Agomelatine–hydro­quinone (1:1) cocrystal: novel polymorphs and their thermodynamic relationship

Polymorphism of active pharmaceutical ingredients (APIs) is of significance in the pharmaceutical industry because it can affect the quality, efficacy and safety of the final drug product. In this regard, polymorphic behavior of cocrystals is no exception because it can influence the development of cocrystals as potential drug formulations. The current contribution aims to introduce two novel polymorphs [forms (III) and (IV)] of agomelatine–hydro­quinone (AGO-HYQ) cocrystal and to describe the thermodynamic relationship between the cocrystal polymorphs. All polymorphs were characterized using powder X-ray diffraction, differential scanning calorimetry, hot-stage microscopy and solubility measurements. In addition, the crystal structure of form (II), which has been previously solved from powder diffraction data [Prohens et al. (2016), Cryst. Growth Des. 16, 1063–1070] and form (III) were determined from the single-crystal X-ray diffraction data. Thermal analysis revealed that AGO-HYQ cocrystal form (III) exhibits a higher melting point and a lower heat of fusion than those of form (II). According to the heat of fusion rule, the polymorphs are enantiotropically related, with form (III) being stable at higher temperatures. Our results also show that the novel form (IV) is the most stable form at ambient conditions and it transforms into form (II) on heating, and therefore, the two polymorphs are enantiotropically related. Furthermore, solubility and van't Hoff plot results suggest that the transition points are approximately 339 K for the pair form (IV)–(II) and 352 K for the pair form (II)–(III).

Computing details

Data collection: CrysAlis PRO 1.171.38.46 (Rigaku OD, 2015) for form_II; CrysAlis PRO 1.171.39.46 (Rigaku OD, 2018) for form_III. Cell refinement: CrysAlis PRO 1.171.38.46 (Rigaku OD, 2015) for form_II; CrysAlis PRO 1.171.39.46 (Rigaku OD, 2018) for form_III. Data reduction: CrysAlis PRO 1.171.38.46 (Rigaku OD, 2015) for form_II; CrysAlis PRO 1.171.39.46 (Rigaku OD, 2018) for form_III. For both structures, program(s) used to solve structure: ShelXT (Sheldrick, 2015); program(s) used to refine structure: SHELXL (Sheldrick, 2015); molecular graphics: Olex2 (Dolomanov et al., 2009); software used to prepare material for publication: Olex2 (Dolomanov et al., 2009).

(form_II)

Crystal data

C15H17NO2·C6H6O2	Dx = 1.248 Mg m^−3
Mr = 353.40	Cu Kα radiation, λ = 1.54184 Å
Orthorhombic, P212121	Cell parameters from 7942 reflections
a = 7.2015 (1) Å	θ = 5.5–72.4°
b = 12.2326 (1) Å	µ = 0.70 mm^−1
c = 21.3487 (3) Å	T = 298 K
V = 1880.67 (4) Å^3	Needle
Z = 4	0.61 × 0.53 × 0.45 mm
F(000) = 752

Data collection

SuperNova, Dual, Cu at zero, AtlasS2 diffractometer	3600 independent reflections
Radiation source: micro-focus sealed X-ray tube, SuperNova (Cu) X-ray Source	3470 reflections with I > 2σ(I)
Mirror monochromator	Rint = 0.029
Detector resolution: 5.2945 pixels mm^-1	θmax = 72.7°, θmin = 4.2°
ω scans	h = −8→8
Absorption correction: gaussian CrysAlisPro 1.171.38.46 (Rigaku Oxford Diffraction, 2015) Numerical absorption correction based on gaussian integration over a multifaceted crystal model Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −15→11
Tmin = 0.262, Tmax = 1.000	l = −20→26
9920 measured reflections

Refinement

Refinement on F^2	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.046	w = 1/[σ^2(Fo^2) + (0.0849P)^2 + 0.0729P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.123	(Δ/σ)max < 0.001
S = 1.05	Δρmax = 0.15 e Å^−3
3600 reflections	Δρmin = −0.21 e Å^−3
249 parameters	Absolute structure: Flack x determined using 1335 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
0 restraints	Absolute structure parameter: −0.04 (11)
Primary atom site location: dual

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O3	0.6326 (2)	0.72316 (18)	0.17564 (9)	0.0601 (5)
O2	0.7104 (3)	0.64128 (14)	0.28586 (8)	0.0603 (5)
O4	−0.0882 (2)	0.72363 (19)	0.08696 (9)	0.0664 (5)
O1	1.1265 (4)	0.94932 (16)	0.33596 (11)	0.0835 (7)
N1	0.7197 (3)	0.50144 (18)	0.35358 (10)	0.0551 (5)
C19	0.0870 (3)	0.72433 (18)	0.11141 (10)	0.0473 (5)
C3	1.1675 (3)	0.75966 (19)	0.36562 (9)	0.0488 (5)
H3	1.068493	0.737459	0.340699	0.059*
C18	0.1219 (3)	0.71991 (18)	0.17521 (10)	0.0455 (5)
H18	0.023349	0.716685	0.203314	0.055*
C2	1.2646 (3)	0.68147 (19)	0.40241 (9)	0.0451 (5)
C16	0.4513 (3)	0.72339 (18)	0.15620 (10)	0.0445 (4)
C17	0.3025 (3)	0.72026 (17)	0.19730 (10)	0.0448 (4)
H17	0.324234	0.718367	0.240228	0.054*
C13	0.6531 (3)	0.55069 (18)	0.30278 (11)	0.0491 (5)
C7	1.4165 (3)	0.7172 (2)	0.44006 (10)	0.0518 (5)
C1	1.2131 (3)	0.56926 (18)	0.40433 (10)	0.0474 (5)
C11	1.0576 (3)	0.52604 (19)	0.36370 (11)	0.0509 (5)
H11A	1.074479	0.448074	0.357661	0.061*
H11B	1.063835	0.560835	0.322922	0.061*
C8	1.5043 (3)	0.6424 (2)	0.48072 (12)	0.0605 (6)
H8	1.603093	0.665713	0.505400	0.073*
C4	1.2186 (4)	0.8671 (2)	0.36663 (11)	0.0601 (6)
C14	0.5035 (4)	0.4901 (2)	0.26812 (13)	0.0612 (6)
H14A	0.384711	0.507932	0.285762	0.092*
H14B	0.524527	0.412813	0.271715	0.092*
H14C	0.505713	0.510689	0.224740	0.092*
C21	0.4159 (3)	0.7294 (2)	0.09249 (11)	0.0541 (5)
H21	0.514323	0.732485	0.064350	0.065*
C20	0.2360 (3)	0.7310 (2)	0.07048 (11)	0.0566 (6)
H20	0.214368	0.736622	0.027659	0.068*
C10	1.3019 (4)	0.5000 (2)	0.44545 (12)	0.0594 (6)
H10	1.264949	0.427233	0.447462	0.071*
C6	1.4698 (4)	0.8287 (3)	0.43667 (13)	0.0647 (7)
H6	1.572654	0.852234	0.459293	0.078*
C12	0.8675 (3)	0.5464 (2)	0.39204 (11)	0.0541 (5)
H12A	0.862390	0.513608	0.433371	0.065*
H12B	0.848721	0.624505	0.396765	0.065*
C9	1.4465 (4)	0.5360 (3)	0.48441 (14)	0.0675 (7)
H9	1.502402	0.488047	0.512465	0.081*
C5	1.3747 (4)	0.9019 (2)	0.40135 (14)	0.0710 (8)
H5	1.412195	0.974598	0.399986	0.085*
C15	0.9477 (6)	0.9246 (3)	0.3117 (2)	0.0942 (12)
H15A	0.958256	0.868388	0.280506	0.141*
H15B	0.895032	0.989017	0.293151	0.141*
H15C	0.868846	0.899623	0.345022	0.141*
H1	0.674 (4)	0.437 (3)	0.3605 (13)	0.062 (8)*
H4	−0.158 (4)	0.732 (3)	0.1187 (17)	0.075 (10)*
H3A	0.647 (5)	0.701 (3)	0.2125 (18)	0.079 (10)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O3	0.0365 (7)	0.0861 (12)	0.0577 (10)	0.0024 (8)	−0.0015 (7)	0.0149 (9)
O2	0.0618 (10)	0.0568 (9)	0.0625 (10)	−0.0068 (8)	−0.0157 (8)	0.0094 (8)
O4	0.0422 (8)	0.1001 (14)	0.0570 (10)	−0.0004 (9)	−0.0080 (8)	0.0029 (10)
O1	0.1123 (19)	0.0583 (11)	0.0799 (13)	−0.0007 (12)	−0.0021 (14)	0.0182 (10)
N1	0.0487 (10)	0.0594 (11)	0.0571 (11)	−0.0099 (9)	−0.0090 (9)	0.0093 (9)
C19	0.0412 (10)	0.0526 (11)	0.0482 (11)	0.0016 (9)	−0.0045 (9)	−0.0007 (9)
C3	0.0513 (11)	0.0562 (11)	0.0388 (9)	−0.0024 (9)	−0.0015 (9)	−0.0013 (8)
C18	0.0413 (9)	0.0499 (10)	0.0454 (10)	0.0023 (9)	0.0064 (8)	0.0022 (9)
C2	0.0401 (10)	0.0570 (11)	0.0381 (9)	0.0006 (8)	0.0023 (8)	−0.0047 (9)
C16	0.0365 (9)	0.0501 (10)	0.0471 (11)	0.0018 (8)	−0.0019 (8)	0.0047 (9)
C17	0.0444 (10)	0.0511 (10)	0.0390 (9)	0.0037 (9)	0.0014 (8)	0.0028 (9)
C13	0.0410 (10)	0.0540 (11)	0.0523 (11)	0.0006 (9)	−0.0045 (9)	−0.0011 (9)
C7	0.0390 (10)	0.0737 (14)	0.0426 (10)	−0.0045 (10)	0.0023 (9)	−0.0119 (10)
C1	0.0417 (10)	0.0560 (11)	0.0444 (10)	0.0053 (9)	−0.0019 (9)	−0.0047 (9)
C11	0.0500 (12)	0.0519 (11)	0.0508 (12)	0.0006 (9)	−0.0065 (10)	−0.0043 (9)
C8	0.0419 (10)	0.0895 (17)	0.0500 (12)	0.0035 (12)	−0.0084 (10)	−0.0113 (12)
C4	0.0751 (16)	0.0564 (12)	0.0488 (12)	−0.0057 (11)	0.0102 (12)	0.0057 (10)
C14	0.0516 (12)	0.0654 (13)	0.0667 (15)	−0.0015 (11)	−0.0163 (12)	−0.0032 (12)
C21	0.0437 (10)	0.0743 (14)	0.0443 (11)	0.0005 (10)	0.0089 (9)	0.0027 (11)
C20	0.0530 (13)	0.0778 (15)	0.0391 (10)	0.0029 (11)	−0.0016 (9)	−0.0005 (11)
C10	0.0562 (13)	0.0591 (12)	0.0630 (14)	0.0074 (11)	−0.0080 (12)	0.0006 (11)
C6	0.0543 (13)	0.0817 (17)	0.0580 (14)	−0.0199 (13)	0.0053 (11)	−0.0148 (13)
C12	0.0485 (11)	0.0676 (13)	0.0463 (11)	−0.0059 (10)	−0.0057 (10)	0.0021 (10)
C9	0.0604 (14)	0.0833 (17)	0.0586 (14)	0.0181 (13)	−0.0164 (12)	0.0027 (13)
C5	0.0842 (19)	0.0667 (15)	0.0620 (15)	−0.0286 (14)	0.0137 (15)	−0.0042 (12)
C15	0.125 (3)	0.0640 (16)	0.094 (2)	0.0183 (19)	−0.033 (2)	0.0065 (16)

Geometric parameters (Å, º)

O3—C16	1.370 (2)	C1—C11	1.512 (3)
O3—H3A	0.84 (4)	C1—C10	1.377 (3)
O2—C13	1.236 (3)	C11—H11A	0.9700
O4—C19	1.365 (3)	C11—H11B	0.9700
O4—H4	0.85 (4)	C11—C12	1.517 (3)
O1—C4	1.371 (3)	C8—H8	0.9300
O1—C15	1.421 (4)	C8—C9	1.369 (4)
N1—C13	1.330 (3)	C4—C5	1.412 (4)
N1—C12	1.453 (3)	C14—H14A	0.9600
N1—H1	0.87 (3)	C14—H14B	0.9600
C19—C18	1.386 (3)	C14—H14C	0.9600
C19—C20	1.387 (3)	C21—H21	0.9300
C3—H3	0.9300	C21—C20	1.378 (3)
C3—C2	1.421 (3)	C20—H20	0.9300
C3—C4	1.366 (3)	C10—H10	0.9300
C18—H18	0.9300	C10—C9	1.403 (4)
C18—C17	1.384 (3)	C6—H6	0.9300
C2—C7	1.427 (3)	C6—C5	1.356 (4)
C2—C1	1.422 (3)	C12—H12A	0.9700
C16—C17	1.386 (3)	C12—H12B	0.9700
C16—C21	1.386 (3)	C9—H9	0.9300
C17—H17	0.9300	C5—H5	0.9300
C13—C14	1.503 (3)	C15—H15A	0.9600
C7—C8	1.411 (4)	C15—H15B	0.9600
C7—C6	1.418 (4)	C15—H15C	0.9600
C16—O3—H3A	114 (2)	C9—C8—H8	119.5
C19—O4—H4	104 (2)	O1—C4—C5	114.5 (2)
C4—O1—C15	117.2 (2)	C3—C4—O1	124.6 (3)
C13—N1—C12	123.6 (2)	C3—C4—C5	120.8 (3)
C13—N1—H1	115 (2)	C13—C14—H14A	109.5
C12—N1—H1	122 (2)	C13—C14—H14B	109.5
O4—C19—C18	122.9 (2)	C13—C14—H14C	109.5
O4—C19—C20	118.4 (2)	H14A—C14—H14B	109.5
C18—C19—C20	118.8 (2)	H14A—C14—H14C	109.5
C2—C3—H3	119.8	H14B—C14—H14C	109.5
C4—C3—H3	119.8	C16—C21—H21	119.7
C4—C3—C2	120.4 (2)	C20—C21—C16	120.6 (2)
C19—C18—H18	119.8	C20—C21—H21	119.7
C17—C18—C19	120.35 (19)	C19—C20—H20	119.6
C17—C18—H18	119.8	C21—C20—C19	120.8 (2)
C3—C2—C7	118.8 (2)	C21—C20—H20	119.6
C3—C2—C1	122.5 (2)	C1—C10—H10	119.0
C1—C2—C7	118.6 (2)	C1—C10—C9	121.9 (2)
O3—C16—C17	123.0 (2)	C9—C10—H10	119.0
O3—C16—C21	118.22 (19)	C7—C6—H6	119.1
C17—C16—C21	118.72 (19)	C5—C6—C7	121.8 (2)
C18—C17—C16	120.75 (18)	C5—C6—H6	119.1
C18—C17—H17	119.6	N1—C12—C11	111.9 (2)
C16—C17—H17	119.6	N1—C12—H12A	109.2
O2—C13—N1	121.6 (2)	N1—C12—H12B	109.2
O2—C13—C14	122.5 (2)	C11—C12—H12A	109.2
N1—C13—C14	115.9 (2)	C11—C12—H12B	109.2
C8—C7—C2	119.4 (2)	H12A—C12—H12B	107.9
C8—C7—C6	122.3 (2)	C8—C9—C10	119.3 (2)
C6—C7—C2	118.3 (2)	C8—C9—H9	120.3
C2—C1—C11	120.91 (19)	C10—C9—H9	120.3
C10—C1—C2	119.4 (2)	C4—C5—H5	120.2
C10—C1—C11	119.6 (2)	C6—C5—C4	119.7 (2)
C1—C11—H11A	109.1	C6—C5—H5	120.2
C1—C11—H11B	109.1	O1—C15—H15A	109.5
C1—C11—C12	112.45 (19)	O1—C15—H15B	109.5
H11A—C11—H11B	107.8	O1—C15—H15C	109.5
C12—C11—H11A	109.1	H15A—C15—H15B	109.5
C12—C11—H11B	109.1	H15A—C15—H15C	109.5
C7—C8—H8	119.5	H15B—C15—H15C	109.5
C9—C8—C7	121.1 (2)

Polymorph of Agometaline-hydroquinone (1:1) cocrystal (form_III)

Crystal data

C15H17NO2·C6H6O2·	F(000) = 752
Mr = 353.40	Dx = 1.245 Mg m^−3
Monoclinic, P21	Cu Kα radiation, λ = 1.54184 Å
a = 7.3330 (1) Å	Cell parameters from 12027 reflections
b = 29.3095 (4) Å	θ = 3.0–72.3°
c = 8.8046 (1) Å	µ = 0.70 mm^−1
β = 94.748 (1)°	T = 293 K
V = 1885.85 (4) Å^3	Needle, colourless
Z = 4	0.52 × 0.16 × 0.12 mm

Data collection

SuperNova, Dual, Cu at home/near, AtlasS2 diffractometer	7276 independent reflections
Radiation source: micro-focus sealed X-ray tube, SuperNova (Cu) X-ray Source	6726 reflections with I > 2σ(I)
Mirror monochromator	Rint = 0.031
Detector resolution: 5.2945 pixels mm^-1	θmax = 72.8°, θmin = 3.0°
ω scans	h = −8→7
Absorption correction: gaussian CrysAlisPro 1.171.39.46 (Rigaku Oxford Diffraction, 2018) Numerical absorption correction based on gaussian integration over a multifaceted crystal model Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −36→36
Tmin = 0.667, Tmax = 1.000	l = −10→10
20956 measured reflections

Refinement

Refinement on F^2	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.049	w = 1/[σ^2(Fo^2) + (0.0818P)^2 + 0.0942P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.133	(Δ/σ)max = 0.001
S = 1.06	Δρmax = 0.14 e Å^−3
7276 reflections	Δρmin = −0.23 e Å^−3
497 parameters	Absolute structure: Flack x determined using 2905 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
1 restraint	Absolute structure parameter: −0.13 (7)
Primary atom site location: dual

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O6	1.5047 (3)	0.71165 (9)	1.3203 (3)	0.0674 (6)
O2	1.0691 (4)	0.34859 (9)	0.5717 (2)	0.0799 (7)
O4	0.6484 (3)	0.65400 (10)	0.8765 (3)	0.0760 (6)
O7	0.9640 (3)	0.30435 (10)	0.3189 (3)	0.0743 (6)
O8	0.2316 (3)	0.29514 (10)	0.1162 (3)	0.0750 (7)
O5	0.7733 (3)	0.68286 (12)	1.1446 (3)	0.0846 (8)
O1	0.7118 (7)	0.45650 (12)	0.3444 (4)	0.1168 (12)
N2	1.0625 (4)	0.33104 (9)	0.8181 (3)	0.0610 (6)
N1	0.5312 (4)	0.67609 (10)	0.6465 (3)	0.0666 (6)
C34	1.3247 (4)	0.70460 (9)	1.2678 (3)	0.0512 (6)
C13	1.1485 (4)	0.33506 (10)	0.6928 (3)	0.0587 (7)
C31	0.9572 (4)	0.69011 (11)	1.1819 (3)	0.0571 (6)
C40	0.4119 (4)	0.29761 (10)	0.1739 (3)	0.0547 (6)
C41	0.5396 (4)	0.27323 (10)	0.1014 (3)	0.0574 (6)
H41	0.502195	0.254923	0.018324	0.069*
C38	0.6524 (4)	0.32671 (11)	0.3500 (3)	0.0572 (6)
H38	0.689941	0.344485	0.434319	0.069*
C33	1.1909 (4)	0.72616 (10)	1.3438 (3)	0.0570 (6)
H33	1.224473	0.745784	1.424261	0.068*
C39	0.4679 (4)	0.32449 (11)	0.2988 (3)	0.0583 (6)
H39	0.382268	0.341020	0.348373	0.070*
C1	0.6750 (4)	0.41301 (11)	0.8778 (4)	0.0633 (7)
C37	0.7799 (4)	0.30247 (10)	0.2753 (3)	0.0524 (6)
C36	1.0883 (4)	0.66899 (12)	1.1045 (3)	0.0619 (7)
H36	1.053762	0.649682	1.023336	0.074*
C28	0.6691 (4)	0.67249 (11)	0.7532 (3)	0.0620 (7)
C11	0.8633 (5)	0.39295 (11)	0.8936 (3)	0.0638 (7)
H11A	0.905654	0.391835	1.000866	0.077*
H11B	0.945148	0.412864	0.843371	0.077*
C42	0.7227 (4)	0.27576 (10)	0.1512 (3)	0.0569 (6)
H42	0.808066	0.259391	0.100813	0.068*
C2	0.6021 (4)	0.43238 (9)	0.7382 (4)	0.0642 (7)
C27	0.3535 (4)	0.65668 (11)	0.6623 (3)	0.0618 (7)
H27A	0.260785	0.675775	0.609269	0.074*
H27B	0.330918	0.656096	0.769235	0.074*
C32	1.0090 (4)	0.71878 (11)	1.3011 (3)	0.0592 (7)
H32	0.920264	0.733301	1.353207	0.071*
C12	0.8743 (4)	0.34523 (11)	0.8268 (4)	0.0619 (7)
H12A	0.813230	0.323855	0.889758	0.074*
H12B	0.811179	0.344780	0.725564	0.074*
O3	0.3279 (11)	0.54997 (18)	1.1596 (6)	0.161 (3)
C35	1.2729 (4)	0.67640 (11)	1.1470 (3)	0.0585 (6)
H35	1.361440	0.662250	1.093621	0.070*
C3	0.7016 (5)	0.43392 (10)	0.6080 (4)	0.0694 (8)
H3	0.819107	0.421822	0.611995	0.083*
C26	0.3380 (5)	0.60850 (12)	0.5983 (4)	0.0697 (8)
H26A	0.353780	0.609339	0.490039	0.084*
H26B	0.435139	0.589856	0.647200	0.084*
C7	0.4216 (5)	0.45099 (11)	0.7306 (6)	0.0858 (12)
C18	0.2502 (6)	0.56915 (11)	0.8934 (5)	0.0786 (10)
H18	0.366447	0.580781	0.882898	0.094*
C19	0.2079 (10)	0.55178 (15)	1.0326 (8)	0.119 (2)
C5	0.4444 (9)	0.47123 (14)	0.4709 (8)	0.1113 (19)
H5	0.391022	0.483413	0.380356	0.134*
C8	0.3232 (6)	0.44940 (15)	0.8619 (8)	0.1022 (17)
H8	0.206871	0.462214	0.858528	0.123*
C29	0.8492 (5)	0.69121 (16)	0.7160 (5)	0.0872 (11)
H29A	0.904322	0.707624	0.802303	0.131*
H29B	0.831158	0.711459	0.630371	0.131*
H29C	0.927919	0.666599	0.691378	0.131*
C16	0.1559 (5)	0.58701 (12)	0.6225 (5)	0.0808 (11)
C4	0.6261 (7)	0.45311 (11)	0.4757 (5)	0.0857 (12)
C17	0.1177 (5)	0.56930 (11)	0.7673 (6)	0.0817 (11)
C14	1.3475 (5)	0.32275 (13)	0.7044 (4)	0.0743 (9)
H14A	1.364039	0.294859	0.650013	0.111*
H14B	1.390303	0.318797	0.809548	0.111*
H14C	1.415718	0.346723	0.660918	0.111*
C6	0.3512 (7)	0.47090 (15)	0.5935 (8)	0.1066 (17)
H6	0.235774	0.484252	0.588341	0.128*
C9	0.3942 (7)	0.42972 (17)	0.9920 (8)	0.1066 (16)
H9	0.325511	0.428051	1.076030	0.128*
C10	0.5689 (6)	0.41206 (14)	1.0000 (5)	0.0849 (10)
H10	0.616893	0.399048	1.090991	0.102*
C24	−0.1521 (13)	0.5676 (3)	0.5239 (16)	0.195 (7)
H24	−0.242386	0.567468	0.443257	0.234*
C22	−0.0582 (7)	0.55074 (14)	0.7833 (10)	0.126 (3)
C25	0.0230 (8)	0.58584 (18)	0.5026 (8)	0.126 (2)
H25	0.048102	0.597021	0.407704	0.152*
C15	0.8954 (10)	0.4438 (2)	0.3465 (6)	0.1168 (19)
H15A	0.938922	0.449556	0.248418	0.175*
H15B	0.907319	0.411883	0.369881	0.175*
H15C	0.966316	0.461186	0.422604	0.175*
C20	0.0310 (18)	0.5343 (2)	1.0421 (16)	0.186 (6)
H20	0.001775	0.522632	1.135300	0.223*
C21	−0.0957 (13)	0.5332 (2)	0.9278 (19)	0.184 (6)
H21	−0.210197	0.521003	0.941532	0.221*
C23	−0.1875 (12)	0.5510 (3)	0.6546 (19)	0.201 (8)
H23	−0.302862	0.538703	0.664362	0.241*
C30	0.5085 (16)	0.5581 (3)	1.1400 (9)	0.170 (4)
H30A	0.546256	0.539286	1.059089	0.255*
H30B	0.581640	0.551213	1.232595	0.255*
H30C	0.524207	0.589672	1.114445	0.255*
H2	1.117 (5)	0.3233 (13)	0.899 (5)	0.070 (10)*
H5A	0.755 (6)	0.6733 (16)	1.050 (6)	0.094 (14)*
H8A	0.149 (6)	0.3048 (16)	0.187 (5)	0.087 (12)*
H6A	1.584 (6)	0.7018 (15)	1.261 (5)	0.080 (12)*
H7	0.996 (7)	0.3220 (18)	0.411 (6)	0.105 (14)*
H1	0.545 (5)	0.6888 (14)	0.565 (5)	0.074 (11)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O6	0.0471 (11)	0.0896 (15)	0.0658 (12)	−0.0090 (10)	0.0052 (9)	−0.0088 (11)
O2	0.0872 (17)	0.0967 (17)	0.0531 (11)	0.0042 (14)	−0.0109 (11)	0.0057 (11)
O4	0.0684 (15)	0.0968 (16)	0.0611 (12)	−0.0069 (12)	−0.0045 (10)	0.0083 (11)
O7	0.0419 (11)	0.1112 (18)	0.0687 (13)	0.0071 (11)	−0.0014 (9)	−0.0137 (13)
O8	0.0435 (11)	0.124 (2)	0.0568 (11)	−0.0011 (12)	−0.0016 (9)	0.0031 (12)
O5	0.0415 (11)	0.145 (2)	0.0671 (13)	0.0008 (13)	0.0040 (9)	−0.0159 (14)
O1	0.169 (4)	0.095 (2)	0.0786 (19)	−0.005 (2)	−0.031 (2)	0.0194 (15)
N2	0.0579 (14)	0.0710 (14)	0.0520 (12)	0.0054 (11)	−0.0074 (11)	0.0092 (10)
N1	0.0646 (16)	0.0801 (16)	0.0549 (13)	−0.0025 (13)	0.0041 (11)	0.0095 (12)
C34	0.0455 (14)	0.0583 (13)	0.0499 (13)	−0.0010 (10)	0.0048 (10)	0.0069 (10)
C13	0.0616 (17)	0.0597 (14)	0.0529 (14)	−0.0026 (12)	−0.0071 (12)	−0.0043 (11)
C31	0.0439 (14)	0.0773 (17)	0.0502 (13)	0.0037 (12)	0.0047 (11)	0.0032 (12)
C40	0.0428 (14)	0.0751 (16)	0.0458 (12)	−0.0029 (12)	0.0016 (10)	0.0115 (11)
C41	0.0549 (16)	0.0668 (15)	0.0502 (13)	−0.0025 (12)	0.0032 (11)	−0.0051 (11)
C38	0.0507 (15)	0.0715 (16)	0.0490 (13)	0.0018 (12)	0.0023 (10)	−0.0052 (11)
C33	0.0600 (16)	0.0573 (14)	0.0533 (14)	0.0040 (12)	0.0025 (12)	−0.0044 (11)
C39	0.0468 (15)	0.0773 (17)	0.0513 (13)	0.0100 (13)	0.0077 (11)	0.0019 (12)
C1	0.0574 (17)	0.0601 (15)	0.0718 (17)	−0.0090 (13)	0.0027 (14)	−0.0077 (13)
C37	0.0418 (13)	0.0666 (14)	0.0483 (12)	0.0031 (11)	0.0021 (10)	0.0034 (11)
C36	0.0504 (15)	0.0789 (18)	0.0560 (14)	0.0012 (13)	0.0025 (11)	−0.0119 (13)
C28	0.0586 (17)	0.0645 (15)	0.0631 (16)	−0.0025 (13)	0.0073 (12)	−0.0035 (13)
C11	0.0583 (17)	0.0771 (18)	0.0548 (14)	−0.0053 (14)	−0.0036 (12)	−0.0007 (13)
C42	0.0506 (15)	0.0659 (15)	0.0542 (13)	0.0086 (12)	0.0048 (11)	−0.0043 (12)
C2	0.0574 (17)	0.0458 (13)	0.087 (2)	−0.0072 (12)	−0.0054 (15)	−0.0078 (13)
C27	0.0561 (17)	0.0705 (16)	0.0578 (15)	0.0023 (13)	−0.0008 (12)	0.0055 (12)
C32	0.0528 (15)	0.0686 (16)	0.0569 (14)	0.0145 (13)	0.0097 (12)	−0.0007 (12)
C12	0.0537 (16)	0.0670 (16)	0.0639 (16)	−0.0035 (13)	−0.0016 (12)	0.0109 (12)
O3	0.249 (7)	0.137 (3)	0.105 (3)	0.069 (4)	0.070 (4)	0.056 (3)
C35	0.0468 (14)	0.0758 (17)	0.0538 (14)	0.0062 (13)	0.0085 (11)	−0.0080 (12)
C3	0.075 (2)	0.0510 (14)	0.0778 (19)	−0.0056 (13)	−0.0202 (16)	0.0012 (13)
C26	0.072 (2)	0.0742 (18)	0.0622 (16)	0.0108 (16)	0.0026 (15)	−0.0035 (14)
C7	0.065 (2)	0.0455 (14)	0.142 (4)	−0.0020 (13)	−0.019 (2)	−0.0159 (18)
C18	0.079 (2)	0.0557 (15)	0.105 (3)	0.0082 (15)	0.032 (2)	0.0095 (16)
C19	0.160 (5)	0.066 (2)	0.142 (5)	0.024 (3)	0.080 (4)	0.020 (3)
C5	0.127 (4)	0.066 (2)	0.128 (4)	0.009 (2)	−0.068 (4)	0.007 (2)
C8	0.062 (2)	0.070 (2)	0.178 (5)	−0.0069 (17)	0.026 (3)	−0.036 (3)
C29	0.068 (2)	0.094 (2)	0.102 (3)	−0.0191 (19)	0.0168 (19)	−0.006 (2)
C16	0.068 (2)	0.0599 (16)	0.110 (3)	0.0075 (15)	−0.0156 (19)	−0.0276 (18)
C4	0.117 (3)	0.0578 (17)	0.076 (2)	−0.0068 (18)	−0.030 (2)	0.0066 (15)
C17	0.065 (2)	0.0469 (14)	0.136 (3)	0.0019 (14)	0.021 (2)	−0.0148 (18)
C14	0.066 (2)	0.079 (2)	0.078 (2)	0.0093 (16)	0.0033 (16)	−0.0064 (16)
C6	0.088 (3)	0.066 (2)	0.157 (5)	0.012 (2)	−0.041 (3)	−0.009 (3)
C9	0.088 (3)	0.090 (3)	0.148 (5)	−0.011 (2)	0.044 (3)	−0.023 (3)
C10	0.079 (2)	0.086 (2)	0.092 (2)	−0.0103 (19)	0.022 (2)	−0.016 (2)
C24	0.107 (7)	0.130 (7)	0.327 (15)	0.019 (5)	−0.103 (9)	−0.114 (9)
C22	0.067 (3)	0.0529 (18)	0.263 (8)	−0.0038 (18)	0.038 (4)	−0.032 (3)
C25	0.107 (4)	0.098 (3)	0.163 (5)	0.014 (3)	−0.055 (4)	−0.055 (3)
C15	0.161 (6)	0.113 (4)	0.077 (3)	−0.037 (4)	0.011 (3)	0.020 (2)
C20	0.222 (10)	0.072 (3)	0.294 (13)	0.025 (5)	0.202 (10)	0.042 (6)
C21	0.128 (6)	0.065 (3)	0.379 (19)	−0.008 (4)	0.147 (9)	−0.007 (6)
C23	0.069 (4)	0.088 (4)	0.44 (2)	−0.002 (3)	−0.003 (9)	−0.108 (9)
C30	0.224 (10)	0.181 (8)	0.103 (5)	0.045 (7)	0.003 (5)	0.054 (5)

Geometric parameters (Å, º)

O6—C34	1.378 (3)	C12—H12A	0.9700
O6—H6A	0.86 (5)	C12—H12B	0.9700
O2—C13	1.237 (4)	O3—C19	1.366 (9)
O4—C28	1.234 (4)	O3—C30	1.371 (11)
O7—C37	1.374 (3)	C35—H35	0.9300
O7—H7	0.97 (5)	C3—H3	0.9300
O8—C40	1.379 (3)	C3—C4	1.369 (5)
O8—H8A	0.95 (5)	C26—H26A	0.9700
O5—C31	1.378 (4)	C26—H26B	0.9700
O5—H5A	0.88 (5)	C26—C16	1.507 (6)
O1—C4	1.364 (6)	C7—C8	1.414 (8)
O1—C15	1.396 (7)	C7—C6	1.401 (8)
N2—C13	1.321 (4)	C18—H18	0.9300
N2—C12	1.450 (4)	C18—C19	1.385 (7)
N2—H2	0.82 (4)	C18—C17	1.413 (6)
N1—C28	1.327 (4)	C19—C20	1.404 (13)
N1—C27	1.439 (4)	C5—H5	0.9300
N1—H1	0.82 (4)	C5—C4	1.432 (7)
C34—C33	1.385 (4)	C5—C6	1.324 (8)
C34—C35	1.375 (4)	C8—H8	0.9300
C13—C14	1.499 (4)	C8—C9	1.348 (8)
C31—C36	1.372 (4)	C29—H29A	0.9600
C31—C32	1.373 (4)	C29—H29B	0.9600
C40—C41	1.376 (4)	C29—H29C	0.9600
C40—C39	1.387 (4)	C16—C17	1.426 (7)
C41—H41	0.9300	C16—C25	1.376 (6)
C41—C42	1.379 (4)	C17—C22	1.418 (6)
C38—H38	0.9300	C14—H14A	0.9600
C38—C39	1.391 (4)	C14—H14B	0.9600
C38—C37	1.383 (4)	C14—H14C	0.9600
C33—H33	0.9300	C6—H6	0.9300
C33—C32	1.372 (4)	C9—H9	0.9300
C39—H39	0.9300	C9—C10	1.378 (7)
C1—C11	1.496 (5)	C10—H10	0.9300
C1—C2	1.418 (5)	C24—H24	0.9300
C1—C10	1.379 (5)	C24—C25	1.418 (13)
C37—C42	1.381 (4)	C24—C23	1.295 (18)
C36—H36	0.9300	C22—C21	1.420 (16)
C36—C35	1.391 (4)	C22—C23	1.416 (15)
C28—C29	1.491 (5)	C25—H25	0.9300
C11—H11A	0.9700	C15—H15A	0.9600
C11—H11B	0.9700	C15—H15B	0.9600
C11—C12	1.522 (5)	C15—H15C	0.9600
C42—H42	0.9300	C20—H20	0.9300
C2—C3	1.410 (5)	C20—C21	1.312 (16)
C2—C7	1.428 (5)	C21—H21	0.9300
C27—H27A	0.9700	C23—H23	0.9300
C27—H27B	0.9700	C30—H30A	0.9600
C27—C26	1.521 (5)	C30—H30B	0.9600
C32—H32	0.9300	C30—H30C	0.9600
C34—O6—H6A	115 (3)	C27—C26—H26A	109.2
C37—O7—H7	115 (3)	C27—C26—H26B	109.2
C40—O8—H8A	113 (3)	H26A—C26—H26B	107.9
C31—O5—H5A	110 (3)	C16—C26—C27	112.1 (3)
C4—O1—C15	118.8 (3)	C16—C26—H26A	109.2
C13—N2—C12	122.8 (2)	C16—C26—H26B	109.2
C13—N2—H2	121 (3)	C8—C7—C2	118.9 (4)
C12—N2—H2	116 (3)	C6—C7—C2	118.3 (5)
C28—N1—C27	122.9 (3)	C6—C7—C8	122.8 (5)
C28—N1—H1	121 (3)	C19—C18—H18	119.8
C27—N1—H1	116 (3)	C19—C18—C17	120.4 (5)
O6—C34—C33	117.8 (2)	C17—C18—H18	119.8
C35—C34—O6	123.1 (3)	O3—C19—C18	124.2 (6)
C35—C34—C33	119.1 (3)	O3—C19—C20	118.2 (8)
O2—C13—N2	121.7 (3)	C18—C19—C20	117.6 (9)
O2—C13—C14	121.5 (3)	C4—C5—H5	119.5
N2—C13—C14	116.8 (3)	C6—C5—H5	119.5
C36—C31—O5	121.6 (3)	C6—C5—C4	121.0 (4)
C36—C31—C32	119.7 (3)	C7—C8—H8	119.3
C32—C31—O5	118.7 (3)	C9—C8—C7	121.4 (4)
O8—C40—C39	122.3 (3)	C9—C8—H8	119.3
C41—C40—O8	118.0 (3)	C28—C29—H29A	109.5
C41—C40—C39	119.6 (2)	C28—C29—H29B	109.5
C40—C41—H41	119.8	C28—C29—H29C	109.5
C40—C41—C42	120.4 (3)	H29A—C29—H29B	109.5
C42—C41—H41	119.8	H29A—C29—H29C	109.5
C39—C38—H38	120.0	H29B—C29—H29C	109.5
C37—C38—H38	120.0	C17—C16—C26	121.3 (3)
C37—C38—C39	120.0 (3)	C25—C16—C26	118.8 (5)
C34—C33—H33	119.8	C25—C16—C17	119.9 (5)
C32—C33—C34	120.5 (3)	O1—C4—C3	124.7 (4)
C32—C33—H33	119.8	O1—C4—C5	116.2 (4)
C40—C39—C38	119.9 (3)	C3—C4—C5	119.1 (5)
C40—C39—H39	120.0	C18—C17—C16	122.1 (3)
C38—C39—H39	120.0	C18—C17—C22	119.5 (5)
C2—C1—C11	121.1 (3)	C22—C17—C16	118.4 (5)
C10—C1—C11	119.7 (3)	C13—C14—H14A	109.5
C10—C1—C2	119.2 (3)	C13—C14—H14B	109.5
O7—C37—C38	122.3 (2)	C13—C14—H14C	109.5
O7—C37—C42	118.1 (2)	H14A—C14—H14B	109.5
C42—C37—C38	119.6 (2)	H14A—C14—H14C	109.5
C31—C36—H36	119.9	H14B—C14—H14C	109.5
C31—C36—C35	120.2 (3)	C7—C6—H6	119.1
C35—C36—H36	119.9	C5—C6—C7	121.8 (4)
O4—C28—N1	121.1 (3)	C5—C6—H6	119.1
O4—C28—C29	122.0 (3)	C8—C9—H9	120.1
N1—C28—C29	116.9 (3)	C8—C9—C10	119.8 (5)
C1—C11—H11A	108.8	C10—C9—H9	120.1
C1—C11—H11B	108.8	C1—C10—H10	118.8
C1—C11—C12	113.8 (3)	C9—C10—C1	122.3 (5)
H11A—C11—H11B	107.7	C9—C10—H10	118.8
C12—C11—H11A	108.8	C25—C24—H24	119.7
C12—C11—H11B	108.8	C23—C24—H24	119.7
C41—C42—C37	120.4 (3)	C23—C24—C25	120.6 (10)
C41—C42—H42	119.8	C17—C22—C21	118.2 (8)
C37—C42—H42	119.8	C23—C22—C17	118.2 (8)
C1—C2—C7	118.4 (4)	C23—C22—C21	123.6 (8)
C3—C2—C1	122.3 (3)	C16—C25—C24	119.9 (8)
C3—C2—C7	119.3 (3)	C16—C25—H25	120.0
N1—C27—H27A	109.2	C24—C25—H25	120.0
N1—C27—H27B	109.2	O1—C15—H15A	109.5
N1—C27—C26	111.8 (3)	O1—C15—H15B	109.5
H27A—C27—H27B	107.9	O1—C15—H15C	109.5
C26—C27—H27A	109.2	H15A—C15—H15B	109.5
C26—C27—H27B	109.2	H15A—C15—H15C	109.5
C31—C32—H32	119.8	H15B—C15—H15C	109.5
C33—C32—C31	120.5 (3)	C19—C20—H20	117.9
C33—C32—H32	119.8	C21—C20—C19	124.2 (9)
N2—C12—C11	111.4 (3)	C21—C20—H20	117.9
N2—C12—H12A	109.3	C22—C21—H21	119.9
N2—C12—H12B	109.3	C20—C21—C22	120.1 (7)
C11—C12—H12A	109.3	C20—C21—H21	119.9
C11—C12—H12B	109.3	C24—C23—C22	122.9 (9)
H12A—C12—H12B	108.0	C24—C23—H23	118.6
C19—O3—C30	117.0 (5)	C22—C23—H23	118.6
C34—C35—C36	120.1 (3)	O3—C30—H30A	109.5
C34—C35—H35	119.9	O3—C30—H30B	109.5
C36—C35—H35	119.9	O3—C30—H30C	109.5
C2—C3—H3	119.8	H30A—C30—H30B	109.5
C4—C3—C2	120.4 (4)	H30A—C30—H30C	109.5
C4—C3—H3	119.8	H30B—C30—H30C	109.5