Pressure-Stabilized Solvates of Xylazine ... - ACS Publications

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Pressure-Stabilized Solvates of Xylazine Hydrochloride ‡ ,† Anna Olejniczak,† Kristıne rziņ ̅ Krukle-Be ̅ ̅ a, and Andrzej Katrusiak* †

Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland Faculty of Chemistry, University of Latvia, Jelgavas iela 1, LV-1004 Riga, Latvia

‡

S Supporting Information *

ABSTRACT: High pressure strongly favors the highestdensity polymorph Z of active pharmaceutical ingredient 2(2,6-xylidino)-5,6-dihydro-4H-1,3-thiazine hydrochloride (xylazine hydrochloride, XylHCl) up to about 0.1 GPa only, but still higher pressure destabilizes this structure. Above 0.1 GPa, XylHCl preferentially crystallizes as solvates with CH2Cl2, CHCl3, or (CH3)2CHOH depending on the solvent used. However, when XylHCl·H2O is dissolved in any of these solvents, the high-pressure crystallizations yield the hydrate XylHCl·H2O only. The single crystals of the CH2Cl2, CHCl3, and (CH3)2CHOH solvates could be grown in situ in a diamond anvil cell, which allowed their structure determination from the single-crystal diffraction data. At 0.4 GPa the XylHCl· H2O hydrate undergoes a pressure-induced phase transition doubling the unit cell dimensions.

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INTRODUCTION Polymorphism1 and solvatomorphism2 can be used for controlling physical and chemical properties3 of active pharmaceutical ingredients (API). After the synthesis of an API it can transform during several stages of processing like crystallization, milling, freeze−drying, wet granulation, and mixing with excipients before the final incorporation into tablets. In the tablets API can be exposed to a considerable range of temperature and humidity,4,5 which can trigger further transformations.6 The effects of high pressure on the crystals of organic compounds,7−18 as well as technologically important mechanochemical and tableting effects, have been studied.4 High-pressure investigations relevant to the pharmaceutical compounds include three main aspects: (i) pressure-induced solid phase transitions;18−20 (ii) high pressure effect on the crystal structure;8,9,21 and (iii) synthesis of new polymorphs and solvates at high pressure.22,23 2-(2,6-Xylidino)-5,6-dihydro-4H-1,3-thiazine hydrochloride, xylazine hydrochloride, denoted XylHCl, is an adrenergic αagonist used as a sedative, analgesic, and muscle relaxant in veterinary medicine and is highly soluble in water and alcohol. The cation can exists in two resonance forms (Figure 1), of which the positive charge on the exocyclic nitrogen was suggested by Carpy et al.24 There are several reports about its structures25−27 and phase transitions.26,28−32 Four polymorphs (labeled A, M, Z, and X)29 and several solvates of XylHCl, the most stable of which is the monohydrate denoted H1,30 were reported. The crystals of XylHCl are hygroscopic and form hydrates when exposed to the moisture in air. Therefore, the structures of polymorphs A, X, and Z were studied by powder X-ray diffraction (PXRD, Table 1), while for the M form only the unit-cell dimensions were determined.25,26,33 © 2016 American Chemical Society

Figure 1. Two resonance forms of the xylazine hydrochloride (XylHCl).

It was established that polymorphs A, Z, and X differ considerably in their crystal structures, but fragments of the Hbonding networks are similar. In the X and Z forms of the XylHCl two chloride anions and two xylazine cations are connected by hydrogen bonds forming a tetramer described by graph R24(12), shown in Figure 2.34−36 In polymorph A only one chloride anion and one xylazine moiety are connected by two hydrogen bonds described by R12(6). In hydrate H1 the water molecules and the chloride anions between two xylazine moieties are hydrogen bonded into tetramer R24(8), and these xylazine moieties are further H-bonded with this tetramer into a hexamer R46(16). The molecular packing in polymorph X and in hydrate H1 are similar.26 XylHCl is also known to form various Received: February 17, 2016 Revised: May 19, 2016 Published: May 23, 2016 3756

DOI: 10.1021/acs.cgd.6b00264 Cryst. Growth Des. 2016, 16, 3756−3762

Crystal Growth & Design

Article

Table 1. Selected Crystallographic Data of Polymorphs A, X, and Z of XylHCl (C12H17N2S+Cl−) and Its Hydrate H1 (C12H17N2S+Cl−·H2O) A1

form Temperature (K) Crystal system Space group a (Å) b (Å) c (Å) β (deg) V (Å3) Z/Z′ Dcalc (g/cm3)

293

Z1

X1

293

H12

293

100

P21/c 12.1035(12) 8.3806(4) 13.5145(7) 94.897(6) 1365.85(17) 4/1 1.25

P21/c 13.4546(2) 8.6547(1) 12.7732(2) 109.210(2) 1404.56(4) 4/1 1.30

monoclinic P21/c 11.5735(3) 8.70728(17) 14.8636(3) 115.1461(18) 1355.90(5) 4/1 1.26

P21/n 12.4480(4) 11.6219(2) 9.3615(3) 97.411(3) 1343.00(7) 4/1 1.27

1

Powder X-ray diffraction, ref 25. 2Single-crystal X-ray diffraction, ref 27.

Figure 3. Crystallization conditions of different XylHCl polymorphs and solvates. The forms obtained at ambient pressure have been encircled in blue, and those at high pressure conditions in red.

Figure 2. Hydrogen-bonding patterns of XylHCl and its solvates described with the graph notation.

directly supported on steel backing plates.38 Single-crystals of neat XylHCl and its solvates were obtained from saturated solution of different forms of XylHCl in particular solvents (Figure 3). The Z form of neat XylHCl (Figure 4a) was obtained from form A dissolved

solvates, for example, with CH2Cl2, CHCl3, or (CH3)2CHOH. However, these solvates are unstable at ambient conditions and their structures are unknown. Presently we have investigated the effects of pressure on the stability and preferred crystallization of XylHCl. We have recrystallized XylHCl at various thermodynamic conditions at high pressure and determined the resulting structures and interactions.

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EXPERIMENTAL SECTION

Xylazine hydrochloride (XylHCl) sample was kindly provided by JSC Grindeks, Riga, Latvia, (specified purity >99%) and consisted of pure monohydrate H1. The purity of this hydrate was confirmed by comparing its powder X-ray diffraction (PXRD) pattern with those given in the literature.33 Commercially available solvents (methanol, chloroform, dichloromethane, and isopropanol) were used as received without further purification. In order to prepare pure anhydrous form A, the supplied XylHCl was recrystallized from water, and the obtained form H1 was kept at 100 °C for 2 days. The purity of the resulting form A was confirmed by comparing its PXRD powder pattern (Figure S1) to those reported previously.33 The PXRD patterns were determined on a Bruker D8 Advance diffractometer equipped with a position sensitive LynxEye detector and using copper radiation (Cu Kα) at the wavelength of 1.54180 Å. Program Diffrac Plus XRD Commander v 2.6.1 was used for powder diffraction data collections and program Diffrac.EVA v 3.0 for the data anlysis. The diffraction patterns were acquired with the scan speed of 0.2s/0.02° from 7° to 30° on the 2θ scale. High-Pressure Crystal Growth. High-pressure diffraction experiments on XylHCl were performed on the samples crystallized in situ in a modified high-pressure diamond anvil-cell (DAC),37 with the anvils

Figure 4. Single-crystals of XylHCl polymorphs Z and XylHCl solvates viewed through a polarizing microscope, all at 296 K: (a) form Z at 0.11 GPa; (b) hydrate H1 at 0.34 GPa; (c) hydrate H2 at 0.41 GPa; (d) XylHCl·CHCl3 solvate at 0.21 GPa; (e) XylHCl·CH2Cl2 solvate at 0.13 GPa; and (f) XylHCl·(CH3)2CHOH solvate at 0.21 GPa. In photographs (a−c) many small crystals precipitated, apart from one big single crystal. Small irregular ruby chips are included in the DAC chamber for pressure calibration. 3757



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Table 2. Selected Crystallographic Data of Neat XylHCl and Its Hydrates at 296 K as a Function of Pressure Form

Z

Formula Pressure (GPa) Crystal system Space group a (Å) b (Å) c (Å) β (deg) V (Å3) Z/Z′ Dcalc (g·cm−3) R1 (I > 2σ1) wR2 (I > 2σ1) R1 (all data) wR2 (all data) Solvent

C12H17N2S+Cl¯ 0.11

C12H17N2S+Cl¯·H2O 0.12 0.19

H1

P21/n 12.4207(15) 11.578(2) 9.3303(19) 97.448(13) 1330.5(4) 4/1 1.282 0.0404 0.883 0.0594 0.966 methanol

P21/c 13.47(4) 8.649(3) 13.025(12) 109.3(2) 1432(5) 4/1 1.274 0.0995 0.2798 0.1330 0.3214 methanol

H2 0.23 monoclinic P21/c 13.52(2) 8.6272(5) 12.882(6) 110.29(11) 1410(3) 4/1 1.295 0.0619 0.1606 0.0815 0.1785 chloroform

P21/c 13.491(4) 8.626(4) 12.8826(14) 109.630(17) 1412.1(8) 4/1 1.293 0.0988 0.2646 0.1577 0.3254 methanol

0.34

C12H17N2S+Cl¯·H2O 0.41 0.60

P21/c 13.522(9) 8.6312(4) 12.880(2) 110.04(4) 1412.2(10) 4/1 1.293 0.0705 0.1940 0.0958 0.2255 methanol

P21/c 26.9826(15) 8.5823(4) 12.8071(7) 110.809(16) 2772.3(4) 8/2 1.317 0.0686 0.1699 0.1210 0.2045 methanol

P21/c 26.9813(12) 8.5497(4) 12.7364(5) 111.078(12) 2741.5(3) 8/2 1.332 0.0660 0.1511 0.1027 0.1749 methanol

Table 3. Selected Crystallographic Data of Solvates XylHCl·CHCl3 and XylHCl·CH2Cl2 at 296 K as a Function of Pressure C12H17N2S+Cl¯·CHCl3

Formula Pressure (GPa) Crystal system Space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z/Z′ Dcalc (g·cm−3) R1 (I > 2σ1) wR2 (I > 2σ1) R1 (all data) wR2 (all data) Solvent

0.08

0.21

C12H17N2S+Cl¯·CH2Cl2

0.41

1.02

0.13

P1̅ 9.416(11) 9.531(11) 11.516(11) 66.31(11) 68.37(10) 66.21(11) 839.3(19) 2/1 1.484 -

P1̅ 8.868(2) 9.528(3) 11.986(7) 68.32(4) 69.95(4) 67.50(3) 845.2(6) 2/1 -

-

-

chloroform

dichloromethyl

triclinic P1̅ 9.544(3) 9.828(3) 11.898(2) 66.75(2) 69.02(2) 64.68(3) 902.6(4) 2/1 1.384 0.0878 0.2403 0.1104 0.2696 chloroform

P1̅ 9.473(4) 9.763(4) 11.798(3) 66.45(3) 69.04(3) 64.82(4) 881.7(6) 2/1 1.417 0.0822 0.2199 0.1021 0.2451 chloroform

P1̅ 9.436(5) 9.694(3) 11.703(3) 66.20(3) 68.85(4) 64.77(4) 862.6(6) 2/1 1.448 0.0736 0.1853 0.0943 0.2207 chloroform

in CH3OH; hydrates H1 and H2 (Figure 4b,c) were obtained in the DAC from H1 dissolved in CH3OH and CHCl3 (the crystallizations from both these solvents yielded the same form H1); the CHCl3, CH2Cl2, and (CH3)2CHOH solvates were obtained from saturated solution of form A in the corresponding solvents (Figure 4d−f, respectively). The precipitation of the crystalline sample in the form of fine powder was induced by isothermal compression, and then the single crystals were grown at isochoric conditions from one seed crystal left in the dissolved sample at 320 K (form H1), 365 K (the CHCl3 and CH2Cl2 solvates), 328 K (the (CH3)2CHOH solvate), and 356 K (form Z) by slowly cooling the sample to 296 K. The single crystals of particular phases, the hydrate, and other solvates could be obtained only in the low pressure range and all our attempts to recrystallize the sample at higher pressure and temperature resulted in the chemical decomposition manifested by the formation of black residue in the chamber, except for the (CH3)2CHOH solvate, which is stable up to 2.38 GPa at least. All these other solvates are formed at ambient conditions, which was confirmed by comparing the powder diffraction patterns measured with those calculated from the high-pressure structures. However, these solvates are highly susceptible to the surrounding conditions and after removing the crystal from the solution they easily transform to the M form, which hampered the structural investigations. The crystallizations were observed through polarizing microscope, so the quality of the crystals could be assessed

and the crystallization conditions could be controlled and adjusted. In this way each of the single crystals was obtained in about 4 h. Pressure in the DAC chamber was calibrated by the rubyfluorescence method39 with a Photon Control spectrometer affording a precision of 0.02 GPa; the calibration was performed before and after the diffraction measurement. Single-Crystal X-ray Diffractometry (SCXRD). The diffraction data were measured with a KUMA KM4-CCD diffractometer using Mo Kα radiation at 296 K. CrysAlisPro 171.37.3140 was used for recording reflections41 and preliminary data reduction. The intensities were corrected for the effects of DAC absorption, sample shadowing by the gasket, and sample absorption, and the reflections overlapping with diamond reflections were eliminated. OLEX2−1.2,42 SHELX-L, and SHELX-S43 were used to solve and refine structures by direct methods, and refined by full-matrix least-squares. Anisotropic temperature factors were generally applied for non-hydrogen atoms, but the isotropic thermal parameters were occasionally retained for the atoms with unreasonable thermal ellipsoids. The H atoms in the structures were calculated from molecular geometry, with the N−H distance equal 0.86 Å, C−H 0.97 Å, O−H 0.83 Å, and the Uiso factors of H atoms constrained to 1.2 (for H atoms of NH, OH, CH, and CH2 groups) and 1.5 (for CH3 groups) times Ueq of the carrier atoms. The diffraction data recorded for XylHCl·CH2Cl2 solvate allowed the determination of the unit-cell parameters only. The crystal data and 3758



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Table 4. Selected High-Pressure Crystallographic Data of the Solvate XylHCl·(CH3)2CHOH at 296 K C12H17N2S+Cl¯·(CH3)2CHOH

Formula Pressure (GPa) Crystal system Space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z/Z′ Dcalc (g·cm−3) R1 (I > 2σ1) wR2 (I > 2σ1) R1 (all data) wR2 (all data) Solvent

0.21

0.60

1.38

2.38

P1̅ 9.2592(18) 9.5035(18) 9.623(2) 99.603(17) 101.283(18 105.329(16 779.2(3) 2/1 1.351 0.0752 0.2068 0.0835 0.2196 isopropanol

P1̅ 9.1097(19) 9.348(2) 9.295(3) 99.71(2) 101.67(2) 105.224(19) 727.1(3) 2/1 1.447 0.1104 0.2937 0.1195 0.3074 isopropanol

triclinic P1̅ 9.438(4) 9.791(8) 10.260(7) 100.08(6) 100.52(5) 105.57(6) 872.5(10) 2/1 1.206 0.0852 0.2000 0.1356 0.2502 isopropanol

P1̅ 9.3618(12) 9.6385(12) 9.9549(18) 99.598(13) 100.963(13) 105.460(11) 827.2(2) 2/1 1.272 0.627 0.1558 0.0734 0.1646 isopropanol

Figure 5. Compression of XylHCl (form Z) and its solvates. Parameters of XylHCl form Z are marked in black, hydrates in blue, the CHCl3 solvate in green, and the (CH3)2CHOH solvate in red. refinement details are summarized in Tables 2−4. Structural drawings have been prepared using the X-Seed interface of POV-Ray.44,45

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Compression of unit-cells of the crystals investigated is presented in Figure 5. In the pressure range presently studied, there are no clear indications of solid−solid phase transitions except for the clearly observed doubling of parameter a in the hydrate at 0.37 GPa. Compression of XylHCl·H2O. The product of highpressure crystallization from methanol solution in the confined space of the DAC chamber depends on whether anhydrate or hydrate form of XylHCl was used. In the case where the hydrate was used the hydrate crystals were obtained in the DAC, while any polymorphs of neat XylHCl resulted in polymorph Z, which is the stable form below 318 K at ambient pressure29 and up to 0.11 GPa. It indicate that XylHCl displays a strong preference for the hydrate formation. The XylHCl structure determined at 0.11 GPa is similar to that determined previously from PXRD data at ambient conditions. 25 Recrystallizations above 0.11 GPa yield hydrate H1, stable up to 0.37 GPa. Above this pressure the unit-cell parameter a doubles (Table 2) and a new polymorph, denoted H2, is formed. This phase transition was indicated by the appearance of additional reflections. We have not detected the volume change between these phases, which indicates that the

RESULTS AND DISCUSSION

The products of in situ crystallizations depend on the conditions of temperature, pressure, solvent, sample form, and concentration.4,23,46−51 Four forms of XylHCl are known at ambient conditions (A, M, Z, and X), but all recrystallizations at high pressure yielded either the neat compound in the Z form or solvates. Form Z could be obtained at 0.11 GPa at most. It shows that polymorph Z is more stable than other neat polymorphs at high pressure, which is consistent with the highest density of form Z at ambient pressure (Table 1). However, high pressure favors the formation of different solvates, depending on the applied solvent (Figure 3). In this way the solvates with CHCl3, CH2Cl2, and (CH3)2CHOH have been obtained, while high-pressure recrystallizations yielded the neat compound in form Z to 0.11 GPa only. In high-pressure conditions we could obtained single crystals of very good quality suitable for X-ray diffraction structural studies (Figure 4). 3759



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and H2 (for both A and B moieties) can be described by the same graphs R24(8) and R46(16). The asymmetric unit of H1 consists of one cation−anion pair and one water molecule, while in hydrate H2 two such units, denoted A and B, are independent. The space group symmetry of both hydrate phases H1 and H2 is P21/c. The structure of hydrate phases is governed by several types of hydrogen bonds, mainly CH···S, H2O/NH/CH···Cl−, and NH/CH···O, linking molecules and ions into a threedimensional network. At the phase transition at 0.37 GPa, the hydrogen-bond pattern is retained, while the symmetryindependent ions and water molecules slightly rotate and shift in the structure (Figure S2). The conformation of cations, measured by torsion angles, changes only by few degrees between the low and high-pressure phases H1 and H2 (Table S2). Compression of Solvate XylHCl·CHCl3. High-pressure crystallizations from the chloroform solution resulted in hydrate H1, when the hydrate crystals were used for preparing the solution, and in the CHCl3 solvate when the nonsolvated form of XylHCl was dissolved. The XylHCl·CHCl3 solvate is stable up to 1 GPa, and above this pressure it decomposes. It crystallizes in triclinic space group P1̅ (Table 3) and solvent molecules are located in the structure channels. In the structure of solvate XylHCl·CHCl3 the shortest hydrogen bond is NH···Cl− between anion and H atoms from both N atoms of the cation, joining them into pairs, which can be described by graph descriptor R21(6). In this respect it is similar to the crystal structure of XylHCl polymorph A.26 The anion and cation also form short contacts CH2···Cl−, CH···Cl−, and Cl−···Cl. All these short contacts together with very weak CH···S hydrogen bonds join the molecules and ions into sheets along the (110) planes (Figure 7). There is no significant change in the conformation of the cation when the pressure is increased. Compression of XylHCl·(CH3)2CHOH. Recrystallization of XylHCl polymorph A from (CH3)2CHOH at 0.21 GPa yielded the (CH3)2CHOH solvate (Table 4). After increasing pressure to 0.6 GPa or to 1.38 GPa, without heating, the crystals remained stable in their form. However, at 2.38 GPa the crystal quality significantly deteriorated, and at still higher pressure, the single crystal was destroyed. Like the CHCl3 solvate, the

transition is either continuous in character or the volume change is very subtle. We found that the transition is connected mainly with displacements of cations and anions, as illustrated in Figure 6. Thus, this transition can be described as the

Figure 6. Superimposed structures of hydrates H1(blue molecules) and H2 (red molecules, the unit cell doubled along [x]) viewed along b.

displacive one. The displacive phase transitions are often continuous and are not associated with the crystal volume change, consistently with our experiment. It remains stable up to 0.60 GPa, above which another transformation occurs shattering the single crystal into small fragments, which hindered the single-crystal X-ray analysis. The structure of this new crystal form above 0.60 GPa has not been determined and this transformation can be either a phase transition to another polymorph of the hydrate or decomposition of the hydrate to the neat XylHCl or to a hydrate of changed stoichiometry. The crystal structure of ambient-pressure hydrate H1 is closely related to the high-pressure hydrate H2: there are no significant differences in the geometrical parameters of ions and molecules in both hydrates, and the molecular arrangement is similar (Figure 6). The main hydrogen bond patterns in the H1

Figure 7. Structure of solvate XylHCl·CHCl3 at 1.03 GPa with the shortest intermolecular and interionic contacts indicated: (a) viewed along the b axis, and (b) along a. Intermolecular contacts shorter than the sum of van der Waals radii minus 0.20 Å for all atoms and plus 0.10 Å for the S atom are shown as dashed lines. 3760



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(CH3)2CHOH solvate is triclinic. The length of unit-cell axes, and the molecular conformation and arrangement of xylazine cations are similar; however, the arrangement of chloride anions and solvent molecules is different. Moreover, the (CH3)2CHOH molecule is partly disordered in two positions in all measured structures. The (CH3)2CHOH solvate structure is mainly governed by CH/CH2/CH3/OH/NH···Cl−, OH···N, and NH···O bonds. These short contacts link molecules and ions into a three-dimensional network (Figure 8).

Figure 9. Crystal volume per formula unit, Vf (p), as a function of pressure in unsolvated XylHCl (two black up-triangles, at 0.1 MPa and 0.1 GPa), its hydrate (seven blue up-triangles), (CH3)2CHOH solvate (red up-triangles), CH2Cl2 solvate (green up-triangles), and CHCl3 solvate (dark green up-triangles), as a function of pressure. The differences between solvates volume Vf and the molecular volume (calculated from the density of liquids or as V/Z for the crystals) of neat solvents have been plotted in the same colors, but with the open triangles down. The dashed line marks the transition pressure of hydrate H1.

Figure 8. Crystal structure of XylHCl·(CH3)2CHOH at 0.60 GPa. The shortest contacts between ions and molecules are marked with dashed lines.

The compression of XylHCl polymorph Z and of the investigated solvates is plotted in Figure 9. The volume difference between the hydrate and the anhydrate is slightly smaller than the molecular volume of water.52 Therefore, the formation of hydrates can be favored by a better space filling of ions and water molecules compressed together than that of neat XylHCl and water separately. Some volume gain relative to the neat components is the most frequent case for the solvates crystallized at high pressure,53 and only few exceptions are known.23,54 This latter case can be connected to the formation of new types of cohesion forces, which would strongly favor the formation of the solvate, even despite the unfavorable volume change. The volume of other solvates and the unsolvated form Z decreases at different rates with increasing pressure.55,56

XylHCl. However, above 0.11 GPa the formation of solvates is strongly preferred. The solvates are more stable at the highpressure conditions. All the high-pressure single crystals could be obtained at about 0.1 GPa and up to 1 GPa. Above 1.0 GPa the crystals started to decompose, except the XylHCl· (CH3)2CHOH solvate, which remained stable up to 2.38 GPa.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b00264. Powder patterns of A form ant hydrate H1 (Figure S1), the shortest intermolecular interactions (Figure S2, Table S1), pictures of crystal growth (Figures S3−S7), unit-cell packing of XylHCl neat form and its solvates (Figure S8), torsion angles (Table S2) (PDF)

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CONCLUSIONS Relatively low pressure up to 0.11 GPa can be used for controlling the formation of XylHCl polymorph Z, while higher pressure can be applied for obtaining XylHCl solvates. Their structures could be solved and refined by single-crystal diffraction data, owing to the stable thermodynamic conditions in the diamond anvil cell. The high-pressure crystallizations yield single crystal of the solvates, which could be studied by Xray diffraction. At ambient conditions only powders of the solvates could be obtained, and when exposed to air their composition changed, which hampered powder-diffraction structural determinations. The ambient-pressure crystallization of XylHCl strongly depends on the sample form, solvent, and concentration (Figure 3). High pressure favors only form Z, i.e., the highestdensity form of four ambient-pressure polymorphs of neat

Accession Codes

CCDC 1454078−1454091 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. 3761



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