Codeine dihydrogen phosphate hemihydrate

The cation of the title structure [systematic name: (5α,6α)-6-hydr­oxy-7,8-didehydro-4,5-epoxy-3-meth­oxy-17-methylmorphin­anium dihydrogen phosphate hemihydrate], C₁₈H₂₂NO₃⁺·H₂PO₄⁻·0.5H₂O, has a T-shaped conformation. The dihydrogen phosphate anions are linked by O—H...O hydrogen bonds to give an extended ribbon chain. The codeine cations are linked together by O—H...O hydrogen bonds into a zigzag chain. There are also N—H...O bonds between the two types of hydrogen-bonded units. Addditionally, they are connected to one another via O...H—O—H...O bridging water mol­ecules. The asymmetric unit contains two codeine hydrogen cations, two dihydrogen phosphate anions and one water molecule. This study shows that the water mol­ecules are firmly bound within a complex three-dimensional hydrogen-bonded framework.

S1. Comment

Codeine, a natural alkaloid of the opium poppy plant, is used as an analgesic for the treatment of mild to moderate pain, as an antitussive (cough depressant) and as an antidiarrhoeal agent. Codeine is mainly produced from morphine in a semi-synthetic process. It is included in the WHO model list of essential drugs, and it is the most widely used narcotic drug in medical practice. The annual world production (2007) of codeine is 350 tons (1 ton = 1.016 tonne [Please check]), and 45% of this amount is produced in the United Kingdom and the United States (International Narcotics Control Board, 2009). Codeine is a highly addictive substance because the human body metabolizes approximately 10% of administered codeine to form morphine. In fact, codeine cough remedies are among the most commonly abused pharmaceutical drugs.

The most important codeine salts are the phosphate, sulfate and hydrochloride salts. It is known that each of these salts, as well as the base, can exist in at least one hydrated form. In the case of the phosphate, a hemihydrate and a sesquihydrate are specified in individual monographs of the European Pharmacopoeia, and a hemihydrate is mentioned in the United States Pharmacopoeia, but a crystal structure of a codeine phosphate has not been reported so far. Single crystals of the title compound, (I), were produced as part of a comprehensive study of the solid-state properties of codeine.

The asymmetric unit of (I) is composed of two codeine hydrogen cations (c), two dihydrogen phosphate anions (p) and one water molecule (w). A least-squares fit confirms that the two cations have the same geometry (see Fig. 1). They adopt the characteristic T conformation, which is known from related compounds of the opiate family, e.g. morphine monohydrate (Bye, 1976) and morphine derivatives (Reference?), the free base form of codeine (Canfield et al., 1987), codeine monohydrate (Bel'skii et al., 1988), codeine hydrobromide dihydrate (Kartha et al., 1962) and codeine derivatives (Grant et al., 1993; Kolev et al., 2006; Liebman et al., 1978). Using the nomenclature commonly applied to opiates, the mean planes defined by the rings A/B/C and D/E (see the scheme) form angles of 89.36 (5) and 88.66 (5)°, respectively, in the two independent cations of (I).

Adjacent dihydrogen phosphate anions of (I) are joined together by dimeric (p)O—H···O(p) hydrogen bonds to give an infinite ribbon chain with an R²₂(8) ring motif (Bernstein et al., 1995), as shown in Fig. 2. These phosphate chains run along the c axis. A systematic comparison with chemically related crystal structures reveals that the dimeric ring is the preferred supramolecular synthon in the aggregation of hydrogen phosphate anions. Furthermore, the ribbon chain motif of (I) is present in 34 of the 230 dihydrogen phosphate structures that are included in the current version of the Cambridge Structural Database [Version 5.30 (Allen, 2002), refcodes ACUXIG, BIDPEJ, CEXPAX, CLQUON01, CPAIMZ, DASNUH, DAYHOB, DUNHID, EDUQUP, EJEGAB, FEDMIL, FIJHEL, GEJYEA, GEXXAI, GOLTOQ, HEXRIM, ISUZIF, LELJOC, LELXIJ, MATKAT, MPHAZP, NELVUV, PAMRAX, PIFJAQ, PROCPH, REZNEP, SASBIX, SEGGER, SEPHEB, SODCUJ, XAPRUC, MIKPUS, SIBMUM, SIBQEA]. Among the other R²₂(8)-based motifs is a second type of ribbon chain, which is topologically distinct from the chain observed in (I).

Independent codeine units are linked to one another through (c)O—H···O(c) hydrogen bonds by employing the hydrogen-bond donor and acceptor functions, respectively, of their hydroxy and methoxy groups. The resulting infinite zigzag chain of codeine molecules is depicted in Fig. 3. It propagates parallel to the a axis and lies approximately perpendicular to the hydrogen-bonded dihydrogen phosphate chains mentioned above. Fig. 3 shows also that these two chain types are (c)N—H···.O(p) hydrogen-bonded to one another via the donor function of the protonated amino group of codeine. Thus, each hydrogen-bonded codeine chain is connected to a multitude of hydrogen-bonded phosphate chains and vice versa, to give a complex three-dimensional hydrogen-bonded network.

The water molecule acts as an additional (c)O···H—O—H···O(p) bridge between the hydroxy group of codeine and a phosphate chain. Additional R³₄(16) rings are formed due to these bonds (see Fig. 3), but only one independent codeine unit engages in this kind of interaction. Altogether, one unprotonated phosphate O atom accepts two hydrogen bonds, and the other accepts one hydrogen bond.

The crystal structure of (I) differs fundamentally from those of the free base, the monohydrate and the hydrobromide dihydrate of codeine in terms of molecuar packing. This is presumably due to the very specific hydrogen-bonding capabilities of the dihydrogen phosphate anions. The observation that the water molecules of the hemihydrate are firmly bound within a hydrogen-bonded framework is in accordance with the experimentally observed hydration/dehydration behaviour (see below).

S2. Experimental

Codeine phophate was provided by Siegfried Ltd (Zofingen, Switzerland). Suitable single crystals were obtained by slow evaporation of a dimethylformamide (DMF) solution of codeine phosphate on a watch glass. The hemihydrate displays a prismatic habit and forms druses (see Fig. 4 in the Supplementary material). Thermogravimetric analysis of the hemihydrate showed that the dehydration is very slow and proceeds over a wide temperature range, between about 323 and 463 K. The measured total mass loss of about 2.3% confirms the presence of 0.5 mol water per mol codeine dihydrogen phosphate. Gravimetric water vapour sorption experiments indicate that the hemihydrate is stable between 10 and 80% relative humidity (298 K). Over desiccants, the crystals slowly release water. The formation of a dihydrate was observed above 90% relative humidity.

S3. Refinement

All H atoms were identified in a difference map. Methyl H atoms were idealized and included as rigid groups that were allowed to rotate but not tip (C—H = 0.98 Å) and refined with U_iso(H) = 1.5U_eq(C). H atoms bonded to primary (C—H = 1.00 Å), secondary CH₂ (C—H = 0.99 Å) and aromatic C atoms (C—H = 0.95 Å) were positioned geometrically and refined with U_iso(H) = 1.2U_eq(C). H atoms attached to N and O were refined with restrained distances [N—H = 0.86 (2) and O—H = 0.82 (2) Å], and their U_iso parameters were refined freely. The absolute configuration of this structure was known prior to this study and was confirmed by the refined Flack (1983) parameter.

Computing details

Data collection: CrysAlis CCD (Oxford Diffraction, 2003); cell refinement: CrysAlis RED (Oxford Diffraction, 2003); data reduction: CrysAlis RED (Oxford Diffraction, 2003); program(s) used to solve structure: SIR2002 (Burla et al., 2003); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP/SHELXTL (Sheldrick, 2008) and Mercury (Bruno et al., 2002); software used to prepare material for publication: publCIF (Westrip, 2009).

Figures

	Fig. 1. The asymmetric unit of (I), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary size. H atoms not involved in hydrogen bonding have been omitted for clarity and hydrogen bonds are represented by dashed lines.
	Fig. 2. A portion of the complex three-dimensional hydrogen-bonded network of (I), viewed along the a axis. The central hydrogen-bonded phosphate ribbon chain (denoted p) is additionally hydrogen-bonded to four codeine chains. The two independent codeine cations are denoted I and II. The water molecules (w) act as (c)O···H—O—H···O(p) bridges between the cation and anion chains. P atoms, water O atoms (dark) and all atoms directly engaged in hydrogen bonding, are drawn as balls. Two R^34(16) rings are indicated by asterisks (*).
	Fig. 3. A portion of the complex three-dimensional hydrogen-bonded network of (I), showing a single chain of hydrogen-bonded codeine cations and two bridging water molecules (w). The segments represent four phosphate (p) chains which are hydrogen bonded to the codeine chain. The line types and colour scheme used are the same as in Fig. 2.

(5α,6α)-6-hydroxy-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinanium dihydrogen phosphate hemihydrate

Crystal data

C18H22NO3^+·H2O4P^−·0.5H2O	F(000) = 860
Mr = 406.36	Dx = 1.468 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 8283 reflections
a = 6.9113 (2) Å	θ = 3.0–29.2°
b = 33.4470 (9) Å	µ = 0.20 mm^−1
c = 8.0716 (2) Å	T = 173 K
β = 99.778 (3)°	Prismatic fragment, colourless
V = 1838.74 (9) Å^3	0.32 × 0.16 × 0.16 mm
Z = 4

Data collection

Oxford Diffraction Gemini-R Ultra diffractometer	5393 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.025
Graphite monochromator	θmax = 25.5°, θmin = 3.1°
Detector resolution: 10.3822 pixels mm^-1	h = −8→6
ω (1° width) scans	k = −40→33
12119 measured reflections	l = −9→9
5825 independent reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.046	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.115	w = 1/[σ^2(Fo^2) + (0.0799P)^2 + 0.6365P] where P = (Fo^2 + 2Fc^2)/3
S = 1.02	(Δ/σ)max < 0.001
5825 reflections	Δρmax = 0.52 e Å^−3
530 parameters	Δρmin = −0.39 e Å^−3
12 restraints	Absolute structure: Flack (1983), with how many Friedel pairs?
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.10 (9)

Special details

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

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
O1	0.7497 (4)	0.55224 (7)	0.7220 (3)	0.0237 (5)
O2	0.1919 (4)	0.46152 (7)	0.8492 (3)	0.0237 (5)
H2	0.227 (6)	0.4847 (7)	0.845 (5)	0.028*
O3	0.5612 (3)	0.47199 (7)	0.7674 (3)	0.0181 (5)
N1	0.5601 (4)	0.36418 (8)	0.2909 (3)	0.0182 (6)
H1	0.482 (5)	0.3467 (9)	0.327 (4)	0.022*
C1	0.7123 (5)	0.50307 (11)	0.3123 (4)	0.0210 (7)
H1B	0.7361	0.5101	0.2035	0.025*
C2	0.7553 (5)	0.53014 (10)	0.4441 (4)	0.0204 (7)
H2B	0.8135	0.5550	0.4242	0.024*
C3	0.7160 (4)	0.52209 (10)	0.6043 (4)	0.0168 (7)
C4	0.6350 (5)	0.48440 (10)	0.6283 (4)	0.0165 (7)
C5	0.4635 (5)	0.43353 (9)	0.7259 (4)	0.0156 (7)
H5B	0.5102	0.4137	0.8165	0.019*
C6	0.2380 (5)	0.43935 (10)	0.7104 (4)	0.0183 (7)
H6B	0.1812	0.4121	0.7187	0.022*
C7	0.1473 (5)	0.45537 (10)	0.5439 (4)	0.0207 (7)
H7BA	0.0526	0.4762	0.5378	0.025*
C8	0.1963 (5)	0.44112 (10)	0.4034 (4)	0.0193 (7)
H8BA	0.1363	0.4511	0.2967	0.023*
C9	0.4355 (5)	0.40152 (10)	0.2569 (4)	0.0176 (7)
H9B	0.3244	0.3954	0.1638	0.021*
C10	0.5523 (5)	0.43667 (10)	0.2001 (4)	0.0218 (7)
H10C	0.6626	0.4258	0.1501	0.026*
H10D	0.4657	0.4517	0.1112	0.026*
C11	0.6333 (5)	0.46520 (10)	0.3395 (4)	0.0162 (7)
C12	0.6096 (4)	0.45709 (10)	0.5014 (4)	0.0152 (7)
C13	0.5219 (4)	0.41939 (9)	0.5583 (4)	0.0142 (6)
C14	0.3493 (5)	0.40881 (10)	0.4174 (4)	0.0163 (6)
H14B	0.2889	0.3833	0.4484	0.020*
C15	0.6695 (5)	0.38424 (10)	0.5869 (4)	0.0175 (7)
H15C	0.7860	0.3926	0.6685	0.021*
H15D	0.6078	0.3614	0.6363	0.021*
C16	0.7352 (5)	0.37061 (10)	0.4249 (4)	0.0188 (7)
H16C	0.8218	0.3911	0.3877	0.023*
H16D	0.8106	0.3454	0.4454	0.023*
C17	0.6156 (5)	0.34674 (11)	0.1355 (4)	0.0244 (8)
H17E	0.7122	0.3641	0.0954	0.037*
H17F	0.4985	0.3446	0.0484	0.037*
H17G	0.6724	0.3201	0.1605	0.037*
C18	0.7774 (5)	0.54043 (11)	0.8942 (4)	0.0244 (8)
H18D	0.6518	0.5316	0.9225	0.037*
H18E	0.8270	0.5632	0.9655	0.037*
H18F	0.8723	0.5184	0.9129	0.037*
O1A	0.2322 (4)	0.54616 (7)	0.8095 (3)	0.0265 (6)
O2A	−0.3450 (4)	0.63779 (8)	0.6868 (4)	0.0432 (8)
H2'	−0.291 (7)	0.6164 (9)	0.699 (6)	0.052*
O3A	0.0512 (4)	0.62916 (7)	0.7809 (3)	0.0242 (5)
N1A	0.2297 (4)	0.72176 (9)	1.3122 (4)	0.0245 (7)
H1'	0.151 (5)	0.7422 (9)	1.294 (5)	0.029*
C1A	0.3185 (6)	0.58439 (12)	1.2382 (5)	0.0292 (8)
H1AA	0.3700	0.5741	1.3465	0.035*
C2A	0.3206 (5)	0.56109 (11)	1.0979 (5)	0.0248 (8)
H2A	0.3800	0.5354	1.1116	0.030*
C3A	0.2394 (5)	0.57363 (10)	0.9374 (4)	0.0185 (7)
C4A	0.1603 (5)	0.61211 (10)	0.9217 (4)	0.0191 (7)
C5A	−0.0379 (5)	0.66622 (10)	0.8353 (4)	0.0233 (8)
H5A	−0.0199	0.6884	0.7564	0.028*
C6A	−0.2585 (5)	0.65951 (11)	0.8324 (5)	0.0311 (9)
H6A	−0.3198	0.6867	0.8203	0.037*
C7A	−0.3046 (5)	0.64306 (11)	0.9930 (5)	0.0299 (9)
H7AB	−0.4030	0.6231	0.9889	0.036*
C8A	−0.2119 (5)	0.65560 (11)	1.1413 (5)	0.0282 (8)
H8AB	−0.2482	0.6457	1.2420	0.034*
C9A	0.0904 (5)	0.68707 (10)	1.3181 (4)	0.0228 (7)
H9A	0.0092	0.6933	1.4062	0.027*
C10A	0.1994 (6)	0.64772 (11)	1.3688 (4)	0.0267 (8)
H10A	0.3255	0.6539	1.4424	0.032*
H10B	0.1200	0.6315	1.4348	0.032*
C11A	0.2404 (5)	0.62328 (10)	1.2219 (4)	0.0222 (7)
C12A	0.1738 (5)	0.63628 (9)	1.0614 (4)	0.0171 (7)
C13A	0.0772 (5)	0.67605 (9)	1.0122 (4)	0.0182 (7)
C14A	−0.0489 (5)	0.68559 (10)	1.1484 (4)	0.0218 (7)
H14C	−0.1085	0.7127	1.1248	0.026*
C15A	0.2257 (5)	0.71002 (10)	1.0084 (4)	0.0219 (7)
H15A	0.3112	0.7034	0.9254	0.026*
H15B	0.1540	0.7349	0.9711	0.026*
C16A	0.3526 (5)	0.71706 (11)	1.1787 (5)	0.0269 (8)
H16A	0.4432	0.6942	1.2067	0.032*
H16B	0.4327	0.7414	1.1738	0.032*
C17A	0.3549 (6)	0.73019 (13)	1.4793 (5)	0.0371 (10)
H17A	0.4633	0.7109	1.4994	0.056*
H17B	0.2752	0.7278	1.5683	0.056*
H17C	0.4080	0.7574	1.4794	0.056*
C18A	0.2487 (5)	0.56154 (11)	0.6469 (4)	0.0236 (8)
H18A	0.1249	0.5743	0.5971	0.035*
H18B	0.2773	0.5396	0.5745	0.035*
H18C	0.3551	0.5812	0.6580	0.035*
P1	0.14829 (13)	0.30863 (3)	0.80912 (11)	0.0224 (2)
O1P	0.0691 (5)	0.33355 (8)	0.9366 (3)	0.0365 (7)
O2P	0.3034 (4)	0.27828 (9)	0.8965 (3)	0.0325 (6)
H2P	0.298 (7)	0.2735 (14)	0.995 (3)	0.039*
O3P	−0.0025 (4)	0.28590 (8)	0.6872 (3)	0.0289 (6)
O4P	0.2637 (5)	0.33724 (8)	0.7065 (3)	0.0378 (7)
H4P	0.301 (7)	0.3274 (13)	0.623 (4)	0.045*
P2	0.20431 (13)	0.28152 (3)	0.31333 (10)	0.0209 (2)
O5P	0.1133 (5)	0.25202 (9)	0.4298 (3)	0.0442 (8)
H5P	0.098 (8)	0.2635 (14)	0.516 (4)	0.053*
O6P	0.2978 (4)	0.25740 (8)	0.1937 (3)	0.0349 (7)
O7P	0.0241 (5)	0.30399 (15)	0.2190 (4)	0.0712 (13)
H7P	0.018 (10)	0.301 (2)	0.116 (3)	0.085*
O8P	0.3404 (4)	0.30920 (8)	0.4242 (3)	0.0335 (6)
O1W	−0.0600 (4)	0.41038 (8)	1.0012 (4)	0.0343 (6)
H1W	−0.028 (7)	0.3880 (6)	0.973 (5)	0.041*
H2W	−0.001 (6)	0.4278 (8)	0.959 (5)	0.041*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0282 (13)	0.0159 (12)	0.0261 (12)	−0.0048 (10)	0.0025 (10)	−0.0049 (10)
O2	0.0287 (13)	0.0195 (12)	0.0269 (13)	−0.0035 (11)	0.0160 (11)	−0.0051 (11)
O3	0.0241 (12)	0.0175 (11)	0.0132 (10)	−0.0072 (9)	0.0042 (9)	−0.0040 (9)
N1	0.0159 (14)	0.0204 (14)	0.0191 (14)	−0.0044 (11)	0.0050 (11)	−0.0037 (12)
C1	0.0171 (16)	0.0304 (19)	0.0154 (16)	0.0008 (14)	0.0019 (13)	0.0078 (15)
C2	0.0133 (15)	0.0194 (17)	0.0287 (18)	0.0000 (13)	0.0042 (14)	0.0056 (15)
C3	0.0133 (15)	0.0153 (16)	0.0206 (16)	0.0058 (13)	0.0000 (13)	−0.0008 (13)
C4	0.0113 (15)	0.0217 (16)	0.0154 (15)	0.0029 (13)	−0.0010 (12)	0.0002 (13)
C5	0.0215 (17)	0.0118 (15)	0.0141 (15)	−0.0054 (13)	0.0047 (13)	0.0006 (13)
C6	0.0209 (16)	0.0158 (16)	0.0206 (16)	−0.0048 (13)	0.0102 (13)	−0.0042 (14)
C7	0.0119 (15)	0.0192 (16)	0.0319 (18)	0.0001 (13)	0.0065 (14)	−0.0053 (15)
C8	0.0118 (15)	0.0253 (18)	0.0195 (17)	−0.0037 (14)	−0.0009 (13)	−0.0013 (15)
C9	0.0140 (15)	0.0220 (17)	0.0159 (15)	0.0015 (13)	0.0004 (12)	−0.0005 (13)
C10	0.0228 (17)	0.0236 (18)	0.0200 (16)	0.0058 (15)	0.0066 (14)	0.0015 (15)
C11	0.0140 (15)	0.0195 (16)	0.0140 (15)	0.0018 (13)	−0.0010 (13)	0.0007 (13)
C12	0.0068 (14)	0.0216 (17)	0.0157 (15)	0.0018 (12)	−0.0025 (12)	−0.0011 (13)
C13	0.0133 (15)	0.0153 (15)	0.0137 (15)	−0.0009 (13)	0.0011 (12)	−0.0023 (12)
C14	0.0145 (15)	0.0172 (16)	0.0170 (15)	−0.0023 (13)	0.0019 (12)	−0.0011 (13)
C15	0.0188 (16)	0.0143 (15)	0.0187 (16)	−0.0002 (13)	0.0006 (13)	0.0012 (14)
C16	0.0134 (15)	0.0156 (16)	0.0261 (17)	0.0000 (13)	−0.0005 (13)	−0.0011 (14)
C17	0.0210 (18)	0.0273 (19)	0.0255 (18)	−0.0020 (15)	0.0049 (14)	−0.0080 (16)
C18	0.0247 (18)	0.0280 (19)	0.0213 (17)	−0.0031 (15)	0.0064 (15)	−0.0055 (15)
O1A	0.0341 (14)	0.0191 (12)	0.0273 (13)	0.0045 (11)	0.0082 (11)	−0.0026 (11)
O2A	0.0375 (17)	0.0243 (15)	0.0571 (18)	0.0065 (13)	−0.0224 (14)	−0.0089 (14)
O3A	0.0286 (13)	0.0166 (12)	0.0240 (12)	0.0053 (10)	−0.0056 (10)	−0.0025 (10)
N1A	0.0158 (15)	0.0224 (16)	0.0340 (17)	0.0028 (12)	0.0000 (13)	−0.0068 (13)
C1A	0.032 (2)	0.031 (2)	0.0251 (19)	0.0136 (16)	0.0089 (15)	0.0088 (17)
C2A	0.0258 (18)	0.0202 (18)	0.0304 (19)	0.0103 (15)	0.0106 (15)	0.0023 (15)
C3A	0.0167 (16)	0.0187 (17)	0.0218 (16)	−0.0009 (13)	0.0080 (13)	−0.0026 (14)
C4A	0.0165 (16)	0.0186 (16)	0.0217 (17)	−0.0023 (13)	0.0018 (13)	0.0053 (14)
C5A	0.0268 (18)	0.0137 (16)	0.0275 (18)	0.0047 (14)	−0.0010 (15)	−0.0007 (14)
C6A	0.0217 (19)	0.0173 (19)	0.047 (2)	0.0072 (15)	−0.0136 (16)	−0.0085 (17)
C7A	0.0124 (16)	0.0194 (17)	0.057 (2)	0.0024 (14)	0.0044 (16)	−0.0054 (18)
C8A	0.0161 (17)	0.0214 (18)	0.048 (2)	−0.0001 (14)	0.0089 (16)	−0.0025 (17)
C9A	0.0186 (16)	0.0217 (17)	0.0277 (19)	0.0045 (14)	0.0026 (14)	−0.0005 (15)
C10A	0.0314 (19)	0.030 (2)	0.0187 (16)	0.0105 (17)	0.0034 (15)	0.0033 (15)
C11A	0.0214 (18)	0.0248 (19)	0.0209 (17)	0.0033 (15)	0.0055 (14)	0.0022 (15)
C12A	0.0144 (15)	0.0146 (15)	0.0235 (17)	0.0024 (12)	0.0070 (13)	0.0003 (14)
C13A	0.0140 (16)	0.0116 (15)	0.0274 (18)	0.0020 (12)	−0.0006 (13)	0.0026 (13)
C14A	0.0134 (16)	0.0140 (16)	0.037 (2)	0.0020 (13)	0.0030 (14)	−0.0009 (15)
C15A	0.0203 (17)	0.0176 (17)	0.0286 (19)	−0.0016 (14)	0.0067 (15)	−0.0009 (14)
C16A	0.0161 (17)	0.0236 (19)	0.042 (2)	−0.0031 (14)	0.0064 (16)	−0.0036 (16)
C17A	0.025 (2)	0.047 (3)	0.034 (2)	0.0026 (18)	−0.0079 (17)	−0.0129 (19)
C18A	0.0261 (19)	0.0268 (19)	0.0190 (17)	−0.0008 (15)	0.0070 (14)	−0.0018 (15)
P1	0.0285 (5)	0.0184 (4)	0.0216 (4)	−0.0020 (4)	0.0084 (4)	−0.0007 (4)
O1P	0.0549 (18)	0.0278 (14)	0.0310 (15)	0.0114 (13)	0.0194 (13)	0.0026 (12)
O2P	0.0413 (16)	0.0394 (15)	0.0185 (12)	0.0127 (13)	0.0104 (11)	−0.0027 (12)
O3P	0.0303 (14)	0.0305 (14)	0.0259 (12)	−0.0089 (11)	0.0044 (10)	0.0040 (11)
O4P	0.0580 (19)	0.0293 (15)	0.0310 (15)	−0.0236 (14)	0.0214 (14)	−0.0088 (13)
P2	0.0214 (4)	0.0231 (5)	0.0182 (4)	−0.0040 (4)	0.0036 (4)	0.0006 (4)
O5P	0.071 (2)	0.0366 (16)	0.0293 (15)	−0.0330 (16)	0.0213 (15)	−0.0104 (13)
O6P	0.0569 (19)	0.0252 (14)	0.0247 (14)	0.0009 (13)	0.0132 (13)	−0.0020 (11)
O7P	0.050 (2)	0.138 (4)	0.0271 (15)	0.048 (2)	0.0129 (15)	0.023 (2)
O8P	0.0394 (15)	0.0362 (15)	0.0281 (13)	−0.0188 (13)	0.0143 (12)	−0.0093 (13)
O1W	0.0364 (16)	0.0260 (14)	0.0457 (17)	−0.0040 (13)	0.0218 (13)	−0.0025 (14)

Geometric parameters (Å, º)

O1—C3	1.378 (4)	N1A—C17A	1.501 (5)
O1—C18	1.427 (4)	N1A—C9A	1.514 (5)
O2—C6	1.424 (4)	N1A—H1'	0.868 (19)
O2—H2	0.814 (19)	C1A—C2A	1.377 (5)
O3—C4	1.374 (4)	C1A—C11A	1.406 (5)
O3—C5	1.465 (4)	C1A—H1AA	0.9500
N1—C17	1.491 (4)	C2A—C3A	1.386 (5)
N1—C16	1.495 (4)	C2A—H2A	0.9500
N1—C9	1.515 (4)	C3A—C4A	1.396 (5)
N1—H1	0.878 (19)	C4A—C12A	1.377 (5)
C1—C2	1.390 (5)	C5A—C6A	1.537 (5)
C1—C11	1.411 (5)	C5A—C13A	1.547 (5)
C1—H1B	0.9500	C5A—H5A	1.0000
C2—C3	1.392 (5)	C6A—C7A	1.491 (6)
C2—H2B	0.9500	C6A—H6A	1.0000
C3—C4	1.406 (5)	C7A—C8A	1.326 (5)
C4—C12	1.361 (5)	C7A—H7AB	0.9500
C5—C13	1.550 (4)	C8A—C14A	1.502 (5)
C5—C6	1.554 (5)	C8A—H8AB	0.9500
C5—H5B	1.0000	C9A—C14A	1.536 (5)
C6—C7	1.483 (5)	C9A—C10A	1.537 (5)
C6—H6B	1.0000	C9A—H9A	1.0000
C7—C8	1.326 (5)	C10A—C11A	1.506 (5)
C7—H7BA	0.9500	C10A—H10A	0.9900
C8—C14	1.503 (5)	C10A—H10B	0.9900
C8—H8BA	0.9500	C11A—C12A	1.370 (5)
C9—C14	1.535 (4)	C12A—C13A	1.511 (4)
C9—C10	1.539 (5)	C13A—C15A	1.535 (5)
C9—H9B	1.0000	C13A—C14A	1.547 (5)
C10—C11	1.509 (5)	C14A—H14C	1.0000
C10—H10C	0.9900	C15A—C16A	1.518 (5)
C10—H10D	0.9900	C15A—H15A	0.9900
C11—C12	1.371 (4)	C15A—H15B	0.9900
C12—C13	1.504 (4)	C16A—H16A	0.9900
C13—C14	1.543 (4)	C16A—H16B	0.9900
C13—C15	1.548 (4)	C17A—H17A	0.9800
C14—H14B	1.0000	C17A—H17B	0.9800
C15—C16	1.525 (4)	C17A—H17C	0.9800
C15—H15C	0.9900	C18A—H18A	0.9800
C15—H15D	0.9900	C18A—H18B	0.9800
C16—H16C	0.9900	C18A—H18C	0.9800
C16—H16D	0.9900	P1—O1P	1.498 (3)
C17—H17E	0.9800	P1—O3P	1.511 (3)
C17—H17F	0.9800	P1—O2P	1.556 (3)
C17—H17G	0.9800	P1—O4P	1.569 (3)
C18—H18D	0.9800	O2P—H2P	0.821 (19)
C18—H18E	0.9800	O4P—H4P	0.829 (19)
C18—H18F	0.9800	P2—O6P	1.487 (3)
O1A—C3A	1.377 (4)	P2—O8P	1.502 (3)
O1A—C18A	1.432 (4)	P2—O7P	1.541 (3)
O2A—C6A	1.424 (5)	P2—O5P	1.567 (3)
O2A—H2'	0.81 (2)	O5P—H5P	0.816 (19)
O3A—C4A	1.377 (4)	O7P—H7P	0.83 (2)
O3A—C5A	1.484 (4)	O1W—H1W	0.825 (19)
N1A—C16A	1.490 (5)	O1W—H2W	0.817 (19)
C3—O1—C18	116.6 (3)	C2A—C1A—C11A	120.3 (3)
C6—O2—H2	111 (3)	C2A—C1A—H1AA	119.9
C4—O3—C5	107.4 (2)	C11A—C1A—H1AA	119.9
C17—N1—C16	111.9 (3)	C1A—C2A—C3A	122.6 (3)
C17—N1—C9	112.9 (3)	C1A—C2A—H2A	118.7
C16—N1—C9	112.2 (2)	C3A—C2A—H2A	118.7
C17—N1—H1	106 (2)	O1A—C3A—C2A	117.1 (3)
C16—N1—H1	109 (2)	O1A—C3A—C4A	125.7 (3)
C9—N1—H1	104 (3)	C2A—C3A—C4A	117.0 (3)
C2—C1—C11	120.2 (3)	O3A—C4A—C12A	112.6 (3)
C2—C1—H1B	119.9	O3A—C4A—C3A	127.4 (3)
C11—C1—H1B	119.9	C12A—C4A—C3A	119.7 (3)
C1—C2—C3	122.3 (3)	O3A—C5A—C6A	109.5 (3)
C1—C2—H2B	118.8	O3A—C5A—C13A	106.1 (3)
C3—C2—H2B	118.8	C6A—C5A—C13A	113.5 (3)
O1—C3—C2	117.5 (3)	O3A—C5A—H5A	109.2
O1—C3—C4	125.9 (3)	C6A—C5A—H5A	109.2
C2—C3—C4	116.5 (3)	C13A—C5A—H5A	109.2
C12—C4—O3	113.2 (3)	O2A—C6A—C7A	114.0 (3)
C12—C4—C3	120.1 (3)	O2A—C6A—C5A	111.3 (3)
O3—C4—C3	126.5 (3)	C7A—C6A—C5A	113.5 (3)
O3—C5—C13	106.8 (2)	O2A—C6A—H6A	105.7
O3—C5—C6	109.0 (3)	C7A—C6A—H6A	105.7
C13—C5—C6	112.0 (2)	C5A—C6A—H6A	105.7
O3—C5—H5B	109.7	C8A—C7A—C6A	121.7 (3)
C13—C5—H5B	109.7	C8A—C7A—H7AB	119.1
C6—C5—H5B	109.7	C6A—C7A—H7AB	119.1
O2—C6—C7	114.1 (3)	C7A—C8A—C14A	119.3 (4)
O2—C6—C5	110.9 (3)	C7A—C8A—H8AB	120.3
C7—C6—C5	112.4 (3)	C14A—C8A—H8AB	120.3
O2—C6—H6B	106.3	N1A—C9A—C14A	107.6 (3)
C7—C6—H6B	106.3	N1A—C9A—C10A	112.3 (3)
C5—C6—H6B	106.3	C14A—C9A—C10A	114.5 (3)
C8—C7—C6	121.0 (3)	N1A—C9A—H9A	107.4
C8—C7—H7BA	119.5	C14A—C9A—H9A	107.4
C6—C7—H7BA	119.5	C10A—C9A—H9A	107.4
C7—C8—C14	118.2 (3)	C11A—C10A—C9A	113.9 (3)
C7—C8—H8BA	120.9	C11A—C10A—H10A	108.8
C14—C8—H8BA	120.9	C9A—C10A—H10A	108.8
N1—C9—C14	105.6 (2)	C11A—C10A—H10B	108.8
N1—C9—C10	111.9 (3)	C9A—C10A—H10B	108.8
C14—C9—C10	115.4 (3)	H10A—C10A—H10B	107.7
N1—C9—H9B	107.9	C12A—C11A—C1A	116.4 (3)
C14—C9—H9B	107.9	C12A—C11A—C10A	119.6 (3)
C10—C9—H9B	107.9	C1A—C11A—C10A	123.3 (3)
C11—C10—C9	114.1 (3)	C11A—C12A—C4A	123.6 (3)
C11—C10—H10C	108.7	C11A—C12A—C13A	126.2 (3)
C9—C10—H10C	108.7	C4A—C12A—C13A	109.7 (3)
C11—C10—H10D	108.7	C12A—C13A—C15A	112.9 (3)
C9—C10—H10D	108.7	C12A—C13A—C14A	105.8 (3)
H10C—C10—H10D	107.6	C15A—C13A—C14A	108.7 (3)
C12—C11—C1	116.0 (3)	C12A—C13A—C5A	101.0 (3)
C12—C11—C10	119.7 (3)	C15A—C13A—C5A	112.3 (3)
C1—C11—C10	123.8 (3)	C14A—C13A—C5A	115.8 (3)
C4—C12—C11	124.3 (3)	C8A—C14A—C9A	114.1 (3)
C4—C12—C13	109.9 (3)	C8A—C14A—C13A	110.1 (3)
C11—C12—C13	125.2 (3)	C9A—C14A—C13A	107.3 (3)
C12—C13—C14	105.6 (2)	C8A—C14A—H14C	108.4
C12—C13—C15	113.1 (3)	C9A—C14A—H14C	108.4
C14—C13—C15	110.1 (2)	C13A—C14A—H14C	108.4
C12—C13—C5	100.9 (2)	C16A—C15A—C13A	112.5 (3)
C14—C13—C5	115.5 (3)	C16A—C15A—H15A	109.1
C15—C13—C5	111.4 (3)	C13A—C15A—H15A	109.1
C8—C14—C9	114.8 (3)	C16A—C15A—H15B	109.1
C8—C14—C13	109.7 (3)	C13A—C15A—H15B	109.1
C9—C14—C13	107.2 (3)	H15A—C15A—H15B	107.8
C8—C14—H14B	108.3	N1A—C16A—C15A	111.0 (3)
C9—C14—H14B	108.3	N1A—C16A—H16A	109.4
C13—C14—H14B	108.3	C15A—C16A—H16A	109.4
C16—C15—C13	112.6 (3)	N1A—C16A—H16B	109.4
C16—C15—H15C	109.1	C15A—C16A—H16B	109.4
C13—C15—H15C	109.1	H16A—C16A—H16B	108.0
C16—C15—H15D	109.1	N1A—C17A—H17A	109.5
C13—C15—H15D	109.1	N1A—C17A—H17B	109.5
H15C—C15—H15D	107.8	H17A—C17A—H17B	109.5
N1—C16—C15	109.9 (3)	N1A—C17A—H17C	109.5
N1—C16—H16C	109.7	H17A—C17A—H17C	109.5
C15—C16—H16C	109.7	H17B—C17A—H17C	109.5
N1—C16—H16D	109.7	O1A—C18A—H18A	109.5
C15—C16—H16D	109.7	O1A—C18A—H18B	109.5
H16C—C16—H16D	108.2	H18A—C18A—H18B	109.5
N1—C17—H17E	109.5	O1A—C18A—H18C	109.5
N1—C17—H17F	109.5	H18A—C18A—H18C	109.5
H17E—C17—H17F	109.5	H18B—C18A—H18C	109.5
N1—C17—H17G	109.5	O1P—P1—O3P	115.80 (17)
H17E—C17—H17G	109.5	O1P—P1—O2P	110.82 (15)
H17F—C17—H17G	109.5	O3P—P1—O2P	108.23 (15)
O1—C18—H18D	109.5	O1P—P1—O4P	107.52 (16)
O1—C18—H18E	109.5	O3P—P1—O4P	108.61 (14)
H18D—C18—H18E	109.5	O2P—P1—O4P	105.34 (17)
O1—C18—H18F	109.5	P1—O2P—H2P	115 (3)
H18D—C18—H18F	109.5	P1—O4P—H4P	116 (3)
H18E—C18—H18F	109.5	O6P—P2—O8P	115.08 (16)
C3A—O1A—C18A	116.7 (3)	O6P—P2—O7P	110.35 (17)
C6A—O2A—H2'	103 (4)	O8P—P2—O7P	111.5 (2)
C4A—O3A—C5A	107.3 (2)	O6P—P2—O5P	108.11 (16)
C16A—N1A—C17A	111.0 (3)	O8P—P2—O5P	107.76 (14)
C16A—N1A—C9A	112.7 (3)	O7P—P2—O5P	103.3 (2)
C17A—N1A—C9A	112.9 (3)	P2—O5P—H5P	110 (4)
C16A—N1A—H1'	112 (3)	P2—O7P—H7P	110 (5)
C17A—N1A—H1'	105 (3)	H1W—O1W—H2W	110 (3)
C9A—N1A—H1'	103 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O1A	0.81 (2)	2.08 (2)	2.868 (3)	163 (4)
N1—H1···O8P	0.88 (2)	1.85 (2)	2.720 (4)	173 (4)
O2A—H2′···O1^i	0.81 (2)	2.17 (3)	2.938 (4)	160 (5)
N1A—H1′···O3P^ii	0.87 (2)	1.81 (2)	2.659 (4)	165 (4)
O2P—H2P···O6P^iii	0.82 (2)	1.69 (2)	2.505 (3)	172 (5)
O4P—H4P···O8P	0.83 (2)	1.78 (2)	2.601 (4)	170 (5)
O5P—H5P···O3P	0.82 (2)	1.81 (2)	2.609 (4)	165 (5)
O7P—H7P···O1P^iv	0.83 (2)	1.88 (5)	2.552 (4)	136 (6)
O1W—H1W···O1P	0.83 (2)	1.98 (2)	2.798 (4)	172 (5)
O1W—H2W···O2	0.82 (2)	2.06 (2)	2.862 (4)	167 (4)

Symmetry codes: (i) x−1, y, z; (ii) −x, y+1/2, −z+2; (iii) x, y, z+1; (iv) x, y, z−1.