CRYSTAL GROWTH & DESIGN 2005 VOL. 5, NO. 2 427-438
Articles Hydrophobic vs. Hydrophilic: Ionic Competition in Remacemide Salt Structures Gareth R. Lewis,*,† Gerry Steele,† Lorraine McBride,‡ Alastair J. Florence,‡ Alan R. Kennedy,# Norman Shankland,‡,⊥ William I. F. David,| Kenneth Shankland,| and Simon J. Teat§ AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K., Department of Pharmaceutical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, U.K., Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K., CrystallografX Limited, 38 Queen Street, Glasgow G1 3DX, U.K., ISIS Facility, CCLRC Rutherford Appleton Laboratory, Chilton, Oxfordshire, OX11 0QX, U.K., and CCLRC Daresbury Laboratory, Daresbury, Warrington, Cheshire, WA4 4AD, U.K. Received May 20, 2004;
Revised Manuscript Received November 25, 2004
ABSTRACT: Remacemide [2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide] was developed as a potential antagonist for epilepsy, Parkinsonism, and Huntington’s disease. This paper investigates hydrophilic and hydrophobic intermolecular interactions that occur within the series of crystal structures comprising remacemide 1 and six of its salts [2 ) chloride; 3 ) nitrate; 4 ) acetate (C2H3O2-); 5 ) hydrogenfumarate (C4H3O4-); 6 ) naphthalene-2-sulfonate (napsilate, C10H7O3S-); 7 ) 1-hydroxynaphthalene-2-carboxylate (xinafoate, C11H7O3-)]. The hydrophilic interactions are described through graph set analyses of the hydrogen bond motifs and networks. The lattice of 1 comprises unidirectional, one-dimensional chains of molecules parallel to the c-axis. In 2, the cation-anion hydrogen bonding imposes a well-defined hydrophilic stratum structure on the lattice. As the cation itself is amphiphilic, a natural consequence of this is the creation of two-dimensional stacked layers with alternating hydrophilic and hydrophobic character (lattice bilayers). This tendency to form bilayers within the lattice is also observed in structures 3-5 (polar anions) and structures 6-7 (amphiphilic anions). Relatively few well-directed intermolecular interactions are observed between aromatic rings, either in 1 or in the hydrophobic layers of 2-7. Therefore, it is concluded that it is the hydrophilic hydrogen bond interactions that dominate the crystal packing and drive the segregation into lattice bilayers in the salt crystal structures. Introduction Remacemide [2-amino-N-(1-methyl-1,2-diphenylethyl)acetamide, Figure 1] is a noncompetitive, low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist that was investigated as a potential treatment for epilepsy, Parkinsonism, and Huntington’s disease.1 It acts by decreasing excitatory neurotransmission by blockade of the channel site of the NMDA complex. An additional action is to block fast sodium channels. After administration, remacemide is transformed to a deglycinated * Corresponding author. E-mail:
[email protected]. † AstraZeneca R&D Charnwood. ‡ Department of Pharmaceutical Sciences, University of Strathclyde. # Department of Pure and Applied Chemistry, University of Strathclyde. ⊥ CrystallografX Limited. | CCLRC Rutherford Appleton Laboratory. § CCLRC Daresbury Laboratory.
Figure 1. The molecular structure of the remacemide cation. Atoms C(2)-(6), C(10)-(12) and N(2) are used to define the geometric parameters listed in Table 4.
metabolite with ca. 140-fold the potency of the parent compound in binding to the NMDA channel complex [the (S)-enantiomer being the more potent]. At the
10.1021/cg049836u CCC: $30.25 © 2005 American Chemical Society Published on Web 01/26/2005
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Table 1. Crystal Data for 1-7a structure
1
2
3
4
5b
6
7
data collection temperature/K crystal system space group [No.] a/Å b/Å c/Å R/° β/° γ/° V/Å3 Z solvation µ/mm-1 reflections collected independent reflections Rint final R1 [I > 2σ(I)]
123 monoclinic P21/c [14] 8.9200(10) 16.524(2) 9.8570(10) 90 93.836(10) 90 1449.6(3) 4
150 monoclinic P21 [4] 10.660(3) 8.712(2) 17.624(3) 90 90.77(2) 90 1636.7(7) 4
123 monoclinic P21/a [14] 11.724(4) 8.932(4) 15.872(4) 90 95.93(2) 90 1653(1) 4
130 monoclinic P21/c [14] 15.4018(5) 6.7683(2) 17.3531(4) 90 93.133(2) 90 1806.25(9) 4
293 triclinic P1 [1] 7.522(1) 8.722(2) 15.911(1) 99.16(1) 93.33(1) 73.92(2) 990.1(3) 2
150 monoclinic Cc [9] 11.9187(10) 31.801(3) 7.9304(7) 90 128.382(2) 90 2356.3(4) 4
0.077 3207 2797 0.0498 0.0409
0.234 4203 3996 0.0286 0.0344
0.096 3757 2916 0.0271 0.0540
c c c c c
0.072 3610 3259
150 triclinic P1 h [2] 9.7297(4) 14.4323(3) 19.4269(4) 104.859(2) 90.490(2) 95.546(2) 2622.82(13) 4 0.4EtOH, 0.5H2O 0.163 21073 10091 0.0247 0.0564
a
0.044
0.086 7384 4848 0.0344 0.0494
Standard uncertainties in parentheses. b From ref 4. c See Table 3. Table 2. The Variable Count Scheme Used in Data Collection for Structure 4a
scan #
2θ range/°
scan rate ° min-1
sample rate/ms
step size 2θ/°
time min
1 2 3 4 5 6 7
2.5-42.5 22.5-42.5 32.5-42.5 2.5-42.5 22.5-42.5 32.5-42.5 22.5-32.5
1 0.5 0.25 1 0.5 0.25 0.25
60 120 240 60 120 240 240
0.001 0.001 0.001 0.001 0.001 0.001 0.001
40 40 40 40 40 40 40
aData were collected in a series of seven runs, with the scan rate and detector sample rate set to give an equivalent step size of 0.001° 2θ. The majority of the data collection time is spent in the high-angle region of the diffraction pattern.
sodium fast channel, the active metabolite has twice the potency of the parent, and there is no difference in the enantiomer potency. This paper reports the crystal structure of remacemide and six of its salts. Different salts of the same active drug are distinct products in themselves, with different physicochemical profiles that underpin clinical efficacy, safety, and product quality.2 In the case of remacemide, the salts were synthesized as part of a preformulation program within which the factors of specific interest included solubility (specifically low aqueous solubility for a pediatric suspension formulation) and taste (the HCl salt of the drug tasting unpleasant on the palate). While the chemical process for making salt forms is routine, it is less straightforward to understand ahead
of time how hydrogen bond (H-bond) motifs and crystal packing will be affected by switching a halide, say, to a bulkier organic anion such as xinafoate. That said, progress is being made in quantifying the extent to which the stronger H-bond motifs can be exchanged reliably from one network structure to another.3 Here, we are concerned with the extent to which H-bond motifs and hydrophobic interactions in remacemide (1) recur across structures containing six of the anions that featured in the salt selection process: 2 ) chloride (Cl-); 3 ) nitrate (NO3-); 4 ) acetate (CH3COO-); 5 ) hydrogenfumarate (C4H3O4-); 6 ) naphthalene-2-sulfonate (napsilate, C10H7O3S-); 7 ) 1-hydroxynaphthalene-2-carboxylate(xinafoate,C11H7O3-). The motivation for the study comes from a desire to move toward a better understanding of the relationship between structure and properties and of how crystal structures might be used to guide the salt selection process. Experimental Section 1. Data Collection and Analysis. The structures of 1, 2, and 3 were determined from single crystal samples on a laboratory diffractometer. Smaller single crystals of salts 6 and 7 yielded structures obtained from synchrotron X-ray diffraction data. The microcrystalline salt 4 was not suited to singlecrystal diffraction; hence, the structure was obtained from synchrotron X-ray powder diffraction data. The crystal structure data for 5 were taken from an AstraZeneca internal company report.4 Crystal structure and refinement details are summarized in Table 1.
Table 3. Rietveld Refinement Details for 4a space group Z unit cell refinement unit cell constants data range observations refined parameters restraints distance angle constraints strict (equal ITF) thermal parameters Rietveld agreement factors profile constraints aStandard uncertainties in parentheses.
P21/c 4 whole pattern a ) 15.4018(5) Å, b ) 6.7683(2) Å, c ) 17.3531(4) Å, β ) 93.133(2)° 2-37° 7001 163 restrained to Z-matrix values ( 0.001 Å restrained to Z-matrix values ( 0.1° all H ) 3.00 Å2 all aromatic C equal; all other C equal; N(1) ) O(1) acetate: all atoms equal all atoms isotropic χ2 ) 1.7624, Rp ) 8.48, Rwp ) 9.15, RE ) 6.89 χ2 ) 4.91
Ionic Competition in Remacemide Salt Structures 2. Single Crystal Diffraction Data, Structure Solution and Refinement. Measurements on 1, 2, and 3 were made with a Rigaku AFC7S diffractometer and Mo-KR radiation (λ ) 0.71069 Å) using ω/2θ scans. Measurements on structures 6 and 7 were made using Si(111) monochromated synchrotron radiation (λ ) 0.6892 Å) and a Siemens SMART CCD areadetector diffractometer using standard procedures and programs for Station 9.8 of Daresbury SRS.5,6 All structures were solved by Direct methods and refined to convergence against F2 using all unique reflections.7 Non-H-atoms were treated anisotropically, whereas hydrogen (H-) atoms bound to nitrogen (N-) or oxygen (O-) atoms were refined isotropically. The exception is one NH3 group in structure 6, for which the atoms were placed in calculated positions and in a riding mode, with refinement of only a torsional parameter to provide the orientation of the group. All other H-atoms were assigned ideal normalized geometries and refined in riding modes. The large decay corrections given for 6 and 7 include corrections for synchrotron beam decay, as well as corrections for crystal decay.8 The structure of 6 is affected by some disorder. To model this a site occupancy factor (SOF) for the solvate ethanol and the adjacent major position of the disordered sulfonate was refined to 79.1(4)%. The H-atoms of the ethanol and water molecules were located in difference syntheses and modeled as riding atoms. 3. Powder Diffraction Data, Structure Solution and Refinement. Diffraction data from a sample of structure 4 contained in a 1.0 mm capillary were collected at 130 K on the high-resolution X-ray powder diffractometer BM16 at the European Synchrotron Radiation Facility,9 using an incident wavelength of 0.8507473 Å. The diffraction data collection scheme shown in Table 2 was implemented to improve the accuracy of the structure factor estimates at high diffraction angles. The unit cell indexed to a monoclinic cell [a ) 15.4020, b ) 6.7725, c ) 17.3627 Å, β ) 93.09 °, V ) 1808 Å3, F(20) ) 251, M(20) ) 52, DICVOL-9110] and a tentative assignment of space group P21/c was confirmed by an excellent Pawley fit11 to data in the range 2-27°, resulting in a profile χ2(χ2pawley) of 1.1. The initial structure solution was performed using the SA procedure, described previously,12 that is now implemented in the DASH computer program.13 Rietveld refinement (using the program SR15LS)14 of the solved crystal structure output from the SA program gave a profile χ2(χ2Rietveld) of 1.8 with only the scale factor and overall temperature factor refined, confirming the solved structure to be substantially correct. A subsequent fully slack constrained Rietveld refinement gave an excellent fit to the data (Table 3, Figure 2). 4. Structure Analyses. Graph set analysis of H-bond motifs15 was conducted using the RPLUTO software.16 Structure visualization was performed using Materials Studio.17 The packing efficiency of the molecules within each structure was evaluated using a packing coefficient, k, defined by k ) ZVmol/ Vcell.18 The molecular volume, Vmol, is a summation of the component ion and solvent volumes, computed as Connolly surfaces19 (using a probe radius of 1.2 Å in the CERIUS2 software,20 Table 4).
Results 1. Crystal Structure Analysis. The discussion of the structures of 1-7 is divided into molecular and crystal structure aspects. The key features of the structures are discussed below, with more detailed analysis provided in Supporting Information. All of the H-bonds observed in the crystal structures of 2-7 are shown in Supporting Information, along with the binary level graph set descriptors. Geometric details of the H-bonds are listed in Table 5. All structures are racemic except 5, which is the (S)enantiomer. The crystal structures of 2, 5, and 6 each contain two unique molecules (salts) in the asymmetric unit. Structure 6 is the only solvate in the series, the
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asymmetric unit comprising two cations, two anions, one water molecule, and a partially present ethanol molecule to give the molecular formula [remacemide][naphthalene-2-sulfonate]‚0.4EtOH‚0.5H2O. In terms of polarity, the anions in structures 2-5 are hydrophilic, while the anions in structures 6 and 7 are amphiphilic. It is not known whether these seven structures are the most thermodynamically favorable forms. a. Molecular Structure and Conformational Analysis. There are notable similarities among the remacemide conformations observed in the crystal structures of 1-7. The comparability of 1 and 7 in Figure 3 is particularly striking, as is the comparability of the six molecules in crystal structures 2, 3, 4, and 6. Such similarities arise out of the fact that “observed structures tend to concentrate in low lying regions of the potential energy surface”,21 and, as expected, the associated molecular heats of formation have a relatively narrow spread (2.5 kcal mol-1, Table 4). The close conformational similarity of 1 and 7 is underlined by the fact that geometry optimizations starting from the crystal structure conformations converged to the same geometry (8.246 kcal mol-1, Table 4). Likewise, the crystal structure conformations of 2, 3, 4, and 6 also optimized to a common geometry (10.118 kcal mol-1, Table 4). In general terms, the relationship between the conformations shown in Figure 3 can be described with reference to torsion angles τ1 and τ2 in Table 4. Thus, starting from 1 (or 7), driving τ1 in the direction of +60° shifts the conformation toward 5a; from 5a, driving τ2 in the direction of +60° shifts the conformation toward 5b; finally, from 5b, driving τ2 in the direction of -60° shifts the conformation toward 2, 3, 4, and 6. b. Crystal Structures. The crystal structures of 1-7 are first described in turn, and then significant structural trends and motifs across this series are discussed. Almost all of the H-bonds in these structures are moderate interactions.22 Remacemide 1. The crystal structure of 1 is the simplest of all the structures, as there are no anions to compete with interactions between the remacemide molecules. The lattice comprises unidirectional, 1-D chains of H-bonded molecules parallel to the c-axis, which are propagated by the 21 screw. Despite the directionality of the chains, the crystal is not polar as neighboring chains alternate in their orientation (Figure 4). In addition, the H-atoms of each amine group are aligned with the centroid of an adjacent benzyl aromatic ring, but with a separation of >3.0 Å. It is possible that these contacts may provide a small stabilizing contribution to the lattice energy, but these are not significant interactions. Neighboring 1-D chains are slightly interdigitated, with close edge-to-face (ef) contacts between phenyl rings.23 These interactions are centrosymmetric, resulting in the four aromatic rings from each pair of participating molecules being involved in two such contacts (Figure 5). [Remacemide][chloride] 2. Protonating remacemide and introducing an accompanying chloride ion into the lattice results in the formation of two-dimensional stacked layers with alternating hydrophilic and hydrophobic character (lattice bilayers, Figure 6). The chloride anions H-bond to five amine and one amide protons from
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Figure 2. Final observed (points), calculated (line), and difference [(yobs - ycalc)/σ(yobs)] profiles for the Rietveld refinement of 4.
four nearest neighbor remacemide cations, imposing a well-defined hydrophilic stratum structure on the lattice. As the cation itself is amphiphilic, a natural consequence of this is the creation of a lattice bilayer, with hydrophobic strata of interacting aromatic rings (Figure 6). The hydrophilic stratum in the structure of 2 comprises a total of nine unique H-bonds involving combinations of all potential donors and acceptors in the asymmetric unit. The two-dimensional network formed by all of these hydrophilic interactions contains
three second level graph set motifs propagating throughout the structure (Figure 7, Table 1, Supporting Information). With the C(5) and C(12) aromatic rings in close proximity in the hydrophobic layer of the structure, it may be anticipated that a series of directed phenyl‚‚‚ phenyl interactions would be present. However, while several contacts are observed, there are no close or welldirected interactions between the phenyl rings. The only prevalent interaction is the weak ef between the benzyl
Ionic Competition in Remacemide Salt Structures
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Table 4. Selected Geometric Parameters and Other Structural Data for 1-7a structure
1
5
2
3
4
6
angle-widening at the C(3) chiral center C(5)-C(3)-[C(4) or C(11)]b/° angle-narrowing at the C(3) chiral center N(2)-C(3)-[C(4) or C(11)]c/° orientation of amide carbonyl wrt. C(5) aromatic ringd τ1 ) C(2)-N(2)-C(3)-C(5)/° orientation of aromatic rings across C(3)-C(11)d τ2 ) C(5)-C(3)-C(11)-C(12)/° angle between mean aromatic ring planes ring 1 ) [C(5)-C(10)]; ring 2 ) [C(12)-C(17)]/° orientation of C(5) aromatic ring wrt. C(11) methylened τ3 ) C(11)-C(3)-C(5)-[C(6) or C(10)]e/° orientation of C(5) aromatic ring wrt. C(4) methyld τ3′ ) C(4)-C(3)-C(5)-[C(6) or C(10)]e/° remacemide heat of formationf/kcal mol-1 (1 kcal mol-1 ) 4.187 kJ mol-1) volume of remacemide cationg/Å3 volume of aniong/Å3 packing coefficient,h k Fcalc (from crystal structure refinement)/ Mg m-3
112.0(2)
113.3(3)
7
112.9(3), 112.5(4)
113.2(2), 113.3(2)
113.5(2)
111.7(7)
113.1(2), 114.4(2)
106.2(2)
106.3(3)
106.4(3), 106.3(3)
104.4(2), 104.8(2)
104.7(2)
105.1(6)
103.1(2), 104.3(2)
86.4(5), 71.8(5)
58.1(4), 68.5(3)
63.1(3)
47(1)
63.7(3), 65.1(3)
-63.4(2) -62.3(4) 171.7(2)
-179.2(2) -159.4(3), 56.2(5)
-75.1(3), -71.3(3) -57.9(3) -73.8(9) -60.7(2), -62.2(2)
75.4(1)
78.4(2)
51.6(3), 50.0(3)
51.6(2), 38.7(2)
22.3(2)
7.5(3)
-70.2(4), 73.5(5)
-68.0(3), -79.8(3) -75.7(3) -62(1)
-84.4(2), -73.0(3)
74.2(2)
63.8(3)
-18.2(5), -46.7(6) -12.9(4), -25.0(3) -25.6(4) -10(1)
-36.3(3), -22.2(3)
8.246
8.246
7.654, 8.106
10.118, 10.118
10.118
10.118
10.118, 10.118
243.5
257.5 179.1 0.74 1.287
218.5, 221.6 113.0, 110.9 0.67 1.289
266.6, 276.8 38.5, 38.6 0.76 1.237
274.6 65.0 0.82 1.331
244.6 78.0 0.71 1.208
271.8, 270.5 191.3, 191.5 0.77 1.275
0.67 1.230
39.1(2)
54.5(6)
33.8(1), 49.1(1)
a Standard uncertainties in parentheses. b Measured to C(11) in 1, 7, and C(4) in the other structures. Mean angle about C(3) (averaged across all 10 molecules) ) 109.42°. c Measured to C(4) in 1, 7, and C(11) in the other structures. d Each molecule viewed and measured as shown in Figure 3, with its chiral center in the same relative configuration as (R)-remacemide. e Measured to the atom [C(6) or C(10)] returning the smaller angle. f Calculated for an isolated, uncharged remacemide molecule using the AM1 method implemented in the program WinMopac 7.21,31 inputting in turn each of the 10 crystal structure geometries and optimizing all degrees of freedom to a final gradient norm of 0.01 or less. g Computed as Connolly surfaces19 in the CERIUS2 molecular modeling software.20 In 6, volume EtOH ) 72.1 Å3, volume H2O ) 29.0 Å3. h k ) ZVmol/Vcell where Vmol is the sum of the volumes of the constituent molecules in the formula unit,18 as given by the Connolly surfaces. For cubic close packing of spheres, k ) 0.74, while for crystals of organic compounds, k generally lies in the range 0.60-0.80.
aromatic ring and the phenyl ring of the nearestneighbor molecule. The rings are nearly orthogonal, but the donor H-atoms are situated above a C-H-bond of the acceptor, as opposed to the greater electron density of the C6 ring. For these interactions, the C-H‚‚‚π separations lie in the range 3.0-3.1 Å. No other faceto-face π‚‚‚π contacts are observed. [Remacemide][nitrate] 3. Incorporating the larger nitrate anion to give the crystal structure of 3 again results in a lattice bilayer arrangement of hydrophobic and hydrophilic regions (Figure 8). The hydrophilic stratum is formed as a result of highly favorable anioncation H-bonding interactions and, in a fashion entirely analogous to the chloride structure 2, a hydrophobic stratum of interacting aromatic rings forms as a consequence. As in 2, the two-dimensional network formed by the H-bonds lies parallel to the ab-plane, and is summarized in Figure 9. With this number of H-bonds, it is unsurprising that there is a wide range of binary motifs (Table 2, Supporting Information). There are several large ring descriptors, with each remacemide cation participating in one larger motif and a symmetric R22(10) dimer (Figure 10). Despite the close proximity of the C(5) and C(12) aromatic rings, there are no significant individual hydrophobic interactions observed. Nearest-neighbor aromatic rings are generally aligned edge-to-edge, which prevents any clear interaction between regions of opposite polarity [either ef interactions or vertex-to-face (vf)]. [Remacemide][acetate] 4. Structure 4 exhibits the same hydrophobic/hydrophilic lattice bilayer arrangement as structures 2 and 3 (Figure 11). The acetate ion
is H-bonded to the amide proton plus two amine protons, with the third amine proton H-bonded to the amide carbonyl. There is striking similarity between the R22(10) + R44(18) motifs formed in 3 and the combination of a centrosymmetric R22(10) ring with a R43(16) motif in 4 (Figure 12, Table 3, Supporting Information). These features may stem from the fact that the acetate and nitrate ions have comparable volumes (Table 4) and similar geometries. As with 3, there are no significant individual hydrophobic interactions between aromatic rings, despite their close proximity. Nearest-neighbor rings are generally aligned edge-to-edge, which prevents any clear interaction between regions of opposite polarity. [Remacemide][hydrogenfumarate] 5. The crystal structure of 5 again has the lattice bilayer structure, with hydrogenfumarate anions closely associated with the H-bonding moieties of the remacemide cations in the ab-plane (Figure 13). Among the 10 potential H-bond donors in the cations and anions of the asymmetric unit, only one (an amide proton) is not H-bonded. Two notable binary motifs are found in the structure: (a) a C22(12) chain between the ions that runs parallel to the a-axis, and (b) the 10-membered ring formed by a head-to-tail arrangement of remacemide cations, a similar motif to those found in 3 and 4 (Figure 14). The C(5) and C(12) aromatic rings of the remacemide cations in 5 form 2-D sheets in the ab-plane. Despite the close proximity of these moieties, there are few significant individual hydrophobic interactions observed. Nearest-neighbor rings are most often aligned edge-to-edge, which prevents any clear interaction between regions of opposite polarity. However, poorly
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Table 5. H-Bond Geometries in the Crystal Structures of 2-7a structure 2
3
4
5
6
7
H-bond 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 10 1 2 3 4 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4 5
contact N-H‚‚‚Cl N-H‚‚‚Cl N-H‚‚‚Cl N-H‚‚‚Cl N-H‚‚‚Cl N-H‚‚‚O C-H‚‚‚O N-H‚‚‚O N-H‚‚‚Cl N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚N N-H‚‚‚O N-H‚‚‚O N-H‚‚‚N N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O O-H‚‚‚O O-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O O-H‚‚‚O O-H‚‚‚O O-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O O-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O N-H‚‚‚O
donor atomb N1 N1 N1 N1′ N1′ N1′ C1′ N2 N2′ N1 N1 N1 N1 N1 N1 N1 N2 N2 N1 N2 N1 N1 N1 O(A) O(A) N1 N1 N1 N1′ N2 N1′ N1′ O(W) O(W) O(S) N1 N1 N1 N1 N1 N2 N1′ N1′ N1′ N2′ O(H) N1 N1 N1 N2
donor moleculec R(A) R(A) R(A) R(B) R(B) R(B) R(B) R(A) R(B) R R R R R R R R R R R R R R HF HF R R R R R R R W W S R R R R R R R R R R XF R R R R
acceptor atomd Cl Cl Cl Cl Cl O(R) O(R) O(R)′ Cl O(R) O(A) O(A) O(A) O(A) O(A) N(A) O(A) O(A) N(A) O(A) O(A) O(A) O(R) O(A) O(A) O(A) O(A) O(R)′ O(R) O(A) O(A) O(A) O(A) O(A) O(A) O(A) O(A) O(A) O(W) O(S) O(R)′ O(A) O(A) O(A) O(R) O(A) O(R) O(A) O(A) O(A)
acceptor moleculec Cl-
ClClClClR(A) R(A) R(B) ClR NO3NO3NO3NO3NO3NO3NO3NO3NO3MeCO2MeCO2MeCO2R HF HF HF HF R R HF HF HF NS NS NS NS NS NS W S R NS NS NS R XF R XF XF XF
d/Å
D/Å
θ/°
2.16 2.15 2.23 2.18 2.11 2.12 2.49 1.91 2.33 1.79 2.60 2.53 2.00 2.37 1.91 2.46 2.38 2.08 2.58 1.79 1.63 1.78 1.98 1.58 1.60 1.78 1.85 1.80 1.86 2.00 1.88 1.77 1.88 1.85 1.88 2.24 2.17 2.26 2.37 1.85 1.97 1.95 1.84 1.77 1.89 1.55 1.82 1.99 1.74 1.85
3.152(3) 3.102(3) 3.199(3) 3.177(3) 3.071(3) 2.793(3) 2.939(3) 2.803(3) 3.307(3) 2.798(3) 2.905(3) 2.905(3) 2.919(3) 3.101(3) 2.908(3) 3.420(3) 3.206(3) 3.024(3) 3.304(3) 2.679(14) 2.636(18) 2.743(17) 2.941(16) 2.538(1) 2.556(1) 2.709(1) 2.824(1) 2.783(1) 2.843(1) 2.998(1) 2.835(1) 2.753(1) 2.857(3) 2.820(4) 2.841(5) 2.948(3) 2.906(3) 2.947(3) 2.878(3) 2.792(3) 2.971(2) 2.868(6) 2.766(3) 2.771(4) 2.902(2) 2.459(3) 2.767(3) 2.970(3) 2.734(3) 2.829(3)
166 156 161 169 158 122 104 147 163 174 97 101 150 129 172 158 139 156 129 145 176 158 158 164 163 152 163 162 163 170 158 163 172 166 167 126 128 124 110 154 171 150 150 172 177 152 155 163 167 164
a The N-H, C-H, and O-H distances were normalized to the default values in RPLUTO, i.e., 1.009, 1.083, and 0.983 Å, respectively. Standard uncertainties for D are given in parentheses. b N1 ) terminal NH3 amine group, N2 ) amide CONH proton; O(A) ) anion carboxylic acid proton; O(W) ) water molecule; O(S) ) ethanol solvent molecule; O(H) ) anion hydroxyl group proton. c R ) remacemide cation where R(A), R(B) differentiates chirality of the different donor molecules (see text); most anions shown by formulas, else HF ) hydrogenfumarate, NS ) napsilate, XF ) xinafoate; W ) water molecule; S ) ethanol solvent molecule. d Cl ) chloride anion; O(R) ) amide CONH carbonyl oxygen; O(A) ) anion O-atoms; O(W) ) water O-atom; O(S) ) ethanol O-atom; N(A) ) anion N-atom.
aligned offset-face-to-face (off) π‚‚‚π interactions and ef contacts are present in the layer (Figure 15). [Remacemide][naphthalene-2-sulfonate]‚ 0.4EtOH‚0.5H2O 6. In terms of polarity, the anions in 2-5 are hydrophilic. Structure 6 introduces a variation to this theme by incorporating into the lattice an anion that is amphiphilic, namely, naphthalene-2-sulfonate (napsilate). Thus, 6 is distinguished from 2-5 by the fact that both the cation and the anion are amphiphilic. That said, the same hydrophobic/hydrophilic lattice bilayer arrangement that characterizes 2-5 is once again observed in 6 (Figure 16), with segregated layers of molecules forming in the ab-plane. The naphthalene moiety forms part of the hydrophobic stratum of interacting aromatic rings, while the charged sulfonate is an
integral part of the hydrophilic stratum, which also accommodates the solvent of crystallization. A total of 13 unique intermolecular H-bonds are observed in the structure of 6, involving combinations of all potential donors and acceptors in the asymmetric unit. The hydrophilic solvent of crystallization clearly plays a key part in stabilizing the lattice bilayer configuration, participating in 5 of the 13 H-bonds. As in the structure of 3, several ring motifs are observed (Table 5, Supporting Information), and as with structure 1, an amide‚‚‚amide chain is formed, propagating a C22(8) motif in the direction of the a-axis (Figure 17). Despite the close proximity of the cation and anion aromatic rings within the hydrophobic layers of the abplane, no significant individual intermolecular inter-
Ionic Competition in Remacemide Salt Structures
Crystal Growth & Design, Vol. 5, No. 2, 2005 433
Figure 3. The conformation of remacemide molecules in the crystal structures of 1-7. For ease of comparison, each molecule is viewed along the C(3)-C(4) bond, with its chiral center in the same relative configuration as (R)-remacemide.
Figure 4. Chains of remacemide molecules along the c-axis in the crystal structure of 1, which propagate as a 1-D [C(4)] motif. Note that in this and subsequent figures, atoms not directly relevant to the point of the figure have been omitted for clarity.
actions are observed. As in the crystal structure of 5, nearest-neighbor aromatic rings are often aligned edgeto-edge, preventing any clear interaction between regions of opposite polarity. [Remacemide][1-hydroxynaphthalene-2-carboxylate] 7. The xinafoate anion is of comparable size to napsilate and similarly contains three H-bond accepting O-atoms. Consequently, the structure of 7 is similar to that of 6, comprising layers of interdigitated molecules, with hydrophilic regions containing the amide/amine groups of remacemide plus the hydroxy/carboxylate moieties of the anions, and hydrophobic regions comprising naphthalene and phenyl rings (Figure 18). The two-dimensional network formed by H-bonds in the ac-plane is summarized in Figure 19. There are only three second level graph set motifs that propagate
Figure 5. Centrosymmetric, pairwise, ef interactions between 1-D chains of remacemide molecules in the structure of 1. Dashed lines indicate H‚‚‚C separations of
