First Evidence of Polymorphism in Furosemide Solvates - Crystal

Mar 21, 2017 - Several polymorphs of solvates of furosemide with dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) have been obtained, and their ...
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First Evidence of Polymorphism in Furosemide Solvates Alina A. Beloborodova,*,†,‡ Vasily S. Minkov,§ Denis A. Rychkov,†,∥ Tatyana V. Rybalova,†,‡ and Elena V. Boldyreva†,∥ †

Novosibirsk State University, Novosibirsk, Russia N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of Siberian Branch of Russian Academy of Sciences (SB RAS), Novosibirsk, Russia § Max Planck Institute for Chemistry, Hahn-Meitner-Weg 1, Mainz, Germany ∥ Institute of Solid State Chemistry and Mechanochemistry Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk, Russia ‡

S Supporting Information *

ABSTRACT: Several polymorphs of solvates of furosemide with dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) have been obtained, and their crystal structures were solved and analyzed. The structures differ from each other in both conformation of the furosemide molecule (particularly with respect to the orientation of the furanylmethylamino fragment) and molecular packing. The arrangement of solvent moleculesDMSO and DMFis different in different polymorphs: either in the channels or between the layers. Layered polymorphs can be formed on rapid crystallization using water as an antisolvent, whereas a slower crystallization on evaporation promotes the growth of channeled structures. Despite different crystal structures, F-DMSO-I, F-DMSO-II, FDMSO-III, and F-DMF-II give the same phase on desolvation, namely, furosemide polymorph I, which is the thermodynamic form at ambient conditions.

1. INTRODUCTION Polymorphism is very important for chemical sciences and technology since properties of different polymorphs may differ.1,2 Multiple local energy minima corresponding to different molecular packing of the same organic molecules can be rather close in energies, giving rise to coexistence of different polymorphs under the same conditions. A crystal structure is a result of optimizing the balance between molecular conformational energies and multiple intermolecular interactions of different types.3,4 The similarity in the energies of different polymorphs is often the result of an interplay between these two contributions. The increase in conformer energy is compensated by the resulting gain in intermolecular interactions and vice versa. Quite often, molecules with molecular fragments that are prone to rotation along a particular bond vector crystallize in different conformational polymorphs.1,5 Polymorphism of individual organic compounds is very widespread, and many reviews and books1,5−10 are devoted to this phenomenon, in addition to numerous articles describing the original results. The ability of organic compounds to form multicomponent crystals (MCC)salts, cocrystals and crystal solvatesis well documented. More often, MCC differ in stoichiometry, whereas true polymorphs have been reported more rarely.11−20 © 2017 American Chemical Society

Furosemide (4-chloro-2-[(2-furanylmethyl)amino]-5-sulfamoylbenzoic acid) is a common loop diuretic drug for treating heart failure and edema. The crystal structure of furosemide has been first reported in 1978.21 Furosemide has two molecular fragments with significant rotational freedom about their respective covalent bonds, namely, the furanylmethylamino and sulfamoyl fragments, and can therefore adopt different conformations. With a vast diversity of conformational energy minima, furosemide is prone to crystallization as different polymorphs (ref 22, CSD version 5.38, November 2016). A systematic study of polymorphism of furosemide23,24 and its capacity to form different salts, 25,26 solvates, 27,28 and cocrystals25,29−36 was started only in the past few years. To date, the crystal structures of three polymorphs have been reported,24 with the structure of the fourth high-temperature phase remaining unknown.23 The existence of polymorphism of furosemide and nicotinamide cocrystals has been documented, with four different crystal structures solved and refined from Xray powder diffraction data.31 However, only one crystal structure was found to be even roughly comparable with that further refined by single crystal X-ray diffraction.33 The Received: August 9, 2016 Revised: March 17, 2017 Published: March 21, 2017 2333

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with a molybdenum X-ray tube and a Ruby CCD detector. Data collection for all furosemide DMSO solvate samples was done at ambient temperature, whereas that for F(DMF)-II and F(DMF)-IV was done at low temperature, 150 K, to improve the diffraction data. The crystal structure F(DMF)-II at 150 K remains the same as at ambient temperature, as was confirmed by comparison of the powder diffractions at low (calculated based on CIF file) and at ambient temperature. For F(DMF)-IV only one diffraction experiment was accomplished because this form could be found only once as an impurity in the batch of F(DMF)-I. The single crystal was not damaged on cooling, and this suggests that the phase transition that occurred on cooling from ambient temperature is not likely (though not absolutely excluded, since some low-temperature phase transitions are reversible and preserve single-crystals intact).37 The data collection, indexing, and integration of reflections, as well as data reduction were performed using X-Area38 and CrysAlis39 software. Crystal structures were refined using SHELXL40,41 integrated in the XStep32 shell.42 The anisotropic displacement parameters (ADPs) of C9, C10, C11, and O3 atoms in the furanyl ring of furosemide were found to be significantly larger than the ADPs for other atoms in the molecule for all solvates. This is likely because of an absence of hydrogen bonds, resulting in an increase in mobility of the fragment. H atoms were found in difference Fourier electron density maps, and their positions were refined using appropriate restraints, Uiso(H) = 1.5Ueq(C) for terminal methyl H atoms, and 1.2Ueq (parent atom) for internal chain H atoms. Solvent molecules in F(DMSO)-I and F(DMF)-III were found to be disordered over two positions with occupancies of 0.633(2)/0.367(2) for molecule A and 0.517(2)/ 0.483(3) for molecule B in F(DMSO)-I and 0.593(13)/0.407(13) in F(DMF)-III. Space group settings suggested by structure-solution software for F(DMSO)-I (P21/a), F(DMSO)-III, and F(DMF)-III (P1/n) were transformed into the standard setting (P21/c) using WinGX v2014.1. In the case of F(DMSO)-I and F(DMF)-III, the solvate molecules in the structure are disordered. The disordering ratios for the two DMSO molecules in the asymmetric unit are not equal: 0.633(2):0.367(2) and 0.517(2):0.483(2) for A and B molecules, respectively. The disordering is most pronounced for the sulfur atom of DMSO molecules, whereas other non-hydrogen atoms occupy the same positions. This is especially true for oxygen atoms of both A and B molecules, which participate in the formation of hydrogen bonds with furosemide molecules. In contrast to that, the DMF molecule is disordered over two positions (occupancy is 0.593(13) and 0.407(13) for A and B moiety) preserving only the N3 atom site common for both A and B molecules in F(DMF)-III. In this case even the acceptor O6 is disordered, though it participates in a short O1−H1···O6 hydrogen bond. Parameters characterizing data collection and refinement, as well as crystal data, are summarized in Table 1. Mercury,43 ORTEP-3,44 and PLATON45 were used for visualization and analysis of the crystal structures. The structural data for three polymorphs of furosemide DMSO solvate, as well as for three new polymorphs of furosemide DMF solvate, have been deposited as CIFs at the Cambridge Crystallographic Data Base (CCDC No. 1024301, 1024439, 1024440, 1410395−1410397) and are also available as Supporting Information (SI). All structural data can be downloaded freely from the following site: http://www.ccdc.cam.ac.uk. Infrared Spectroscopy. ATR IR spectra were recorded using a Digilab Excalibur 3100 spectrometer equipped with a MIRacle ATR (Pike) accessory in the frequency range of 4500 to 600 cm−1 with a resolution of 2 cm−1. Computational Techniques. Molecular energies of different conformers were estimated in the gas phase. Geometry optimizations were carried out at the B3LYP/6-311++G(d,p)46−49 level of theory (LOT), with addition of the Grimme D350 empirical dispersion corrections. In each case, the molecules were allowed to fully relax. All calculations were performed using the Gaussian0951 package. Input molecular geometries for the different conformers in the solvate structures were taken from the corresponding experimental X-ray

existence of furosemide solvates with DMSO F(DMSO) has been reported,27 but their crystal structures remained unknown. In the present work we report for the first time the crystal structures of the previously obtained27 and several new solvates of furosemide with dimethyl sulfoxide and dimethylformamide (hereinafter referred to as F(DMSO) and F(DMF), respectively). We document for the first time the existence of polymorphs of these solvates and discuss the differences in their crystal structures in relation to the crystallization conditions.

2. EXPERIMENTAL SECTION Materials. Samples of commercially available furosemide (SigmaAldrich, CAS No. 54-31-9) were dissolved in dimethyl sulfoxide (DMSO) and in dimethylformamide (DMF) at ∼70 °C. Saturated solutions were left at ambient temperature to cool. After several days, colorless, elongated prism-shaped crystals of a stoichiometric furosemide and DMF solvate, F(DMF)-II, precipitated. The cooled solution of furosemide in DMSO was divided into two vessels. In the first vessel water was gently added as an antisolvent by forming a layer at the surface without mixing; the volume of water was approximately one-eighth the volume of the prepared saturated solution. This vessel was capped and placed in a refrigerator at a temperature of ∼1 °C allowing water to diffuse deep into the vessel gradually. After a couple of weeks colorless block-shaped crystals of stoichiometric DMSO solvate of furosemide, F(DMSO)-I, grew at the bottom of the vessel. The second vessel (without any water added) was kept without a cap at ambient conditions, and, after several months of very slow solvent evaporation, colorless plate-shaped crystals of another polymorph, F(DMSO)-II, precipitated. The crystal structure F(DMSO)-III was obtained by slow crystallization method at long holding of solution furosemide-DMSO in a refrigator at 1 °C for 3−6 months. A few crystals of F(DMF)-III and F(DMF)-IV could be found as impurities also in several batches with F(DMF)-I after 3−6 months; the such long holding time of crystallization of the forms was regarded as a slow crystallization method. Crystals of quality sufficient for single crystal Xray diffraction analysis were covered by low viscosity CryoOil (MiTeGen) to protect them from desolvation during data collection. X-ray powder diffraction patterns measured for F(DMSO)-I, -III, and F(DMF)-II samples (Figure 1) agreed well with the pattern calculated based on the model derived from a single-crystal X-ray diffraction (see below). X-ray Diffraction. Single-crystal X-ray diffraction experiments were carried out using a STOE IPDS-II diffractometer equipped with a molybdenum X-ray tube (λ = 0.71073 Å) and an image plate detector, and an Oxford Diffraction Gemini Ultra R diffractometer equipped

Figure 1. Powder diffraction patterns. (1) − F(DMSO)-I; (2) − F(DMSO)-III; (3) − F(DMF)-II; (4) − Form I of furosemide formed on desolvation of the three above-mentioned solvates. 2334

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Table 1. Crystal Data, Data Collection, and Structure Refinement Parameters for Crystal Structures of Furosemide Solvates with DMSO and DMF F(DMSO)-I moiety formula

F(DMSO)-II

F(DMSO)-III

C12H11ClN2O5S, C2H6OS

F(DMF)-II

F(DMF)-III

F(DMF)-IV

C12H11ClN2O5S, C3H7NO

Mr/ g mol−1 space group Z/Z′ T/ K crystal size/mm

408.86 403.83 P21/c P1̅ P21/c P1̅ P21/c P1̅ 8/2 2/1 4/1 2/1 4/1 4/2 295 150 295 150 0.53 × 0.25 × 0.11 0.46 × 0.30 × 0.06 0.41 × 0.26 × 0.12 0.44 × 0.21 × 0.14 0.52 × 0.24 × 0.06 0.46 × 0.29 × 0.17 Oxford Diffraction Oxford Diffraction Oxford Diffraction Gemini Ultra R Stoe IPDS-II Gemini Ultra R Stoe IPDS-II Gemini Ultra R Stoe IPDS-II diffractometer

a/Å b/Å c/Å α (deg) β (deg) γ (deg) V/Å3 Dcalc/g cm−3 μ/mm−1 no. of measured independent and observed [I > 2σ(I)] reflections θmin (deg) θmax (deg) range of h k l

Rint R[F2 > 2σ(F2)] wR(F2) S no. of parameters Δρmax/e Å−3 Δρmin/e Å−3

9.9091(2) 36.5182(6) 9.7950(2) 90.00 91.487(2) 90.00 3543.25(12) 1.533 0.49 61111 8785 7543

8.9287(8) 9.7082(8) 10.4363(9) 80.333(7) 86.392(7) 86.467(7) 888.82(13) 1.528 0.483 10403 4392 3109

8.3908(2) 19.9061(4) 11.8794(3) 90 112.584(2) 90 1832.04(8) 1.482 0.47 27682 4549 3552

8.9641(6) 10.1485(7) 10.3271(7) 90.796(5) 102.321(5) 101.533(5) 897.74(11) 1.494 0.367 11030 4627 3897

4.9375(1) 20.4394(4) 18.2451(3) 90 98.507(2) 90 1821.03(6) 1.473 0.36 26745 4353 3260

10.0100(5) 13.8559(7) 14.3242(8) 63.921(4) 83.567(4) 82.096(4) 1764.53(17) 1.520 0.373 19575 8746 7140

2.06 28.28 −13 → 13 −48 → 48 −13 → 13 0.028 0.055 0.142 1.09 519 0.43 −0.41

1.98 28.27 −11 → 10 −12 → 12 −13 → 13 0.0349 0.0462 0.1221 1.041 261 0.556 −0.421

2.05 28.27 −11 → 11 −26 → 26 −15 → 15 0.033 0.051 0.139 1.03 250 1.01 −0.96

2.02 28.70 −12 → 12 −13 → 13 −13 → 13 0.0242 0.0286 0.0744 1.053 289 0.343 −0.351

1.50 27.88 −6 → 6 −26 → 26 −23 → 23 0.037 0.043 0.123 1.03 305 0.35 −0.29

1.58 28.28 −12 → 13 −18 → 18 −18 → 19 0.0471 0.0560 0.1355 1.071 488 0.463 −0.753

diffraction data obtained in this work and in ref 27. Frequency calculations were subsequently performed in order to verify true local minima. Energy profiles were produced as a function of dihedral angles τ2 and τ3 (C2−N1−C8−C12 and N1−C8−C12−O3, respectively, see Scheme 1) for the furosemide molecule using the same LOT as mentioned above, with 5° steps. At every step, all parameters were allowed to fully relax, except the defined dihedral angles. Input molecular geometry was taken from furosemide I (FURSEM13) crystal structure. Energies of the experimental molecular conforma-

tions in solvate structures were plotted to the dihedral angle energy profiles using the experimental dihedral angle value.

3. RESULTS AND DISCUSSION Three and four polymorphs of furosemide solvates with DMSO and DMF, respectively, have been crystallized in this work. All solvate polymorphs crystallize in a 1:1 molar ratio of components in centrosymmetric space groups (triclinic P1̅ and monoclinic P21/c). The asymmetric units of all the solvates are plotted in Figure 2. In contrast to previously investigated furosemide solvates with tetrahydrofuran and 1,4-dioxane,27 the new solvates with DMF and DMSO were rather stable to desolvation under ambient conditions. The first visible signs of desolvation, such as opacification of a crystal, or appearance of localized spots of nontransparent polycrystalline areas of furosemide phase on the crystal surface, were observed only after a couple of weeks at ambient conditions, while for the solvates with THF and 1,4dioxane they were observed already after 1 day. The products of desolvation of F(DMSO)-I,II,III and F(DMF)-II did not depend on the sample particle size: large single crystals (larger than 0.5 × 0.5 × 0.5 mm3) and fine powder (∼1 μm) invariantly gave the same polymorph of furosemide, Form-I (Figure 1, pattern 4). The products of desolvation F(DMF)-III, IV were not studied, since only a few crystals of these solvates

Scheme 1. Labels of Furosemide Molecule and Torsion Angles τ1 (C4−C5−S1−N2), τ2 (C2−N1−C8−C12), and τ3 (N1−C8−C12−O3)

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Figure 2. Asymmetric units of F(DMSO)-I (a), F(DMSO)-II (b), F(DMSO)-III (c), F(DMF)-II (d), F(DMF)-III (e), and F(DMF)-IV (f) showing the atom-numbering schemes. Displacement ellipsoids are drawn at the 50% probability level, and hydrogen atoms are drawn as spheres with a fixed radius. Interactions that are formally classified as hydrogen bonds based on purely geometric criteria (PLATON) are shown by dashed and dotted blue and green lines.

shown that among 60 conformers, including 8 of the present structures, 27 conformers have trans orientation of τ 2 furanylmethylamino fragment (45% of total amount conformers), 18 - gauche+ (30%) and 15 - gauche− (25%). Analysis of the gas phase potential energy surface for rotation about the τ2 and τ3 dihedral angles suggests that the energy barriers associated with rotation of τ2 and τ3 do not exceed 10 kJ/mol even for an isolated molecule (see Figure S1, SI). These barriers are only slightly higher than thermal energy, and all orientations can therefore be expected to exist and interchange in solution, where such barriers are likely to be even lower. In contrast, the energy barrier to rotation about τ1 is considerably higher, 25 kJ/mol,24 and is invariant across known experimental structures. The furanylmethylamino fragment forms a strong intramolecular hydrogen bond N1−H2···O2, which tightly binds the carboxylate and secondary amino groups, thus restricting rotation about the N1−C2 bond. Stabilization of slightly higher energy conformations in the crystal structures is likely due to optimized intermolecular interactions and packing. Molecular conformations of pharmaceutically active molecules are considered to be potentially important in relation to molecular recognition, in particular, to their interaction with targets and biological activity.52−56 Extended research is dedicated to the problem of correlating molecular conformations in solution and in the crystalline state with the interactions with solvent, anions, or coformers.57−67 Different molecular conformations can coexist at the same experimental conditions in different solid polymorphs,6,68 and even in the same phase (structures having high Z′ values).69−76 As possible reasons for this coexistence of different conformers in the same solid phase one considers the effects of local environment in solution “snap-shot” on crystallization, the effect of different local intermolecular noncovalent interactions ranging from specific hydrogen bonds to van der Waals interactions, as well as optimizing packing energy of the whole crystal and minimizing mechanical stress. The latter factor becomes especially important at high pressures. Of special interest are the cases, when the molecular conformation in a crystal

were found as impurities in several batches with F(DMF)-I. Desolvation of F(DMF)-I has been described in ref 27; it gives Form-I or Form III, depending on the size of the parent solvate crystals. An overlay of all the molecular conformations in the solvates and, for a comparison, in all the polymorphs of furosemide is shown in Figure 3. Molecular conformation is characterized by

Figure 3. Overlay of furosemide conformations presented in (a) three polymorphs of DMSO solvate (dark and light brown - A and B conformers in F(DMSO)-I, purple - conformer in F(DMSO)-II, burgundy - conformer in F(DMSO)-III), and (b) four polymorphs of DMF solvate (red and orange - A and B conformers in F(DMF)-I, green - conformer in F(DMF)-II, magenta - conformer in F(DMF)-III, dark and light blue - A and B conformers in F(DMF)-IV). Overlay was done by C1, C3, and C5 atoms of the benzene ring. H atoms at the C8 atoms are hidden for clarity.

three torsional angles, τ1, τ2, and τ3 (Scheme 1). The first angle, τ1, describes the conformation of the sulfamoyl fragment (C4− C5−S1−N2). The latter two angles are related to rotation along the N1−C8 and C8−C12 bonds, respectively, and describe the conformation of the furanylmethylamino fragment (τ2 - C2−N1−C8−C12, τ3 - N1−C8−C12−O3). The values of the τ1, τ2, and τ3 torsional angles are summarized in Table 2. Depending on the τ2 and τ3 values, the furanylmethylamino fragment can adopt gauche− (G−), gauche+ (G+), and trans (T) conformations. The analysis of the molecular conformation of furosemide of previously known furosemide-containing crystal structures, including some O-derivatives (see Table S1, SI), has 2336

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Table 2. Selected Torsional Angles τ1 (C4−C5−S1−N2), τ2 (C2−N1−C8−C12), τ3 (N1−C8−C12−O3) Characterizing Conformation of Furosemide Molecule in Different DMSO and DMF Solvates torsional angles, °

a

solvate

τ1

τ2

τ3

conformation

F(DMSO)-I, molecule A F(DMSO)-I, molecule B F(DMSO)-II F(DMSO)-III F(DMF)-I, molecule Aa F(DMF)-I, molecule Ba F(DMF)-II F(DMF)-III F(DMF)-IV, molecule A F(DMF)-IV, molecule B

66.6(3) 68.3(2) 65.6(2) 64.3(2) 65.6(2) 62.6(2) 67.49(12) 74.56(17) 60.9(3) 62.7(3)

86.9(4) 86.2(3) −79.7(3) 87.2(3) −179.7(2) −169.0(2) −73.04(15) −87.5(3) 88.2(4) 81.5(3)

−84.2(4) −49.2(4) −159.0(2) 72.3(3) −55.2(3) −59.9(3) 165.87(11) 69.1(3) −75.4(3) 56.3(3)

G+G+G¯ G+G¯T G+G+G+ G+TG¯ G+G¯T G+G¯G+ G+G+G¯ G+G+G+

Data for F(DMF)-I are taken from ref 27.

Figure 4. Crystal packing of layered crystal structures of (a) F(DMSO)-I and (b) F(DMF)-I. Intramolecular and intermolecular hydrogen bonds and short contacts (PLATON) are shown as dotted pink and blue lines, respectively. Solvent molecules of DMSO and DMF are shown as balls and sticks for clarity.

either of the same, or another, remote site of the same molecule.57−62 In the case of furosemide, however, no straightforward correlation between a conformation and a selected type of intermolecular interaction or contact could be suggested. This is not surprising since for a very conformationally flexible molecule, with negligible energy penalty to distortion, no strong directional interactions are necessary to create a new conformation. Numerous, weak interactions in a solid are sufficient to offset any minor energy penalty to conformational distortion. This seems to be the case of furosemide conformational variability. IR-spectra, while being distinctly different not merely for each solvate, but also for each polymorph of the same solvate, do not show an obvious correlation between a molecular conformation and the position of vibrational bands (Figure S4, SI). The multiple interactions responsible for changing the molecular conformations in the crystalline furosemide solvates include furosemide−furosemide and furosemide−solvent interactions. The immediate environment of the furanylmethylamino fragment in all crystal structures includes both the solvent molecule and the furosemide molecules. The exceptions are the structures of F(DMSO)-I and F(DMF)-I, where only furosemide molecules can influence the conformation of the furanylmethylamino fragment.

depends on the crystallization conditions, the chemical composition of the crystalline phase being the same.77,78 Attempting to rationalize the factors that can influence on the conformations of furosemide in pure polymorphs and its MCC, including the solvates obtained and studied in this work, we have compared the immediate contacts of the furosemide in the crystal structures and have also analyzed general types of molecular packing. Formal analysis based on the geometric parameters, interatomic distances and angles, can suggest the existence of various possible intermolecular contacts and interactions24−36,79−82 (Schemes S1 and S2, Tables S2−S4, Figure S2 and S3, SI). However, not all of these “contacts” necessarily correspond to real hydrogen bonds and attractive interactions. A special careful and detailed theoretical and experimental study of the electronic structure is needed to prove the existence of “true” hydrogen bonds or other types of attractive interactions, which are affected by intramolecular charge density distribution.3,83−85 It is likely that the existence of N−H···Cl and D−H···OS hydrogen bonds is highly disputable, as discussed by Gavezzotti et al.86 and Tantardini et al.83 In some systems a conformational change in a molecular fragment has been correlated directly with a specific interaction 2337

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Figure 5. Crystal packing of channeled crystal structures of (a) F(DMSO)-II, (b) F(DMSO)-III, (c) F(DMF)-II, (d) F(DMF)-III, and (e) F(DMF)IV. Intramolecular and intermolecular hydrogen bonds and short contacts (PLATON) are shown as dotted pink and blue lines, respectively. Solvent molecules of DMSO and DMF are shown as balls and sticks for clarity.

correlation between conformation of furosemide and type of crystal packing is absent. One can suppose that if solvent−solvent (S−S) interactions are numerous and strong, and if furosemide-solvate (F−S) interactions dominate, then solvent molecules play a key role in the formation of crystal structure, and a structure adopts the layered crystal structure. Conversely, if furosemide−furosemide (F−F) interactions are numerous and strong, then the solvent molecules must adapt to the space between the furosemide molecules, and packing adopts a channeled crystal structure. The analysis of crystal structures helps to understand the influence of crystallization technique on the polymorphism of F(DMSO) and F(DMF). The water added slowly and without mixing to furosemide solutions in organic solvents serves as antisolvent. The layered structures formed when this crystallization technique is used (F(DMSO)-I and F(DMF)I) have a higher contribution of S−S and F−S interactions. In the case of F(DMSO)-I the solvent molecules have the closest arrangement and serve as link between furosemide’s layers. In turn, the solvent molecules in F(DMF)-I link furosemide molecules with each other by hydrogen bonds; the strong hydrogen bonds F−F, according to PLATON, are absent. Whereas crystallization by very slow evaporation of organic solutions, namely, when crystals from solution were taken after three months or more, the role of F−F interactions increases channeled crystal structures are formed (F(DMSO)-II, III, F(DMF)-II, III, IV). Notably, no direct correlation between molecular conformation and the type of crystal structure (layered or channeled) seems to exist.

Remarkably, different molecular conformations of furosemide can be found in the solvates formed not only with different solvents, but also with the same solvent (Figure 3). At the same time, crystallization from different solvents gives solvates with different compositions but similar molecular conformations (F(DMSO)-II and F(DMF)-II; F(DMSO)-I and F(DMF)-IV; F(DMSO)-III and F(DMF)-IV). This suggests that the solvent can influence molecular conformation directly via intermolecular furosemide−solvent interactions, as well as indirectly, by modifying the crystallization rate. The latter influences the packing of furosemide molecules in the crystal and the nature of the furosemide−furosemide interactions. All crystal structures of furosemide solvate polymorphs can be divided into two groups according to the arrangement of solvent molecules. The first group includes layered crystal structures of F(DMSO)-I and F(DMF)-I in which layers formed by furosemide molecules alternate with the solvate layers (Figure 4). The remaining five crystal structures (F(DMSO)-II, F(DMSO)-III, F(DMF)-II, F(DMF)-III, and F(DMF)-IV) belong to the second type (Figure 5). In these crystals, molecules of solvent are locked in the channels formed by furosemide molecules. In this respect the channel crystal structures resemble the previously described structures of solvates of furosemide with tetrahydrofuran and dioxane.27 Among channel crystal structures, the crystal packing and conformation of furosemide molecule in F(DMSO)-II and F(DMF)-II is quite similar, whereas the layered (F(DMSO)-I and F(DMF)-I) structures differ much from each other by conformation of furosemide and crystal packing. The 2338

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4. CONCLUSIONS Furosemide remains a very interesting system, concealing surprises despite the fact that this system has been under investigation for several decades. A furosemide molecule shows high conformational diversity due to the presence of sulfamoyl and furanylmethylamino fragments. As a result, furosemide crystallizes in different crystal forms, such as polymorphs, salts, and solvates. The present study demonstrated for the first time that not only furosemide itself, but also the furosemide solvates, can be polymorphic, even if they have the same composition and stoichiometry. The solvates of furosemide with DMSO and DMF in a 1:1 stoichiometric ratio crystallize as different polymorphs of different structural typeslayered and channeleddepending on the crystallization method. Crystallization with water as an antisolvent slowly diffusing into the solution leads to formation of layered crystal structures with both solvent molecules, whereas slow crystallization by evaporation of the solvent from saturated solutions leads to formation of channel-type crystal structures. The previously known crystal structures of furosemide solvates with 1,4dioxane and THF also follow this trend.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01191. Schemes S1−S2; Figures S1−S4; Tables S1−S4 (PDF) Accession Codes

CCDC 1024301, 1024439−1024440, and 1410395−1410397 contain 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 data_request@ccdc. cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Alina A. Beloborodova: 0000-0002-5878-3074 Denis A. Rychkov: 0000-0001-9269-1627 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The study has been supported by the Ministry of Education and Science of the Russian Federation (Project 1828). The Siberian Supercomputer Center of the Siberian Branch of the Russian Academy of Sciences (SB RAS) is gratefully acknowledged for providing supercomputer facilities. A.A.B. thanks Dr. B. Zakharov for assistance with structure refinement and preparing final versions of CIFs. The authors would like to acknowledge Mr. Adam A. L. Michalchuck, and Mr. Christian Tantardini for the assistance with the interpretation of data and improving the paper.

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REFERENCES

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