Rosiglitazone maleate 0.25-hydrate: a pseudopolymorphic form

The present 0.25-hydrated form of rosiglitazone maleate [systematic name: (±)-2-({2-[2,4-dioxo-1,3-thiazolidin-5-yl­methyl)phenoxy]ethyl}methylamino)pyridinium maleate 0.25-hydrate], C₁₈H₂₀N₃O₃S⁺·C₄H₃O₄^-·0.25H₂O, is a racemate with two independent moieties in the unit cell. Although the cation geometry does not differ substantially from that in the previously reported hydro­chloride, the packing is quite different, the main feature being the formation of hydrogen-bonded tetra­mers, linked head-to-tail into weakly inter­acting chains.

S1. Comment

Several drugs in the thiazolidinedione group (see scheme) have been reported to present antidiabetic effects, such troglitazone, pioglitazone and rosiglitazone. Probably as a consequence of having appeared on the market previously, troglitazone and pioglitazone have already been the subject of a thorough structural characterization of the many polymorphic or pseudo-polymorphic forms known, and a number of entries can be found in the Cambridge Structural Database (CSD, version of November 2006 with 2007 updates; Allen, 2002). Rosiglitazone (either as such or in its protonated version, hereinafter H-rosiglitazone) presents instead an interesting challenge from a structural point of view: two main forms with similar therapeutic properties are on the pharmaceutical market to date, namely the hydrochloride monohydrate, (I), and the maleate, nebulously described in different patents (for example, Blackler et al., 1999a,b; Blackler, Browne et al., 2000; Blackler, Giles et al., 2000; Blackler, Giles & Sasse, 2000; Giles et al., 1999; Lynch et al., 1999) in a variety of hydration states (.nH₂O, where n ranges from zero to 0.6) and with significant differences in their X-ray powder diffraction diagrams. So far, only the hydrochloride monohydrate, (I), has been structurally characterized (Cantello et al., 1994) in an enantiomerically pure sample of biochemical origin.

In the present work, we try to fill this gap in the literature, reporting the crystal and molecular structure of the title maleate 0.25-hydrate, (II), hitherto structurally uncharacterized. Our results show that compound (II), as formed by crystallization from ethyl acetate of a commercial sample of synthetic origin, is a racemate, in space group P2₁/n, composed of two independent units (hereinafter Za and Zb) of the protonated H-rosiglitazone cation (±)-5-(4-{2-[methyl(2-pyridyl)amino]-ethoxy}benzyl)thiazolidine-2,4-dione⁺, with the charge balance provided by two independent hydrogenmaleate anions (hereinafter Hma^-), and one-half of a hydration water molecule, thus giving a minimum formula of C₁₈H₂₀N₃O₃S⁺·C₄H₃O₄^-·0.25H₂O. As in (I), both Z units in (II) are cationic, bearing one H atom at N3. In the former structure, charge balance is achieved through the presence of a Cl^- counterion, whereas in (II), the counterions are two hydrogenmaleate ions Hma^-.

A general view of the full asymmetric unit of (II) (Fig. 1) shows most of the key points. Firstly, it is apparent that both independent cations (Za and Zb) in (II) are geometrically very similar both to one another (Table 1) and to the cation in (I), despite the presence in (I) of just a single enantiomer. The main overall differences reside in the C8—O3—C11—C12 torsion angle at the ethoxy site (179.2° for Za, 20.5° for Zb and 177.9° for Zc) [Zc is the cation in (I)] and the C13—N2—C14—N3 torsion angle at the methylpyridylamino site (-178° for Za, 7.7° for Zb and 1.5° for Zc), which result in the terminal groups being oriented in different directions. Fig. 2 clarifies these differences through the least-squares fitting of individual moieties onto each other. It is apparent that the conformation of the cation Zc in (I) is somewhere between those of Za and Zb in (II)

The unique acidic H atoms in both anions make two rather strong almost linear intramolecular O···H—O bonds (Table 2) defining a closed ring each and giving the molecule the appearance of a `crab'. This is rather common in isolated Hma^- units: a search of the CSD gave a total of 115 reported cases of uncoordinated singly protonated Hma^- anions, of which 113 showed this arrangement, while the H-atom locations in the remaining two structures were uncertain. Although unusually short for conventional O···H—O interactions, the H···O distances in (II) (1.576 and 1.617 Å) lie in the longest quartile of the reported H···O range for uncoordinated Hma^- units (1.809–1.1223 Å). Thus, the intramolecular maleate hydrogen bonds found in (II) can be typified as comparatively weak when contrasted with their counterparts in the literature, in spite of their strength when evaluated in absolute terms.

It is interesting to compare the packing schemes of (I) and (II). The former presents, as characteristic features, a unique enantiomer and a counterion which can only behave as a hydrogen-bond acceptor, whereas the latter is a racemate counterbalanced by a flexible hydrogen-bonding donor/acceptor. Fig. 3 shows schematically the way in which the hydrochloride (I) packs, with the independent components defining a two-dimensional structure, tightly bound in a plane and loosely connected in the perpendicular direction by much weaker interactions. Structure (II) instead presents a much more complex disposition: the two independent Za and Zb molecules are tightly related to their counterparts at (1 - x, -y, 1 - z) through hydrogen-bonding interactions mediated by N—H groups in the molecules and O—H groups in the Hma^- anions (Fig. 4 and Table 2). Thus, a kind of tetramer builds up with two representatives of each hand, which only leaves available for inter-tetrameric interaction two out of the four N3—H3N groups, N3B—H3NB and its symmetric image through the tetramer centring. The remaining two, in turn, are devoted to construction of the tetramer via intra-tetrameric hydrogen bonds (Table 2). Thus, the external linkage is achieved at both sides of the rod-like group, defining a zigzag chain running along [011]. Interchain interactions, as in the case of (I), involve the much weaker C—H···O bonds (Table 2).

The (depleted) solvent water molecule attaches via hydrogen bonding (only inferred by the O···O distances and their relative disposition) at the extreme end of the tetramers, occupying a sort of capping position (Fig 1). Its occupation factor of 0.5 is a result of the position of the solvate in the `exclusion zone' of a centre of symmetry in the structure: the solvate lies ca 2.6 Å away from its own symmetry-related image and accordingly they are mutually exclusive, leading to a maximum possible presence for each one of 1/2, precisely as deduced from the refinement.

Comparison of the (calculated) X-ray powder diffraction of (II) with the experimental diagrams presented in the different patents in the literature suggests a best match with that in WO 9931093 (Lynch et al., 1999). The water fraction, however, is slightly lower (0.25 mol in the present form versus 0.40 mol in the patent), a fact which should not surprise since the result from the Karl Fischer titration employed in the patent characterization may include some surface-adsorbed water, in contrast with the purely crystallographic water reported here.

Related literature

For related literature, see: Allen (2002); Blackler et al. (1999a, 1999b); Blackler, Browne, Coakley, Giles & Morrissey (2000); Blackler, Giles & Sasse (2000); Blackler, Giles, Moore & Sasse (2000); Cantello et al. (1994); Giles et al. (1999); Lynch et al. (1999).

S2. Experimental

The raw material (a commercial sample of anhydrous rosiglitazone maleate, obtained from Dr Reddy's Laboratories) was recrystallized from ethyl acetate, and the title hydrate was reproducibly obtained, though in a low yield, as colourless needles suitable for single-crystal X-ray diffraction. The X-ray powder diffraction diagram of this product, (II), showed significant differences from the starting material, but since the solvent was used as bought, without further purification, the origin of the (depleted) solvent water molecule cannot be determined with certainty.

S3. Refinement

H atoms attached to C atoms were placed in geometrically idealized positions and allowed to ride, with C—H = 0.93–0.98 Å. H atoms bonded to N and O atoms in the organic components were clearly located in a difference Fourier map and were refined with restrained distances N—H = O—H = 0.85 (3) Å. In all cases, U_iso(H) = 1.2U_eq(parent).

The occupancy of the water molecule was clearly less than unity, and its site-occupancy factor refined to -0.5 [should this be ~0.5 ?]; the occupancy was then fixed at 0.5. The H atoms of the water component could not be found and were omitted from the model.

Computing details

Data collection: SMART-NT (Bruker, 2001); cell refinement: SAINT-NT (Bruker, 2001); data reduction: SAINT-NT (Bruker, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL-NT (Bruker, 2001); software used to prepare material for publication: SHELXTL-NT (Bruker, 2001) and PLATON (Spek, 2003).

Figures

	Fig. 1. The asymmetric unit of (II), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level. H atoms have been omitted for clarity.
	Fig. 2. Schematic least-squares fitting of the different moieties of H-rosiglitazone. (a) Za in (II) versus Zb in (II). (b) Za in (II) versus Zc in (I). (c) Zb in (II) versus Zc in (I). (See text for details).
	Fig. 3. (a) The hydrogen-bonding scheme in the hydrochloride, (I). (b) A packing view normal to that shown in (a).
	Fig. 4. (a) The hydrogen-bonding scheme in the maleate, (II), leading to tetramer formation. (b) A packing view of (II), showing the chain formation in the cell. [Symmetry codes: (i) Please complete; (iii) Please complete]

(±)-5-(4-{2-[methyl(2-pyridyl)amino]ethoxy}benzyl)-1,3-thiazolidine-2,4-dione maleate 0.25-hydrate

Crystal data

C18H20N3O3S^+·C4H3O4^−·0.25H2O	Z = 4
Mr = 478.01	F(000) = 1000
Triclinic, P1	Dx = 1.388 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 9.3145 (8) Å	Cell parameters from 2567 reflections
b = 12.3555 (10) Å	θ = 2.3–22.7°
c = 20.8280 (17) Å	µ = 0.19 mm^−1
α = 105.475 (2)°	T = 298 K
β = 96.330 (3)°	Needle, colourless
γ = 93.276 (2)°	0.52 × 0.12 × 0.11 mm
V = 2286.6 (3) Å^3

Data collection

Bruker Model? CCD area-detector diffractometer	9856 independent reflections
Radiation source: fine-focus sealed tube	5102 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.058
ϕ and ω scans	θmax = 28.1°, θmin = 1.7°
Absorption correction: multi-scan (SADABS; Sheldrick, 2001)	h = −12→12
Tmin = 0.90, Tmax = 0.98	k = −15→15
19294 measured reflections	l = −27→26

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.063	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.154	H atoms treated by a mixture of independent and constrained refinement
S = 0.95	w = 1/[σ^2(Fo^2) + (0.0685P)^2] where P = (Fo^2 + 2Fc^2)/3
9856 reflections	(Δ/σ)max < 0.001
624 parameters	Δρmax = 0.43 e Å^−3
6 restraints	Δρmin = −0.26 e Å^−3

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
S1A	0.83045 (9)	0.25951 (7)	0.57547 (4)	0.0576 (2)
O1A	0.7512 (3)	0.3157 (2)	0.69688 (11)	0.0803 (7)
O2A	0.6478 (3)	0.51656 (19)	0.54675 (11)	0.0935 (8)
O3A	0.9801 (2)	−0.01814 (17)	0.28142 (10)	0.0584 (5)
N1A	0.6965 (3)	0.4307 (2)	0.62982 (12)	0.0532 (6)
H1NA	0.642 (3)	0.469 (2)	0.6550 (12)	0.064*
N2A	1.0072 (3)	−0.1703 (2)	0.15756 (12)	0.0533 (6)
N3A	0.8298 (3)	−0.3243 (2)	0.13203 (13)	0.0645 (7)
H3NA	0.850 (3)	−0.350 (3)	0.1670 (11)	0.077*
C1A	0.7539 (3)	0.3394 (3)	0.64472 (15)	0.0536 (8)
C2A	0.7016 (3)	0.4430 (3)	0.56702 (15)	0.0566 (8)
C3A	0.7790 (3)	0.3518 (2)	0.52401 (13)	0.0498 (7)
H3A	0.8668	0.3862	0.5128	0.060*
C4A	0.6809 (3)	0.2899 (3)	0.45892 (14)	0.0583 (8)
H4A1	0.5971	0.2517	0.4699	0.070*
H4A2	0.6466	0.3447	0.4364	0.070*
C5A	0.7575 (3)	0.2052 (2)	0.41192 (13)	0.0467 (7)
C6A	0.8503 (3)	0.2400 (2)	0.37148 (14)	0.0534 (8)
H6A	0.8641	0.3161	0.3736	0.064*
C7A	0.9212 (3)	0.1634 (2)	0.32878 (14)	0.0496 (7)
H7A	0.9805	0.1876	0.3012	0.060*
C8A	0.9052 (3)	0.0506 (2)	0.32636 (14)	0.0460 (7)
C9A	0.8174 (3)	0.0144 (2)	0.36738 (14)	0.0533 (8)
H9A	0.8077	−0.0612	0.3669	0.064*
C10A	0.7441 (3)	0.0928 (3)	0.40918 (14)	0.0540 (8)
H10A	0.6839	0.0685	0.4363	0.065*
C11A	0.9705 (3)	−0.1359 (2)	0.27664 (14)	0.0550 (8)
H11A	0.8705	−0.1679	0.2648	0.066*
H11B	1.0082	−0.1483	0.3191	0.066*
C12A	1.0604 (3)	−0.1890 (3)	0.22246 (14)	0.0569 (8)
H12A	1.1604	−0.1574	0.2358	0.068*
H12B	1.0578	−0.2694	0.2176	0.068*
C13A	1.0693 (4)	−0.0698 (3)	0.14290 (16)	0.0743 (10)
H13A	1.0884	−0.0885	0.0970	0.111*
H13B	1.1582	−0.0418	0.1722	0.111*
H13C	1.0021	−0.0130	0.1498	0.111*
C14A	0.8922 (3)	−0.2315 (3)	0.11774 (14)	0.0516 (7)
C15A	0.8302 (3)	−0.2054 (3)	0.06092 (14)	0.0560 (8)
H15A	0.8687	−0.1428	0.0497	0.067*
C16A	0.7121 (4)	−0.2710 (3)	0.02059 (16)	0.0762 (10)
H16A	0.6732	−0.2529	−0.0179	0.091*
C17A	0.6515 (4)	−0.3623 (3)	0.0365 (2)	0.0828 (11)
H17A	0.5704	−0.4052	0.0099	0.099*
C18A	0.7121 (4)	−0.3888 (3)	0.09185 (19)	0.0707 (10)
H18A	0.6733	−0.4516	0.1027	0.085*
S1B	0.38884 (8)	0.23694 (7)	0.59213 (4)	0.0574 (2)
O1B	0.3568 (2)	0.2727 (2)	0.72028 (11)	0.0757 (7)
O2B	0.1208 (2)	0.46134 (18)	0.58703 (10)	0.0675 (6)
O3B	0.4261 (2)	−0.02971 (15)	0.27328 (9)	0.0566 (5)
N1B	0.2267 (3)	0.3735 (2)	0.66051 (12)	0.0561 (7)
H1NB	0.185 (3)	0.400 (2)	0.6950 (10)	0.067*
N2B	0.4764 (3)	−0.1170 (2)	0.12567 (12)	0.0597 (7)
N3B	0.3132 (3)	−0.2556 (2)	0.05237 (12)	0.0590 (7)
H3NB	0.323 (3)	−0.233 (2)	0.0174 (10)	0.071*
C1B	0.3235 (3)	0.2972 (2)	0.66881 (15)	0.0525 (7)
C2B	0.1998 (3)	0.3939 (2)	0.59881 (14)	0.0486 (7)
C3B	0.2802 (3)	0.3173 (2)	0.54768 (13)	0.0466 (7)
H3B	0.3449	0.3642	0.5299	0.056*
C4B	0.1743 (3)	0.2421 (3)	0.48935 (14)	0.0599 (8)
H4B1	0.1139	0.1927	0.5066	0.072*
H4B2	0.1113	0.2894	0.4710	0.072*
C5B	0.2460 (3)	0.1712 (3)	0.43353 (14)	0.0496 (7)
C6B	0.3032 (3)	0.2176 (3)	0.38795 (15)	0.0579 (8)
H6B	0.2999	0.2945	0.3932	0.070*
C7B	0.3656 (3)	0.1548 (2)	0.33458 (14)	0.0526 (7)
H7B	0.4031	0.1889	0.3045	0.063*
C8B	0.3715 (3)	0.0407 (2)	0.32666 (13)	0.0449 (7)
C9B	0.3181 (3)	−0.0077 (2)	0.37131 (14)	0.0551 (8)
H9B	0.3232	−0.0843	0.3665	0.066*
C10B	0.2555 (3)	0.0579 (3)	0.42457 (15)	0.0591 (8)
H10B	0.2191	0.0238	0.4549	0.071*
C11B	0.5199 (3)	0.0215 (2)	0.23829 (14)	0.0557 (8)
H11C	0.5997	0.0669	0.2694	0.067*
H11D	0.4674	0.0700	0.2162	0.067*
C12B	0.5766 (3)	−0.0713 (3)	0.18687 (14)	0.0610 (8)
H12C	0.6664	−0.0422	0.1754	0.073*
H12D	0.5987	−0.1320	0.2068	0.073*
C13B	0.4704 (4)	−0.0478 (3)	0.07825 (16)	0.0789 (10)
H13D	0.4944	−0.0911	0.0358	0.118*
H13E	0.5384	0.0176	0.0957	0.118*
H13F	0.3743	−0.0247	0.0722	0.118*
C14B	0.3927 (3)	−0.2145 (3)	0.11324 (14)	0.0500 (7)
C15B	0.3815 (3)	−0.2773 (3)	0.15966 (15)	0.0576 (8)
H15B	0.4336	−0.2520	0.2024	0.069*
C16B	0.2948 (4)	−0.3748 (3)	0.14206 (18)	0.0690 (9)
H16B	0.2896	−0.4173	0.1726	0.083*
C17B	0.2126 (4)	−0.4131 (3)	0.0784 (2)	0.0800 (11)
H17B	0.1512	−0.4792	0.0668	0.096*
C18B	0.2249 (4)	−0.3513 (3)	0.03432 (17)	0.0699 (9)
H18B	0.1724	−0.3750	−0.0084	0.084*
O1C	0.3046 (3)	0.8045 (2)	0.93542 (12)	0.0986 (9)
O2C	0.4279 (3)	0.6563 (2)	0.90212 (12)	0.0940 (8)
O3C	0.5276 (3)	0.5631 (3)	0.80131 (15)	0.1010 (9)
H3OC	0.501 (5)	0.589 (4)	0.8408 (11)	0.121*
O4C	0.5112 (3)	0.5744 (2)	0.69720 (14)	0.0999 (8)
C1C	0.3528 (4)	0.7339 (3)	0.89154 (18)	0.0682 (9)
C2C	0.3165 (3)	0.7399 (3)	0.82091 (16)	0.0591 (8)
H2C	0.2483	0.7898	0.8152	0.071*
C3C	0.3662 (3)	0.6854 (3)	0.76549 (16)	0.0623 (9)
H3C	0.3255	0.7019	0.7268	0.075*
C4C	0.4757 (4)	0.6023 (3)	0.7543 (2)	0.0734 (10)
O4D	−0.2554 (4)	0.8195 (3)	0.8429 (2)	0.1501 (14)
O3D	−0.1114 (4)	0.7308 (3)	0.89656 (17)	0.1142 (10)
H3OD	−0.049 (4)	0.683 (3)	0.888 (2)	0.137*
O2D	0.0371 (3)	0.5716 (2)	0.86740 (11)	0.0802 (7)
O1D	0.0939 (3)	0.4532 (2)	0.77597 (12)	0.0870 (8)
C4D	−0.1712 (5)	0.7477 (4)	0.8409 (3)	0.0964 (13)
C3D	−0.1308 (4)	0.6792 (4)	0.7762 (2)	0.0891 (13)
H3D	−0.1733	0.6987	0.7388	0.107*
C2D	−0.0466 (4)	0.5960 (3)	0.76152 (17)	0.0746 (10)
H2D	−0.0361	0.5703	0.7162	0.089*
C1D	0.0329 (3)	0.5378 (3)	0.80466 (18)	0.0635 (9)
O1W	0.1198 (6)	0.9703 (6)	0.9730 (3)	0.137 (3)	0.50

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1A	0.0614 (5)	0.0605 (5)	0.0556 (5)	0.0166 (4)	0.0104 (4)	0.0207 (4)
O1A	0.1008 (18)	0.0976 (18)	0.0524 (14)	0.0236 (15)	0.0115 (13)	0.0337 (14)
O2A	0.163 (3)	0.0583 (15)	0.0746 (17)	0.0440 (16)	0.0325 (17)	0.0301 (13)
O3A	0.0620 (13)	0.0528 (13)	0.0615 (13)	0.0085 (10)	0.0199 (11)	0.0119 (11)
N1A	0.0573 (16)	0.0519 (17)	0.0480 (17)	0.0050 (13)	0.0117 (12)	0.0078 (13)
N2A	0.0566 (16)	0.0553 (16)	0.0488 (15)	0.0075 (13)	0.0077 (13)	0.0148 (13)
N3A	0.0712 (19)	0.0628 (19)	0.0595 (18)	0.0119 (15)	0.0126 (16)	0.0140 (15)
C1A	0.0529 (18)	0.060 (2)	0.0464 (19)	0.0039 (15)	−0.0019 (14)	0.0152 (16)
C2A	0.077 (2)	0.0459 (19)	0.0448 (19)	0.0005 (16)	0.0074 (16)	0.0092 (15)
C3A	0.0552 (18)	0.0466 (17)	0.0460 (17)	0.0000 (14)	0.0073 (14)	0.0107 (14)
C4A	0.0592 (19)	0.062 (2)	0.0509 (19)	0.0131 (16)	0.0019 (15)	0.0106 (16)
C5A	0.0488 (17)	0.0525 (19)	0.0351 (16)	0.0087 (14)	−0.0026 (13)	0.0081 (14)
C6A	0.063 (2)	0.0490 (19)	0.0462 (18)	0.0049 (16)	−0.0025 (15)	0.0142 (15)
C7A	0.0517 (18)	0.0511 (19)	0.0459 (17)	−0.0026 (14)	0.0053 (14)	0.0150 (15)
C8A	0.0439 (16)	0.0476 (18)	0.0428 (17)	0.0025 (14)	0.0022 (13)	0.0076 (14)
C9A	0.0641 (19)	0.0451 (18)	0.0512 (18)	0.0009 (15)	0.0128 (16)	0.0127 (15)
C10A	0.0611 (19)	0.055 (2)	0.0450 (18)	−0.0034 (16)	0.0105 (15)	0.0133 (15)
C11A	0.0601 (19)	0.053 (2)	0.0516 (18)	0.0086 (15)	0.0061 (15)	0.0127 (15)
C12A	0.0521 (18)	0.060 (2)	0.0541 (19)	0.0117 (15)	0.0012 (15)	0.0085 (16)
C13A	0.073 (2)	0.079 (2)	0.074 (2)	0.0014 (19)	0.0200 (19)	0.024 (2)
C14A	0.0525 (18)	0.0539 (19)	0.0464 (18)	0.0140 (16)	0.0121 (15)	0.0064 (15)
C15A	0.0584 (19)	0.072 (2)	0.0440 (18)	0.0167 (17)	0.0099 (15)	0.0228 (16)
C16A	0.073 (2)	0.103 (3)	0.045 (2)	0.021 (2)	0.0009 (18)	0.008 (2)
C17A	0.062 (2)	0.084 (3)	0.082 (3)	0.006 (2)	−0.002 (2)	−0.008 (2)
C18A	0.065 (2)	0.056 (2)	0.079 (3)	−0.0011 (18)	0.008 (2)	−0.0002 (19)
S1B	0.0526 (5)	0.0627 (5)	0.0590 (5)	0.0110 (4)	0.0071 (4)	0.0191 (4)
O1B	0.0804 (16)	0.0943 (17)	0.0556 (14)	0.0003 (13)	−0.0060 (12)	0.0334 (13)
O2B	0.0758 (15)	0.0606 (14)	0.0685 (15)	0.0235 (12)	0.0105 (12)	0.0179 (12)
O3B	0.0653 (13)	0.0478 (12)	0.0526 (12)	0.0023 (10)	0.0183 (10)	0.0033 (10)
N1B	0.0607 (17)	0.0619 (18)	0.0423 (16)	0.0017 (14)	0.0107 (12)	0.0079 (14)
N2B	0.0758 (18)	0.0600 (17)	0.0415 (15)	0.0043 (15)	0.0082 (13)	0.0110 (13)
N3B	0.0769 (18)	0.0598 (18)	0.0410 (16)	0.0076 (15)	0.0120 (14)	0.0129 (14)
C1B	0.0521 (18)	0.0529 (19)	0.0509 (19)	−0.0067 (15)	0.0001 (15)	0.0166 (16)
C2B	0.0517 (18)	0.0455 (18)	0.0471 (19)	−0.0011 (15)	0.0059 (14)	0.0113 (15)
C3B	0.0491 (16)	0.0495 (17)	0.0427 (17)	0.0031 (14)	0.0064 (13)	0.0152 (14)
C4B	0.0497 (18)	0.074 (2)	0.0466 (18)	0.0085 (16)	0.0013 (14)	0.0018 (16)
C5B	0.0446 (17)	0.056 (2)	0.0431 (17)	0.0055 (14)	−0.0009 (13)	0.0071 (15)
C6B	0.067 (2)	0.0476 (19)	0.0560 (19)	0.0119 (16)	0.0033 (16)	0.0100 (16)
C7B	0.0609 (19)	0.0500 (19)	0.0498 (18)	0.0083 (15)	0.0108 (15)	0.0167 (15)
C8B	0.0410 (16)	0.0470 (18)	0.0417 (17)	0.0034 (13)	−0.0008 (13)	0.0060 (14)
C9B	0.066 (2)	0.0467 (18)	0.0519 (19)	0.0036 (15)	0.0105 (16)	0.0126 (15)
C10B	0.0578 (19)	0.075 (2)	0.0464 (18)	−0.0013 (17)	0.0103 (15)	0.0194 (17)
C11B	0.0563 (19)	0.061 (2)	0.0467 (18)	0.0014 (16)	0.0058 (15)	0.0109 (16)
C12B	0.0519 (18)	0.075 (2)	0.0514 (19)	0.0094 (16)	0.0110 (15)	0.0068 (17)
C13B	0.108 (3)	0.068 (2)	0.059 (2)	−0.007 (2)	0.007 (2)	0.0196 (19)
C14B	0.0594 (19)	0.054 (2)	0.0373 (17)	0.0196 (16)	0.0139 (14)	0.0080 (15)
C15B	0.068 (2)	0.066 (2)	0.0456 (18)	0.0236 (18)	0.0182 (15)	0.0200 (17)
C16B	0.094 (3)	0.064 (2)	0.066 (2)	0.031 (2)	0.037 (2)	0.0313 (19)
C17B	0.091 (3)	0.065 (2)	0.081 (3)	0.004 (2)	0.032 (2)	0.008 (2)
C18B	0.084 (2)	0.060 (2)	0.057 (2)	−0.0027 (19)	0.0094 (18)	0.0035 (18)
O1C	0.137 (2)	0.101 (2)	0.0527 (16)	0.0005 (18)	0.0089 (16)	0.0164 (15)
O2C	0.0931 (19)	0.125 (2)	0.0781 (18)	0.0135 (17)	−0.0071 (14)	0.0595 (17)
O3C	0.096 (2)	0.115 (2)	0.120 (2)	0.0430 (17)	0.0179 (19)	0.073 (2)
O4C	0.106 (2)	0.107 (2)	0.092 (2)	0.0338 (16)	0.0391 (17)	0.0221 (17)
C1C	0.067 (2)	0.086 (3)	0.051 (2)	−0.010 (2)	0.0039 (18)	0.022 (2)
C2C	0.0514 (18)	0.071 (2)	0.058 (2)	0.0087 (16)	−0.0005 (16)	0.0270 (18)
C3C	0.062 (2)	0.080 (2)	0.050 (2)	0.0121 (18)	0.0012 (16)	0.0276 (18)
C4C	0.066 (2)	0.068 (2)	0.087 (3)	−0.0007 (19)	0.019 (2)	0.020 (2)
O4D	0.126 (3)	0.128 (3)	0.238 (4)	0.065 (2)	0.056 (3)	0.097 (3)
O3D	0.132 (3)	0.126 (3)	0.097 (2)	0.059 (2)	0.045 (2)	0.028 (2)
O2D	0.0934 (17)	0.1016 (18)	0.0466 (14)	0.0296 (14)	0.0123 (12)	0.0163 (13)
O1D	0.0944 (18)	0.0979 (19)	0.0629 (16)	0.0126 (16)	0.0274 (14)	0.0044 (14)
C4D	0.078 (3)	0.089 (3)	0.143 (5)	0.017 (2)	0.027 (3)	0.061 (3)
C3D	0.060 (2)	0.127 (4)	0.098 (3)	−0.007 (2)	0.005 (2)	0.066 (3)
C2D	0.062 (2)	0.104 (3)	0.061 (2)	−0.015 (2)	0.0060 (19)	0.033 (2)
C1D	0.052 (2)	0.081 (3)	0.056 (2)	−0.0072 (18)	0.0095 (17)	0.018 (2)
O1W	0.119 (4)	0.229 (7)	0.123 (5)	0.112 (5)	0.043 (4)	0.118 (5)

Geometric parameters (Å, º)

S1A—C1A	1.764 (3)	N2B—C12B	1.452 (4)
S1A—C3A	1.811 (3)	N2B—C13B	1.467 (4)
O1A—C1A	1.201 (3)	N3B—C18B	1.341 (4)
O2A—C2A	1.210 (3)	N3B—C14B	1.349 (4)
O3A—C8A	1.368 (3)	N3B—H3NB	0.86 (3)
O3A—C11A	1.428 (3)	C2B—C3B	1.519 (4)
N1A—C2A	1.362 (4)	C3B—C4B	1.530 (4)
N1A—C1A	1.368 (4)	C3B—H3B	0.9800
N1A—H1NA	0.84 (3)	C4B—C5B	1.503 (4)
N2A—C14A	1.336 (3)	C4B—H4B1	0.9700
N2A—C13A	1.458 (4)	C4B—H4B2	0.9700
N2A—C12A	1.469 (3)	C5B—C10B	1.371 (4)
N3A—C18A	1.371 (4)	C5B—C6B	1.372 (4)
N3A—C14A	1.374 (4)	C6B—C7B	1.382 (4)
N3A—H3NA	0.87 (3)	C6B—H6B	0.9300
C2A—C3A	1.513 (4)	C7B—C8B	1.380 (4)
C3A—C4A	1.533 (4)	C7B—H7B	0.9300
C3A—H3A	0.9800	C8B—C9B	1.354 (4)
C4A—C5A	1.502 (4)	C9B—C10B	1.394 (4)
C4A—H4A1	0.9700	C9B—H9B	0.9300
C4A—H4A2	0.9700	C10B—H10B	0.9300
C5A—C10A	1.372 (4)	C11B—C12B	1.510 (4)
C5A—C6A	1.398 (4)	C11B—H11C	0.9700
C6A—C7A	1.369 (4)	C11B—H11D	0.9700
C6A—H6A	0.9300	C12B—H12C	0.9700
C7A—C8A	1.380 (4)	C12B—H12D	0.9700
C7A—H7A	0.9300	C13B—H13D	0.9600
C8A—C9A	1.385 (4)	C13B—H13E	0.9600
C9A—C10A	1.385 (4)	C13B—H13F	0.9600
C9A—H9A	0.9300	C14B—C15B	1.401 (4)
C10A—H10A	0.9300	C15B—C16B	1.351 (4)
C11A—C12A	1.510 (4)	C15B—H15B	0.9300
C11A—H11A	0.9700	C16B—C17B	1.403 (5)
C11A—H11B	0.9700	C16B—H16B	0.9300
C12A—H12A	0.9700	C17B—C18B	1.351 (4)
C12A—H12B	0.9700	C17B—H17B	0.9300
C13A—H13A	0.9600	C18B—H18B	0.9300
C13A—H13B	0.9600	O1C—C1C	1.228 (4)
C13A—H13C	0.9600	O2C—C1C	1.269 (4)
C14A—C15A	1.383 (4)	O3C—C4C	1.265 (4)
C15A—C16A	1.380 (4)	O3C—H3OC	0.87 (3)
C15A—H15A	0.9300	O4C—C4C	1.235 (4)
C16A—C17A	1.367 (5)	C1C—C2C	1.495 (4)
C16A—H16A	0.9300	C2C—C3C	1.319 (4)
C17A—C18A	1.354 (5)	C2C—H2C	0.9300
C17A—H17A	0.9300	C3C—C4C	1.480 (5)
C18A—H18A	0.9300	C3C—H3C	0.9300
S1B—C1B	1.763 (3)	O4D—C4D	1.212 (4)
S1B—C3B	1.808 (3)	O3D—C4D	1.304 (5)
O1B—C1B	1.203 (3)	O3D—H3OD	0.85 (3)
O2B—C2B	1.198 (3)	O2D—C1D	1.257 (4)
O3B—C8B	1.382 (3)	O1D—C1D	1.258 (4)
O3B—C11B	1.420 (3)	C4D—C3D	1.487 (6)
N1B—C1B	1.371 (4)	C3D—C2D	1.320 (5)
N1B—C2B	1.374 (4)	C3D—H3D	0.9300
N1B—H1NB	0.85 (3)	C2D—C1D	1.460 (5)
N2B—C14B	1.345 (4)	C2D—H2D	0.9300
C1A—S1A—C3A	93.03 (14)	N1B—C1B—S1B	110.0 (2)
C8A—O3A—C11A	118.5 (2)	O2B—C2B—N1B	124.1 (3)
C2A—N1A—C1A	118.3 (3)	O2B—C2B—C3B	125.0 (3)
C2A—N1A—H1NA	120 (2)	N1B—C2B—C3B	110.8 (3)
C1A—N1A—H1NA	120 (2)	C2B—C3B—C4B	111.1 (2)
C14A—N2A—C13A	120.0 (3)	C2B—C3B—S1B	106.99 (18)
C14A—N2A—C12A	122.1 (3)	C4B—C3B—S1B	112.5 (2)
C13A—N2A—C12A	117.1 (2)	C2B—C3B—H3B	108.7
C18A—N3A—C14A	121.8 (3)	C4B—C3B—H3B	108.7
C18A—N3A—H3NA	109 (2)	S1B—C3B—H3B	108.7
C14A—N3A—H3NA	129 (2)	C5B—C4B—C3B	114.3 (2)
O1A—C1A—N1A	125.3 (3)	C5B—C4B—H4B1	108.7
O1A—C1A—S1A	124.5 (3)	C3B—C4B—H4B1	108.7
N1A—C1A—S1A	110.2 (2)	C5B—C4B—H4B2	108.7
O2A—C2A—N1A	124.5 (3)	C3B—C4B—H4B2	108.7
O2A—C2A—C3A	123.2 (3)	H4B1—C4B—H4B2	107.6
N1A—C2A—C3A	112.3 (3)	C10B—C5B—C6B	116.7 (3)
C2A—C3A—C4A	110.6 (2)	C10B—C5B—C4B	122.5 (3)
C2A—C3A—S1A	106.12 (19)	C6B—C5B—C4B	120.8 (3)
C4A—C3A—S1A	112.7 (2)	C5B—C6B—C7B	122.7 (3)
C2A—C3A—H3A	109.1	C5B—C6B—H6B	118.6
C4A—C3A—H3A	109.1	C7B—C6B—H6B	118.6
S1A—C3A—H3A	109.1	C8B—C7B—C6B	119.0 (3)
C5A—C4A—C3A	112.5 (2)	C8B—C7B—H7B	120.5
C5A—C4A—H4A1	109.1	C6B—C7B—H7B	120.5
C3A—C4A—H4A1	109.1	C9B—C8B—C7B	119.9 (3)
C5A—C4A—H4A2	109.1	C9B—C8B—O3B	117.0 (3)
C3A—C4A—H4A2	109.1	C7B—C8B—O3B	123.1 (3)
H4A1—C4A—H4A2	107.8	C8B—C9B—C10B	119.7 (3)
C10A—C5A—C6A	117.9 (3)	C8B—C9B—H9B	120.1
C10A—C5A—C4A	121.7 (3)	C10B—C9B—H9B	120.1
C6A—C5A—C4A	120.3 (3)	C5B—C10B—C9B	122.0 (3)
C7A—C6A—C5A	120.8 (3)	C5B—C10B—H10B	119.0
C7A—C6A—H6A	119.6	C9B—C10B—H10B	119.0
C5A—C6A—H6A	119.6	O3B—C11B—C12B	107.9 (2)
C6A—C7A—C8A	120.4 (3)	O3B—C11B—H11C	110.1
C6A—C7A—H7A	119.8	C12B—C11B—H11C	110.1
C8A—C7A—H7A	119.8	O3B—C11B—H11D	110.1
O3A—C8A—C7A	115.2 (2)	C12B—C11B—H11D	110.1
O3A—C8A—C9A	124.8 (3)	H11C—C11B—H11D	108.4
C7A—C8A—C9A	120.0 (3)	N2B—C12B—C11B	113.9 (2)
C8A—C9A—C10A	118.7 (3)	N2B—C12B—H12C	108.8
C8A—C9A—H9A	120.6	C11B—C12B—H12C	108.8
C10A—C9A—H9A	120.6	N2B—C12B—H12D	108.8
C5A—C10A—C9A	122.2 (3)	C11B—C12B—H12D	108.8
C5A—C10A—H10A	118.9	H12C—C12B—H12D	107.7
C9A—C10A—H10A	118.9	N2B—C13B—H13D	109.5
O3A—C11A—C12A	106.2 (2)	N2B—C13B—H13E	109.5
O3A—C11A—H11A	110.5	H13D—C13B—H13E	109.5
C12A—C11A—H11A	110.5	N2B—C13B—H13F	109.5
O3A—C11A—H11B	110.5	H13D—C13B—H13F	109.5
C12A—C11A—H11B	110.5	H13E—C13B—H13F	109.5
H11A—C11A—H11B	108.7	N2B—C14B—N3B	118.7 (3)
N2A—C12A—C11A	111.9 (2)	N2B—C14B—C15B	124.3 (3)
N2A—C12A—H12A	109.2	N3B—C14B—C15B	117.0 (3)
C11A—C12A—H12A	109.2	C16B—C15B—C14B	119.7 (3)
N2A—C12A—H12B	109.2	C16B—C15B—H15B	120.1
C11A—C12A—H12B	109.2	C14B—C15B—H15B	120.1
H12A—C12A—H12B	107.9	C15B—C16B—C17B	121.0 (3)
N2A—C13A—H13A	109.5	C15B—C16B—H16B	119.5
N2A—C13A—H13B	109.5	C17B—C16B—H16B	119.5
H13A—C13A—H13B	109.5	C18B—C17B—C16B	118.3 (3)
N2A—C13A—H13C	109.5	C18B—C17B—H17B	120.8
H13A—C13A—H13C	109.5	C16B—C17B—H17B	120.8
H13B—C13A—H13C	109.5	N3B—C18B—C17B	119.8 (3)
N2A—C14A—N3A	120.7 (3)	N3B—C18B—H18B	120.1
N2A—C14A—C15A	122.5 (3)	C17B—C18B—H18B	120.1
N3A—C14A—C15A	116.8 (3)	C4C—O3C—H3OC	118 (3)
C16A—C15A—C14A	121.0 (3)	O1C—C1C—O2C	124.6 (3)
C16A—C15A—H15A	119.5	O1C—C1C—C2C	116.6 (4)
C14A—C15A—H15A	119.5	O2C—C1C—C2C	118.7 (3)
C17A—C16A—C15A	120.8 (3)	C3C—C2C—C1C	130.0 (3)
C17A—C16A—H16A	119.6	C3C—C2C—H2C	115.0
C15A—C16A—H16A	119.6	C1C—C2C—H2C	115.0
C18A—C17A—C16A	118.6 (3)	C2C—C3C—C4C	131.0 (3)
C18A—C17A—H17A	120.7	C2C—C3C—H3C	114.5
C16A—C17A—H17A	120.7	C4C—C3C—H3C	114.5
C17A—C18A—N3A	120.9 (3)	O4C—C4C—O3C	123.2 (4)
C17A—C18A—H18A	119.5	O4C—C4C—C3C	116.0 (4)
N3A—C18A—H18A	119.5	O3C—C4C—C3C	120.8 (3)
C1B—S1B—C3B	93.02 (14)	C4D—O3D—H3OD	110 (3)
C8B—O3B—C11B	117.1 (2)	O4D—C4D—O3D	119.8 (5)
C1B—N1B—C2B	119.0 (3)	O4D—C4D—C3D	121.8 (5)
C1B—N1B—H1NB	114 (2)	O3D—C4D—C3D	118.4 (4)
C2B—N1B—H1NB	127 (2)	C2D—C3D—C4D	132.6 (4)
C14B—N2B—C12B	123.0 (3)	C2D—C3D—H3D	113.7
C14B—N2B—C13B	121.8 (3)	C4D—C3D—H3D	113.7
C12B—N2B—C13B	115.2 (3)	C3D—C2D—C1D	130.6 (4)
C18B—N3B—C14B	124.2 (3)	C3D—C2D—H2D	114.7
C18B—N3B—H3NB	109 (2)	C1D—C2D—H2D	114.7
C14B—N3B—H3NB	126 (2)	O2D—C1D—O1D	122.7 (3)
O1B—C1B—N1B	125.3 (3)	O2D—C1D—C2D	120.4 (3)
O1B—C1B—S1B	124.7 (3)	O1D—C1D—C2D	116.9 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O3C—H3OC···O2C	0.87 (3)	1.58 (3)	2.420 (4)	164 (5)
N1A—H1NA···O4C	0.84 (3)	1.94 (3)	2.767 (4)	167 (3)
N1B—H1NB···O1D	0.85 (3)	1.95 (3)	2.795 (3)	176 (3)
O3D—H3OD···O2D	0.85 (3)	1.62 (3)	2.452 (3)	167 (5)
N3B—H3NB···O1C^i	0.86 (3)	1.88 (3)	2.724 (3)	168 (3)
N3A—H3NA···O1D^ii	0.87 (3)	2.02 (3)	2.858 (4)	161 (3)
C3B—H3B···O2A^iii	0.98	2.45	3.289 (4)	144
C6B—H6B···O2A^iii	0.93	2.33	3.187 (4)	153
C15A—H15A···O1W^iii	0.93	2.30	3.189 (8)	159

Symmetry codes: (i) x, y−1, z−1; (ii) −x+1, −y, −z+1; (iii) −x+1, −y+1, −z+1.