Solvates of Sildenafil Saccharinate. A New Host ... - ACS Publications

Solvates of Sildenafil Saccharinate. A New Host Material

CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 6 1468-1478

Rahul Banerjee, Prashant M. Bhatt, and Gautam R. Desiraju* School of Chemistry, UniVersity of Hyderabad, Hyderabad 500 046, India ReceiVed March 2, 2006; ReVised Manuscript ReceiVed March 30, 2006

ABSTRACT: Sildenafil saccharinate (SS) forms solvates with a large number of solvents, which are included in distorted hexagonal cavities constituted with N(+)-H‚‚‚N(-) and C-H‚‚‚O interactions. All these solvates, except the methanolate, are isostructural and contain various host-guest O-H‚‚‚O and C-H‚‚‚O interactions and also an intramolecular N-H‚‚‚O hydrogen bond in the sildenafil entity. The C-H‚‚‚O bonds, in particular, are strong and numerous and play an important role in stabilizing the crystal packing at several levels. The solute-solvent ratio varies among the isostructural solvates because of differences in guest size. Solvents with smaller volume occupy the peripheries of the cavity, while larger solvents are located within the cavity. All the solvates are converted easily to the apohost upon heating, and this transformation is associated with a rearrangement of several C-H‚‚‚O interactions in the structure. The apohost could also be prepared by grinding the two components, and this procedure led to mixtures of crystalline and amorphous forms. When this ground sample was heated at 120 °C, it was converted into the crystalline SS apohost. In this family of host-guest compounds the host framework is largely invariant and robust, and the guest molecules only play a bystander role in the packing. The totally different crystal structure of the methanol solvate argues in favor of using the term pseudopolymorph to describe modulations in the structural landscape of a host-guest system. Introduction There is much recent interest in the solid-state properties of solvates,1 host-guest compounds,2 bicomponent crystals,3 and pseudopolymorphs.4 The presence of solvent in the crystal confers unique properties to solvates. For example, the solubility and dissolution rate of a hydrate are often different from those of the corresponding anhydrate and this can result in a difference in the bioavailability of a drug.5 In some solvates, the solvent molecules act as space-fillers, whereas in others, the solvent molecules are essential components of the packing with specific host‚‚‚guest interactions, mainly hydrogen bonds.6 The majority of drugs are administered as solids. This means that solid-state properties can significantly influence the performance of the final product.7 Solvation therefore has a huge commercial impact at all stages of active pharmaceutical ingredient (API) development. Identifying all the relevant solvates/pseudopolymorphs in the early stages of drug development is, accordingly, crucial.8 This paper describes the crystal structures of 11 solvates of the 1:1 saccharin salt of the well-known an anti-impotency drug, sildenafil.9 Sildenafil citrate (Viagra) is used to treat male erectile dysfunction. Although this block-bluster drug has been in the news for several years, relatively little work has been done on the structural aspects except for a recent report on sildenafil citrate dihydrate.10 We have recently reported the use of saccharin as a salt former in API formulation and development.11 Accordingly, we prepared the 1:1 salt of saccharin and sildenafil (SS) and report here its solvates with the following solvents: MeCN, DMF, DMSO, 1,4-dioxane, EtOH, ethylene glycol, formamide, MeOH, MeNO2, pyrrolidinone, and water. Experimental Section Sample Preparation and Crystallization. A commercial sample of sildenafil was used and saccharin (Loba chemicals) was recrystallized from acetone prior to use. The salt was prepared with quantitative conversion by grinding 1:1 molar proportions of dry sildenafil and saccharin. Typically, 50-300 mg was hand ground for time periods ranging from 15 min to 1 h. A good indication for complete SS * E-mail: [email protected].

formation is obtained from the bathochromic shift in the CdO stretching frequency (1720 cm-1 in saccharin to 1690 cm-1 in the salt) of the IR spectrum. The ground material was dissolved in the appropriate solvent, and solvated crystals were obtained by slow cooling. Single crystals appeared after 1 or 2 days at room temperature. Melting points were recorded on a Fisher-Johns apparatus and were also calculated from the onset temperature of the endotherm in the differential scanning calorimetry (DSC). IR spectra were recorded on a Jasco 5300 spectrometer. The 1H NMR spectra were recorded at 200 MHz on a Bruker ACF instrument. SS. 1H NMR (CDCl3) δ 10.85 (s, 1H), 8.57 (d, 1H), 7.84 (m, 1H), 7.65 (m, 4H), 7.16 (d, 1H), 4.30 (s, 5H), 3.49 (m, 8H), 2.94 (m, 2H), 2.85 (s, 3H), 1.86 (m, 2H), 1.58 (m, 3H), 1.05 (m, 3H); IR (cm-1) 3298, 2959, 1695, 1657, 1581 1456, 1359, 1287, 1149, 1028; mp 208 °C. X-ray Crystallography. SS was crystallized from the several solvents listed in Scheme 1. Diffraction quality single crystals appeared after 1 or 2 days at room temperature and were characterized by singlecrystal X-ray diffraction. X-ray diffraction intensities for all solvates reported in this paper were collected on a Bruker SMART CCD APEX diffractometer (Bruker Systems Inc.)12 using Mo KR X-radiation. Data were processed using the Bruker SAINT package (Bruker Systems Inc.)13 with structure solution and refinement using SHELX97.14 The structures of all the compounds were solved by direct methods and refined by full-matrix least-squares on F2. H-atoms were located in all these structures and refined freely with isotropic displacement parameters. Crystal data and details of data collection, structure solution, and refinement are summarized in Table 1. Crystallographic data (excluding structure factors) for the structures reported in this paper have been deposited with the CCDC as deposition Nos. CCDC 600018-600029 (see also Table 1). Copies of the data can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB2 lEZ, U.K. (fax + 44 (1223) 336 033; e-mail [email protected]). Thermal Analysis. Thermogravimetric analysis (TGA) of solvates of SS confirmed the stoichiometry of host and guest, and DSC confirmed the temperature of guest release from the host framework. The host/guest stoichiometry determined from the X-ray structure matches with the ratio from weight loss in TGA for all solvates except for the methanolate. Differential scanning calorimetry (DSC) was performed on a Mettler Toledo DSC 822e module and thermogravimetry (TG) was performed on Mettler Toledo TGA/SDTA 851e module. Crystals taken from the mother liquor were blotted dry on filter paper and placed in open alumina pans for the TG experiment and in crimped but vented aluminum sample pans for the DSC experiment. The sample amount in each case was 5-10 mg. The temperature range was typically

10.1021/cg0601150 CCC: $33.50 © 2006 American Chemical Society Published on Web 05/12/2006

Solvates of Sildenafil Saccharinate Scheme 1.

Crystal Growth & Design, Vol. 6, No. 6, 2006 1469

Schematic Drawing of Sildenafil Saccharinate and Solvents Incorporated in the Lattice

25-250 °C at a heating rate of 0.5 °C min-1. The samples were purged with a stream of N2 flowing at 150 mL min-1 for DSC and 50 mL min-1 for TG. X-ray Powder Diffraction. Powder X-ray diffraction (PXRD) traces were recorded on a PNAlytical 1830 (Philips Systems Inc) diffractometer using Cu KR X-radiation at 35 kV and 25 mA. Diffraction patterns were collected over a range of 5-45° 2θ at a scan rate of 1° 2θ min-1. Samples were ground to a particle size of >20 µm and loaded in an 18 mm an Al sample holder at room temperature. Vigorous grinding was avoided to minimize potential phase transformations or solvent loss at room temperature. The programs X’Pert High Score were used for processing and comparing powder patterns. Powder Cell 2.3 was used for calculating PXRD patterns and for profile fitting.15 Rietveld refinement of unit-cell parameters, a displacement parameter, a background polynomial function, peak shape asymmetry terms, and an overall temperature factor was carried out using the known singlecrystal structures as models. The PXRD patterns of these solvates show that these solvates are stable at room temperature and that the bulk sample contains a single phase. Rietveld refinement (Rp ) 18.39, Rwp ) 24.81) of the experimental powder patterns with respect to the simulated peaks of the crystal structure provides an estimate of the crystallographic purity of the sample (see Supporting Information). To study the crystallization of SS in the solid state, the hand ground sample was heated slowly to 150 °C in an oil bath. The temperature settings of the oil bath were set successively at T ) 60, 90, 120, and 150 °C (approximately 30 min at each step). Approximately 50 mg of the sample was taken from the flask when the system reached the respective temperature. The removed material was cooled to room temperature and X-ray data were collected. Calculations. All calculations were carried out on Indigo Solid Impact and Indy workstations from Silicon Graphics. The Dreiding 2.21 force field with the charge equilibration option was used for crystalpacking energy calculations (Cerius2).16 All interatomic distances, packing coefficients, and related calculations were carried out with the PLATON program.17

Results and Discussion In all the salts, the N-atom of the piperazine ring of sildenafil, to which is attached the methyl group, is protonated, and the saccharin moiety exists as the anion. Several C-H‚‚‚O hydrogen bonds between the (sildenafil)+ cation and (saccharin)- anion stabilize the host lattice. All the inclusion complexes, except

the methanolate, are isostructural and are mediated by various host-guest O-H‚‚‚O or C-H‚‚‚O interactions. Crystal Structure of Sildenafil Saccharinate (SS) Apohost. SS was prepared by grinding, and this procedure led to mixtures of crystalline and amorphous forms. PXRD patterns indicated that the amorphous content in the sample obtained by grinding is considerable at room temperature. When this hand ground sample was heated, DSC traces showed a crystallization exotherm at 120 °C. The peak profiles varied little between 30 and 90 °C but changed as the sample temperature reached 120 °C. Figure 1 shows that the overall PXRD pattern becomes significantly sharper at 120 °C with more intense lines indicating higher crystallinity. Yellow colored prismatic crystals of SS apohost were obtained serendipitously while heating the DMSO solvate of SS at 150 °C. The SS apohost crystallizes in the centrosymmetric space group P1h with one (sildenafil)+ cation and one (saccharin)anion in the asymmetric unit. The crystal structure of SS apohost contains mainly two types of intermolecular interactions. The first is an N(+)-H‚‚‚N(-) interaction between N(+)-H of (sildenafil)+ and N(-) of (saccharin)- leading to a SS unit, and the other is a strong C-H‚‚‚O interaction that joins these SS units. Two of these SS units form a 14-membered supramolecular synthon I, consisting of two N(+)-H‚‚‚N(-) and two C-H‚‚‚O hydrogen bonds between two (sildenafil)+ and two (saccharin)- ions (Scheme 2, Figure 2). The second distinctive pattern is a supramolecular synthon II, consisting of four C-H‚‚‚O hydrogen bonds. In the apohost, the pyrazolopyrimidone ring system and the benzene ring are almost coplanar, enabling an intramolecular N-H‚‚‚O hydrogen bond between the pyrazolopyrimidone N-H group and the O-atom in the ethoxy group. Isostructural Solvates of SS. All the solvates of SS, with the exception of the methanolate, are isostructural with space group P1h and similar unit cell parameters and host molecule arrangements. The guest atoms are disordered in some cases. Guest disorder may be because (1) the point group symmetry of the guest is lower than the site symmetry of the void or (2)

1470 Crystal Growth & Design, Vol. 6, No. 6, 2006

Banerjee et al.

Table 1. Crystallographic Data and Structure Refinement Parameters of Different Solvates Studied in This Paper compound

SS apohost

structural formula

(C22H31N6O4S) (C7H4NO3S)

formula weight crystal system space group T (K) a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Z Fcalc (g/cm3) µ (mm-1) R1 [I > 2σ(I)] wR2 goodness-of-fit reflns collected unique reflns obsd reflns crystal size (mm3) CCDC no.

657.76 triclinic P1h 298(2) 10.3848(10) 11.1915(11) 14.3155(14) 80.025(2) 70.988(2) 89.912(2) 1546.5(3) 2 1.412 0.231 0.0534 0.1230 1.031 11556 5440 3636 0.33 × 0.29 × 0.19 600026

(SS)(CH3NO2)

(SS)(CH3CN)

(SS)(HCONH2)

(SS)2(HOC2H4OH)

(SS)2(C4H8O2)

(C22H31N6O4S) (C7H4NO3S) (CH3NO2) 718.56 triclinic P1h 100(2) 9.904(3) 12.121(3) 14.746(4) 87.369(3) 75.491(3) 89.243(3) 1711.9(7) 2 1.394 0.220 0.0573 0.1616 1.067 9594 5795 4556 0.17 × 0.16 × 0.14 600021

(C22H31N6O4S) (C7H4NO3S) (C2H3N) 698.21 triclinic P1h 100(2) 9.8766(12) 11.8949(14) 14.5924(17) 86.0090(10) 73.1880(10) 89.0450(10) 1637.1(3) 2 1.418 0.223 0.0360 0.0931 1.061 16134 5754 5304 0.25 × 0.22 × 0.13 600023

[(C22H31N6O4S) (C7H4NO3S)]2 (CH3NO) 702.53 triclinic P1h 298(2) 9.7746(8) 12.1473(10) 14.4824(12) 87.0150(10) 75.2760(10) 88.6890(10) 1660.8(2) 2 1.405 0.223 0.0437 0.1257 1.049 15991 5835 5140 0.50 × 0.40 × 0.28 600027

[(C22H31N6O4S) (C7H4NO3S)]2 (C2H6O2) 1377.08 triclinic P1h 298(2) 9.8344(10) 11.9909(12) 14.4669(14) 85.5520(10) 73.6810(10) 88.6810(10) 1632.3(3) 2 1.401 0.224 0.0496 0.1321 1.053 14500 5739 4631 0.43 × 0.39 × 0.10 600029

(C22H31N6O4S) (C7H4NO3S) (C4H8O2) 1402.84 triclinic P1h 100(2) 10.1077(7) 11.7836(9) 14.4197(11) 85.1150(10) 71.8480(10) 88.2100(10) 1626.0(2) 2 1.433 0.227 0.0430 0.1100 1.034 15654 5703 5205 0.40 × 0.24 × 0.20 600028

compound

(SS)(H2O)2

(SS)2(C2H6SO)

(SS)2(C4H7NO)

(SS)2(C2H5OH)

(SS)2(C3H7NO)

(SS)(CH3OH)

structural formula

(C22H31N6O4S) (C7H4NO3S) (H2O)2 693.22 triclinic P1h 100(2) 9.6860(9) 11.8441(11) 14.4976(13) 93.7430(10) 107.5540(10) 90.2610(10) 1581.8(3) 2 1.457 0.234 0.0533 0.1445 1.136 11155 5568 5039 0.44 × 0.38 × 0.10 600024

[(C22H31N6O4S) (C7H4NO3S)]2 (C2H6SO) 1392.92 triclinic P1h 100(2) 9.912(3) 11.977(4) 14.587(5) 86.226(5) 72.561(5) 89.305(5) 1648.5(9) 2 1.384 0.251 0.1066 0.2407 1.052 12052 5786 3256 0.48 × 0.24 × 0.16 600020

[(C22H31N6O4S) (C7H4NO3S)]2 (C4H7NO) 1400.11 triclinic P1h 298(2) 10.0172(14) 12.0024(17) 14.510(2) 85.071(2) 72.648(2) 87.666(2) 1658.7(4) 2 1.383 0.220 0.0650 0.1802 1.085 9016 4735 3556 0.42 × 0.32 × 0.26 600025

[(C22H31N6O4S) (C7H4NO3S)]2 (C2H6O) 1360.76 triclinic P1h 100(2) 9.7393(13) 11.8275(16) 14.4853(19) 93.674(2) 107.399(2) 90.050(2) 1588.6(4) 2 1.442 0.230 0.0493 0.1121 1.020 14780 6326 4824 0.46 × 0.24 × 0.22 600018

[(C22H31N6O4S) (C7H4NO3S)]2 (C3H7NO) 1387.88 triclinic P1h 100(2) 9.8323(8) 11.8486(10) 14.4885(12) 86.2120(10) 72.4360(10) 89.5080(10) 1605.6(2) 2 1.429 0.228 0.0411 0.1096 1.039 12397 6457 5810 0.24 × 0.20 × 0.02 600022

(C22H31N6O4S) (C7H4NO3S) (CH4O) 689.11 monoclinic C2/c 100(2) 40.736(4) 8.1842(7) 20.6300(18) 90.00 104.870(2) 90.00 6647.6(10) 8 1.378 0.220 0.0720 0.1286 0.977 8262 5371 3237 0.26 × 0.22 × 0.10 600019

formula weight crystal system space group T (K) a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Z Fcalc (g/cm3) µ (mm-1) R1 [I > 2σ(I)] wR2 goodness-of-fit reflns collected unique reflns obsd reflns crystal size (mm3) CCDC no.

the guest does not fit tightly enough in the available cavity due to poor host‚‚‚guest interactions. In the crystalline saccharinates, two (sildenafil)+ and two (saccharin)- ions are connected with N(+)-H‚‚‚N(-) and C-H‚‚‚OdS hydrogen bonds to form a centrosymmetric tetramer synthon III (Scheme 2). These tetramers are connected to one another by two distinct sets of centrosymmetric C-H‚‚‚OdC hydrogen bonds to form a distorted hexagonal cavity (Figure 3). Several strong intermolecular C-H‚‚‚O hydrogen bonds (d, 2.23-2.44 Å) stabilize these hexagonal host frameworks, which are linked along [100] by other short and linear C-H‚‚‚O bonds (d, 2.24 Å; θ, 173.9°) to complete the structure. These latter C-H‚‚‚O bonds are from the aromatic C-H group of the (sildenafil)+ cation to the CdO group of the (saccharin)- anion. Hexagonal cavities share a common face and propagate in one dimension to generate an independent 1D cage structure (see Supporting Information). In these cages are located the guest molecules, which are stabilized by host‚‚‚guest

C-H‚‚‚O hydrogen bonds. In summary, C-H‚‚‚O hydrogen bonds are significant in all aspects of these crystal structures. It is interesting to note that the unit cell dimensions and cavity size in these solvates do not depend on the volume of the solvent molecule but only on the nature and the strength of the (sildenafil)+ cation and (saccharin)- anion interactions. Guestinduced host assembly clearly does not operate here. The variations in the solute-solvent ratio arise because the sizes of the guests are different while the cavity size is fixed. Solvents with smaller volume like MeCN, MeNO2, and formamide occupy the peripheral regions of the cavity. Bigger solvents such as DMSO, DMF, pyrrolidinone, EtOH, 1,4-dioxane, and ethylene glycol are located within the cavity. These solvents occupy the special position i even if the solvent lacks a molecular inversion center (DMSO, DMF, pyrrolidinone, EtOH). As a result, such solvents are disordered. Water, however, which is the smallest solvent in the series, is located within the cavity, and this is rationalized by the higher guest-host stoichiometry

Solvates of Sildenafil Saccharinate


Table 2. Hydrogen Bonds in Crystal Structures of the Compounds in This Study H-bridge

d(H‚‚‚A), Å

D(X‚‚‚A), Å

θ(∠X-H‚‚‚A), deg

H-bridge

d(H‚‚‚A), Å

D(X‚‚‚A), Å

θ(∠X-H‚‚‚A), deg

N-H‚‚‚N N-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

1.75 1.85 2.21 2.33

2.754(3) 2.653(3) 3.197(5) 3.363(4)

173.7 134.4 151.0 158.1

C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

2.39 2.33 2.43

3.440(4) 3.379(4) 3.388(4)

161.9 164.0 147.2

N-H‚‚‚N N-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

1.77 1.85 2.26 2.29

2.781(4) 2.675(4) 3.324(4) 3.337(4)

177.9 136.5 168.5 162.2

C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

2.27 2.32 2.35

3.332(4) 3.290(4) 3.356(4)

167.3 148.2 154.4

N-H‚‚‚N N-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

1.73 1.79 2.17 2.24

2.739(2) 2.634(2) 3.204(2) 3.294(2)

175.2 138.2 158.6 162.7

C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

2.26 2.27 2.27

3.297(2) 3.249(2) 3.332(4)

160.6 156.5 167.3

N-H‚‚‚N N-H‚‚‚O C-H‚‚‚O

1.77 1.83 2.26

2.775(3) 2.647(2) 3.337(3)

176.1 136.2 172.1

(SS)(HCONH2) C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

2.26 2.28 2.37

3.290(3) 3.326(3) 3.323(3)

157.8 161.0 146.0

N-H‚‚‚N N-H‚‚‚O C-H‚‚‚O

1.76 1.82 2.23

2.765(3) 2.644(3) 3.278(4)

174.3 136.7 162.0

(SS)2(HOC2H4OH) C-H‚‚‚O C-H‚‚‚O

2.21 2.31

3.275(4) 3.351(4)

166.6 160.9

N-H‚‚‚N N-H‚‚‚O C-H‚‚‚O

1.76 1.82 2.23

2.765(3) 2.644(3) 3.278(4)

174.3 136.7 164.0

C-H‚‚‚O C-H‚‚‚O

2.23 2.31

3.287(4) 3.351(4)

164.6 160.9

N-H‚‚‚N N-H‚‚‚O O-H‚‚‚O O-H‚‚‚O

1.75 1.83 1.72 2.17

2.755(3) 2.652(3) 2.698(4) 3.154(5)

177.6 136.0 172.5 174.4

O-H‚‚‚O C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

2.26 2.22 2.24 2.28

3.154(5) 3.252(4) 3.302(4) 3.314(4)

151.1 158.9 167.8 158.6

N-H‚‚‚N N-H‚‚‚O C-H‚‚‚O

1.81 1.87 2.25

2.773(9) 2.686(8) 3.286(9)

158.8 136.0 159.8

(SS)2(C2H6SO) C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

2.31 2.32 2.43

3.347(10) 3.349(9) 3.284(14)

160.8 159.2 134.6

N-H‚‚‚N N-H‚‚‚O C-H‚‚‚O

1.74 1.86 2.29

2.736(5) 2.651(5) 3.346(7)

170.0 132.7 165.1

(SS)2(C4H7NO) C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

2.24 2.29 2.34

3.265(6) 3.348(7) 3.151(2)

157.8 165.6 130.7

N-H‚‚‚N N-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

1.75 1.86 2.23 2.27

2.751(3) 2.648(3) 3.273(3) 3.312(4)

175.8 132.9 161.1 160.5

(SS)2(C2H5OH) C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

2.24 2.39 2.45

3.277(3) 3.191(7) 3.470(3)

159.6 129.5 157.1

N-H‚‚‚N N-H‚‚‚O C-H‚‚‚O

1.72 1.85 2.27

2.726(2) 2.651(2) 3.310(2)

175.9 134.2 160.7

(SS)2(C3H7NO) C-H‚‚‚O C-H‚‚‚O

2.21 2.26

3.256(2) 3.301(2)

162.3 160.1

N-H‚‚‚O N-H‚‚‚O O-H‚‚‚N C-H‚‚‚O

1.69 1.83 1.76 2.32

2.690(6) 2.800(5) 2.715(6) 3.392(6)

168.8 159.4 164.6 171.4

2.32 2.36 2.46

3.308(6) 3.400(6) 3.499(6)

151.6 160.7 160.2

SS Apohost

(SS)(CH3NO2)

(SS)(CH3CN)

(SS)2(C4H8O2)

(SS)(H2O)2

(SS)(CH3OH)

in this case. In all these isostructural solvates, an intramolecular N-H‚‚‚O hydrogen bond between the pyrazolopyrimidone N-H group and the O-atom of the ethoxy group of the (sildenafil)+ cation is observed. To summarize, the isostructural solvates of sildenafil saccharinate studied here can be divided into two groups based on the order/disorder of the guest molecules and host-guest stoichiometry: (i) MeNO2, MeCN, formamide, ethylene glycol, 1,4-dioxane, and water (guest molecule is ordered); (ii) DMSO, DMF, ethanol, and pyrrolidinone (guest molecule is disordered). Solvents that are larger in size than the cavity formed by (sildenafil)+ cation and (saccharin)- anion, say, iso-amyl

C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O

alcohol, do not yield any solvated crystals.18 The overall effect of the geometry of the solvent molecule and the strength of the solute-solvent interactions are reflected in the higher value of the packing coefficient of these solvates (Table 3). A higher Ck value (∼0.70 in all these solvates compared to 0.68 for the apohost) indicates more compact packing, which may arise from stronger solute-solvent interactions. It is presumed that by reorganizing this hexagonal cage framework, host molecules are able to wrap around the guest molecule more tightly, that is, the crystal structure achieves more efficient close packing compared to the alternative of an open apohost structure. To summarize, one can also say that a number of host‚‚‚guest


Figure 1. PXRD patterns of SS recorded at different temperatures. The sample, which is a mixture of amorphous and crystalline forms at room temperature, transforms to crystalline SS around 120 °C. Note the increase in intensity of peaks and the overall simplification of the profile at higher temperatures.

C-H‚‚‚O interactions and a more compact packing drive SS to crystallize in this hexagonal cage lattice with solvent molecules occupying the surface or interior of the cavity. There is a subtle relationship between synthon III of these isostructural solvates and the tetramer synthon I of the SS apohost (Figure 4). A slight movement of the SS unit generates Scheme 2.

a

Banerjee et al.

synthon III from synthon I. It is to be noted here that all these isostructral solvates lose guest irreversibly upon heating and that the resulting polycrystalline mass is identical to the apohost (see Supporting Information). The good agreement between calculated and experimental PXRD patterns in the final Rietveld refinement (Rp ) 20.39, Rwp ) 27.81) vindicates the correctness of the argument. One can say that the organic host compound SS undergoes a phase transition upon guest release. To actively facilitate this dynamic process, the host molecules undergo significant positional or orientational rearrangement. This transformation is associated with a rearrangement of several C-H‚‚‚O interactions between the molecular components. Nitromethane (SS)‚(CH3NO2), Formamide (SS)‚(HCONH2), and Acetonitrile (SS)‚(CH3CN) Solvates. SS crystallizes as a 1:1 MeNO2 solvate (SS)‚(CH3NO2) (space group, P1h , Z′ ) 1 + 1 + 1). The tetramer synthon III is the basic structural unit here, and two of these tetrameric units self-assemble with two C-H‚‚‚O hydrogen bonds to form the hexagonal cavity (Figure 5a). Two MeNO2 molecules occupy the surface of this cavity and complete the solute-solvent cluster. The ordered MeNO2 guest bonds to the host via two other C-H‚‚‚O interactions (d, 2.27 Å; θ, 167.3°). The packing of the formamide solvate (SS)‚(HCONH2) and the MeCN solvate (SS)‚(CH3CN) is similar to that of (SS)‚(CH3NO2) with synthon III and the hexagonal cavity being the basic structural units. The 1:1 solute-solvent module is found again. Two guest molecules occupy the surface of this hexagonal cavity and are inversion related (Figure 5). Host‚‚‚guest C-H‚‚‚O and N-H‚‚‚O hydrogen bonds further stabilize the structure. Ethylene Glycol Solvate, (SS)2‚(HOCH2CH2OH). This is a variation of the 1:1 solvate in which the centrosymmetric guest molecule occupies the special position i in the crystal lattice. As a result, there is a half molecule of ethylene glycol in the crystallographic asymmetric unit instead of one. The guest is trapped inside the hexagonal cavity and makes weak C-H‚‚‚O hydrogen bonds with the host (Figure 6). It is not unusual to encounter a family of host-guest systems in which the host lattice is invariant. However, it is quite unusual for an organic host that is so very acceptor-rich (OdC and SO2) to trap a donor-rich guest like ethylene glycol without any conventional hydrogen bond.19 So far there are only two

Supramolecular Synthons Discussed in This Studya

Note the intramolecular N-H‚‚‚O hydrogen bond between the pyrazolopyrimidone N-H group and the O-atom of the ethoxy group.



Figure 2. Stereoview of the packing diagram of SS apohost. Note the tetramer synthon I and the supramolecular synthon II. Intramolecular N-H‚‚‚O hydrogen bonds between the pyrazolopyrimidone N-H group and the O-atom of the ethoxy group are also shown.

Figure 3. Stereoview of the host framework in the isostructural solvates of SS down [001] to show the distorted hexagonal cavity. Ordered/ disordered guest molecules are present at the surface or inside the hexagonal voids. Table 3. Packing Coefficients of Different Solvates Compared to the Apohost guest molecule

n

packing coefficient

water dioxane MeCN MeNO2 formamide ethylene glycol apohost

2 0.5 1 1 1 0.5

0.711 0.703 0.702 0.690 0.684 0.679 0.680

examples in the literature where there are activated donor and acceptor groups present in a sterically unhindered situation and yet no conventional (N-H‚‚‚O, O-H‚‚‚O, etc.) or unconventional (C-H‚‚‚O, O-H‚‚‚π, etc.) hydrogen bonding is found.20 It is also interesting to note that ethylene glycol has been trapped in its less stable staggered conformation.21 This guest adopts a more stable gauche conformation in its native crystal structure (P212121, Z′ ) 1).22 The energy difference between

the gauche and the staggered conformations was estimated to be 3.2 kcal mol-1 (DFT) and 2.02 kcal mol-1 (HF). Like the ethylene glycol solvate, the 1,4-dioxane solvate, (SS)2‚(C4H8O2) is also a variation of the basic 1:1 solvate structure. The guest molecule occupies a special position, and the host-guest domains are stabilized by weak C-H‚‚‚O hydrogen bonds (see Supporting Information). Sildenafil Saccharinate Dihydrate, (SS)‚(H2O)2. SS was crystallized from water, a solvent that is smaller in size than the others in this study. The crystal structure of (SS)‚(H2O)2 is isostructural to the solvates described so far and with an identical arrangement of host atoms in the crystal lattice (Figure 7). Since the cavity size is fixed and guest molecules are small, four water molecules self-assemble inside the cavity to form an O-H‚‚‚O (d, 1.88 Å; θ, 146.6°) tetramer. Unlike other solvates, there is an O-H‚‚‚O interaction (d, 1.72 Å; θ, 172.5°) between solute and solvent.


Banerjee et al.

Figure 4. Relationship between the crystal structures of the apohost and the isostructural solvates.

DMF Solvate, (SS)2‚(C3H7NO). In a CSD study, Desiraju and Nangia pointed out that DMF has the highest tendency for inclusion in crystals because of its multipoint recognition via strong and weak hydrogen bonding with the solute/host molecule.4f The crystal structure of (SS)2‚(DMF) is triclinic and centrosymmetric like other solvates. The guest (DMF) molecule is disordered with a 50% site occupancy factor. Although the CdO group in DMF is a potential acceptor, there are no strong hydrogen bonds between solute and solvent (Figure 8). Ethanol Solvate, (SS)2‚(C2H5OH). The electron density in the host cavity is diffused for (SS)2‚(EtOH) because the guest atoms are disordered. It is therefore difficult to reliably determine the host/guest stoichiometry from X-ray data alone. TGA measurements confirmed the 2:1 host/guest stoichiometry. DMSO Solvate, (SS)2‚(C2H6SO). In this structure too, the 2:1 solute-solvent module is found. The disordered DMSO molecule is inside the cavity and lies on an inversion center. The fact that the crystals of the DMSO solvate are of poor diffraction quality and that SS apohost was obtained while heating the DMSO solvate at 150 °C is noteworthy and suggests that solvation may be taken as an example of interrupted crystallization.23 Pyrrolidinone Solvate, (SS)2‚(C4H7NO). Considering the crystal structure of other disordered solvates, it was expected that the guest atoms in the crystal structure of (SS)2‚ (pyrrolidinone) would also be disordered. The 2:1 solutesolvent module is found. The pyrrolidinone molecule is inside the cavity and is disordered over two positions with a 50% site occupancy factor. Conformational Pseudopolymorphism. Sildenafil saccharinate methanolate, (SS)‚(MeOH), takes the space group C2/c, and the asymmetric unit contains one (sildenafil)+ cation, one (saccharin)- anion, and one MeOH guest molecule (Figure 9). In this case, the solvent molecules participate actively in the structural organization rather than merely playing a space-filling (bystander) role. The distorted hexagonal cavity that is a characteristic of the other (isostructural) solvates is absent. Instead, two methanol molecules are interleaved between two (sildenafil)+ and (saccharin)- ions via N(+)-H‚‚‚O (d, 1.69 Å; θ, 168.8°) and O-H‚‚‚N(-) (d, 1.75 Å; θ, 164.6°) bonds to give a totally different structure. Two (sildenafil)+ cations are also connected to each other by an N-H‚‚‚O dimer synthon.

(Sildenafil)+ cations and (saccharin)- anions are linked with C-H‚‚‚OdS hydrogen bonds. The pyrazolopyrimidone ring system and the benzene ring are not coplanar. As a result, the intramolecular N-H‚‚‚O hydrogen bond that is seen in the other solvates is absent. The energy difference between the coplanar and the twisted conformation of the (sildenafil)+ cation is 3.21 kcal mol-1. Pseudopolymorphs are defined as solvated forms of a compound with different crystal structures or differences in the nature of the included solvent or the solute-solvent stoichiometry. Here, there are three variations in the structural landscape:24 the SS apohost, the isostructural solvates, and the methanolate. The term pseudopolymorph is particularly well suited to such situations. Further, structural variations between (SS)‚(MeOH) and the isostructural solvates are associated with conformational variations of the major component in the crystal (sildenafil), so the term conformational pseudopolymorphism is also appropriate (Figure 10).25 Thermal Analysis. Of the 11 solvated crystal structures described in this chapter, only the MeNO2, MeCN, 1,4-dioxane, formamide, water, ethylene glycol, and MeOH guests are ordered. Several authors have emphasized the importance of TGA and DSC measurements on host-guest compounds to obtain information about host framework stability, guest enclathration specificity, host‚‚‚guest binding, and enthalpy of guest release.2f TGA measurements confirm the host/guest stoichiometry obtained from the site occupancy of atoms in X-ray structures. It is sometimes difficult to locate and accurately assign the occupancy of disordered guest atoms from difference Fourier maps, particularly for heavily disordered guests. TGA shows that release of guest from the host framework occurs at the first endotherm temperature in DSC. The second endotherm at ∼ 208 °C corresponds to the melting of pure SS host (see Supporting Information). Evolution of MeOH occurs at 40-60 °C because the host molecules do not surround the guest in the cavity architecture of the other solvates. The Tonset values are much higher than the normal boiling point of the guest for EtOH (121 °C), 1,4-dioxane (166 °C), MeCN (158 °C), MeNO2 (132 °C), and DMF (165 °C). This could be due to the tight binding of these guests in the hexagonal cavity of SS. Similarly, Tonset values are much lower than the normal boiling point of the guest



Figure 6. Crystal structure of (SS)2‚(HOC2H4OH) down [001] to show the hexagonal cavity. Ordered ethylene glycol guest molecule occupies the void between two SS tetramers.

Figure 7. Crystal structure of (SS)‚(H2O)2 down the c-axis to show the hexagonal cavity. Four water molecules occupy the voids between two SS tetramers to form an O-H‚‚‚O tetramer. Figure 5. Packing diagram of (a) (SS)‚(MeNO2), (b) (SS)‚(HCONH2), and (c) (SS)‚(MeCN) down [001] to show the hexagonal cavity. Ordered guest molecules are present on the surface of the cavity.

for H2O (76 °C), ethylene glycol (144 °C), and DMSO (149 °C). The reason for these unusual Tonset values is still unclear. Tonset and Tbp values for all the guest molecules are listed in Table 4.

Calculations. Lattice energies were calculated by minimizing the experimental X-ray structure in Cerius2 (Dreiding 2.21). Since the space group, crystal packing, and number of host molecules are same in all the structures, lattice energies were calculated to get a qualitative picture of hydrogen bond energy. Minimized crystal lattice energies for the host and host-guest crystal structures are listed in Table 5. According to latticeenergy minimizations, the crystal structures of the solvated forms


Banerjee et al.

Figure 9. Packing diagram of (SS)‚(MeOH) down the b axis. Note the N-H‚‚‚O dimer synthon, which is not found in the other solvates. MeOH molecules are interleaved between two SS units.

Figure 8. Crystal structure of (SS)2‚(DMF) as a prototype example. Guest molecules are disordered. Table 4. Thermal Analysis (TGA and DSC) on Some Solvates of SS

solvent

obsd weight loss from TG (%)

MeNO2 MeCN H2O HOC2H4OH DMF DMSO EtOH 1,4-dioxane pyrrolidinone MeOHa

8.75 5.54 5.91 4.82 4.69 4.63 3.28 6.8 6.3

calcd weight loss from host/guest ratio in X-ray (%)

guest release, Ton (°C)

bp of guest (°C)

8.47 (1:1) 5.89 (1:1) 5.16 (1:2) 4.50 (2:1) 5.29 (2:1) 5.69 (2:1) 3.39 (2:1) 6.19 (2:1) 5.98 (2:1) (1:1)

136 160 88 148 172 153 124 166 157 43

102 81 100 198 153 189 78 97 180 65

a TGA of methanol solvate was difficult to measure because it was unstable at room temperature.

are found to be more stable than the apohost structure (∼370 and 333.1 kcal mol-1 respectively). This result is in agreement with the observation that SS yields solvated crystals rather than the apohost upon crystallization from common solvents. Conclusions The following observations are noteworthy: (i) sildenafil saccharinate, SS, may be crystallized from a large number of

Figure 10. Overlay diagram of (sildenafil)+ cation in SS‚(MeOH), (SS)‚(H2O), and SS apohost. Note the conformational differences between the pyrazolopyrimidone ring system and the benzene ring.

polar and nonpolar solvents in a solvated form; (ii) amorphous SS is converted to crystalline SS upon slow heating; (iii) the solvates are isostructural, and there is the formation of N(+)H‚‚‚N(-) and C-H‚‚‚O mediated tetramer synthons, which are linked with C-H‚‚‚O hydrogen bonds to form a distorted

Table 5. Lattice Energy Calculations on Solvates of SS in Cerius2 (Drieding 2.21) H-bond energy guest molecule CH3NO2 CH3CN HCONH2 H2O 1,4-dioxane OHC2H4OH apohost

vdW energy

total energy

n

solvent surface area (Å2/uc)

solvent volume (Å3/uc)

with solvent

without solvent

with solvent

without solvent

with solvent

without solvent

1 1 1 2 0.5 0.5

76.31 66.57 62.10 38.68 72.28 82.89

51.65 44.96 40.66 21.62 54.22 57.43

-7.11 -7.28 -16.23 -28.29 -7.43 -10.85

-6.84 -7.17 -7.26 -6.70 -6.94 -6.90 -6.17

-132.2 -135.9 -127.9 -108.7 -133.2 -130.1

-113.2 -116.9 -120.4 -119.7 -118.2 -119.1 -129.6

-373.8 -346.8 -373.6 -405.0 -379.8 -343.2

-292.9 -302.3 -296.4 -305.7 -299.9 -303.1 -333.1


hexagonal cavity; (iv) the dimensions of the cavity in these solvates are the same in all cases, and the crystal packing does not depend on the nature of the solvent molecule; perhaps this signifies that in the nucleation stage the host cavity is first formed and that the guest molecules have a simple space-filling role; (v) ethylene glycol occupies the hexagonal cavity in a sterically unencumbered way, but remarkably, it forms no hydrogen bond; (vi) the methanol solvate is quite distinctive and has a different thermochemical behavior as compared to the other solvates. A traditional view is that host frameworks must be assembled with strong hydrogen bonds to sustain an open architecture for guest inclusion. However, recent examples from the literature demonstrate that weak hydrogen bonds can also be considered as effective design elements in the crystal engineering of host structures.26 The advantage of using several types of hydrogen bonds is that the strong hydrogen bonds provide mechanical robustness to the host framework while the weak interactions give flexibility and adaptability. In the present context, solvates of sildenafil saccharinate show a high degree of isostructurality possibly because of the strong hydrogen bonds, but they are able to transform to an apohost structure with a similar host topology because of the flexibility afforded by the weak hydrogen bonds. Another conclusion of this work is that the term pseudopolymorph is well suited to describing structure and property modulations in a solute-solvent system. Finally we note that careful experimental work may be required to obtain new pseudopolymorphs. To this end, the solvate forming propensities of sildenafil citrate have also been examined. However, preliminary experiments indicate that it does not form solvates as easily as sildenafil saccharinate. Acknowledgment. We thank the DST for financial support. R.B. and P.M.B. thank the UGC and CSIR for the award of SRF. Supporting Information Available: ORTEP diagrams (50% probability), DSC, and TGA of sildenafil saccharinate (SS) apohost and its solvates, 2D packing of the hexagonal cavities in the solvates of SS, and VTPXRD of sildenafil saccharinate dihydrate. This material is available free of charge via the Internet at http://pubs.acs.org.


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