API!cocrystal formerstoichiometry of the cocrystal is 2:1. Within the crystal lattice,the ACZ molecules are connected through hydrogen bondsbased on motifs I, IIa, and IIIa (Scheme 3) to give 2D layersrunning parallel to (11 #1) (Figure 8a). The conformation ofthese layers can be described as rectangular undulated, thusproviding cavities located alternately above and below the meanplane of the layer (Figure 8b). In the cavities, discrete entities ofthe 2HBAM cocrystal former molecules are embedded (Figure 8c),which interact with one of the independent ACZ moleculesthrough Ocarboxamide···Sthiadiazole and Ncarboxamide-H···Osulfonamidebonds (Table 4) to form the heterodimeric motif V (Scheme 4and Figure 8d). So far, there are relatively few reports on O···Sinteractions.26 The distance of the intermolecular O···S bond,2.978(4) Å, is significantly less than the sum of the van der Waalsradii of oxygen and sulfur (3.30 Å), but longer than the intra-molecular O···S contacts in the thiadiazole carboxamide fragments,2.730(3) and 2.737(3) Å. The host!guest interactions arecompleted by Ncarboxamide-H···Osulfonamide and C2HBAM-H···Osulfonamidecontacts between the guest and surrounding ACZ molecules(Table S1, Supporting Information). A further interestingobservation is that the ACZ homodimer (motif I) forming the

bottom of the cavity is significantly distorted from planarity,although there are no short -···- contacts between the participatingentities. This is shown by the dihedral angle formed between themean planes of the thiadiazole rings: 19.5°. The O!H function in2HBAM is involved in an intramolecular O!H···O hydrogen bondwith the neighboring carboxyl group and only participates in anadditional weak C!H···O contact. In the third dimension, the 2Dlayers are translation stacked and held together by dipole···dipoleand van der Waals forces.

3.8. Acetazolamide-2-aminobenzamide Trihydrate(4:2:3). The asymmetric unit of ACZ-2ABAM-H2O iscomposed of four ACZ, two 2ABAM, and three watermolecules. Thus, as for the case of ACZ-2HBAM, the API!cocrystal former stoichiometry of the cocrystal is 2:1. In thecrystal structure, the four independent ACZ molecules formhomodimers with hydrogen bonds based on motif I. Furtherconnection through Nsulfonamide-H···Ocarboxamide and Nsulfonamide-H···Osulfonamide gives 2D hydrogen layers propagating parallelto the ac plane (Figure 9a). In the third dimension, the2D double-layers are cross-linked via Ow-H···Ocarboxamide,Ow-H···Osulfonamide, and Nsulfonamide-H···Ow hydrogen bondswith all three independent crystal lattice water molecules(O5, O6, and O7). Thus, in contrast to the crystal structure ofACZ-2HBAM, an overall 3D hydrogen-bonded network hasformed (Figure 9b). Although the homodimeric cyclic motifs IIaand IIIa which are common for ACZ are not observed in this

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



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

structures has been documented recently by comparativestructural analyses of different series of cocrystals.27

As for ACZ-2HBAM, the arrangement of the ACZ moleculesgenerates cavities, in which discrete 2ABAM molecules areembedded through Namine-H···Osulfonamide, Ncarboxamide-H···Osulfonamide, and C!H2ABAM···Ocarboxamide interactions(Table 4 and Figure 9c). In contrast to ACZ-2HBAM, in thiscase no heterodimeric motif is formed. A possible reason mightbe that the carboxamide function of 2ABAM is compromised instrong C!O···H!Ow and N!H···Ow hydrogen bonds withwater molecules. Similar to ACZ-2HBAM, the NH2 function isinvolved in an intramolecular N!H···O hydrogen bond withthe neighboring carboxamide group. The inclusion of thecocrystal former generates two crystallographically independent2D layers of the composition [(ACZ)2(2ABAM)]n, each ofwhich is formed by two independent ACZ and oneindependent 2ABAM (Figure 9d).

3.9. Acetazolamide-picolinamide (1:2). The asymmetricunit of ACZ-PAM consists of one crystallographicallyindependent ACZ molecule and two cocrystal former entities,now giving a 1:2 API!cocrystal former stoichiometry of thecocrystal. Within the crystal lattice, the ACZ molecules formdimeric units based on motif IIa, and each ACZ molecule bindsone of the two independent PAM molecules, giving theheterodimeric motif VII (Scheme 4 and Figure 10a,b). Thispattern is similar to motif VIII (Scheme 4), which had formedbetween ACZ and 4HBA in the 1:1 cocrystal ACZ-4HBA11

and is known also from a series of cocrystals derived fromsulfathiazole 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 ofindependent PAM molecules to give 1D chains running alongaxis c. Motif IX can be considered as an expanded pattern of

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

Scheme 4. Hydrogen-Bonding Patterns Relevant for the Discussion of the Supramolecular Organization in the CrystalStructures 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.



motif IIIa (Scheme 3). At the same time, the two independentPAM 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 thecocrystal former.29

The hydrogen-bonding patterns based on the above-mentioned motifs (IIa, VII, IX, and X) generate 2D double-layers parallel to (110) (Figure 10d). In the third dimension,the double layers are stacked and held together by Ccarboxamide-H···Osulfonamide, dipole···dipole and van der Waals forces. Ofthese, the C!H···O interactions are sustained betweenneighboring ACZ molecules, forming the so far unknownhomodimeric motif IId (Scheme 4).3.10. Acetazolamide-2,3-dihydroxybenzoic Acid

(3:1). The asymmetric unit of ACZ-23DHBA contains threeACZ and one 23DHBA molecule, showing that the API!cocrystal former stoichiometry of the cocrystal is 3:1. Thecrystal lattice consists of a complex 3D hydrogen-bondedskeleton setup by ACZ molecules. Two of the threeindependent ACZ molecules (S1 and S21) form homodimericunits based on motif I, which are further connected byNsulfonamide-H···Osulfonamide and Nsulfonamide-H···Ocarboxamide bondsto a 3D framework having channels in the direction of axis a(Figure 11a). A more profound analysis reveals that thisskeleton contains 2D wave-like layers running parallel to the abplane (Figure 11b), which are linked in the third dimension byhomodimeric Nsulfonamide-H···Osulfonamide bonds based on motifIIIa.

The channels of the 3D skeleton are occupied by 1D chainsof the third independent ACZ molecule (S41) and discrete23DHBA molecules. The chains are sustained by homodimericunits based on motifs I and IIa (Figure 11c), and connected tothe 2D layers via Nsulfonamide-H···Ocarboxamide and Nsulfonamide-H···Osulfonamide hydrogen bonds, which generate an expandedpattern of motif IIa (motif IIe, Scheme 4) and strengthen the3D hydrogen bonded framework. The 23DHBA molecules areconnected to all three independent ACZ molecules viaO23DHBA-H···Osulfonamide, C23DHBA-H···Osulfonamide, andSthiadiazole···O23DHBA contacts (Figure 11d). Of these, theinteraction with ACZ (S1) occurs via the heterodimeric motifVI (Figure 11e), which is structurally related to motif V(Scheme 4). Nevertheless, in this case the O···S interaction issignificantly longer than that in ACZ-2HBAM, 2.978(4) Åversus 3.254(4) Å, and has a value close to the sum of the vander 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 asalt. Examination of the Fourier difference maps revealed thatthere is a hydrogen atom in close proximity to one of theoxygen atoms belonging to the COOH group. In addition, theC!O and C!O bond lengths for the carboxyl groups in the23DHBA molecules are in the expected range for COOHgroups when compared to the COO! moieties (1.335(6) and1.228(6) Å, respectively). In deprotonated benzoic acids withdelocalized carboxylate functions, the C!O distance isapproximately 1.25 Å; otherwise, the average C!O and C!Odistances are 1.31 Å and 1.21 Å, respectively.23

Figure 9. In the crystal structure of ACZ-2ABAM-H2O, hydrogen-bonding interactions between the ACZ molecules generate 2D hydrogen bondedlayers (a), which are cross-linked further by water molecules to a 3D hydrogen bonded network (b). The 2ABAM molecules are included withincavities (c), whereby the connectivity between ACZ and 2ABAM generates 2D layers (d). Note: Only one of the crystallographically independent2D layers (d) is shown.



3.11. Comparative Analysis of the Hydrogen-BondingInteractions. In order to detect the similarities and differ-ences between the supramolecular arrangements of the ACZmolecules in the different structures and to gain a more profoundinsight into the factors that govern the formation of crystalsbetween two chemical compounds, we have systematically analyzedthe hydrogen-bonding patterns found in the polymorphs andcocrystals of ACZ. For this purpose, we arranged a series ofparameters suitable for the characterization of hydrogen bondedsupramolecular aggregates in Table 5. They include (i) thenumber of donor and acceptor atoms that participate in hydrogenbonds for each component and the corresponding sum for theentire cocrystal, (ii) the dimensions of the hydrogen-bondingpatterns for ACZ, the cocrystal former, and the correspondingoverall cocrystal structure, and (iii) the type of particular homo- andheterodimeric motifs exhibited in the different crystalstructures. For better comparison, the cocrystals have beenordered according to decreasing molar content of ACZ (3:1,2:1, 1:1, and 1:2). At this point, it is important to mention thata series of cocrystals with varying composition of stoichiometryare rare and that there is probably no precedent for a cocrystalseries 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 thecrystal structures of the polymorphs and the cocrystals knownfor ACZ. In all solid phases included in this table, each ACZ

molecule uses all three possible N!H donor sites for hydrogen-bonding interactions. ACZ has five oxygen and nitrogenacceptor atoms, and additionally, the sulfur atom of thethiadiazole ring can form intra- and intermolecular O···Sinteractions. However, in all cases a maximum of four acceptoratoms is involved in the formation of the hydrogen bondednetworks. Under these circumstances, it can be expected thatpossible cocrystal formers must have several donor andacceptor atoms for being able to penetrate into the supra-molecular structure of ACZ. Indeed, the results show that thereagents which were able to form a cocrystal with ACZ containat 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-bondedfragment from its proper solid-state organization within thecrystal structure of the cocrystal. In four cocrystals, the cocrystalformers were included in the form of discrete molecules, and inthe remaining two samples in the form of hydrogen-bondeddimeric aggregates, whereby one consisted of a water-expandedhomodimeric pattern (NAM).This indicates that ACZ is the dominant building block for

hydrogen bonding in at least four of the six cocrystals. In allcrystal structures listed in Table 5, the ACZ molecules areconnected with each other by hydrogen bonds, with a cleardominance of the cyclic homodimeric motifs I and IIa. Motif Iappears in both polymorphs of ACZ and three cocrystals, whilemotif IIa is only found in ACZ form A but in five of the sixcocrystals. Interestingly, motif I is only found in the ACZ-richcocrystals ACZ-23DHBA (3:1), ACZ-2HBAM (2:1), andACZ-2ABAM (2:1), in which part of the ACZ molecules interactwith the cocrystal former. The remaining ACZ moleculesexhibit heterodimeric synthons (motifs V, VI, VII, and VIII) orother strong hydrogen-bonding interactions with the cocrystalformer at the thiadiazole acetamide or thiadiazole sulfonamidesite. Particularly interesting is the finding that the conforma-tional flexibility of the sulfonamide groups allows for the forma-tion of extended 2D and 3D hydrogen-bonded aggregates ofvarying topology. In the crystal structures of ACZ-2HBAM,ACZ-2ABAM-H2O, and ACZ-4HBA, the ACZ molecules form2D layers having either planar or undulated topology. Of these, thelayers in ACZ-2HBAM and ACZ-2ABAM-H2O have semi-spherical and spherical cavities, respectively, in which the cocrystalformers are located. In ACZ-4HBA, the cocrystal former cross-links the 2D layers, giving the crystal structure the appearance ofan intercalation or pillared compound. The 2D layers in the crystalstructures of ACZ-2HBAM, ACZ-2ABAM-H2O, and ACZ-4HBA show moderate to strong similarity with the structuralorganization of the 2D layers found in ACZ form A (Figure S6,Supporting Information). Thus, the conformational flexibility ofthe sulfonamide group enables ACZ to adapt its extended supra-molecular structure by topological variations to the presence ofvaried guest molecules.In ACZ-23DHBA, the linkage of ACZ molecules generates a

3D porous framework, in which the channels are filled byadditional ACZ molecules and the cocrystal former. Theinclusion of the cocrystal former within cavities or channels inACZ-2HBAM, ACZ-2ABAM-H2O, and ACZ-23DHBA re-sembles the corresponding networks to inclusion complexes orclathrates. Under this angle of view, only ACZ-NAM-H2O andACZ-PAM seem to be true two-component networks becausein this case, discrete homodimeric entities of each ACZ and thecocrystal former are hydrogen bonded to each other to formthe overall 2D and 3D networks.

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



ACZ forms cocrystals with carboxylic acids and carboxamidesvia two types of double-bridged heterodimeric synthons. InACZ-4HBA and ACZ-PAM, the thiadiazole-carboxamide frag-ment 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 atthe 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 differentkinds of interactions, a hydrogen bond and a S···O contact. Incontrast, the cocrystal hydrates ACZ-2ABAM-H2O and ACZ-NAM-H2O do not present a heterodimeric motif, and in thesesamples, ACZ and the cocrystal former are linked by singleN!H···O, N!H···N, and C!H···O interactions.

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 23DHBAmolecules. 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 andCocrystals of ACZ

donor and acceptor atoms withH-bonds (D/A)a

dimension of hydrogenbondingb

type of homo- and heterodimeric hydrogen-bonding motifs

cocrystal formerACZ/cocrystalformer ratio ACZ coformer sum ACZc coformerc sumd ACZc coformerc

ACZ-coformerd

ACZ form A 3/3 3/3 2D I, IIa, IIIaACZ form B 3/4 3/4 3D IACZ-23DHBA 3:1 9/10 1/0 10/10 3D 0D 3D I, IIa, IIe, IIIa VIACZ-2HBAM 2:1 6/8 3/1 9/9 2D 0D 2D I, IIa, IIIa VACZ-2ABAM-H, ACZ-2ABAM-1/2H2O

2:1 12/16 6/2 18/18 2D 0D 3D I, IIc

ACZ-4HBA 1:1 3/4 2/2 5/6 2D 0D 3D IIa VIIIACZ-NAM-H2O 1:1 3/3 2/2 5/5 0D 0D 3D IIaACZ-PAM 1:2 3/3 4/4 7/7 0D 0D 2D IIa, IId X VII, IXaOnly intermolecular hydrogen bonds are considered. ACZ-2ABAM-H2O and ACZ-NAM-H2O contain additional donor and acceptor atoms at thewater molecules. Bifurcated hydrogen bonds were counted as single interactions. bOnly O!H···O, O!H···N, N!H···O, and N!H···N hydrogenbonds 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.



4. CONCLUSIONSThe above-described structural analyses have shown thatACZ is a strong self-complementary building block capable ofgenerating extended 2D and 3D hydrogen bonded networks ofvaried topology. This is probably the reason why only twoof the six cocrystals known so far for this API are true two-component networks, while the majority of the cocrystalsresemble inclusion or clathrate complexes of ACZ, in which thecocrystal formers are located in channels, voids, or semisphericalcavities. Because of the differences in the topology, it can beproposed that the cocrystal formers exercise a template effectduring the self-assembly process.The research described herein is part of an ongoing study.

We are currently carrying out cocrystal phase stability experi-ments in water and dry/humid atmospheres at varying tem-peratures, and examining changes in intrinsic solubility anddissolution rates, in order to reveal to what extent the structuralvariations within the cocrystals of ACZ influence thebiopharmaceutical properties of this API.

! ASSOCIATED CONTENT*S Supporting InformationTG analysis of ACZ-2ABAM-H2O, ACZ-2ABAM-1/2H2O,and ACZ-2ABAM; IR spectra for ACZ-2HBAM and ACZ-PAM; topology and hydrogen-bonding connectivities of ACZin 2D hydrogen bonded layers present in the cocrystalstructures; listing of all hydrogen-bonding interactions; X-raycrystallographic information files (CIF) for compounds ACZ-2HBAM, ACZ-2ABAM-H2O, ACZ-PAM, and ACZ-23DHBA.This material is available free of charge via the Internet athttp://pubs.acs.org.

! AUTHOR INFORMATIONCorresponding Author*(D.H.-R.) E-mail: [email protected]. (H.H.) Fax: (+52) 77-73-29-79-97. E-mail: [email protected].

! ACKNOWLEDGMENTSThis work received support from Consejo Nacional de Ciencia yTecnologia (CONACyT) in form of a postgraduate fellowship forJIAG and through project No. CB2007-83440.

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