New Multicomponent Sulfadimethoxine Crystal ... - ACS Publications

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New Multicomponent Sulfadimethoxine Crystal Forms: Sulfonamides as Participants in Supramolecular Interactions Sofia Domingos,† Auguste Fernandes,† M. Teresa Duarte,† and M. Fátima M. Piedade*,†,‡ †

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal ‡ Departamento de Química e Bioquímica da FCUL, Campo Grande, 1749-016 Lisbon, Portugal S Supporting Information *

ABSTRACT: Sulfadimethoxine (SDM) cocrystal formation was screened using coformers with cyclic amines, amide, carboxylic acid, and sulfonamide based moieties. Eight new multicomponent crystal forms were obtained by solution crystallization and liquid-assisted grinding techniques, showing a preference for the amine derivatives. Cocrystals were obtained with isonicotinamide (SDM:ISO) and 4,4′-bipyridine (SDM:BIP:ACE; SDM:BIP:H2O), and molecular salts were synthesized with piperazine (SDM:PIP), 4,4′-trimethylenedipiperidine (SDM:TRI), and 1,4-diazabicyclo[2.2.2]octane (two anhydrous polymorphic forms (SDM:DABCO) and one hydrate (SDM:DABCO:H2O)). The new forms were fully characterized by X-ray diffraction. Structural characterization shows the disruption of the typical R22(8) sulfonamide synthon, while the supramolecular arrangement is achieved through several new synthons. In cocrystals, the amide nitrogen Nsulfonamide behaves as the best donor and bonds to the Oacetamide of ISO, while with BIP the interaction is established with the NBIP atom. In salts, charge assisted hydrogen bonds are established, predominantly with the amide nitrogen, the best acceptor, or the sulfonyl O atom, but there is a strong competition with the N atom of the pyrazine ring (Npyrazine). Thermal behavior and physicochemical properties were assessed by thermogravimetric analysis, differential scanning calorimetry, variable temperature powder X-ray diffraction, and hot-stage microscopy techniques. As expected, the molecular salts reveal higher solubility in water than the cocrystals, an important aspect for the improvement of SDM performance.

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promising antitumor and anti-glaucoma agents15,16 Encouraging for us, while crystal engineers, were also the recent reports on sulfacetamide solubility modulation through cocrystallization.17,18 Sulfadimethoxine (SDM, hereafter) belongs to the class of sulfonamide antibiotics and has been commonly used in veterinary medicine. Molecules in this drug class usually contain multiple functional groups, thus exhibiting interesting solid-state properties and the possibility to occur in multiple stable forms, including polymorphic ones.19−21 Also, it has been reported that the sulfone moiety is a good hydrogen bond acceptor, due to the highly polar nature of the sulfur−oxygen bond, playing an important role in the formation of hydrogen bond interactions responsible for the crystal packing in this class of drugs.21−23 Previous reports on sulfonamide hydrogen bonding indicate that the amide proton is the best donor and that the carbonyl, sulfanyl, and activated aromatic nitrogen groups are the best acceptors.20 A systematic study on aryl-substituted sulfonamides, presented in 2011, disclosed the formation of a competitive heterosynthon when using pyridine N-oxide derivatives.24

INTRODUCTION Crystal engineering, the rational design of functional molecular solids, has emerged as an important cross-disciplinary area of research.1−3 It comprises the understanding of intermolecular interactions in the context of crystal packing and the exploitation of such interactions in the design of new solid forms, as polymorphs, salts, molecular salts, solvates, and cocrystals, with the desired physical and chemical properties.1,4,5 In fact, designing structures with tailor-made properties is the ultimate crystal engineers’ challenge,6 and at the same time it is a major opportunity in the pharmaceutical field.7−10 Pharmaceutical cocrystallization, a process by which a drug molecule and a generally regarded as safe (GRAS) coformer are combined into a single crystal lattice, is now a well-known method to prepare novel solid-state forms of active pharmaceutical ingredients (APIs) with tailored physicochemical properties.8,11,12 Following our interest in studying specific interactions of drug molecules bearing sulfone moieties,13 we recently turned our attention to the comprehensive world of sulfonamides. This family of antibacterial drugs was one of the first to be developed, but bacteria soon developed several resistances to them.14 Nowadays this family of compounds has re-emerged as © 2016 American Chemical Society

Received: September 11, 2015 Revised: February 18, 2016 Published: February 18, 2016 1879

DOI: 10.1021/acs.cgd.5b01320 Cryst. Growth Des. 2016, 16, 1879−1892

Crystal Growth & Design

Article

Figure 1. Pyridine-substituted benzenesulfonamides R22(8) synthons: (a) R22(8) based on N−Hsulfonamide···Nimine hydrogen bonds (Type I); (b) R22(8) based on N−Hamide···Osulfone hydrogen bonds (Type II).

Figure 2. Sulfadimethoxine R22(8) synthon. Figure 3. Compounds used in synthesis of new multicomponent crystal forms: isonicotinamide (ISO); 4,4′-bipyridine (BIP); piperazine (PIP); trimethylenedipiperidine (TRI); DABCO − successful reactions (red); theophylline (TEO); saccharin (SAC); caprolactam (CAP); morpholine (MORF); salicylic acid (SA); acetylsalicylic acid (ASA); paracetamol (PAR) − unsuccessful reactions (black).

Other studies have shown that in sulfonamide salts the deprotonated amide nitrogen atom acts as the best acceptor.21 These results reveal that a wide panoply of hydrogen bond interactions is possible and synthon competition is high in this type of systems. In this work a Cambridge Structural Database (CSD) quest on pyridine−substituted benzenesulfonamides was performed using the filters “3D coordinates determined, R-factor < 0.075, not polymeric, organic molecules only”, giving 244 hits. From these 244 structures, only the polymorphic forms with the smaller R-factor were considered (191). The search found 98 structures of pure sulfonamides, from which 5 are hydrates and 24 are solvates. From the remaining structures, 69 are cocrystals (including 3 hydrates and 7 solvates) and 20 are salts (including 4 hydrates and 2 solvates). The most resilient hydrogen bond found in this subset involves primary amines and oxygen atoms of the sulfoxide group, representing 83% of the occurrences. Recurring to the graph set notation to describe these supramolecular interactions, different geometries were found, ranging from discrete (D) assemblies to chains (C) and rings (R). The most common synthon is the C11(8) chain involving the N−Hterminal amine···Osulfone hydrogen bond, which competes with the occurrence of the R22(8) well-known synthon. In this survey the homosynthon is obtained in two different ways: one making use of two N−Hamide···Nimine hydrogen bonds (Type I) (23%) (Figure 1a) and the other by two N−Hsulfonamide···Osulfone hydrogen bonds (Type II) (16%) (Figure 1b). While the first one is maintained in 12% of the multicomponent forms, the second one is always disrupted, suggesting

that the N−Hamide···Nimine R22(8) synthon is the more robust of the two ring motifs. The previously referred C11(8) chain is maintained in most of the multicomponent forms. SDM is known to exist in four polymorphs,25 all of them based on the C11(8) chain and on the R22(8) eight-membered ring (Figure 2), the sulfonamide homosynthon based on Type II hypothesis. In all of them, there is a competition for the terminal NH2 from the Npyrazine. In order to study the impact of the R22(8) synthon disruption in the crystal packing and possibly in the API physicochemical modifications, we report herein the synthesis of novel multicomponent SDM crystal forms. Solution crystallization and liquid-assisted grinding (LAG) techniques12,26 were used to screen SDM with various coformers, namely, amides, amines, and carboxylic acid derivatives (Figure 2), resulting in the production of novel cocrystals with isonicotinamide and 4,4′-bipyridine and novel salts with piperazine, 4,4′-trimethylenedipiperidine, and 1,4-diazabicyclo[2.2.2]octane.

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EXPERIMENTAL SECTION

Synthesis. All reagents and solvents were supplied by Sigma-Aldrich and used without further purification. 1880



Article

Table 1. Crystallographic Details for Compounds 1−8 chemical formula Mr temp/K wavelength (Å) morphology, color crystal size/mm crystal system space group a/Å b/Å c/Å α/deg β/deg γ/deg V/Å3 Z calculated density/mg·cm−3 absorption coefficient/mm−1 Θ min (deg) Θ max (deg) reflections collected/unique Rint GOF threshold expression R1 (obs) wR2 (obs) R1 (all) wR2 (all) chemical formula Mr temp/K wavelength (Å) morphology, color crystal size/mm crystal system space group a/Å b/Å c/Å α/deg β/deg γ/deg V/Å3 Z calculated density/mg·cm−3 absorption coefficient/mm−1 Θ min (deg) Θ max (deg) Rint GOF threshold expression R1 (obs) wR2 (obs) R1 (all) wR2 (all)

1

2

3

4

C12H14N4O4S·C6H6N2O 432.46 150 0.71073 prisms, colorless 0.420 × 0.200 × 0.100 triclinic P1̅ 7.9228(10) 9.2560(12) 15.388(2) 74.650(4) 81.734(4) 66.980(4) 1000.5(2) 2 1.436 0.206 2.456 23.834 11851/2929 0.0364 1.048 >2σ(I) 0.0563 0.1490 0.0786 0.1629 5

C12H14N4O4S·C5H4N·C1.5H3O0.5 417.46 150 0.71073 plate, colorless 0.210 × 0.120 × 0.090 monoclinic P2/c 14.72(3) 8.301(15) 19.34(3) 90 109.12(11) 90 2232(7) 4 1.242 0.180 2.695 25.485 17422/4083 0.0619 0.913 >2σ(I) 0.0625 0.1630 0.1235 0.1764 6

C12H14N4O4S·C5H4N·H2O 484.53 150 0.71069 plates, colorless 0.220 × 0.130 × 0.090 triclinic P1̅ 9.1219(8) 11.3847(9) 11.8935(10) 112.166(4) 98.377(4) 93.249(4) 1123.22(17) 2 1.433 0.192 2.113 25.734 14907/4269 0.0515 0.992 >2σ(I) 0.0439 0.0957 0.0890 0.1168 7

C12H14N4O4S·C2H5N 353.40 273 0.71073 prism, colorless 0.400 × 0.250 × 0.150 monoclinic P21/n 6.3293(4) 13.8838(9) 20.0578(15) 90 98.031(2) 90 1745.3(2) 4 1.345 0.214 2.522 24.995 10840/3036 0.0263 1.081 >2σ(I) 0.0469 0.1210 0.0575 0.1269 8

C24H28N8O8S2·C13H26N2 554.01 150 0.71073 needles, colorless 0.150 × 0.100 × 0.070 monoclinic P21/c 21.576(3) 10.1393(14) 20.625(2) 90 110.990(7) 90 4212.6(9) 6 1.310 0.188 2.270 29.537 0.3213 0.747 >2σ(I) 0.0960 0.1408 0.4362 0.2006

C12H14N4O4S·C6H12N2 422.51 293 0.71073 prisms, colorless 0.500 × 0.200 × 0.10 monoclinic P21/c 13.250(3) 11.340(2) 14.590(3) 90 111.45(3) 90 2040.4(8) 4 1.375 0.197 2.340 26.235 0.0521 0.974 >2σ(I) 0.0567 0.1199 0.1348 0.1411

C24H28N8O8S2·C12H24N4 845.01 100 0.69563 needles, colorless 0.080 × 0.030 × 0.030 monoclinic P21/c 12.8890(1) 25.4170(1) 13.1040(1) 90 111.648(6) 90 3990.1(2) 4 1.407 0.201 1.602 29.888 0.1568 1.086 >2σ(I) 0.0648 0.1515 0.0815 0.1619

C12H14N4O4S·C6H12N2·H2O 439.51 294 0.71073 prisms, colorless 0.200 × 0.200 × 0.200 triclinic P1̅ 9.767 10.583 10.954 97.33 91.72 101.69 1097.9 2 1.330 0.189 2.133 26.372 0.0421 1.070 >2σ(I) 0.0496 0.1317 0.0747 0.1419

Synthesis of SDM:ISO Cocrystal (1:1) (1). SDM (86.1 mg, 0.277 mmol) and ISO (33.9 mg, 0.278 mmol) were dissolved in 3 mL of acetone. The solution was left to crystallize by slow evaporation of the

Different synthetic routes were applied using the coformers previously presented. We report herein all the successful syntheses (Figure 3). 1881



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Figure 4. Experimental conditions and products obtained in the reactions between SDM and ISO, BIP, PIP, TRI, and DABCO. solvent at room temperature. White prismatic crystals were formed after 2−3 days. Synthesis of SDM:BIP Cocrystal Acetone Solvate (2:1:1) (2) and SDM:BIP Cocrystal Hydrate (1:1:1) (3). SDM (79.8 mg, 0.257 mmol) and BIP (40.2 mg, 0.257 mmol) were dissolved in 3 mL of acetone. The solution was covered and left to crystallize by slow evaporation of the solvent at room temperature. A mixture of whitish prismatic crystals (2) and colorless plate crystals (3) was formed after 2−3 days. Cocrystal 2 was isolated by dissolving SDM (79.8 mg, 0.257 mmol) and BIP (40.2 mg, 0.257 mmol) in 10 mL of acetone and left to crystallize by slow evaporation in a desiccator with blue silica gel. This proved to be effective in the separation of the concomitant forms previously identified, as confirmed by powder X-ray diffraction (PXRD) analysis. Cocrystal 3 was also obtained by LAG using SDM (133.0 mg, 0.429 mmol) and BIP (67.0 mg, 0.429 mmol) in a ball mill with 50 μL of water (10 min, 29.8 Hz), as proven by PXRD analysis. Synthesis of SDM:PIP Molecular Salt (2:1) (4). SDM (93.9 mg, 0.303 mmol) and PIP (26.1 mg, 0.303 mmol) were dissolved in a mixture of 3 mL of acetone and 2 mL of water. The solution was left to crystallize by slow evaporation of the solvent at room temperature. After 2−3 days, colorless needle-like crystals were formed. The same salt was also obtained by LAG using SDM (156.5 mg, 0.504 mmol) and PIP (43.5 mg, 0.505 mmol) in a ball mill with 40 μL of acetone (20 min, 29.8 Hz) as proven by PXRD analysis. Synthesis of SDM:TRI Molecular Salt (2:1) (5). SDM (178.8 mg, 0.576 mmol) and TRI (121.2 mg, 0.576 mmol) were dissolved in a mixture of 4 mL of acetone and 2 mL of water. The solution was left to crystallize by slow evaporation of the solvent at room temperature. Whitish needle-like crystals were formed after 2−3 days. Synthesis of SDM:DABCO Molecular Salts: 1:1 (6), 2:2 (7), and SDM:DABCO hydrate (1:1:1) (8). SDM (220.4 mg, 0.710 mmol) and

DABCO (79.6 mg, 0.710 mmol) were dissolved in a mixture of 5 mL of acetone and 1 mL of water. The solution was left to crystallize by slow evaporation of the solvent at room temperature. Three different types of crystals were obtained after 2−3 days, corresponding to two molecular salts polymorphic forms (6) and (7) and to a molecular salt hydrate (8). Molecular salts (6) and (8) were also obtained by LAG using SDM (146.9 mg, 0.473 mmol) and DABCO (53.1 mg, 0.473 mmol) in a ball mill with 50 μL of acetone (15 min, 29.8 Hz) and 40 μL of water (10 min, 29.8 Hz) respectively. PXRD analysis confirmed that both techniques lead to the same product. Single Crystal X-ray Diffraction (SCXRD). Crystals suitable for Xray diffraction study were mounted in a cryoloop with Fomblin protective oil. Data were collected on a Bruker AXS-KAPPA APEX II diffractometer with graphite-monochromated radiation (Mo Kα, λ = 0.71073 Å) at 150 K. The X-ray generator was operated at 50 kV and 30 mA, and the X-ray data collection was monitored by the APEX2 program. All data were corrected for Lorentzian, polarization, and absorption effects using SAINT27 and SADABS28 programs. Crystals of compounds 2 and 5 have a very poor quality, showing very weak diffraction. Solvent molecules in cocrystal 2 were disordered, and attempts to model this were not successful. Because of the very small size of compound 7 crystals, single crystal X-ray high-resolution data were collected at the European Synhcrotron Radiation Facility (ESRF). Time was allocated at beamline BM01A/ SNBL, equipped with a Multipurpose PILATUS@SNBL diffractometer with a Pilatus2M detector; the wavelength used was λ = 0.69563 Å, and data were collected at 100 K. Data were monitored by the CrysAlisPro software.29 SIR9730 and SHELXS-9731 were used for structure solution, and SHELXL-9731 was used for full matrix least-squares refinement on F2. These three programs are included in the package of programs WINGX-Version 1.80.05.32 A full-matrix least-squares refinement was used for the non-hydrogen atoms with anisotropic thermal parameters. 1882



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Table 2. Hydrogen-Bond Distances and Angles for the Previous Reported Crystal Forms d(D−H) (Å)

d(H···A) (Å)

d(D···A) (Å)

DHA (deg)

−1+x, y, z

N−HNH2···OSO2

0.85(6)

2.57(6)

3.394(5)

164(5)

−1−x, 1−y, −z

N−HISO···NNH2

0.89(5)

2.39(4)

3.261(4)

164(4)

1+x, y, z

N−HNSO2···OISO

0.92(4)

1.90(5)

2.779(4)

159(5)

−1+x, y, z

N−HNH2···Npyridine ring

0.95(6)

2.00(6)

2.950(6)

173(2)

x, −y, −1/2+z

N−HNH2···OSO2

1.01(4)

2.22(4)

3.211(9)

167(3)

x, −1+y, z

N−HNH2···OOCH3

0.71(4)

2.49(4)

3.134(9)

151(4)

structure 1

2

3

4

5

6 7

8

sym op

D−H···A

x, y, z

N−HNSO2···NBIP

1.02(3)

1.31(3)

2.825(7)

176(3)

−x, −y, 1−z

N−HNH2···OW

0.92(3)

2.13(3)

2.954(3)

150(2)

x, y, −z

N−HNH2···OW

0.89(3)

2.13(3)

3.016(3)

177(3)

1−x, −y, −z

N−HNH2···NBIP

0.82(3)

1.98(3)

2.793(3)

176(3)

−x, 1−y, 1−z −1+x, y, z

O−HW···NBIP O−HW··· OSO2

0.96(4) 0.79(3)

1.87(4) 2.02(3)

2.826(3) 2.805(3)

170(3) 170(3)

1/2−x, −1/2+y, 1/2−z

N−HNH2···OSO2

0.81(3)

2.36(3)

3.113(3)

155(3)

−1/2−x, −1/2+y, 1/2−z

N−HNH2···OSO2

0.80(4)

2.18(4)

2.979(4)

180(4)

x, y, z

N−HPIP, cation···OSO2

0.91(3)

1.92(3)

2.829(3)

177(3)

−1+x, y, z x, y, z

N−HPIP, cation···Npyrazine ring N−HNH2···Npyrazine ring

1.03(3) 0.99(13)

1.67(3) 2.48(12)

2.701(3) 3.343(10)

179(3) 146(11)

1+x, y, z

N−HNH2···Npyrazine ring

0.99(10)

2.31(10)

3.259(8)

161(7)

x, y, z

N−HNH2···OOCH3

0.99(13)

2.41(12)

3.346(10)

159(8)

1−x, 1−y, −z 1−x, 2−y, −z x, y, z

N−HNH2···OSO2 N−HNH2···OSO2 N−HTRI, cation···OSO2

1.00(10) 0.95(2) 1.00(6)

2.08(10) 2.20(3) 2.18(5)

3.057(9) 3.014(7) 3.153(9)

165(8) 160(3) 164(5)

1−x, 1−y, −z

N−HTRI, cation···OSO2

1.01(7)

1.85(8)

2.745(9)

146(7)

x, 5/2−y, −1/2+z

N−HTRI, cation···OSO2

1.01(2)

1.88(3)

2.854(7)

161(4)

−x, 1/2+y, −1/2−z

N−HTRI, cation···NNSO2

1.05(8)

1.88(8)

2.783(7)

142(7)

x, y, z

N−HTRI, cation···NNSO2

1.006

2.44(7)

2.905(10)

107(5)

x, 3/2−y, −1/2+z

N−HNH2···OSO2

0.95(4)

2.04(4)

2.989(4)

178(5)

x, y, z

N−HDABCO, cation···NNSO2

0.96(3)

1.77(3)

2.732(4)

179(3)

1−x, −y, 1−z

N−HNH2···OSO2

0.91(4)

2.16(3)

3.029(3)

159(2)

x, 1/2−y, 1/2+z

N−HNH2···Npyrazine ring

0.90(4)

2.32(4)

3.215(3)

170(4)

x, y, z


0.96(4)

1.78(4)

2.737(3)

175(3)

x, y, z


0.93(4)

1.82(4)

2.743(3)

173(3)

x, y, −1+z

N−HNH2···NDABCO

0.86(3)

2.17(3)

3.026(3)

178(2)

x, y, −1+z

N−HNH2···NDABCO

0.82(4)

2.40(4)

3.186(3)

161(3)

1−x, −y, 1−z

N−HNH2···OW

0.78(3)

2.33(3)

3.090(4)

168(3)

1−x, −y, −z

O−HW···OSO2

0.82(4)

2.07(4)

2.863(3)

163(4)

x, y, z

O−HW···NNSO2

0.87(5)

2.22(5)

3.029(4)

156(4)

1−x, 1−y, −z 1−x, −y, 1−z

N−HDABCO, cation···Npyrazine ring N−HNH2···NDABCO

0.91(3) 0.78(3)

1.87(3) 2.33(3)

2.778(3) 3.090(4)

177(3) 168(3)

All the hydrogen atoms were inserted in idealized positions and allowed to refine in the parent carbon atom, except those belonging to amide and amine groups, cationic coformers, and water molecules, all of which were located from the electron density map and allowed to refine. MERCURY 3.533 was used for packing diagrams construction and PLATON34 for hydrogen bond interactions calculation. Table 1 summarizes data collection and refinement details. Powder X-ray Diffraction (PXRD). Data were collected in a D8 Advance Bruker AXS θ−2θ diffractometer, with copper radiation source (Cu Kα, λ = 1.5406 Å) and a secondary monochromator, operated at 40 kV and 40 mA. The diffractometer is equipped with an Anton Paar HTK 16N high-temperature chamber and an Anton Paar TCU 2000N temperature control unit. The program MERCURY 3.533 was used to obtain the diffraction patterns calculated from SCXRD data.

The purity of the bulk was always verified by comparison of the calculated and experimental PXRD patterns, depicted in Supporting Information (SI) (Figures S1−S7). Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC). Combined TG-DSC measurements were carried out on a SETARAM TG-DTA 92 thermobalance under airflow with a heating rate of 10 °C·min−1. Because of the grinding instability of compound 2, DSC and TGA measurements were performed in single crystal samples, using a PerkinElmer DSC7 and TGA7 apparatus, under positive nitrogen flow of 25 cm3·min−1 and 38 cm3·min−1, respectively, with a heating rate of 5 K·min−1. The samples weights were in the range of 5−15 mg. Hot-Stage Microscopy (HSM). Hot stage experiments were carried out using a Linkam TP94 device connected to a Linkam LTS350 platinum plate. Images were collected, via the imaging software Cell, 1883



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Figure 5. Crystal packing of SDM:ISO cocrystal: (a) in a view along the b-axis, with linear SDM chains interacting with two antiparallel ISO chains; (b) detail depicting the N−Hterminal amine (SDM)···Osulfone (SDM) (yellow), N−Hsulfonamide (SDM)···O(ISO) (blue), and N−Hamide (ISO)···Nterminal amine (SDM) (green) interactions.

Figure 6. Crystal packing of SDM:BIP cocrystal acetone solvate: (a) in a view along the a-axis depicting the SDM−SDM interactions that give rise to the honeycomb-like arrangement; (b) in a view along the b-axis, showing BIP molecules establishing the connection between two SDM layers; (c) overall crystal packing of 2 revealing the acetone molecules (green) lying in empty spaces of the two SDM honeycomb layers (blue and purple) and BIP molecules (pink). 1884



Article

Figure 7. Crystal packing of SDM:BIP cocrystal hydrate showing: (a) Mode I: in a view along the a-axis, R24(8) synthons are formed through the interaction between two molecules of SDM and two molecules of water that are bridged by BIP molecules, forming a layer in the bc plane; (b) Mode II: R44(20) synthons are formed through the interaction between two molecules of SDM and two molecules of water. with an Olympus SZX10 stereomicroscope. Crystals were placed on an oil drop to allow a better visualization of solvent or decomposition products release. Attenuated Total Reflectance-Infrared (ATR-IR). ATR-IR spectra were recorded on a Nexus 670 Thermo Nicolet spectrometer equipped with ATR accessory (Pike Instruments). Solubility Studies. Preliminary solubility studies were carried out by dissolving 10 mg of each multicomponent form obtained in water, gradually added until complete dissolution. The amount of added water allowed the determination of empiric solubility values. SDM was used for comparison.

Furthermore, our results point toward the preferable formation of molecular salts, instead of cocrystals. SDM:ISO Cocrystal (1). The asymmetric unit of 1 contains one molecule of SDM and one molecule of ISO. SDM chains grow along the a-axis through N−Hterminal amine···Osulfone (2.57(6) Å) hydrogen bonds, with the SDM molecules oriented in a head-to-tail fashion. These chains, based on the C11(8) motif, are bridged by two antiparallel ISO chains through N−Hsulfonamide···OISO (1.90(5) Å) and N−HISO···Nterminal amine 2.39(4) Å) hydrogen bonds, in which the connection between ISO molecules is established via N−Hamine···Npyridine ring interactions (2.00(6) Å) (Figure 5). SDM:BIP Cocrystal Acetone Solvate (2). Cocrystal 2 structure contains one molecule of SDM, half molecule of BIP, and half molecule of acetone in the asymmetric unit. The 2D packing structure is based on N−Hterminal amine···Osulfone (2.22(4) Å), (C11(8) synthon) and N−Hterminal amine···Omethoxy (2.49(4) Å) hydrogen bonds, generating linear SDM chains along the b-axis and zigzag SDM chains along the c-axis, respectively, thus giving rise to a honeycomb-like arrangement (Figure 6a). The overall packing is achieved when this honeycomb motif connects with another one, via BIP molecules (N−Hsulfonamide···NBIP, 1.31(3) Å) (Figure 6b), thus allowing the formation of 3D cages along the a-axis, where acetone molecules lie in the interface of two cages (Figure 6c). SDM:BIP Cocrystal Hydrate (3). This cocrystal structure contains one molecule of SDM, one molecule of BIP, and one molecule of water in the asymmetric unit. In this particular case, SDM molecules connect to each other only through water molecules, which happens in two different modes. In mode I, two molecules of SDM and two molecules of water are interconnected through N−Hterminal amine···Owater (2.13(3) Å) interactions, giving rise to a R42(8) synthon (Figure 7a). Such motifs are bridged by two molecules of BIP through

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RESULTS AND DISCUSSION The following section presents a detailed description of the structural features of new multicomponent crystal forms 1−8 and a thorough analysis of their crystal packing based on hydrogen bond interactions (Table 2). A comparison of the experimental PXRD patterns with those calculated from single crystal X-ray diffraction (SCXRD) data confirmed the phase purity of each crystalline sample (Figures S1−S7). A brief analysis of the thermal stability and physicochemical properties, assessed by TGA, DSC, variable temperature PXRD, and HSM, will also be addressed. Some preliminary results on solubility will be presented. Structural Analysis. In the X-ray crystal structure of SDM (SFDMOX04),25 the sulfonamide nitrogen and oxygen atoms form a homomeric synthon in a R22(8) ring motif through a N−Hsulfonamide···Osulfone (2.21(3) Å) hydrogen bond (Figure 2). These dimeric motifs are associated through N−Hterminal amine··· Npyrazine ring (2.40(4) Å) interactions, creating a linear chain along the b-axis. At the same time N−Hterminal amine···Osulfone (2.64(6) Å) interactions promote the growing along a. In the new multicomponent crystal forms disclosed herein, the typical R22(8) synthon is always disrupted, giving rise to new hydrogen bond motifs, while the chain motifs tend to prevail. 1885



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Figure 8. Crystal packing of SDM:PIP salt depicting: (a) SDM zigzag chains connected via PIP molecules in a view along the a-axis; (b) view along the caxis of the full use of PIP2+ donor capacity (+N−HPIP···Osulfone − blue and +N−HPIP···Npyrazine ring − red) building a R44(22) synthon, which promotes the growing along a.

N−Hsulfonamide···NBIP (1.98(3) Å) and O−Hwater···NBIP (1.87(4) Å) hydrogen bonds, forming a layer in the bc plane (Figure 7a). In mode II, a dimer is formed through the assembly of SDM and water molecules by N−Hterminal amine···Owater (2.13(3) Å) and O−Hwater···Osulfone (2.02(3) Å) hydrogen bonds, promoting the formation of a R44(20) synthon (Figure 7b). This R44(20) synthon is the building block responsible for the 3D supramolecular arrangement and connects the layers formed by mode I. Here we observe that besides the breaking of R22(8) synthon also the C11(8) motif is disrupted due to the water molecules. SDM:PIP Molecular Salt (4). The molecular salt 4 contains deprotonated SDM and protonated PIP in a 2:1 ratio. In this case, one SDM molecule interacts with two other equivalent

SDM molecules through N−Hterminal amine···Osulfone (2.36(3) and 2.18(4) Å) hydrogen bonds, leading to the formation of zigzag chains (C11(8) synthon) along the b-axis, with the SDM molecules oriented in a head-to-tail fashion. These chains are connected via PIP molecules through +N−HPIP···Osulfone and + N−HPIP···Npyrazine ring (1.92(3) and 1.67(3) Å) charge assisted interactions, forming layers in the bc plane (Figure 8a). Furthermore, the piperazinium cation (PIP2+) completes the full use of its donor capacities in the establishment of hydrogen interactions with SDM molecules, allowing the generation of a R44(22) synthon (Figure 8b) and leading to the 3D packing. SDM:TRI Molecular Salt (5). Molecular salt 5 contains deprotonated SDM and diprotonated TRI in a 2:1 ratio. 1886



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Figure 9. Crystal packing of SDM:TRI salt showing: (a) SDM chains formed through the interaction of nonequivalent SDM molecules (blue and gray) in a view along the c-axis; (b) TRI molecules bonding with SDM molecules of four different chains in a view along the c-axis.

upside-down (Figure 10b), with no classical hydrogen bonds between both strands. SDM:DABCO Molecular Salt (7) − Polymorphic Form II. Molecular salt 7 is a polymorphic form of 6, with Z′ = 2, which presents two deprotonated SDM molecules and two protonated DABCO molecules in the asymmetric unit. Because of the presence of two aditional hydrogen bonds the obtained supramolecular arrangement completely differs from Form I. Nonequivalent SDM molecules alternate with each other, creating infinite chains that grow along the b-axis through N−Hterminal amine···Osulfone (2.16(3) Å) (the C11(8) synthon) and N−Hterminal amine···Npyrazine ring (2.32(4) Å) interactions. Parallel SDM chains are linked by nonequivalent alternated DABCO molecules through +N−HDABCO···Nsulfonamide (1.78(4) and 1.82(4) Å) and N−Hterminal amine···NDABCO (2.17 (3) and 2.40(4) Å) hydrogen bonds (Figure 11). SDM:DABCO Salt Hydrate (8). The asymmetric unit of 8 consists of one deprotonated molecule of SDM, one protonated molecule of DABCO, and one molecule of water. Like in SDM:BIP cocrystal hydrate (3), SDM molecules present in this crystal form never connect directly with each other. Instead, the connection is established via water molecules, through

Nonequivalent SDM molecules alternate with each other, forming chains that grow along the a-axis through bifurcated N−Hterminal amine···Npyrazine ring (2.48(12) and 2.31(10) Å) hydrogen bonds and N−Hterminal amine···Omethoxy (2.41(12) Å) interactions (Figure 9a). Along the b-axis chain growth is attained via N−Hterminal amine···Osulfone (2.08(10) and 2.20(3) Å) hydrogen bonds (C11(8) motif), established between nonequivalent SDM molecules of adjacent chains (Figure 9a). TRI molecules are placed in the SDM overall packing through +N−HTRI···Osulfone (2.18(5), 1.85(8), and 1.88(3) Å) and +N−HTRI···Nsulfonamide (1.88(8) and 2.44(7) Å) interactions, involving four different SDM chains (Figure 9b). SDM:DABCO Molecular Salt (6) − Polymorphic Form I. The molecular salt 6 contains a deprotonated SDM molecule and a protonated DABCO molecule in a 1:1 ratio. SDM molecules interact with each other through N−Hterminal amine···Osulfone (2.04(4) Å) hydrogen bonds, forming an infinite chain (C11(8) motif) along the c-axis, in which DABCO molecules are hanging via +N−HDABCO···−Nsulfonamide (1.77(3) Å) hydrogen bond, giving rise to a 2D strand (Figure 10a). This pattern grows in 3D through the interlock of two similar strands pairing 1887



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Figure 10. Crystal packing of SDM:DABCO (1:1) salt: (a) view along the b-axis showing DABCO molecules hanging in a SDM linear chain (b) 3D growing through the interlock of two similar strands of SDM (blue) and DABCO (green) in a view along the b-axis.

of the coformer. In 2, the event takes place at 94−105 °C, while in 3 the interval is larger (80−108 °C) encompassing also the releasing of water adsorbed in the surface the bulk (Figures 13 and 15). The different behavior may also reflect the different packing observed: in 2 the acetone molecules are completely embedded in the voids of the crystal structure, while the water in 3 is strongly bonded to both SDM and BIP molecules. These processes were confirmed by HSM (Figures 14 and 16), with the solvent release/melting of conformer evidenced by “bubbles” formation. Trying to ascertain these results VT-PXRD data acquisition was scheduled but was only possible for compound 3 (Figure 17) as crystalline 2 directly transformed into the reagents upon grinding. Data show that as expected after the water release/coformer melting the obtained pattern is that of SDM. According to DSC, TGA and VT-PXRD data (Figures S11− S13), molecular salt 4 decomposes right after the melting point, at ca. 187 °C. Additionally, the DSC thermogram shows a hump below 100 °C, and the TGA curve shows an approximately 7.4% mass loss at the temperature range of 50−130 °C. Since crystalline 4 does not contain any solvents in its structure, this mass loss can be associated with moisture at the surface of the sample. Both molecular salts 5 and 7 have shown to be stable up until melting at ca. 160 °C and 164 °C respectively (Figures S14− S17). In compound 8, water is released from the structure at ca. 95 °C and melts at ca. 163 °C followed by decomposition (Figures S18−S20).

N−H terminal amine ···O water (2.33(3) Å), O−H water ···O sulfone (2.07(4) Å) and O−Hwater···Nsulfonamide (2.22(5) Å) hydrogen bonds, giving rise to a R42(8) synthon and creating a SDM-water layer within the bc plane (Figure 12a). DABCO molecules interact with SDM molecules through N−Hterminal amine···NDABCO (2.33(3) Å) and +N−HDABCO···−Npyrazine ring (1.87(3) Å) hydrogen bonds (Figure 12b), linking two adjacent SDM−water layers. ATR-IR spectroscopy data for compounds 3−5, 6, and 7 corroborate the structural characterization assessed by SCXRD data (Figure S8). Physicochemical Properties Determination. Thermal stability of the synthesized compounds was assessed by combining data from different techniques, such as variable temperature PXRD (VT-PXRD), DSC, TGA, and HSM. The most relevant results as well some preliminary solubility studies will be presented in this section. The remaining experimental data are presented in SI. It was not possible to determine the physicochemical properties for molecular salt 6, since this was obtained concomitantly with salts 7 and 8 and all isolation attempts failed. According to DSC, TGA, and VT-PXRD data (Figures S9 and S10) cocrystal 1 is stable and does not undergo any significant changes until melting is observed, at ca. 148 °C, followed by decomposition. Crystallines 2 and 3, solvated cocrystals of SMD:BIP present an interesting behavior where releasing of the solvent, respectively, acetone and water, is accompanied by the melting 1888



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Figure 11. Crystal packing of SDM:DABCO (2:2) salt viewed along the a-axis shows nonequivalent SDM molecules (blue and gray) interacting with nonequivalent DABCO molecules (magenta and gray).

Figure 12. Crystal packing of SDM:DABCO salt hydrate depicting: (a) R42(8) synthons formed through the interaction between two molecules of SDM and two molecules of water in a view along a; (b) DABCO molecules established the connection between two SDM−water layers in a view along the a-axis.

Preliminary Solubility Studies. Preliminary solubility studies were carried out for pure SDM and for compounds 1, 3−5, 7, and 8, and as was previously said compound 6 was impossible to isolate and 2 transformed upon grinding. The fact of SDM being completely insoluble in water precluded any attempts for further studies. Here we present the results obtained

when trying to solubilize 1 mg of the different compounds in the minimum amount of water. The most soluble multicomponent form in water is compound 5, SDM:TRI molecular salt; 1 mg was almost immediately solubilized upon the addition of 1 mL of water. The less soluble is compound 3, SDM:BIP:H2O cocrystal. But in conclusion all the 1889



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Figure 13. DSC (black) and TGA (blue) for 2.

Figure 17. (a) Theoretical powder pattern of 3; experimental powder diffraction patterns obtained with 3 at different temperatures: (b) 30 °C; (c) 60 °C; (d) 105 °C; (e) 120 °C; (f) 150 °C; (g) 30 °C after cooling; (h) experimental pure SDM diffractogram; (i) experimental pure BIP diffractogram. It can be easily observed that after 60 °C the cocrystal decomposes.

Figure 14. HSM images obtained for cocrystal 2; (a) 25 °C; (b) 104 °C: appearance of “bubbles” evidence the release of acetone; (c) 176 °C: complete melting and decomposition of the compound.

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CONCLUSIONS In this work, we have investigated the possibility of obtaining new multicomponent crystal forms of SDM and have been successful when using amides and secondary and tertiary amines. These molecules contain nitrogen and/or oxygen atoms that can act as proton acceptors/donors and can, therefore, take part in extended hydrogen bonded networks, suitable for the study of synthon competition. SDM has proved to be sufficiently acidic to transfer the amide proton to PIP, TRI and DABCO, while no protonation of the weakly basic BIP and acidic ISO molecules is observed. In the new multicomponent crystal forms, the typical R22(8) sulfonamide synthon (Type II) is always disrupted, showing this to be the main feature for the formation of the new solid forms. Rationalizing the obtained supramolecular interactions we discuss cocrystals and salts separately, due to the loss of the best proton donor upon deprotonation of SDM. In the three cocrystals forms, the amide nitrogen, Nsulfonamide, interacts with the best acceptor of the coformer moleculethe oxygen atom of the acetamide group in ISO and the nitrogen atom in BIP. Even when water molecules are present in the structure, this interaction is maintained, since the oxygen of the water molecules interact preferentially with the NH2 terminal, breaking the C11(8) synthon. SDM salts present the expected +N−Hcoformer···Nsulfonamide charged hydrogen bond. Competing with this synthon, one the O atoms of the sulfonyl group acts as acceptor toward the cationic N of the coformers as well as the Npyrazine atom. This last motif is not observed in DABCO salts. As in cocrystals the N−Hterminal amine···Osulfone synthon (C11(8)) is observed and is only broken in 8. These results are in accordance with those obtained in previous reports on sulfonamides,20,17,18,24,35 in which amide proton is the best donor and carbonyl, sulfanyl and activated aromatic nitrogen groups are the best acceptors (in this order).

Figure 15. DSC (black) and TGA (blue) for 3.

Figure 16. HSM images obtained for cocrystal 3; (a) 25 °C; (b) 116 °C: release of water “bubbles”; (c) 172 °C: complete melting of the compound.

multicomponent forms have shown some improvement to API aqueous solubility. 1890



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Figure 18. Preliminary solubility studies: (a) Pure SDM (1 mg/10 mL); (b) SDM:ISO cocrystal 1 (1 mg/10 mL); (c) SDM:BIP cocrystal hydrate 3 (1 mg/10 mL); (d) SDM:PIP salt 4 (1 mg/10 mL); (e) SDM:TRI salt 5 (1 mg/3 mL); (f) SDM:DABCO salt 6 (1 mg/10 mL); (g) SDM:DABCO salt hydrate 7 (1 mg/10 mL).

Notes

In general our results confirm the conclusions from CSD search; both in cocrystals and salts the R22(8) Type II synthon is broken, while C11(8) chains are maintained, except in those where the presence of the water molecules completely disrupts them. In the case of hydrates (compounds 3 and 8), water molecules are used as spacers between SDM−SDM molecules; they are not hydrogen bonded to each other, forming tunnels. This is in agreement with DSC results where water release is observed in the 95−97 °C temperature range, as previously reported by Zaworotko et al.36 Solubility tests revealed that compounds obtained in this work are more soluble in water than SDM, the most soluble being the molecular salts as expected. Our results are also in accordance with solubility tests performed by Hornedo and co-workers,37 that foresee the solubility of the multicomponent form to be dependent on the coformer solubility. ISO cocrystal has been shown to be more soluble than BIP cocrystal, all of which have higher solubility than SDM as salt 5 is the one with the highest solubility. This work provides novel and practical leads for further improvements on the physicochemical properties of sulfonamide drugs.

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Authors acknowledge Fundaçaõ para a Ciência e a Tecnologia (FCT) for funding: Projects RECI/QEQ-QIN70189/2012 and PEST-OE/QUI/UI0100/2013 for the Research Grant PTDC/ CTM-BPC/122447/2010 and postdoc Grants SFRH/BPD/ 91397/2012 awarded to S.D. and A.F. respectively This work was ́ developed in the scope of Centro de Quimica Estrutural- IST Project, UID/QUI/00100/2013, financed by national funds through the FCT/MEC. The authors also wish to thank the European Synchrotron Radiation Facility (ESRF, Grenoble, France) for granting access to the BM01A/SNBL beamline through the R&D Project CH-4160 and the help of Dr. V. André and MSc. S. Quaresma in data collection.

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(1) Desiraju, G. R. J. Chem. Sci. 2010, 122, 667−675. (2) Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 8342−8356. (3) Najar, A. A.; Azim, Y. J. Indian Inst. Sci. 2014, 94, 45−67. (4) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311−2327. (5) Wood, P. A.; Feeder, N.; Furlow, M.; Galek, P. T. A.; Groom, C. R.; Pidcock, E. CrystEngComm 2014, 16, 5839−5848. (6) Biradha, K.; Su, C. Y.; Vittal, J. J. Cryst. Growth Des. 2011, 11, 875− 886. (7) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499−516. (8) Zaworotko, M. J. Pharm. Pharmacol. 2006, 58, A91−A91. (9) Shan, N.; Zaworotko, M. J. Drug Discovery Today 2008, 13, 440− 446. (10) Steed, J. W. Trends Pharmacol. Sci. 2013, 34, 185−193. (11) Qiao, N.; Li, M. Z.; Schlindwein, W.; Malek, N.; Davies, A.; Trappitt, G. Int. J. Pharm. 2011, 419, 1−11. (12) Braga, D.; Maini, L.; Grepioni, F. Chem. Soc. Rev. 2013, 42, 7638− 7648. (13) Martins, I.; Martins, M.; Fernandes, A.; Andre, V.; Duarte, M. T. CrystEngComm 2013, 15, 8173−8179. (14) Skold, O. Drug Resist. Updates 2000, 3, 155−160. (15) Temperini, C.; Cecchi, A.; Scozzafava, A.; Supuran, C. T. Org. Biomol. Chem. 2008, 6, 2499−2506. (16) Parasca, O. M.; Gheata, F.; Panzariu, A.; Geangalau, I.; Profire, L. Rev. Med.-Chir. 2013, 117, 558−664. (17) Goud, N. R.; Khan, R. A.; Nangia, A. CrystEngComm 2014, 16, 5859−5869. (18) Suresh, K.; Minkov, V. S.; Namila, K. K.; Derevyannikova, E.; Losev, E.; Nangia, A.; Boldyreva, E. V. Cryst. Growth Des. 2015, 15, 3498−3510. (19) Yang, S.; Guillory, J. K. J. Pharm. Sci. 1972, 61, 26−40. (20) Adsmond, D. A.; Grant, D. J. W. J. Pharm. Sci. 2001, 90, 2058− 2077.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b01320. Figures S1−S7 present the powder diffractograms obtained for solid forms 1−5 plus 7 and 8. Figure S8 presents the ATR-IR spectra of the different forms. Figures S9, S11, S14, S16, and S18 present the DSC traces of the compunds not shown in the main manuscript, S12 and S14 the HSM images of solid forms 4 and 8. Figures S13, S15, S17, and S20 the PXRD-VT diffractograms for forms 4, 5, 7, and 8 (PDF) Accession Codes

CCDC 1423629−1423636 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. 1891



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