Solvates and Molecular Salts with Dioxane, Morpholine, and Piperazine

Nov 3, 2009 - Vânia André,† Dario Braga,‡ Fabrizia Grepioni,*,‡ and M. Teresa Duarte*,† ... T´ecnico, Av. Rovisco Pais 1, 1049-001 Lisbon, ...
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DOI: 10.1021/cg900495s

Crystal Forms of the Antibiotic 4-Aminosalicylic Acid: Solvates and Molecular Salts with Dioxane, Morpholine, and Piperazine

2009, Vol. 9 5108–5116

V^ ania Andre,† Dario Braga,‡ Fabrizia Grepioni,*,‡ and M. Teresa Duarte*,† † Centro de Quı´mica Estrutural, Departamento de Engenharia Quı´mica e Biol ogica, Instituto Superior T ecnico, Av. Rovisco Pais 1, 1049-001 Lisbon, Portugal, and ‡Dipartimento di Chimica “G. Ciamician”, Universita di Bologna, Via Selmi 2, 40126 Bologna, Italy

Received May 6, 2009; Revised Manuscript Received October 1, 2009

ABSTRACT: Reaction of the antibiotic 4-aminosalicylic acid with 6-membered ring compounds, such as dioxane, morpholine, and piperazine, yielded a solvate and three molecular salts. The new crystal forms were obtained using different crystallization techniques, such as grinding/kneading and solution techniques; interestingly, reaction with piperazine yields products with different stoichiometry, depending on the preparation conditions, i.e. solid-state or solution methods. All solid products were characterized by single-crystal X-ray diffraction; thermal stability was evaluated by variable temperature X-ray powder diffraction (VT-XRPD), calorimetric techniques (DSC and TGA), and hot-stage microscopy (HSM). Supramolecular interactions are discussed and compared with those in other similar crystal forms.

Introduction 4-Aminosalicylic acid (ASA) is an antibiotic that has been used since the 1940s in the treatment of tuberculosis. ASA has also been shown to be safe and effective in the treatment of inflammatory bowel diseases, namely distal ulcerative colitis1 and Crohn’s disease.2 Only one crystal form of this active pharmaceutical ingredient is reported in the literature,3 while two cocrystals have been obtained with sulfadimidine4 and with a codified compound reported as VX-950,5 respectively. The aim of this work is to rationalize a path for the development of new acceptable pharmaceutical species of ASA, by using different synthetic techniques with different reagent stoichiometries. We intend to demonstrate the type of interactions that are favorable to form solvates/cocrystals/ salts of this API, as well their dependence so as to apply this knowledge to pharmaceutically acceptable coformers, in a future work. In this paper we report the preparation and characterization of one solvate and three molecular salts6 of ASA with dioxane, morpholine, and piperazine. In the case of piperazine, two salts with different stoichiometries were obtained, depending on the preparation conditions. As clearly illustrated in Scheme 1, we have explored the possibility of hydrogen bonding formation of ASA with molecules chosen according to the following criteria: the three systems employed in this study are simple 6-membered ring compounds similar in shape but differing in their functionality; on passing from dioxane to morpholine and piperazine, we progressively replace the O centers, which can hydrogen bind the OH/NH2 groups of ASA, with NH groups, suitable for both neutral and charged assisted hydrogen bonding with COOH/COO-/NH2 groups of ASA. Although not all these cocrystal formers are approved as inactive ingredients for drug products, they have been shown to be the right “models” for obtaining the most robust synthons, capable of exploitation *Corresponding author e-mail: [email protected]; fabrizia.grepioni@ unibo.it. pubs.acs.org/crystal

Published on Web 11/03/2009

in a useful manner in the development of new pharmaceutically acceptable crystal forms. Importantly, solid products could be obtained by grinding/kneading and were fully characterized as single crystals obtained by conventional solution methods. On the basis of the single crystal data, it was then possible to calculate the theoretical powder diffractograms and compare them with the experimental patterns measured on bulk materials, thus assigning with certainty the products obtained. Mechanochemical reactions have been known for a long time.7,8 Grinding of two or more crystalline materials without the involvement of solvent often induces migration and rearrangement of the constituent molecules, to afford new crystal forms, or leads to topochemical reactions, often with regio- and stereoselectivity.9 When the reaction is carried out in the presence of a minor amount of solvent or directly with the liquid reactant (kneading), usually the rate of cocrystal formation is substantially enhanced. Recently, this method has been successfully utilized in the preparation of supramolecular aggregates,10 metal-organic frameworks,11,12 host-guest complexes11,13 and cocrystals.14,15 The mechanism of cocrystal formation by solid cogrinding has been investigated by several researchers.8,15-18 In the seminal work of Rastogi et al., with picric acid complexes, vapor diffusion was suggested as a mass transfer mechanism.8 Recently, Kaupp has put forward a general mechanism for the intercrystal reactions (A þ B f C) involving three stages.18 Besides the “green” side of these studies, due to the absence or limited use of solvents, there is a growing interest in the potentiality of different crystal forms (solvates, salts, cocrystals, polymorphs) for the same molecule, especially in the cases of active pharmaceutical ingredients (API).19 The main idea is that different forms may be open to innovation and new drug discoveries as well as to intellectual property protection via patenting of new forms of “old” drugs.20 Experimental Section Synthesis. All reagents (Scheme 1) were purchased from Sigma and used without further purification. r 2009 American Chemical Society

Article Scheme 1. Experimental Conditions and Products Obtained in the Reactions of ASA with Dioxane, Morpholine, and Piperazinea

a

Crystallization of 4 was also observed in the same reaction vessel.

Synthesis of the Solvate [C6H3NH2OHCOOH] 3 [C4H8O2]0.5 (1) in a dioxane solution. ASA (0.1001 g, 0.6529 mmol) was dissolved in 4 mL of dioxane and left to crystallize by slow evaporation at room temperature. Colorless plate crystals were formed over 3 days. Synthesis of 1 by Slurry. A 180 mg sample of ASA was suspended in dioxane and stirred in a closed vessel for 5 days. After filtering and drying, X-ray powder diffraction confirmed full conversion into 1. Synthesis of 1 by Kneading. 1 was also obtained by kneading, in an open agate mortar, ASA with a few drops of dioxane. This method, repeated several times, always yielded some unreacted crystalline ASA, as detected by XRPD. Prolonged kneading of the sample yielded an amorphous product. Synthesis of the Molecular Salt [C6H3NH2OHCOO] 3 [C4H8ONH2] (2) by Solution Methods. ASA (0.07548 g, 0.4928 mmol) was dissolved in 4 mL of morpholine and left to crystallize by slow evaporation at room temperature. A powder material was obtained over two weeks. Single crystals were grown from a solution of ASA in a mixture of acetone and morpholine (1:1). Synthesis of 2 by Kneading. 2 was also obtained by adding a few drops of morpholine to solid ASA and kneading the mixture for 5 min, until complete conversion into the product. Synthesis of the molecular salts [C6H3NH2OHCOO] 3 [C4H8(NH2)2]0.5 (3) and [C6H3NH2OHCOO] 3 [C4H8(NH)(NH2)] (4) by solution methods: A solution was prepared with ASA (0.0797 g, 0.5204 mmol) and piperazine (0.0931 g, 1.0808 mmol) in a 1:2 stoichiometric ratio in an ethanol solution. When the solution was boiled for 15 min and left to cool to room temperature, needle shaped brownish crystals of 3 were recovered after 5 days in the middle of the crystallization vessel (see Figure 1). The remaining room temperature solution turns into a dark brown oil, probably due to water adsorption, that forms a rim on the bottom glass wall, where platelike crystals of 4 are formed after 2 weeks (Figure 1). If the solution is not heated, only powder of 4 is formed, as evidenced by XRPD. Synthesis of 4 by Grinding. In an attempt to obtain crystalline 3 by grinding together ASA and piperazine in a 2:1 stoichiometry, an oily product was immediately formed because of either water uptake from the atmosphere by piperazine, which is highly hygroscopic, or formation of an eutectic mixture. The product took a few days to dry and was unexpectedly identified as the molecular salt 4 (1:1) by X-ray powder diffraction. Grinding equimolar mixtures of ASA and piperazine always yielded solid 4. Single Crystal X-ray Diffraction. Crystal structures of 1, 2, 3, and 4 were determined at 150 K on a Bruker AXS-KAPPA APEX II diffractometer with graphite-monochromated radiation (Mo KR, λ = 0.71069 A˚), operated at 50 kV and 30 mA. Data collection and

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refinement details are listed in Table 1. SIR9721 was used for structure solution, and SHELXL-9722 was used for full matrix least-squares refinement on F2. All non-hydrogen atoms were refined anisotropically. In crystalline 2, the hydroxyl group was found to be disordered over two positions, which were refined with an occupancy ratio of 70:30. In 3, the NH2þ piperazine group is modeled over two sites with an occupancy of 75:25. HNH atoms were located from difference Fourier maps and refined. HCH and HOH atoms were added in calculated positions and refined riding on their respective C and O atoms. MERCURY 2.223 was used for packing diagrams. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre with the following deposition numbers: 1, CCDC 730715; 2, CCDC 730714; 3, CCDC 730716; 4, CCDC 730717. These data can be obtained free of charge via www.ccdc.cam.ac.uk or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, U.K., e-mail [email protected]. X-ray Powder Diffraction (XRPD). X-ray powder diffraction data were collected with a Panalytical X’Pert Pro instrument equipped with an X’Celerator detector and an Anton Paar TTK 450 low temperature camera. A Cu anode was used as X-ray source at 40 kV and 40 mA. The program Mercury 2.222 was used for calculation of X-ray powder patterns on the basis of the single crystal structure determinations. The identity of single crystals and the bulk material obtained from solution and grinding/kneading experiments was always verified by comparison of the calculated and observed X-ray powder diffraction patterns. Hot-Stage Microscopy (HSM). Hot stage experiments were carried out using a Linkam TMS94 device connected to a Linkam LTS350 platinum plate. Images were collected, via the imaging software Cell, with an Olympus BX41 stereomicroscope. Crystals were placed on an oil drop to allow a better visualization of solvent or decomposition products release. Differential Scanning Calorimetry (DSC). Calorimetric measurements were performed using a Perkin-Elmer diamond equipped with a model ULSP90 intracooler. Temperature and enthalpy calibrations were performed by using high purity standards (n-decane, benzene, and indium). Samples (3-5 mg) were placed in aluminum open pans. Heating was carried out at 5 °C min-1 in the temperature range 25-160 °C. Thermogravimetric Analysis (TGA). TGA analysis was performed with a Perkin-Elmer TGA-7. Each sample, contained in a platinum crucible, was heated in a nitrogen flow (20 cm3 min-1) at a rate of 5 °C min-1, up to decomposition. The sample weights were in the range 5-10 mg.

Results and Discussion In the following section we will describe the packing features of crystalline forms 1;4 (see Table 2) for a list of relevant hydrogen bonding interactions) and will compare X-ray single crystal and powder X-ray diffraction data for a characterization of the bulk material in all cases. The results of TGA, DSC, and HSM experiments will also be illustrated and discussed. Crystal Structure of the ASA Solvate Form 1. The asymmetric unit of 1 consists of one ASA molecule and half a dioxane molecule, which lies on a crystallographic inversion center. In the crystal packing of 1, both the typical intramolecular hydrogen bond [OOH(H) 3 3 3 OCOOH 2.604(2) A˚] and the ASA dimers formed via the robust supramolecular R22(8) synthon [OCOOH(H) 3 3 3 OCOOH 2.607(2) A˚] (Figure 2a) observed in pure crystalline ASA (refcode AMSALA01) are maintained. Even though the formation of the intramolecular bond is also analogous to what is seen in other salicylic acid derivatives with dioxane, the preservation of the dimers formed by the R22(8) synthon is not so common, and it is usually disrupted when new crystal forms (solvates or cocrystals) are formed.24 This is also the case in the ASA/sulfadimidine

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cocrystal [Refcode VUGMOZ], where the homomeric R22(8) synthon is disrupted and a new R22(8) is formed between the ASA carboxylic moiety and the NNH and Npy of the coformer.4 These dimers interact with each other via N(H) 3 3 3 OOH hydrogen bonds [NNH2 3 3 3 OOH 3.171(2) A˚], forming wavy chains along b. Alternated ASA dimers and dioxane molecules, linked together via NASA(H) 3 3 3 Odioxane hydrogen

Figure 1. Formation of the molecular salts 3 (A) and 4 (B) from the same crystallization batch.

bonds [NNH2 3 3 3 O 2.994(2) A˚], form ladder chains lying at planes c = 0, 1, and c = 1/2, in approximately perpendicular directions (Figure 2b). This ASA 3 0.5dioxane solvate makes full use of the amine donor function, unlike what is seen in the crystals of pure ASA (refcode AMSALA01), thus making the total number of hydrogen bonding interactions in compound 1 (see Figure 2 and Table 2) larger than that in the homomolecular crystal, and this is a possible explanation for the relative ease of formation of the adduct. This crystal structure proved to be the existing form in the bulk product obtained by solution, slurry, and kneading methods. In the latter case, some ASA was always present as unreacted material, maybe due to a nonstoichiometric amount of both reagents or because an equilibrium point in the crystallization process was reached.25 If the bulk material sample is ground/kneaded for a long time, it becomes amorphous, and it is no longer possible to monitor the conversion into the new crystal form 1. Complete conversion into the dioxane solvate is otherwise observed if ASA is dissolved in dioxane and the solution is left to evaporate or

Table 1. Crystallographic Details for Compounds 1, 2, 3, and 4 chemical formula Mr temp/K wavelength (A˚) morphology, color crystal size/mm crystal system space group a/A˚ b/A˚ c/A˚ R/deg β/deg γ/deg V/A˚3 Z calc density/mg 3 cm-3 absorption coeficient/mm-1 θ min (deg) θ max (deg) reflections collected/unique Rint GoF threshold expression R1 (obsd) wR2 (all)

1

2

3

4

C7H7NO3 3 0.5(C4H802) 197.19 150 0.71069 plate, colorless 0.22  0.08  0.04 monoclinic P21/c 13.8650(3) 6.7070(2) 10.5660(3) 90 110.612(2) 90 919.66(4) 4 1.424 0.113 3.14 28.43 12683/2267 0.0499 1.005 >2σ(I) 0.0421 0.1007

C7H6NO3 3 C4H10NO 240.26 150 0.71069 plate, brownish 0.35  0.05  0.04 monoclinic P21/c 6.5660(4) 19.0140(13) 9.381(6) 90 102.228(4) 90 1144.6(7) 4 1.394 0.107 2.14 32.00 17747/3956 0.0784 0.901 >2σ(I) 0.0508 0.1201

2(C7H6NO3) 3 (C4H12N2) 392.41 150 0.71069 needle, brownish 0.40  0.10  0.08 orthorhombic Pbca 10.401(4) 8.426(2) 20.995(7) 90 90 90 1839.9(10) 4 1.417 0.108 2.76 26.37 11859/1876 0.0462 1.103 >2σ(I) 0.0562 0.1961

C7H6NO3 3 C4H10N2 239.28 150 0.71069 plate, brownish 0.18  0.06  0.04 monoclinic P21/c 10.2122(12) 7.6976(8) 15.4938(18) 90 101.915(8) 90 1203.4(2) 4 1.321 0.098 2.69 30.66 21114/3697 0.0488 1.037 >2σ(I) 0.0498 0.1304

Table 2. Hydrogen-Bond Geometries for the Reported Crystal Forms structure 1

2

3

4

sym op x, y, z 2 - x, l - y, 1 - z 1 - x, -l - y, 1 - z x, -1/2 - y, -1/2 þ z x, y, z 1 þ x, y, z 1 - x, -y, 1 - z x, y, -1 þ z x, y, z x, y, z -1/2 þ x, 3/2 - y, 1 - z -1/2 þ x, y, 3/2 - z x, y, z x, 1/2 - y, 1/2 þ z x, y, z 1 - x, 1 - y, -z -x, 1/2 þ y, 1/2 - z x, 3/2 - y, -1/2 þ z

D-H 3 3 3 A OOH 3 3 3 OCOOH OCOOH 3 3 3 OCOOH NNH2 3 3 3 O NNH2 3 3 3 OOH OOH 3 3 3 OCOO NNH2 3 3 3 OOH NNH2,cation 3 3 3 OCOO NNH2,cation 3 3 3 OCOO OOH 3 3 3 OCOO NNH2,cation 3 3 3 OCOO NNH2,cation 3 3 3 OCOO NNH2 3 3 3 OOH OOH 3 3 3 OCOO NNH2 3 3 3 OCOO NNH2,cation 3 3 3 OCOO NNH2,cation 3 3 3 OCOO NNH2,cation 3 3 3 NNH,cation NNH,cation 3 3 3 NNH2

d(D-H) (A˚) 0.82 0.82 0.90(2) 0.90(2) 0.82 0.89(2) 0.90(2) 0.94(2) 0.82 0.90 0.90 0.85(2) 0.82 0.84(2) 0.93(2) 0.93(2) 0.86(2) 0.78(2)

d(H 3 3 3 A) (A˚) 1.88 1.79 2.10(2) 2.31(2) 1.84 2.38(2) 1.89(2) 1.76(2) 1.85 1.82 1.91 2.26(2) 1.80 2.13(2) 1.81(2) 1.75(2) 2.21(2) 2.731(2)

d(D 3 3 3 A) (A˚) 2.604(2) 2.607(2) 2.994(2) 3.171(2) 2.564(3) 3.060(4) 2.754(2) 2.697(2) 2.559(3) 2.701(4) 2.752(3) 3.085(3) 2.528(1) 2.958(2) 2.721(2) 2.672(2) 3.016(2) 3.448(2)

DHA (deg) 146 174 172(1) 162(1) 146 133(1) 161(2) 173(2) 144 166 156 163(2) 147 173(2) 165(2) 167(2) 157(2) 135.1(2)

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Figure 2. (a) Supramolecular arrangement of ASA and dioxane molecules in crystalline 1, showing the synthon, and (b) alternated ASA dimers and dioxane molecules in a view along c, showing the perpendicular ladder chains distinguished by colors (blue for chains at c = 0, 1; and purple at c = 1/2).

Figure 3. Experimental powder diffraction patterns for solvate 1 obtained from (a) solution, (b) slurry, and (c) kneading. (d) Theoretical powder pattern and (e) experimental pure ASA diffractograms are presented to evidence the completeness of the reaction. The areas where the differences are more evident are highlighted in blue.

if slurry experiments of ASA in dioxane are performed. These conclusions were ascertained by XRPD (Figure 3). Crystal Structure of the Molecular Salt 2. The molecular salt 2 contains deprotonated ASA and protonated morpholine in a 1:1 ratio. The hydroxyl group in the anionic moiety was found disordered over two positions, which were refined with an occupancy ratio of 70:30. Due to hydrogen transfer from ASA to morpholine, a carboxylate group is formed, which, in addition to participation in the intra-anion OOH(H) 3 3 3 OCOO bond [OOH 3 3 3 OCOO 2.564(3) A˚], is involved in two charged-assisted hydrogen bonding interactions with the NH2þ group of two morpholine cations [NNH2,cation(H) 3 3 3 OCOO 2.754(2) and 2.697(2) A˚], thus originating large neutral tetrameric units in the crystal (Figure 4a). These tetramers are then linked along a via geometrically nonideal N(H) 3 3 3 OOH interactions

[NNH2 3 3 3 OOH 3.060(4) A˚] between ASA anions (Figure 4b), with the oxygen of the hydroxyl group thus acting as acceptor. The second H atom of the NH2 group from the ASA anion, not involved in the hydrogen bond linking the tetramers, is pointing directly toward a second anion ring from an adjacent tetramer (Figure 4c), thus forming an NH 3 3 3 π interaction [NNH2 3 3 3 Cg 3.456(7) A˚]. Like what is observed in other salts of salicylic acid derivatives and morpholine, the ether moiety of the solvent does not use its acceptor functions and therefore is not involved in any intermolecular interaction. The formation of the intramolecular hydrogen bond and the chargedassisted interactions between the protonated amine group of morpholine and the API’s carboxylate moiety are equally observed in similar compounds.26 Powder X-ray diffraction confirmed that 2 was indeed the bulk product obtained by both solution and kneading (Figure 5). Unlike what is observed with dioxane, when morpholine is used, the new form is quickly obtained by kneading (i.e., by mixing with a few drops of liquid morpholine), once the stoichiometric proportions are attained. Crystal Structure of the Molecular Salt 3. In crystalline 3, both -NH groups on the piperazine molecule have been protonated by the -COOH groups of two ASA molecules; the resulting 4-aminosalicylate anion and piperazinium dication are then present in a 2:1 stoichiometric ratio. The cation is lying on a crystallographic inversion center, exhibiting disorder in the NH2þ moiety (75:25). The typical intramolecular bond OOH(H) 3 3 3 OCOO [OOH 3 3 3 OCOO 2.559(3) A˚] is maintained also in this structure. The anions are arranged in zigzag chains along the c-axis, linked to one another via N(H) 3 3 3 OOH [NNH2 3 3 3 OOH 3.085(3) A˚ ] interactions (Figure 6a); in these chains, adjacent molecules are rotated approximately by 56°. In a view along the c-axis, wavy chains are formed by series of two anions and one cation (Figure 6b); each -NH2þ group on the cation is linked to two different 4-aminosalicylate anions via N(H)þ 3 3 3 Ocharged-assisted hydrogen bonds [NNH2,cation 3 3 3 OCOO

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Figure 4. Packing diagrams for crystalline 2: (a) view along a showing the individual tetramers; (b) view showing the intertetramer interactions and the resulting ASA chains; (c) molecular diagram depicting the N-H 3 3 3 π interaction; the light-blue sphere represents Cg, i.e. the geometrical center of the 6-carbon membered ring. [Only the major image of disorder is shown for the hydroxyl group.].

Figure 5. Experimental X-ray powder diffraction patterns obtained for 2 from (a) solution and (b) kneading, compared with (c) the calculated pattern.

2.701(4) and 2.752(3) A˚ ], similar to the ones observed in other salts of salicylic acid derivatives with piperazine.27 In this structure, while piperazine completely uses its donor capacities in strong hydrogen interactions, the amine moiety of the anion, in a similar way to what is observed in 2, displays a weaker N-H 3 3 Cπ interaction, using the second H atom of the amine moiety, between two anions [shortest ΝΝH2 3 3 3 Cring distance 3.502(8) A˚] (Figure 6c). Due to the very little amount of crystalline 3, obtained in the center of the crystallization vessel, it was not possible to obtain a powder experimental diffractogram for this form. Despite the efforts described in the Experimental Section, grinding techniques did not reproduce this form. These results are similar to the ones performed on the metastable form of paracetamol,28 in which the crystal nucleation at the rim of the evaporating solution was the only way to obtain the metastable form. Crystal Structure of the Molecular Salt 4. In crystalline 4 the anion/cation ratio is 1:1, with only one protonated NH2þ group on the piperazine moiety. The asymmetric unit of this structure consists of one cation and one anion entities. The anionic unit is again characterized by the presence of an ˚ ] intramolecular OOH 3 3 3 OCOO [OOH 3 3 3 OCOO 2.528(1) A hydrogen bond. In crystalline 4, anionic chains are formed along the c-axis ˚ ] via N(H) 3 3 3 OCOO interactions [NNH2 3 3 3 OCOO 2.958(2) A (Figure 7a). Adjacent molecules in the chain are rotated by approximately 69° with respect to each other. Each monoprotonated piperazinium cation is connected to three different anions, to two of them via N(H)þ 3 3 3 Ocharged-assisted hydrogen bonds [NNH2,cation 3 3 3 OCOO 2.672(2) and 2.721(2) A˚] and one hydrogen bond using the

nonprotonated amino moiety NNH(H)ASA 3 3 3 N [NNH2 ˚ 3 3 3 NNH,cation 3.016(2) A]. A fourth longer interaction in which the NH group of piperazine behaves as a donor to the amine moiety of the API [NNH,cation 3 3 3 NNH2 3.448(2) A˚] is also present in the crystal packing of 4 (Figure 7a). Looking at the expanded packing, it is possible to observe alternate columns of anions and cations, where no interaction between anions is seen but where the charged-assisted interactions between ASA anions and cationic piperazine are visible (Figure 7b). No cation-cation interactions are observed throughout the supramolecular array. Unlike the 2:1 stoichiometry, the 1:1 stoichiometry allows full use of both donor and acceptor sites on both cocrystal partners. Although in 3 piperazine is doubly protonated, which causes the electrostatic energy to increase, the higher number of the hydrogen bonds formed in the 1:1 crystal form seems to have a higher influence, and it may be in the origin of its preferential formation in solution and also when both reagents are ground together (see below). As previously mentioned, the 1:1 molecular salt 4 can be obtained both in solution and by grinding the reagents together. Although both starting materials are solid at ambient conditions and no solvent is added, the result of the grinding process is an oily product that takes a few days to dry. This product was identified as form 4 by comparison with the theoretical powder diffractogram (figure 8). The grinding procedure always yields form 4, even for different stoichiometric ratios, in particular when ASA and piperazine are in a 2:1 proportion. Thermal Behavior of the Four Crystalline Forms. The thermal stability of the compounds previously presented was assessed by combining data from different techniques such as variable temperature XRPD, DSC, TGA, and HSM. In crystalline 1, dioxane is released from the structure at ca. 85 °C. This solvent loss was detected in the DSC thermogram as a flat and broad peak observed below 100 °C; as a consequence of solvent loss, the melting point at ca. 150 °C, immediately followed by decomposition, corresponds to the one observed for pure ASA. In the TGA curve (Figure 9), the loss of solvent was evidenced by a 12% mass loss in the temperature range 60-120 °C. The process can be visualized by HSM (Figure 10), with “bubbles” that are released from the crystals at approximately 80 °C. Variable temperature XRPD (Figure 11) was also used to monitor the transition from the solvate form to the pure ASA compound, which is already detectable at 80 °C. These new forms are being investigated as a means of tailoring physicochemical properties, and therefore, it is of

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Figure 6. Crystalline 3: (a) C(6) chains of 4-aminosalicylate anions interacting with piperazinium cations; (b) wavy chains formed by pairs of anions (green) and one cation (blue); (c) molecular diagram depicting the N-H 3 3 3 Cring interaction.

Figure 7. Crystalline 4: (a) C(8) ASA chains formed along a and its interactions with piperazine cations; (b) the alternated columns of anions (green) and cations (blue), in a view along a.

Figure 8. Experimental powder diffraction patterns of 4 as obtained (a) from solution and (b) by grinding, compared with (c) the theoretical powder pattern calculated on the basis of single crystal data.

interest to correlate structural data previously reported with the physical/thermal stability observation described herein. Looking at the crystal packing of 1, it is possible to perceive that the dioxane molecules are arranged in layers, parallel to the b-axis, intercalated between ASA sheets (Figure 12), through which it may be envisaged that the dioxane molecules easily diffuse out of the structure at temperatures close to the solvent boiling point, causing its rearrangement into the known ASA crystalline structure. DSC and TGA measurements on crystalline 2 and 4 show that both species are stable and do not undergo any changes until melting is observed, immediately followed by decomposition (Figures 13 and 15). These data are corroborated by

Figure 9. DSC (a) and TGA (b) traces for crystalline 1.

HSM experiments, in which “bubbles” indicating decomposition are spotted just before melting of the crystals (Figures 14 and 16). For salt 3 it was not possible to perform DSC and TGA measurements, due to the low amount of sample, but observations using HSM (Figure 17) revealed some possible decomposition starting at 131 °C and melting at approximately 155 °C.

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Conclusions The investigation of crystal forms, i.e. solvates, salts, cocrystals, and their respective polymorphs, as well as of amorphous solid phases has become one of the major issues of modern solid-state and materials chemistry.19,29 When new crystal forms imply active pharmaceutical ingredients, such as ASA, the potentials for new discoveries, innovation of existing products, and market protection and intellectual property issues can be very relevant and have been well documented. In this study, we have investigated the possibility of forming new crystal forms between ASA and cyclic 6-membered nonaromatic compounds, such as dioxane, morpholine, and piperazine. These molecules carry nitrogen and/or oxygen atoms that can act as proton acceptors or hydrogen bonding acceptors and can therefore take part in extended hydrogen bonded networks, suitable for the study of synthon competition and cooperation established in this kind of structures. It is well-known that cocrystals and similar crystal derivatives are formed if the free-energy of the multicomponent system is lower than that of the crystalline components on their own.

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A large number of “extra” hydrogen bonding interactions, also reinforced by proton transfer and formation of molecular ions, helps in stabilizing the solid multicomponent systems. As a result, active pharmaceutical ingredients are often commercialized as salts, with suitable counterions. As a matter of fact the ASA molecule is sufficiently acidic to transfer the carboxylic proton to morpholine and piperazine molecules, while no protonation of the weakly basic dioxane molecule is observed. Hence, forms 2, 3, and 4 are perfect examples of molecular salts, as both organic acid and base components are neutral molecules prior to proton transfer.6d This behavior was already expected by analyzing studies of similar structures with other salicylic acid derivatives and

Figure 10. HSM images obtained from crystals of 1. (a) 25 °C; (b) 80 °C: bubbles are due to dioxane release from the structure; (c) 155 °C: melting of pure ASA, formed as a consequence of loss of dioxane, is observed.

Figure 13. (a) DSC and (b) TGA for 2, in which melting/decomposition is observed starting at ca. 140 °C.

Figure 11. Experimental powder diffraction patterns obtained with 1 at different temperatures: (a) generated powder diffraction pattern of 1; (b) 25 °C; (c) 80 °C; (d) the pure ASA pattern.

Figure 14. HSM images for crystalline 2 at (a) 28 °C, (b) 131.5 °C, where bubbles start to be released, indicating decomposition, (c) 140 °C, and (d) 150 °C, showing the complete melting of the product.

Figure 12. (a) Packing diagram of crystalline 1 showing the dioxane layers (in projection) extending throughout the solid in between the thick ASA sheets. Space-filling representation with (b) and without (c) the dioxane layers.

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It is worth pointing out that the piperazinium salts are particularly interesting, as piperazine is employed in pharmaceutical salts. In fact, piperazine is an anthelminthic agent that has been used in the treatment of severe infections due to A. lumbricoides and E. vermicularis30, and furthermore, piperazine analogues and derivatives have recently been shown to have several pharmaceutical activities and have recently been developed.31 Also, morpholine derivatives have recently been used in the treatment and prevention of pain or inflammation as well as depression or anxiety.32 Finally, it is noteworthy that the compounds discussed herein have all been obtained primarily by direct mixing of the crystal partners, whether liquid (such as dioxane, morpholine) or solid (ASA), without solvent being used, thus providing further evidence to the observation that mechanical methods, grinding and kneading, could be a first-choice experimental route to explore when cocrystal formation is sought.

Figure 15. (a) DSC and (b) TGA for 4, in which melting/decomposition is observed starting at ca. 145 °C.

Acknowledgment. The authors acknowledge funding of the Project POCI/QUI/58791/2004 and Ph.D. Grant SFRH/ BD/40474/2007 to Fundac-~ ao para a Ci^encia e Tecnologia and by MiUR (PRIN2006). D.B. and F.G. thank MiUR for financial support (PRIN2006). Supporting Information Available: Crystallographic information files (CIF) are accessible for the four structures reported. This information is available free of charge via the Internet at http:// pubs.acs.org/.

References Figure 16. Images collected in HSM with the molecular salt 4 at (a) 25 °C, (b) 145.2 °C, and (c) 154 °C, where fusion had already occurred.

Figure 17. HSM images obtained from a crystal of the molecular salt 3 at (a) 25 °C and (b) 131 °C, showing the bubbles release associated with decomposition, and at (c) 147 °C and (d) 155 °C, the temperature at which complete melting has already occurred.

these coformers.24,26,27 Therefore, the main interactions present in the crystalline systems reported herein are of the O-H 3 3 3 O, N-H 3 3 3 O, and N(H)þ 3 3 3 O- types. The only exception to this is the piperazinium salt 4, in which an N-H 3 3 3 N bond is observed in addition to the ones previously mentioned. The intramolecular synthon S(6) [O-H 3 3 3 OCOOH/COO-] is never disrupted in any of the salicylic acid derivatives, and ASA crystal forms (ASA, ASA/sulfadimidine, and the four forms presented here) have been shown to be the strongest synthons. It is worth mentioning that the NH2,ASA 3 3 3 OHASA interaction is also maintained in the crystal forms reported in this paper, with the exception of 4. The strong homomeric carboxylic R22(8) synthon observed in ASA, which is maintained in the dioxane solvate, is not possible to form in the molecular salts studied herein due to the proton transfer from the API carboxylic group to the amine moiety of the coformer. This disruption gives rise to charge-assisted N(H)þ 3 3 3 Osupramolecular interaction originating different ring and chain synthons in the molecular salts studied (e.g., R44(10) in 2 and C(6) in 3).

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