Conformational Polymorphism in Racemic Crystals of the Diuretic

Conformational Polymorphism in Racemic Crystals of the Diuretic Drug Chlortalidone Felipe T. Martins,*,†,‡ Ma´rcio D. Bocelli,† Rudy Bonfilio,§ Magali B. de Arau´jo,§ Patrıćia V. de Lima,‡ Person P. Neves,‡ Marcia P. Veloso,‡ Javier Ellena,† and Antoˆnio C. Doriguetto‡

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 7 3235–3244

Instituto de Fı´sica de Saõ Carlos, UniVersidade de Saõ Paulo, CP 369, 13560-970 Saõ Carlos, Saõ Paulo, Brazil, Departamento de Cieˆncias Exatas, UniVersidade Federal de Alfenas, Rua Gabriel Monteiro da SilVa 714, 37130-000 Alfenas, MG, Brazil, Centro de EquiValeˆncia Farmaceûtica do Nućleo Controle de Qualidade da UniVersidade Federal de Alfenas (CEFAR-NCQ/UNIFAL-MG), UniVersidade Federal de Alfenas, Rua Gabriel Monteiro da SilVa 700, 37130-000, Alfenas, MG, Brazil ReceiVed December 4, 2008; ReVised Manuscript ReceiVed April 23, 2009

ABSTRACT: Chlortalidone (HIGROTON) is a diuretic drug widely used in antihypertensive therapy. Thus far, only two solidstate polymorphs of chlortalidone have been reported. We elucidated the structure of chlortalidone form I and a new polymorph. This new phase, namely, chlortalidone form III, was also entirely characterized. It was possible to conclude that it is a conformer with a different orientation of the chlorobenzenesulfonamide moiety. Compared to form I, it has a rotation of about 90° on the axis of the C-C bond bridging the substituted phenyl and isoindolinyl rings. This conformational feature is related to the crystal packing patterns of the chlortalidone forms. Furthermore, certain intermolecular hydrogen bonds are present in both polymorphs, giving rise to ribbons with chlortalidone enantiomers alternately placed into them. The chlortalidone form I and form III crystallize in the triclinic space group P1j as racemic mixtures. Additional conformational details also differentiate the chlortalidone conformers. Slight twists on the isoindolinyl and sulfamyl groups exist. Considering all structural relationships, the fingerprint plots derived from the Hirshfeld surfaces exhibited the characteristics of the chlortalidone form I and form III crystal structures. Introduction The crystalline polymorphism of solids is a very important subject for pharmaceutical sciences. This phenomenon may be defined as the ability of a compound to exist in multiple solidstate structures. In the structures, the molecules have different packing and/or conformational arrangements within crystal networks.1-3 With pharmaceutics, this is particularly important because crystalline forms may have different physical and chemical properties, including dissolution rate, solubility, melting point, density, and physical/chemical stability. Formulated products may also undergo changes in bioavailability and shelf life.4 Therefore, there are many studies in this field. Polymorph formation control and establishment of relationships between solid-state properties and crystal structures are some of the main challenges in polymorphism studies. Drug performance can be influenced by polymorphism. This means that crystal design is a strategy to obtain one or more desired functional properties of an active pharmaceutical ingredient.2 Chlortalidone (CTD) is an active pharmaceutical ingredient with long-acting oral activity. It is clinically used as antihypertensive/diuretic. It is a racemic mixture of 2-chloro-5-(1hydroxy-3-oxo-1-isoindolinyl)benzenesulfonamide (Figure 1). CTD is practically insoluble in water, ether, and chloroform. It is soluble in methanol and slightly soluble in ethanol. Regarding the polymorphisms of CTD, two solid-state phases were previously reported, including form I5 and form II.6 Form I is the clinically preferred solid state for drug product manufacturing. Form I and form II have been well-characterized by powder X-ray diffraction, NMR, and infrared spectroscopy techniques.5,6 However, their respective single-crystal structures * To whom correspondence should be addressed. E-mail: felipemartins@ ursa.ifsc.usp.br. Phone: 55 16 3373 9777. Fax: +55 16 3373 9777. † Universidade de Saõ Paulo. ‡ Departamento de Cieˆncias Exatas, Universidade Federal de Alfenas. § CEFAR-NCQ, Universidade Federal de Alfenas.

Figure 1. Chemical structure of CTD. For atom labeling, see Figure 3.

Figure 2. Scanning electron micrographs of CTD form I (left) and form III (right) crystals. Bar: 100 µm.

remain unknown. To the best of our knowledge, no conclusive study on the stability and solubility of the CTD forms in physiological medium is available. Some incoherent data have been reported concerning the melting range and process of CTD preparation.6 Even though this pharmaceutical ingredient has been known and incorporated into drug formulations for a long time, it has not been well-characterized in terms of its physical behavior.

10.1021/cg801322x CCC: $40.75  2009 American Chemical Society Published on Web 05/18/2009

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Figure 3. Conformers that compose the crystallographic asymmetric units (R-enantiomers) of CTD form I and form III. The hydrogen atoms are represented as arbitrary radius spheres, and the ellipsoids are at the 50% probability level. The graphic was prepared with ORTEP,12 and atom labeling is also arbitrary.

In the present study, we report the crystal structure of CTD form I, which was solved by a single-crystal X-ray diffraction technique. Moreover, a new crystalline CTD form was synthesized using polymorphism screening methods, and its structure was accurately determined. A detailed analysis of their crystal packing and conformational features is comparatively presented. Furthermore, geometric features of similar compounds, whose structures are deposited in the Cambridge Structural Database, were compared with those of the CTD polymorphs. Finally, the results presented in this paper led to new objectives concerning the physical and chemical properties of CTD. These goals include the following: (1) the determination of the CTD form II crystal structure, which remains unavailable, (2) the establishment of relationships between the solid-state properties and polymorphic crystal structures, and (3) the investigation of the physical behaviors of CTD polymorphs in order to avoid undesirable pharmacological effects. Experimental Section Synthesis of CTD Form I. The solution preparation and crystallization procedures yielded single crystals of CTD polymorphs. To prepare crystals of form I, we weighted raw CTD powder (10 mg) and dissolved it in MeOH (5 mL) by vigorous shaking of the mixture at room temperature for 5 min. The newly prepared solution was left standing for 5 days in the dark at 27 °C within a crystal growth chamber. After solvent evaporation, colorless plates were formed on the bottom of the glass crystallizer. A well-shaped clear crystal measuring 0.43 × 0.21 × 0.14 mm3 was selected for the single-crystal X-ray diffraction experiment. Synthesis of CTD Form III. A procedure similar to that previously described was used to prepare crystals of form III. An amount of 10

Martins et al. mg of a commercially acquired sample of CTD powder was added to 5 mL of CH2Cl2. By heating the mixture at 30 °C on a water bath and slowly stirring, a clear solution was obtained after 2 min. This solution was kept standing for 3 days in the dark at 27 °C within the crystal growth apparatus. Prismatic crystals exhibiting a different external morphology from that of the CTD form I crystals were observed at the bottom of the glass crystallizer after crystallization. A well-shaped, clear single crystal of 0.29× 0.26 × 0.16 mm3 was isolated. This was a new CTD polymorph, namely, form III, according to the usual nomenclature. This crystal was selected for the single-crystal X-ray diffraction experiment. Scanning Electron Microscopy. The CTD form I and form II crystals were directly mounted on metallic stubs covered with conductive carbon tape. They were then coated with colloidal gold using a SCD-040 Ion Sputter Balzer apparatus. To acquire scanning micrographs of the crystals, we used a scanning electron microscope (LEO 435 VP) at 15 kV accelerating voltage. Crystallographic Analysis. Room-temperature X-ray diffraction intensities for the selected single crystals of the CTD polymorphs (form I and form III) were measured using graphite-monochromated Mo KR radiation (λ ) 0.71073 Å, Enraf-Nonius Kappa-CCD diffractometer). The data collecting strategy was calculated setting φ scans and ω scans with κ offsets. The detector was a 95 mm CCD camera on a κ-goniostat. The final unit-cell parameters were based on all reflections. The COLLECT program7 was employed for monitoring the diffraction frame acquisition, and the reflections were scaled with the HKL DenzoScalepack package of software.8 Because the absorption coefficient is negligible for CTD, no absorption correction was applied. Crystallographic structures of the CTD polymorphs were solved by direct methods with SHELXS-97.9 All atoms that were asymmetric units (except hydrogen) were readily found from the electronic density map constructed by Fourier synthesis. The model obtained at the beginning was refined by a full-matrix least-squares on F2 with SHELXL-97.10 With regard to the hydrogen atoms, those bonded to carbon atoms were placed in expected positions according to the stereochemical predictions. They were refined with fixed individual displacement parameters 20% greater than the equivalent isotropic displacement parameter of the corresponding carbon atom. Aromatic CsH bond distances were fixed according to the riding model (0.93 Å). N-H amine and O-H hydroxyl hydrogen atoms were localized using the Fourier map. The (x, y, z) fractional coordinates and the isotropic thermal parameter of these H atoms were not constrained during refinements. The programs MERCURY11 and ORTEP-312 were used within the WinGX13 software package to deal with the processed crystallographic data and artwork representations. The determined molecular structures of the CTD conformers were checked with MOGUL.14 MOGUL is a valuable program for analyzing the conformational and geometric features of a molecule. It searches for substructures of compounds deposited at the Cambridge Crystallographic Data Centre (CCDC)15 that are similar to those of a target molecule. Comparison of bond angles and lengths of the newly determined crystal structures of CTD polymorphs with the corresponding parameters of similar structures in the Cambridge Structural Database (CSD,15 version 5.30 of November 2008 with February 2009 update) was useful to strengthen interesting geometric features of the CTD structures. All details concerning the unit cells and structure determinations of CTD form I and form III were grouped in data sets. The files containing such data (the crystallographic information file as a .cif extension document), except for structure factors, were deposited with the Cambridge Structural Data Base under deposit codes CCDC 710464 (CTD form I) and CCDC 710465 (CTD form III). Copies of these files may be retrieved free of charge from The Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK, fax: +44123-336-033; e-mail: [email protected] or http:www.ccdc.ac.uk. To determine the solid-state phase of the CTD polymorphs that crystallized, we calculated the theoretical X-ray powder diffraction peak positions of CTD form I and form III with the PowderCell software16 by inputting the.cif extension files for the CTD structures. These files were created after the structural refinements were finalized. Afterward, the experimental X-ray powder diffractograms reported in the literature for form I5 and form II6 were compared with the simulated X-ray diffraction patterns from the CTD crystal structures. Calculation of Hirshfeld Surface for the CTD Polymorphs. To illustrate the main differences between the crystal structures of the CTD polymorphs, we calculated Hirshfeld surfaces for form I and form III

Polymorphism in Racemic Crystals of Chlortalidone

Crystal Growth & Design, Vol. 9, No. 7, 2009 3237

Table 1. Crystal Data and Structure Determination Parameters for CTD Form I and Form III

empirical formula fw T (K) wavelength (Å) cryst syst space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Z calcd density with crystal data (Mg/m3) absorp coeff (mm-1) F (000) θ range for data acquisition (deg) index ranges no. of reflns collected no. of independent reflns completeness to θ max (%) refinement method data/restraints/params GOF on F2 Final R indices for I > 2σ(I) R indices for all data largest diff. peak and hole (e Å-3)

CTD form I

CTD form III

C14 H11 Cl N2 O4 S 338.76 293(1) 0.71073 triclinic P1j 6.2270(2) 8.3870(3) 14.3640(4) 92.141(2) 101.050(2) 107.024(2) 700.50(4) 2 1.606 0.442 348 3.06-26.03 -7 e h e 6, -10 e k e 10, -17 e l e 17 11 294 2627 [R(int) ) 0.1007] 95.0 full-matrix least-squares on F2 2627/0/215 1.094 R1 ) 0.0498, wR2 ) 0.1349 R1 ) 0.0605, wR2 ) 0.1502 0.304 and -0.425

C14 H11 Cl N2 O4 S 338.76 293(1) 0.71073 triclinic P1j 7.9957(2) 8.1467(2) 11.4761(3) 80.448(2) 79.277(2) 86.106(2) 723.77(3) 2 1.554 0.428 348 3.35-26.68 -9 e h e 10, -10 e k e 10, -14 e l e 14 14 365 2961 [R(int) ) 0.0730] 97.1 full-matrix least-squares on F2 2961/0/215 1.108 R1 ) 0.0534, wR2 ) 0.1416 R1 ) 0.0639, wR2 ) 0.1503 0.361 and -0.614

using the CrystalExplorer program.17 The Hirshfeld surface is a very reliable crystal property when describing packing patterns. Therefore, it allows us to identify a specific polymorph. It is currently used for the rapid interpretation of overall structural features because twodimensional fingerprint plots are readily constructed from these potential maps. Intermolecular interactions present in crystal lattices are used to construct fingerprint graphics by plotting de (external distance, defined as the distance between the calculated Hirshfeld surface and the nearest atom of an adjacent molecule within the crystal) versus di (internal distance, defined as the shortest separation from the calculated Hirshfeld surface to an atom nucleus of the molecule inputted for surface calculation). The distance de is associated with short intermolecular interactions. Relationships between crystal packing pattern and molecular geometry are understood by analyzing parameters present in Hirshfeld fingerprint plots. The di values were of minor importance to us because they provide information on atomic and ionic radii.

Results and Discussion Despite the fact that CTD is a diuretic drug widely used in hypertension treatment, there is little information concerning the crystalline structures of this compound. For the first time, the crystalline structure of one of the two known CTD polymorphs was determined. In addition to the geometric and conformational structure of CTD form I, we discovered a novel solid state phase of this diuretic drug (form III), which could be useful for incorporation into clinical formulations. The morphologies of CTD form I and form III crystals are displayed in Figure 2. The two morphologies are similar. It is difficult to distinguish CTD form I and form III. A concise report of the crystal data and structure refinement parameters for both CTD polymorphs is given in Table 1. In Table 2, the theoretical Bragg peaks from the single crystal structures of CTD form I and form III are given. Additionally, the experimental X-ray powder diffractogram reported in the literature for CTD form I5 is listed. There is agreement between the simulated diffraction peaks from the crystal structure of CTD form I and the observed ones in the experimental powder X-ray diffraction pattern of CTD form I.5 The slight differences observed by comparing the simulated and experimental pattern

of the CTD form I can be attributed to the preferred orientation and overlapping of the Bragg peaks. Both behaviors were observed in this experiment. It is important to emphasize that by matching the powder X-ray diffraction peaks, one of the determined CTD crystal structures can be assigned to the clinically preferred form I. Because the simulated pattern of the second structure determined in this study does not match the experimental one reported as CTD form II, it can be concluded that a new polymorphic form was obtained (form III). CTD form I and form III crystallized in the centrosymmetric triclinic space group with two enantiomeric molecules per unit cell. The difference between the asymmetric units of these polymorphs is shown in Figures 3 and 4, which were prepared with ORTEP-312 and MERCURY,11 respectively. In Figure 3, the R-enantiomer structures of CTD form I and form III are shown. In this figure, 50% probability thermal displacement ellipsoids represent the labeled atoms. In Figure 4, such structures are superimposed in a capped stick fashion. A typical case of conformational polymorphism is described for CTD based on this study. The substituted benzene ring orientation in CTD form I strongly differs from that found in form III. The conformation of the benzenesulfonamide core and the subtle changes occurring in the isoindolinyl ring will be better detailed in sequence. By comparing the bond lengths and valence angles of CTD form I with those of CTD form III (Tables 3 and 4), one can see that the two CTD polymorphs are geometrically similar. Likewise, MOGUL14 analysis also showed that all determined geometric parameters of the CTD form I and form III molecules are in agreement with the corresponding mean values of the related compounds whose crystallographic structures are deposited in the CSD.15 This observation was done by taking into account the fact that all interatomic distances and the most of the valence angles do not statistically vary between CTD form I and form III. Furthermore, the MOGUL mean values for bond angles and lengths were in agreement with those from the refinement of the crystallographically solved asymmetric units

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Table 2. X-ray Diffraction Peaks (Positions in 2θ, Normalized Intensities with I > 1%, and hkl Indices) from the CTD Crystal Structures and from the X-ray Powder Diffractogram Reported in the Literature for Form I5 form I (experimental)a,b

a

form I (crystal structure)

form III (crystal structure)

2θ (deg)

I > 1%

2θ (deg)

I > 1%

h

k

l

2θ (deg)

I > 1%

h

k

l

6.246 11.031 12.141 13.22

50 7 100 40

15.159 15.939 16.239

11 7 11

17.586

78

18.886 20.985

11 25

21.43 21.685

60 82

22.531

24

23.034 23.529

12 35

23.941

37

25.652

22

26.676

32

27.84

16

28.728 29.131

18 8

29.828 30.231

10 9

30.624

19

6.296 11.079 12.192 13.29 15.185 15.215 15.958 16.267 17.606 17.633 17.683 17.85 18.928 21.026 21.104 21.459 21.799 22.264 22.829 22.964 23.099 23.426 23.599 23.766 23.979 24.526 25.377 25.654 25.679 26.427 26.663 26.732 26.763 26.852 28.156 28.763 28.786 29.258 29.687 29.991 30.289 30.508 30.645 30.78 30.851

58.17 6.47 100 36.63 1.54 11.02 5.72 12.56 14.68 9.1 64.22 7.03 11.52 18.29 5.92 45.17 33.81 58.74 34.25 6.18 2.64 8.09 3.45 42.74 3.83 37.24 1.86 1.38 9.82 19.63 3.86 6.23 24.96 5.82 16.66 1.63 16.29 5.57 2.24 12.03 1.63 9.57 3.35 17.44 2.65

0 0 0 0 -1 1 0 -1 -1 0 1 1 -1 0 -1 1 1 0 -1 0 -1 -1 1 0 1 0 0 -1 -1 1 1 -1 0 1 -1 -2 0 -2 -2 -2 -1 1 -2 1 0

0 1 -1 1 0 0 -1 1 0 1 0 -1 1 -1 -1 1 0 2 2 1 1 2 1 2 -2 -2 0 2 -1 -1 -2 0 2 0 1 1 1 1 1 0 -2 -2 0 2 2

1 0 1 1 1 0 2 1 2 2 1 1 2 3 1 0 2 0 0 3 3 1 1 1 1 2 4 2 3 3 2 4 2 3 4 1 4 0 2 1 1 3 2 0 3

7.932 11.012 12.533 12.578 14.564 15.47 15.597 15.903 16.077 17.802 17.825 17.896 18.075 20.77 21.12 22.128 22.32 22.623 22.635 23.952 24.499 24.619 24.705 24.779 24.846 25.233 25.283 25.312 25.343 25.62 26.088 26.11 26.155 26.981 27.468 27.548 27.862 27.991 28.338 28.742 29.026 29.218 29.371 30.026 30.070

3.21 1.54 18.75 29.63 96.03 24.19 100 3.86 10.59 7.85 10.56 18.09 15.51 36.23 43.21 19.33 4.03 21.51 7.29 9.45 96.29 13.41 1.19 3.47 1.86 16.1 14.58 4.66 13.43 4.17 9.83 4.3 1.37 1.24 6.99 4.13 2.98 32.31 14.99 2.69 14.51 2.01 5.48 8.93 3.31

0 0 0 1 0 1 1 0 -1 1 1 0 -1 0 -1 0 0 2 2 0 1 1 0 0 2 1 -1 2 -2 -2 -1 1 2 1 -1 -2 -2 0 -1 1 2 -1 0 2 -2

0 1 1 0 -1 1 1 0 1 0 -1 1 1 -1 0 2 2 0 0 0 2 0 -2 1 1 1 2 0 0 1 2 2 -1 -2 -2 1 -1 -1 0 -1 -1 1 -2 0 0

1 0 1 1 1 0 1 2 0 2 1 2 1 2 2 0 1 1 0 3 0 3 1 3 0 3 0 2 1 0 1 2 1 1 1 1 1 3 3 3 2 3 2 3 2

The experimental powder X-ray diffraction data for form I are in the literature.5 b The wavelength was 1.54056 Å (Cu KR).

Figure 4. Superposition of the CTD conformers (R-enantiomers). The hydrogen atoms of form I (lighted) and form III (darkened) were hidden for clarity.

of the CTD conformers. However, the values of three valence angles in CTD form III were considerably different than those in CTD form I (bold in Table 4). These differences resulted from deformations of the C-C bridge between the two cycles

and the sulfamyl moiety. The N1-C1-C9 valence angle of CTD form III (112.6(2)o) is more expanded than that of CTD form I (110.6(2)o). A steric hindrance arose from a rotation of approximately 90° on the C1-C9 bond axis. This hindrance can explain the angle expansion in CTD form III. Because of this rotation, the benzene ring plane lies above the N1-C1 bond. Consequently, the phenyl and isoindolinyl cores are sterically hindered. In the CTD form I structure, the bulky substituted phenyl group is kept remote from the N1-C1 bond. There is no steric effect within this conformer. In addition, the expansion of the N1-C1-C9 valence angle is associated with the increase in the C3-C8-C1-C9 torsion value, which is 125.7(2)o for CTD form III and 117.8(2)o for CTD form I (Table 5). The main difference between CTD form I and form III is in the C1-C9 bond axis rotation. The CTD conformers show different orientations for the chlorobenzenesulfonamide head. All values of the X-C1-C9-Y dihedral angles differ for the CTD polymorphs (Table 5). The values of these torsions change by about 90°, which is in agreement with the above-mentioned rotation order on the six-membered cycle. The torsions on the C1-C9 bond differed between CTD form I and form III by



Table 3. Experimental Bond Lengths (Å) of the CTD Conformers and Structurally Related Compounds Deposited in the Cambridge Structural Database (CSD) bond

CTD form I

CTD form III

mean value in the CSDa

no. of entries in the CSD

C1-C8 C2-C3 C3-C4 C4-C5 C5-C6 C6-C7 C7-C8 C3-C8 C1-C9 C9-C10 C10-C11 C11-C12 C12-C13 C13-C14 C9-C14 N1-C1 N1-C2 O1-C2 O2-C1 S1-C11 S1-N2 S1-O3 S1-O4 Cl1-C12

1.513(3) 1.473(3) 1.386(3) 1.380(3) 1.387(4) 1.382(3) 1.378(3) 1.382(3) 1.525(3) 1.394(3) 1.394(3) 1.385(3) 1.380(3) 1.382(3) 1.382(3) 1.468(3) 1.346(3) 1.242(2) 1.419(3) 1.786(2) 1.590(2) 1.419(2) 1.429(2) 1.728(2)

1.517(3) 1.467(3) 1.384(3) 1.377(3) 1.389(4) 1.391(3) 1.379(3) 1.381(3) 1.520(3) 1.391(3) 1.388(3) 1.397(3) 1.383(3) 1.381(3) 1.386(3) 1.466(3) 1.342(3) 1.242(3) 1.411(3) 1.781(2) 1.595(2) 1.428(2) 1.431(2) 1.727(2)

1.51(2) 1.48(2) 1.39(2) 1.39(2) 1.37(3) 1.39(2) 1.39(2) 1.39(2) 1.52(1) 1.39(2) 1.39(2) 1.40(2) 1.39(2) 1.38(2) 1.38(2) 1.46(1) 1.35(1) 1.23(2) 1.40(1) 1.77(1) 1.60(2) 1.43(2) 1.43(2) 1.73(2)

28 118 10000 10000 10000 10000 10000 478 30 10000 657 99 4027 10000 10000 16 15 7040 18 90 208 414 414 7183

a

Results from the MOGUL intramolecular analysis.

Table 4. Experimental Valence Angles (deg) of the CTD Conformers and Structurally Related Compounds Deposited in the Cambridge Structural Database (CSD) angle

CTD form I

C1-C8-C3 C1-C8-C7 C1-C9-C10 C1-C9-C14 C2-C3-C4 C2-C3-C8 C3-C4-C5 C3-C8-C7 C4-C5-C6 C4-C3-C8 C5-C6-C7 C6-C7-C8 C8-C1-C9 C9-C10-C11 C9-C14-C13 C10-C11-C12 C10-C9-C14 C11-C12-C13 C12-C13-C14 C1-N1-C2 N1-C1-C8 N1-C1-C9 N1-C2-C3 N1-C1-O2 N1-C2-O1 N2-S1-O3 N2-S1-O4 N2-S1-C11 O1-C2-C3 O2-C1-C8 O2-C1-C9 O3-S1-O4 O3-S1-C11 O4-S1-C11 Cl1-C12-C11 Cl1-C12-C13 S1-C11-C10 S1-C11-C12

109.9(2) 129.1(2) 118.8(2) 122.0(2) 130.4(2) 108.2(2) 117.5(2) 120.9(2) 121.1(2) 121.4(2) 121.0(2) 118.1(2) 115.0(2) 120.5(2) 120.5(2) 119.2(2) 119.2(2) 120.4(2) 120.2(2) 113.7(2) 101.0(2) 110.6(2) 107.1(2) 111.9(2) 125.8(2) 107.7(1) 106.9(1) 106.6(1) 127.0(2) 112.4(2) 105.9(2) 119.6(2) 105.8(1) 109.5(1) 122.0(2) 117.6(2) 117.6(2) 123.1(2)

a

CTD form mean value no. of entries III in the CSDa in the CSD 109.6(2) 129.3(2) 118.9(2) 122.0(2) 129.9(2) 108.3(2) 117.5(2) 121.0(2) 120.9(2) 121.8(2) 121.3(2) 117.4(2) 114.3(2) 120.7(2) 120.7(2) 119.4(2) 119.1(2) 119.9(2) 120.2(2) 113.8(2) 100.7(2) 112.6(2) 107.2(2) 111.5(2) 125.7(2) 108.6(1) 108.6(1) 106.8(1) 127.0(2) 111.2(2) 106.5(2) 118.4(1) 106.1(1) 107.8(1) 121.8(2) 118.3(2) 118.2(2) 122.3(2)

109.6(7) 129.3(8) 120.6(14) 120.6(15) 129.5(26) 108.9(7) 119.8(21) 120.6(10) 120.2(18) 121.4(12) 120.2(18) 120.0(19) 114.4(34) 121.8(12) 121.3(14) 118.4(13) 117.7(20) 120.1(7) 120.1(16) 114.1(17) 101.3(14) 112.4(18) 106.1(4) 111.9(27) 126.1(6) 107.3(16) 107.3(16) 108.2(17) 127.4(42) 112.3(34) 110.9(23) 118.8(20) 107.3(16) 107.3(16) 121.5(8) 118.3(23) 118.2(14) 123.4(16)

Results from the MOGUL intramolecular analysis.

21 15 15 24 74 15 10000 435 10000 433 10000 10000 25 143 10000 77 2646 31 657 17 18 15 15 16 15 414 414 90 118 15 17 208 180 180 99 4027 62 51

Table 5. Dihedral Angles (deg) Significantly Varied for the CTD Polymorphs As a Consequence of Torsions on the Isoindolinyl and Sulfonamide Moieties and Because of the Benzene Ring Rotation torsion

CTD form I

CTD form III

C1-N1-C2-C3 C1-C8-C3-C2 C2-N1-C1-C8 C2-N1-C1-C9 C2-N1-C1-O2 C3-C8-C1-C9 C3-C8-C1-N1 C3-C8-C1-O2 C4-C3-C2-O1 C8-C3-C2-O1 C7-C8-C1-O2 C7-C8-C1-C9 C10-C11-S1-N2 C10-C11-S1-O3 C10-C11-S1-O4 C12-C11-S1-O4 S1-C11-C12-Cl1 C10-C9-C1-C8 C10-C9-C1-N1 C10-C9-C1-O2 C14-C9-C1-C8 C14-C9-C1-N1 C14-C9-C1-O2

-0.1(2) 1.4(2) 0.8(2) -121.4(2) 120.6(2) 117.8(2) -1.4(2) -120.8(2) -1.6(4) 176.8(2) 56.4(3) -65.0(3) 109.6(2) -4.9(2) -135.0(2) 48.4(2) -3.4(3) 172.2(2) -74.2(2) 47.4(2) -8.7(3) 104.9(2) -133.5(2)

2.8(2) -3.3(2) -4.6(2) -126.7(2) 113.6(2) 125.7(2) 4.6(2) -113.7(2) 1.0(4) -179.6(2) 63.4(3) -57.2(3) 114.0(2) -1.7(2) -129.4(2) 49.7(2) 4.9(3) 85.5(2) -160.3(2) -37.7(3) -93.7(2) 20.5(3) 143.0(2)

structure part isoindolinyl ring

sulfonamide

C1-C9 bridge between the benzene and isoindolinyl rings

86.7° (dihedral angle C10-C9-C1-C8), 86.1° (dihedral angle C10-C9-C1-N1), 85.1° (dihedral angle C10-C9-C1-O2), 85.0° (dihedral angle C14-C9-C1-C8), 84.4° (dihedral angle C14-C9-C1-N1) and 83.5° (dihedral angle C14-C9-C1-O2). These gaps did not reach 90° because of the occurrence of small bends within the isoindolinyl ring. In the case of CTD form III, the sp3-hybridized carbon atom attached to the 11-sulfamyl12-chlorophenyl moiety (labeled C1 according to the atom labeling given in Figure 3) subtly deviates from the heterocyclic moiety.

Figure 5. Histogram comparing the N2-S1-O4 angle values for CTD form I and form III with N-S-O angle values of similar compounds found in the CSD by MOGUL searches. Table 6. Geometry of Hydrogen Bonds Connecting the Molecules in CTD Form I (Distances (Å) and Angles (°)) D-H · · · Aa N1-H1 · · · O1 N2-H2b · · · O2c N2-H2c · · · O4d O2-H2a · · · O1e b

D-H

H· · ·A

D· · ·A

0.85(3) 0.75(4) 0.81(3) 0.83(3)

2.15(3) 2.31(4) 2.37(3) 2.02(3)

2.978(3) 3.039(3) 3.135(3) 2.847(2)

D-H · · · A 167(2) 167(4) 159(3) 174(3)

a D, hydrogen donor; A, hydrogen acceptor. b Symmetry operator: -x, -y, -z; c Symmetry operator: -1 + x, y, z; d Symmetry operator: -x, 1 - y, 1 - z. e Symmetry operator: 1 - x, -y, -z.

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Table 7. Geometry of Hydrogen Bonds Connecting the Molecules in CTD Form III (Distances (Å) and Angles (deg)) D-H · · · Aa

D-H

H· · ·A

D· · ·A

N1-H1 · · · O3b N2-H2b · · · O1c N2-H2c · · · O4d O2-H2a · · · O1e

0.82(3) 0.88(3) 0.75(3) 0.90(3)

2.35(3) 2.28(3) 2.33(3) 1.92(3)

3.157(2) 3.107(3) 3.050(4) 2.814(2)

D-H · · · A 175(3) 158(3) 164(3) 173(3)

a D, hydrogen donor; A, hydrogen acceptor. b Symmetry operator: -1 + x, y, z; c Symmetry operator: 1 + x, -1 + y, z; d Symmetry operator: 3 - x, -y, -z. e Symmetry operator: 1 - x, 1 - y, 1 - z.

Variations in several torsions on the five-membered heterocyclic portion of the isoindolinyl ring are described for CDT form I and form III (Table 5). When a plane is fitted through the isoindolinyl moiety, the positions of the atoms C1 and O1 relative to the plane are significantly different in these polymorphs. This finding helps explain the twists reported for CTD form I and form III. The C1 and O1 atoms of CTD form I deviates from the least-squares plane passing through the N1, C2, C3, C4, C5, C6, C7, and C8 atoms by -0.037(2) and 0.107(2) Å, respectively (the root-mean-square deviation (rmsd) of the eight fitted atoms was 0.0233 Å for CTD form I). The distances of the corresponding atoms from the same leastsquares plane calculated for CTD form III measured 0.092(2) Å (C1) and 0.025(2) Å (O1), respectively (rmsd of the eight fitted atoms was 0.0070 Å for CTD form III). Therefore, the sp3-hybridized C1 carbon atom of CTD form I is more coplanar to the isoindolinyl ring than the carbonyl O1 oxygen. Meanwhile, the O1 oxygen atom of CTD form III is less deviated from the isoindolinyl plane than the C1 carbon. Consequently, the dihedral angles formed by the C1 carbon or the O1 oxygen are altered. Each CTD polymorph presents a typical conformation for the isoindolinyl group that is identified by the torsion values given in Table 5. Two other valence angles statistically differed between CTD form I and form III. These angles involve atoms of the sulfonamide moiety. The deviation in the N2-S1-O4 valence angle (106.9(1)o for CTD form I and 108.6(1)o for CTD form III) can be explained as a cooperative effect occurring within

the CTD form III crystalline structure. The O4 oxygen atom is a hydrogen acceptor in an intermolecular hydrogen bond involving N2-H2c · · · O4. In this interaction, the O4 atom is pulled toward the N2-H2c hydrogen donor group. The intramolecular geometry of the sulfamyl moiety is then distorted as follows: (a) The O4-S1-C11 valence angle of CTD form III is contracted because of the N2-S1-O4 angle expansion (109.5(1)o in CTD form I compared to 107.8(1)o in CTD form III). b) The C10-C11-S1-O4 and C12-C11S1-O4 torsions are directly influenced. Their values considerably differ for the two CTD conformers (Table 5). (c) A slight left rotation on the C11-S1 bond axis can be described for CTD form III if the sulfamyl moiety conformation of CTD form I is used as a reference. There are similar gaps between the values of the dihedral angles C10-C11-S1N2 (∆φC10-C11-S1-N2 of CTD ) |φC10-C11-S1-N2 of form I φC10-C11-S1-N2 of form III| ) 4.4°) and C10-C11-S1O3 (∆φC10-C11-S1-O3 of CTD ) |φC10-C11-S1-O3 of form I φC10-C11-S1-O3 of form III| ) 3.2°) in the CTD polymorphs. These torsions are changed because of a synchronous displacement of the N2 and O3 atoms toward the opposite side of the O4 oxygen atom. It is important to note that the N2-H2c · · · O4 hydrogen bond also occurs in the supramolecular structure of CTD form I. However, in this solid phase, it is less oriented than in the crystalline arrangement of CTD form III (the N2 · · · O4 distance is 3.135(3) Å for CTD form I and 3.050(4) Å for CTD form III; the N2-H2c · · · O4 angle measures 159(3)° for CTD form I and 164(3)° for CTD form III). For these reasons, the values for the torsions on the bonds of the sulfonamide group of CTD form I are different than those of CTD form III. The expansion of the N2-S1-O4 valence angle (108.6(1)o) in CTD form III was confirmed by looking at the MOGUL analysis results. A value of 107.3(16)o was found from the average of the 414 CTD-like compounds searched by MOGUL in the CSD.15 This MOGUL mean value reveals that most related compounds present with a dimension for the valence angle that is more similar to that found in CTD form I (106.9(1)o) than that in CTD form III.

Figure 6. Racemic ribbon in (a) CTD form III is more aligned than that in (b) CTD form I.


Figure 7. Centrosymmetric dimer made up of enantiomeric molecules in CTD form I. A projection onto the plane (010) is shown. The hydrogen atoms are represented as spheres of an arbitrary radius. Brackets surround the generalized x, y, and z coordinates of the H1 and O1 atoms.

Figure 8. Stacking of CTD form I dimers (see Figure 7) along the [100] direction. Spheres of arbitrary radii are drawn to represent the O-H and N-H hydrogen atoms involved in the hydrogen bonds. Symmetry operators: (i) -x, -y, -z; (ii) -1 + x, y, z; (iii) -1 - x, -y, -z; (iv) -2 + x, y, z; (v) -2 - x, -y, -z.

There are approximately 30 CTD-like structures possessing one N-S-O valence angle with a value similar to the N2-S1-O4 angle in CTD form III. This finding confirms the influence of N2-H2c · · · O4 contact in CTD form III on the intramolecular geometry of the sulfamyl group. In Figure 5, a MOGUL histogram shows the comparison of the N2-S1-O4 valence angle value in CTD polymorphs with equivalent ones of CTD-like compounds deposited in the CSD. The inspection of the crystal packing in CTD form I and form III revealed that the intermolecular interaction patterns are related in some aspects. The crystal assembly is strongly dependent on the CTD polymorph conformations (Tables 6 and 7). For example, the intermolecular O2-H2a · · · O1 hydrogen bond involving the C2dO1 carbonyl and O2-H2a hydroxyl moieties of the isoindolinyl ring connect the two enantiomeric molecules in CTD form I and form III. These molecules are arranged in a head-to-head manner along the [11j1j] direction in CTD form I and along the [2j11] direction in CTD form III (Tables 6 and 7). Similarly, the N2-H2c · · · O4 hydrogen bond


was reported for both CTD polymorphs. This bond packs the CTD units along the same crystallographic direction when they areconnectedbytheO2-H2a · · · O1interaction.TheN2-H2c · · · O4 bonding also connect two inversely related CTD molecules in a tail-to-tail fashion. Racemic one-dimensional ribbons are formed in CTD form I and form III. In the ribbons, the enantiomers are alternately introduced into the chains. It is important to highlight the role of the O2-H2a · · · O1 bonding in stabilizing both CTD polymorph structures. The geometry of this contact does not significantly vary for CTD form I and form III. CTD form I presents with an O2 · · · O1 distance and O2-H2a · · O1 angle measuring 2.847(2) Å and 174(3)°, respectively. The corresponding values of CTD form III are 2.814(2) Å and 173(3)°, respectively. The N2-H2c · · · O4 interaction is more oriented in CTD form III than in form I. This fact is confirmed by looking at the ribbons of the CTD polymorphs. The backbones of these ribbons are formed by aligned benzene rings. The isoindolinyl rings of adjacent molecules in CTD form I are inversely placed side by side with respect to the mean plane passing through the benzene rings. The isoindolinyl rings of CTD form III molecules are inversely oriented above and below the mean plane crossing through the benzene moieties. In CTD form I, each benzene ring is separated by 0.733(6) Å. The corresponding separation is 0.244(7) Å in CTD form III (Figure 6). The enhanced distance between the benzene rings in the CTD form I ribbons is in agreement with the unfavorable geometric orientation of the N2-H2c · · · O4 hydrogen bond in this conformer. Consequently, the N2-H2c · · · O4 hydrogen interaction plays a minor role in setting the coplanar benzene rings in CTD form I. The configuration of the one-dimensional ribbons appears to be related to the geometry of the hydrogen bonds connecting the enantiomeric CTD units. The arrangement of the molecules into the chains is determined by the orientation of the chlorobenzenesulfonamide group. In this way, certain intermolecular hydrogen bonds in CTD form I or in CTD form III are related to the different conformations. In the crystal packing of CTD form I, the N1-H1 amine group of the isoindolinyl moiety donates its hydrogen to the carbonyl O1 oxygen atom of the same structural motif from a neighboring molecule. This donation gives rise to centrosymmetric dimers (Figure 7). These dimers are stacked along the [100] direction through the O2-H2 · · O1 and N2-H2b · · · O2 hydrogen bonds (Figures 8 and 9). The N2-H2b · · · O2 hydrogen bond contacts molecules by a translational symmetry operation involving the amine tail of the sulfamyl moiety and the hydroxyl branch of the isoindolinyl ring. These groups serve as a hydrogen donor and a hydrogen acceptor group, respectively. This hydrogen interaction is not present in the CTD form III structure. Similarly, the N1-H1 · · · O1 bond is not reported for this polymorph. In the case of CTD form III, the N1-H1 amine group of the isoindolinyl moiety is a hydrogen donor, and the sulfamyl O3 oxygen atom is a hydrogen acceptor. A strong intermolecular contact in CTD form III is described by the hydrogen donation from the N2-H2b group of the sulfamyl branch to the carbonyl O1 oxygen atom. The N1-H1 · · O3 and N2-H2b · · · O1 interactions connect molecules by translational symmetry along the [100] and [1j10] directions. These bonds act as cross-linkers, keeping the linear ribbons of CTD form III three-dimensionally in contact (Figures 10 and 11). In accordance with the crystalline packing and conformational features of the CTD polymorphs, fingerprint plots derived from the Hirshfeld surfaces graphically show the structural differences between CTD form I and form III

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Figure 9. NH2 amine group of the sulfonamide moiety is a hydrogen donor to the hydroxyl O2 and sulfamyl O4 oxygen atoms of CTD form I. Spheres of arbitrary radii represent the O-H and N-H hydrogen atoms. Symmetry operators: (i) -x, 1 - y, 1 - z; (ii) x, 1 + y, 1 + z; (iii) 1 + x, 1 + y, 1 + z; (iv) 1 - x, 1 - y, 1 - z; (v) -1 + x, y, z; (vi) -x, -y, -z; (vii) -1 - x, -y, -z.

Figure 10. One-dimensional ribbon with alternate enantiomeric molecules of CTD form III is stabilized by strong intermolecular hydrogen bonds. Spheres of arbitrary radii represent the O-H and N-H hydrogen atoms. Symmetry operators: (i) 3 - x, -y, -z; (ii) 1 - x, 1 - y, 1 - z; (iii) -2 + x, 1 + y, 1 + z.

(Figure 12). The plots were generated by coordinating twodimensional grids using the (di,de) pairs measured on each individual spot of the calculated Hirshfeld surface.17 In these graphics, the d-values range from 0.4 to 2.6 Å. A color gradient from blue to red represents the proportional contribution of the (di,de) pair to the global Hirshfeld surface. Using this graphic, any regions of the molecule within the crystal chemical environment were screened. By analyzing Figure 12, one can doubtlessly state that the two-dimensional fingerprint plots of the CTD polymorphs have some similarities. Both plots show similar sharp spikes referring to the presence of strong O · · · H hydrogen bonds. The weak C-H · · · O contacts are also shown in the plot area. Weak C-H · · · O hydrogen interactions are described for CTD form I. In this polymorph, there are weak interactions involving the atoms C5-H5 · · · O2 and C6-H6 · · · O3. In CTD form III, there are weak C-H · · · O interactions as the C4-H4 · · · O3, C5-H5 · · · O2, C6-H6 · · · O2, and C7-H7 · · · O1 contacts. The end dots of the symmetric spikes have di and de values at ∼0.70 Å or at ∼1.14 Å. The upper and lower spikes correspond to hydrogen donor and acceptor groups,

Figure 11. One-dimensional ribbons are cross-linked in the CTD form III structure by two strong hydrogen bonds involving sulfonamide and isoindolinyl moieties. The linear ribbon grows as each CTD form III unit is projected onto the (01j 3) plane. Spheres of arbitrary radii represent the O-H and N-H hydrogen atoms. Symmetry operators: (i) 1 + x, -1 + y, z; (ii) x, -1 + y, z; (iii) -1 + x, -1 + y, z; (iv) -2 + x, y, z; (v) -1 + x, y, z.



Figure 12. Full fingerprint graphics of the CTD polymorphs and most of the contacts filling them. The blue color indicates lower proportions of the (di,de) pair; green represents an intermediary frequency; red implies an upper limit fraction greater than 0.1% of the surface points with the same (di,de) combination.

respectively. Moreover, remarkable differences for the fingerprint plots of CTD form I and form III can be seen by looking at the H · · · H and C · · · H contact areas. These contacts are related to conformational features of the CTD solid state forms whose X-ray crystallographic structures were described here for the first time. The H · · · H contact area of the CTD form III fingerprint plot is wider than that of the CTD form I. The point set of the short C · · · H contacts of this last polymorph has an unusual pattern with wings. Short interactions involving the atoms H13 · · · H13 and C13 · · H13 can be seen. These interactions have distances of 2.50 and 2.87 Å, respectively. These connections are for inversely related molecules of CTD form I. The relative orientation of the substituted benzene head is related to these interatomic approximations. The referred contacts can be interpreted from the fingerprint map plotted with the Hirshfeld surface data. Finally, the fingerprint graphics derived from the Hirshfeld surfaces for the CTD polymorphs strengthen the differences and similarities between the CTD form I and form III crystal structures. Conclusion The diuretic drug CTD was crystallographically determined. The crystal structure of the clinically used form I was elucidated for the first time. We additionally reported on another conformer of CTD, namely, form III. Although these results represent an enormous advance in the characterization of polymorphism in CTD, the structure of form II remains unknown. This paper provides the X-ray determination of the other two polymorphs. This information can provide insight into the conformational features and packing pattern of CTD form II. Furthermore, phase transformations involving CTD solid state forms should be exhaustively investigated in order to avoid undesirable bioavailability. This phenomenon is frequently associated with toxicity or pharmacological ineffectiveness of the drugs. Undesirable bio-

availability should be avoided in therapeutic uses of CTD. This drug is used as an antihypertensive medicine whose daily dosages are controlled. Rigorous dosing control is necessary to keep steady-state serum concentrations in a range of effective concentration values. Solubility rates and dissolution profiles of CTD form III are in trials. Additionally, spectroscopic and thermal featuring of this polymorph is being completed. Our research group aims to establish the relationships between the crystal structures of the CTD polymorphs and their physical properties. Acknowledgment. We thank the Brazilian Research Council CNPq (Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico) and FAPESP (Fundaçaõ de Amparo a` Pesquisa do Estado de Saõ Paulo) for research fellowships (A.C.D., J.E., and F.T.M.), and we thank FAPEMIG (Fundaçaõ de Amparo a` Pesquisa do Estado de Minas Gerais) and Ministe´rio da Sau´de (EDT-3310/06, APQ-2011-5.02/07, APQ-6010-5.02/07) of Brazil for financial support. Supporting Information Available: Crystallographic information in CIF format. This material is available free of charge via the Internet at http://pubs.acs.org.

References (1) McCrone, W. C. In Physics and Chemistry of the Organic Solid State; Fox, D., Labes, M. M., Weissberger, A., Eds.; Wiley: New York, 1965; Vol. 2, pp 725-767. (2) Grant, D. J. W. In Polymorphism in Pharmaceutical Solids; Brittain, H. G., Ed.; Dekker: New York, 1999; Vol. 95, pp 1-33. (3) Morissette, S. L.; Soukasene, S.; Levinson, D.; Cima, M. J.; Almarsson, O. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 2180–2184. (4) Lu, J.; Wang, X.-J.; Yang, X.; Ching, C.-B. Cryst. Growth Des. 2007, 7, 1590–1598. (5) Kountourellis, J. E.; Markopoulou, C. K.; Underwood, F. A.; Chapman, B. J. Chem. Eng. Data 1992, 37, 187–191. (6) Kumar, A.; Saxena, A.; Singh, D.; Dhurandhare, V.; Pandya, D. N. WO 2006109318, 2006.

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(7) COLLECT Data Collection Software; Nonius: Delft, The Netherlands, 1998. (8) Otwinowski, Z.; Minor, W. In Methods in Enzymology: Macromolecular Crystallography, Part A; Carter, C. W., Jr., Sweet, R. M., Eds.; Academic Press: New York, 1997; Vol. 276, pp 307-326. (9) Sheldrick, G. M. SHELXS-97: Program for Crystal Structure Resolution; University of Go¨ttingen: Go¨ttingen, Germany, 1997. (10) Sheldrick, G. M. SHELXL-97: Program for Crystal Structure Analysis; University of Go¨ttingen: Go¨ttingen, Germany, 1997. (11) Bruno, I. J.; Cole, J. C.; Edgington, P. R.; Kessler, M. K.; Macrae, C. F.; McCabe, P.; Pearson, J.; Taylor, R. Acta Crystallogr., Sect. B 2002, 58, 389–397. (12) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.

Martins et al. (13) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837–838. (14) Bruno, I. J.; Cole, J. C.; Kessler, M.; Luo, J.; Motherwell, W. D. S.; Purkis, L. H.; Smith, B. R.; Taylor, R.; Cooper, R. I.; Harris, S. E.; Orpen, A. G. J. Chem. Inf. Comput. Sci. 2004, 44, 2133–2144. (15) Allen, F. H. Acta Crystallogr,. Sect. B 2002, 58, 380–388. (16) Kraus, W.; Nolze, G. PowderCell for Windows, Version 2.3; Federal Institute for Materials Research and Testing: Berlin, Germany, 1999. (17) McKinnon, J. J.; Spackman, M. A.; Mitchell, A. S. Acta Crystallogr., Sect. B 2004, 60, 627–668.

CG801322X

Conformational Polymorphism in Racemic Crystals of the Diuretic

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