Niclosamide methanol solvate and niclosamide hydrate: structure, solvent inclusion mode and implications for properties

Structural studies have been carried out of two solid forms of niclosamide [5-chloro-N-(2-chloro-4-nitro­phenyl)-2-hy­droxy­benzamide, NCL], a widely used anthelmintic drug, namely niclosamide methanol monosolvate, C₁₃H₈Cl₂N₂O₄·CH₃OH or NCL·MeOH, and niclosamide monohydrate, denoted H_A. The structure of the methanol solvate obtained from single-crystal X-ray diffraction is reported for the first time, elucidating the key host–guest hydrogen-bonding inter­actions which lead to solvate formation. The essentially planar NCL host mol­ecules inter­act via π-stacking and pack in a herringbone-type arrangement, giving rise to channels along the crystallographic a axis in which the methanol guest mol­ecules are located. The methanol and NCL mol­ecules inter­act via short O—H...O hydrogen bonds. Laboratory powder X-ray diffraction (PXRD) measurements reveal that the initially phase-pure NCL·MeOH solvate readily transforms into NCL monohydrate within hours under ambient conditions. PXRD further suggests that the NCL mono­hydrate, H_A, is isostructural with the NCL·MeOH solvate. This is consistent with the facile transformation of the methanol solvate into the hydrate when stored in air. The crystal packing and the topology of guest-mol­ecule inclusion are compared with those of other NCL solvates for which the crystal structures are known, giving a consistent picture which correlates well with known experimentally observed desolvation properties.

S1. Introduction

Niclosamide (5-chloro-N-(2-chloro-4-nitro­phenyl)-2-hy­droxy­benzamide, hereinafter abbreviated NCL) is an anthelmintic drug which has been marketed for many years to treat tapeworm infestations (Sanphui et al., 2012; Weinbach & Garbus, 1969). Very recently, it has also been investigated for additional therapeutic applications, including anti­bacterial and anti­tumour activities (Helfman, 2011; Imperi et al., 2013; Yo et al., 2012). NCL is a BCS class II drug, virtually insoluble in water, and is formulated as a suspension and in chewable tablet form. Although both NCL anhydrate and monohydrate are available for drug formulation, each has drawbacks; the high affinity of the anhydrate for water and the poorer solubility of the hydrate can cause sedimentation during storage (van Tonder, Maleka, et al., 2004). NCL contains multiple potential hydrogen-bonding sites (NO₂, OH and carbonyl groups) and two Cl atoms which could form halogen bonds (see scheme). Generally, these structural features favour the formation of solvates and cocrystals, which represent, in principle, viable methods for improving the solubility and reducing the hygroscopicity of NCL.

The anhydrous form of NCL is prone to solvate and hydrate formation. The structure of guest-free NCL is built up by the essentially planar molecules inter­acting via moderate (Steiner, 2002) O—H···O hydrogen bonds (O···O = 2.69 Å), weak Cl···NO₂ inter­actions (Cl···O = 3.22 Å) and π-stacking, with a 3.33 Å separation between planes and a 3.74 Å separation between ring centroids. Several solvates, with methanol, di­methyl sulfoxide, di­methyl­formide, di­ethyl ether, tetra­hydro­furan (THF) and tetra­ethyl­ene glycol (TEG), have been identified (Caira et al., 1998; van Tonder, Mahlatji et al., 2004; van Tonder, Maleka et al., 2004), but only the crystal structures of the THF and TEG solvates were determined.

Two NCL monohydrates (H_A and H_B) have been identified to date and the structure of H_B has been determined from single-crystal diffraction data (Caira et al., 1998). This showed the water molecules confined, in pairs, in closed cavities in the structure, accounting for the high temperature of the onset of dehydration (446 K). The structure of monohydrate H_A has remained unknown, although its significantly lower dehydration temperature (373 K) suggests that the water-molecule inclusion mode is substanti­ally different from that in H_B. The relationship between the two NCL monohydrates has been studied further by a range of methods, which consistently suggest that H_A is the kinetically favoured form which readily transforms into H_B (Manek & Kolling, 2004; Tian et al., 2010; van Tonder, Mahlatji et al., 2004).

Physical property measurements reported for the solvates listed above, including solubility, dissolution and thermal properties, reveal a high affinity for water for all of these crystal forms (van Tonder, Mahlatji et al., 2004; van Tonder, Maleka et al., 2004). This may have affected some of the measurements reported, given that, for example, NCL.THF solvate crystals are reported to undergo desolvation within minutes of being removed from the mother liquor (Caira et al., 1998). For the three NCL crystal forms with known crystal structures, the different modes of solvent inclusion observed correlate well with the observed desolvation properties (Caira et al., 1998). In addition to these forms, the structures of four NCL cocrystals, with caffeine, urea, p-amino­benzoic acid and theophylline, as well as NCL theophylline aceto­nitrile solvate, have been reported (Sanphui et al., 2012).

In this study, which is part of a broader study of NCL solvates and cocrystals in single-crystal and bulk form, along with their hydrogen bonding and properties, we report the preparation of both single crystals and single-phase polycrystalline samples of the title NCL methanol solvate, NCL.MeOH, the crystal structure of this solvate, its stability and a description of the solvent inclusion mode in the context of its desolvation properties. We also describe the crystal structure of NCL monohydrate H_A and its effect on the stability of this solid form.

S2. Experimental

S2.1. Single-crystal growth

Single crystals of NCL.MeOH were grown from an equimolar mixture of NCL (100 mg, 0.31 mmol) and nicotinic acid (36.9 mg, 0.30 mmol) heated in MeOH (5 ml). The solution was separated from the solid residue, refluxed for 10 min and cooled to room temperature away from heat. Yellow needles of NCL.MeOH started forming in a matter of hours.

S2.2. Polycrystalline material preparation

NCL.MeOH was prepared by refluxing NCL (100 mg, 0.31 mmol) and MeOH (5 ml) for 30 min followed by cooling to room temperature away from heat. The fine yellow powder of NCL transformed to a yellow microcrystalline material (composed of very fine needles) during this time. NCL monohydrate H_A was prepared by the same method, refluxing NCL (100 mg, 0.31 mmol) and H₂O (3 ml) for 30 min and cooling the product to room temperature. [Repetition removed - OK?]

S2.3. Single-crystal X-ray diffraction

Single-crystal X-ray diffraction data on NCL.MeOH were collected on beamline I19 at Diamond Light Source, using a wavelength of 0.68890 Å and a standard hemisphere data collection (sample-to-detector distance = 60 mm, 2θ detector position 30°). A needle-shaped crystal of approximate dimensions 0.01 × 0.02 × 0.08 mm was selected for data collection. Data were collected as 2 s °^-1 exposures.

S2.4. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. Although the H atoms could be located in difference Fourier maps, geometric placement was used and the bond lengths and angles regularised, with C—H = N—H = 0.95 Å and O—H = 0.85 Å. The H atoms were then treated using a riding model, with U_iso(H) = 1.2U_eq(C,N) or 0.84U_eq(O). The only exception was atom H141, involved in a short O—H···O hydrogen bond, for which the position and isotropic displacement parameter were refined. The Flack parameter (Flack, 1983) could not be refined reliably, so the absolute configuration assignment is arbitrary. [Text added in several places. Please check and confirm.]

S2.5. Powder X-ray diffraction

Powder X-ray diffraction data were collected on a Bruker D8 ADVANCE diffractometer (Cu Kα_1,2 radiation) with a LynxEye detector. Patterns were recorded in 2θ ranges between 2 and 60° with a step size of 0.014°. Data analysis was carried out using Topas Academic software (Coelho et al., 2011).

S3. Results and discussion

S3.1. NCL.MeOH

NCL.MeOH crystallises in the orthorhombic space group P2₁2₁2₁ with one NCL and one MeOH molecule in the asymmetric unit (Fig. 1a). The NCL molecule is essentially planar, with the nitro group O atoms having the largest deviations from the mean plane of 0.06 and -0.07 Å, respectively. Being in the so-called β-conformation (Koshelev & Bekhli, 1974), the molecule contains an intra­molecular N4—H41···O14 hydrogen bond with a donor-to-acceptor distance of 2.588 (9) Å. This geometry is similar to that found in the structure of pure NCL (N···O = 2.63 Å; Sanphui et al., 2012). Each MeOH molecule forms hydrogen bonds with the NCL hydroxyl groups via O14—H141···O22 inter­actions, with O···O = 2.520 (9) Å. This H atom was the only one for which fractional coordinates were refined and the resulting O14—H141 distance is 0.98 (6) Å, reflecting a small degree of proton transfer towards the acceptor in this short O—H···O hydrogen bond.

The Cl···NO₂ inter­action, with Cl10···O21 = 3.215 (5) Å, is comparable with that found in guest-free NCL (3.22 Å; Sanphui et al., 2012). Finally, π–π inter­actions lead to the NCL molecules stacking along the crystallographic a axis and forming a herringbone motif (Fig. 1b). The distance between the planes of the π–π stacked layers is 3.36 Å, comparable with that in pure NCL and some of its cocrystals, with the ring centroids 3.740 (8) Å apart (the standard uncertainty corresponds to the a unit-cell edge). For example, in pure NCL the smallest perpendicular separation between the planes of the stacked layers is 3.34 Å; in the cocrystals with caffeine, urea and p-amino­benzoic acid, these separations are 3.32, 3.34 and 3.38 Å, respectively (Sanphui et al., 2012). The MeOH molecules reside in channels along the a axis, formed in the host NCL framework, as illustrated in the packing and space-filling diagrams in Fig. 2. The Kitaigorodskii packing index for this structure is 73.9%, and it decreases to 65.4% when the MeOH molecules are removed [by heating?].

Refluxing NCL in methanol for 30 min yielded a microcrystalline yellow product, identified by powder X-ray diffraction (PXRD) as the single-phase NCL.MeOH solvate. Fig. 3(a) shows the Pawley fit (Pawley, 1981) to the pattern recorded on the material while still wet (R_wp = 0.0614). Pawley fitting, rather than the Rietveld method, was used for PXRD data analysis because of the severe preferred orientation arising from placing a wet microcrystalline powder consisting of needle-shaped crystals on a flat-plate sample holder. No peaks are unaccounted for, demonstrating unambiguously the phase purity of the product. Fig. 3(b) shows the fit to the PXRD pattern recorded on the sample after it had been stored in air overnight (R_wp = 0.0417). Although NCL.MeOH is still the majority phase, extra peaks (marked in Fig. 3b) have appeared which indicate the presence of NCL hydrate (see below). The instability of NCL.MeOH relative to the hydrate demonstrated here by PXRD is consistent with the conclusions from thermal analysis measurements reported by van Tonder, Mahlatji et al. (2004).

S3.2. NCL monohydrate H_A

The diffraction pattern of the freshly prepared NCL monohydrate H_A (Fig. 3c) was indexed using the positions of 20 reflections up to 25° 2θ (Coelho, 2003). The resulting unit cell and space group P2₁/c were used to carry out a Pawley fit to the observed data set, and the final refined unit cell was a = 3.8590 (2) Å, b = 16.1578 (6) Å, c = 23.047 (1) Å, β = 91.60 (2)° and V = 1436.4 (1) ų. This left a few discrepancies in the fit in the 2θ range between 22 and 30°, which could be accounted for by the presence of a small amount of monohydrate H_B, as shown by the two-phase fit depicted in Fig. 3(c) (R_wp = 0.0284). The unit-cell parameters obtained for monohydrate H_B were a = 11.10 (2) Å, b = 17.20 (3) Å, c = 7.476 (7) Å, β = 99.29 (6)° and V = 1408 (4) ų. This unit-cell volume is smaller than that of H_A, which is consistent with the relative stabilities of the two monohydrates.

The similarity of the unit-cell parameters of monohydrate H_A and NCL.MeOH suggests that these two crystal forms may be essentially isostructural, possessing a very similar packing arrangement of NCL molecules and very similar cavities in which the solvent molecules reside, although this it is not possible to demonstrate this beyond the Pawley fit, through Rietveld refinement of the structure, due to the severity of the preferred orientation and the complexity of the structure relative to the data quality. However, the following factors support the proposed relationship between NCl.MeOH and monohydrate H_A. Firstly, the unit cell found for the latter gives an essentially flawless Pawley fit and has a logical relationship with the size of the unit cell of H_B. Secondly, isostructural methanol solvates and hydrates are known to exist (Clarke et al., 2012). Finally, the proposed structure for monohydrate H_A, with the water molecules residing in continuous channels along the a direction, correlates very well with the observed onset of dehydration at 375 K, significantly below the dehydration temperature of H_B.

S4. Implications of the structure for properties

Desolvation temperatures determined by differential scanning calorimetry (DSC) for NCL monohydrates H_A and H_B, and for the MeOH, THF and TEG solvates, have been reported as 375, 447/472 (two-step process), 363±3, 348±10 and 376±5 K, respectively (van Tonder, Mahlatji et al., 2004; van Tonder, Maleka et al., 2004). The exceptionally high dehydration onset temperature in monohydrate H_B is explained by the fact that, in this crystal structure, the water molecules are found as pairs confined in cavities formed by the NCL molecules. The crystal packing in the THF and TEG solvates is markedly different; solvent molecules are located in continuous channels and in layers alternating with layers of NCL molecules, respectively (Caira et al., 1998). The topology of NCL.MeOH and monohydrate H_A, described above and depicted in Fig. 2, is similar to that of the THF solvate, with the channels along the crystallographic a axis providing pathways for the diffusion of solvent/water molecules out of the crystal, resulting in relatively low desolvation/dehydration temperatures for these solid forms, comparable with those of the NCL.THF and NCL.TEG solvates. Given that NCL.MeOH and monohydrate H_A are isostructural, it is not surprising that the former readily transforms into the latter when stored under ambient conditions. The PXRD data shown in Fig. 3 demonstrate that this solvent molecule exchange transformation occurs in air on a time scale of several hours.

S5. Conclusions

The structure determination of NCL.MeOH, performed using single-crystal synchrotron X-ray diffraction on small needle-shaped crystals grown by reflux, has elucidated the key non-covalent inter­actions. The essentially planar NCL host molecules form a herringbone-type packing arrangement, facilitated by π-stacking. There are channels along the crystallographic a axis in which the methanol guest molecules are located. The methanol guest and NCL host molecules inter­act via O—H···O hydrogen bonds. Powder X-ray diffraction reveals that the initially phase-pure NCL.MeOH solvate readily transforms into NCL monohydrate H_A under ambient conditions.

Indexing and Pawley fitting of the PXRD pattern of NCL monohydrate H_A suggest that this solid form is isostructural with NCL.MeOH. This structural insight is consistent with the low dehydration temperature of H_A relative to monohydrate H_B, and with the transformation of the methanol solvate into the hydrate when stored in air.

The topology and the guest molecule inclusion mode in NCL.MeOH and monohydrate H_A allow us to correlate their relatively low desolvation temperatures with the crystal structure. The continuous channels in which the MeOH and water molecules reside provide pathways for their removal from the material. Our crystallographic results thus give insight into the host–guest inter­actions in NCL.MeOH, which correlate well with the structure–property relationships of the other NCL solvates with known crystal structures.

Related literature

For related literature, see: Caira et al. (1998); Clarke et al. (2012); Coelho (2003); Coelho et al. (2011); Flack (1983); Helfman (2011); Imperi et al. (2013); Koshelev & Bekhli (1974); Manek & Kolling (2004); Pawley (1981); Sanphui et al. (2012); Steiner (2002); Tian et al. (2010); Tonder, Mahlatji, Malan, Liebenberg, Caira, Song & de Villiers (2004); Tonder, Maleka, Liebenberg, Song, Wurster & de Villiers (2004); Weinbach & Garbus (1969); Yo et al. (2012).

Computing details

Data collection: ?; cell refinement: CrystalClear-SM Expert 3.1 b20 (Rigaku, 2012); data reduction: CrystalClear-SM Expert 3.1 b20 (Rigaku, 2012); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: CRYSTALS (Betteridge et al., 2003); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: ?.

Figures

	Fig. 1. (a) The asymmetric unit of NCL.MeOH, with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. Turquoise dashed lines indicate hydrogen bonds. (b) The crystal packing in NCL.MeOH.
	Fig. 2. The location of the MeOH molecules in the NCL host framework. (a) The crystal packing in NCL.MeOH, viewed in the bc plane; interactions shown as thin turqouise lines are discussed in the text. (b) A space-filling diagram, showing the continuous channels in the a direction (guest molecules omitted for clarity).
	Fig. 3. PXRD patterns of NCL.MeOH and NCL hydrate samples synthesized by reflux. (a) Pawley fit to the NCL.MeOH pattern obtained on the wet product. (b) Pawley fit to the PXRD pattern of NCL.MeOH collected after storing in air overnight [Significance of the two types of tick marks here?]. (c) Pawley fit of the PXRD pattern of NCL monohydrate HA (black tick marks), with a small amount of monohydrate HB (blue tick marks).

5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzenecarboxamide

Crystal data

C13H8Cl2N2O4·CH4O	Dx = 1.651 Mg m^−3
Mr = 359.16	? radiation, λ = 0.68890 Å
Orthorhombic, P212121	Cell parameters from 3630 reflections
a = 3.740 (8) Å	θ = 1.1–26.6°
b = 17.42 (4) Å	µ = 0.43 mm^−1
c = 22.18 (5) Å	T = 100 K
V = 1445 (6) Å^3	Needle, yellow
Z = 4	0.08 × 0.02 × 0.01 mm
F(000) = 736

Data collection

CrystalLogic diffractometer	3252 independent reflections
Radiation source: synchrotron, DLS beamline I19	2582 reflections with I > 2.0σ(I)
Double crystal silicon monochromator	Rint = 0.070
Detector resolution: 28.5714 pixels mm^-1	θmax = 26.7°, θmin = 1.4°
profile data from ω scans	h = −4→4
Absorption correction: multi-scan ?	k = −22→16
Tmin = 0.551, Tmax = 1.000	l = −24→28
7663 measured reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.095	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.103	Chebychev polynomial, (Watkin, 1994, Prince, 1982); [weight] = 1.0/[A0*T0(x) + A1*T1(x)··· + An-1]*Tn-1(x)], where Ai are the Chebychev coefficients listed below and x = F /Fmax. Method = robust weighting (Prince, 1982), W = [weight] * [1-(deltaF/6*sigmaF)^2]^2 Ai are: 0.229E + 04 0.149E + 04 0.115E + 04
S = 1.20	(Δ/σ)max = 0.0002124
2582 reflections	Δρmax = 0.48 e Å^−3
212 parameters	Δρmin = −0.71 e Å^−3
0 restraints

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

	x	y	z	Uiso*/Ueq
Cl1	0.4985 (6)	0.48690 (9)	0.70302 (6)	0.0421
C2	0.6038 (16)	0.5628 (4)	0.6573 (3)	0.0331
C3	0.5381 (17)	0.6375 (4)	0.6757 (2)	0.0326
N4	0.3818 (14)	0.6483 (3)	0.7311 (2)	0.0342
C5	0.2934 (19)	0.7156 (4)	0.7580 (3)	0.0356
O6	0.3484 (13)	0.7782 (3)	0.73487 (18)	0.0431
C7	0.1096 (17)	0.7104 (3)	0.8180 (2)	0.0338
C8	0.0300 (18)	0.7808 (3)	0.8448 (2)	0.0346
C9	−0.1352 (16)	0.7806 (3)	0.9014 (3)	0.0325
Cl10	−0.2367 (5)	0.86673 (10)	0.93456 (7)	0.0412
C11	−0.2099 (18)	0.7136 (3)	0.9303 (3)	0.0327
C12	−0.1257 (17)	0.6445 (4)	0.9040 (3)	0.0408
C13	0.0377 (19)	0.6428 (3)	0.8482 (3)	0.0364
O14	0.1197 (13)	0.5750 (2)	0.82245 (19)	0.0428
H141	0.099 (17)	0.526 (4)	0.844 (3)	0.05 (2)*
H121	−0.1802	0.5978	0.9242	0.0490*
H111	−0.3207	0.7146	0.9689	0.0394*
H81	0.0862	0.8277	0.8250	0.0416*
H41	0.3289	0.6031	0.7533	0.0410*
C15	0.6283 (16)	0.6977 (3)	0.6369 (3)	0.0342
C16	0.7821 (19)	0.6811 (4)	0.5806 (3)	0.0372
C17	0.8358 (16)	0.6069 (4)	0.5652 (3)	0.0305
C18	0.755 (2)	0.5467 (3)	0.6020 (3)	0.0363
H181	0.8015	0.4953	0.5899	0.0435*
N19	1.0066 (17)	0.5906 (3)	0.5084 (2)	0.0393
O20	1.0757 (13)	0.6450 (3)	0.47424 (18)	0.0486
O21	1.0812 (15)	0.5245 (3)	0.49504 (18)	0.0530
H161	0.8476	0.7212	0.5538	0.0446*
H151	0.5857	0.7494	0.6484	0.0408*
O22	−0.0002 (15)	0.4570 (2)	0.88503 (18)	0.0508
C23	−0.066 (2)	0.3937 (4)	0.8489 (3)	0.0548
H231	−0.1573	0.3516	0.8714	0.0633*
H233	0.1426	0.3789	0.8273	0.0633*
H232	−0.2424	0.4081	0.8202	0.0633*
H221	0.1378	0.4442	0.9138	0.0429*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0503 (10)	0.0417 (8)	0.0344 (7)	−0.0016 (10)	0.0015 (9)	0.0038 (7)
C2	0.029 (4)	0.037 (3)	0.033 (3)	−0.003 (3)	−0.004 (3)	0.002 (3)
C3	0.023 (3)	0.046 (4)	0.029 (3)	0.003 (3)	−0.001 (3)	0.000 (3)
N4	0.036 (3)	0.043 (3)	0.024 (2)	−0.005 (3)	0.006 (2)	0.003 (2)
C5	0.040 (4)	0.036 (4)	0.031 (3)	−0.004 (3)	0.001 (3)	−0.005 (3)
O6	0.050 (4)	0.043 (3)	0.037 (2)	0.004 (2)	0.006 (2)	0.006 (2)
C7	0.040 (4)	0.034 (3)	0.027 (3)	−0.006 (3)	0.002 (3)	−0.002 (3)
C8	0.036 (4)	0.037 (3)	0.031 (3)	0.001 (4)	0.006 (3)	−0.003 (3)
C9	0.039 (4)	0.033 (3)	0.026 (3)	0.001 (3)	0.000 (3)	−0.004 (3)
Cl10	0.0437 (9)	0.0445 (9)	0.0353 (8)	0.0028 (9)	0.0029 (9)	−0.0018 (8)
C11	0.033 (4)	0.036 (3)	0.028 (3)	−0.007 (3)	0.003 (3)	0.001 (3)
C12	0.042 (4)	0.046 (4)	0.034 (4)	−0.010 (3)	0.010 (3)	−0.009 (3)
C13	0.043 (4)	0.034 (3)	0.032 (3)	0.008 (4)	0.004 (3)	−0.001 (3)
O14	0.062 (4)	0.026 (2)	0.040 (3)	−0.004 (2)	0.009 (2)	0.002 (2)
C15	0.036 (4)	0.035 (4)	0.031 (3)	0.004 (3)	0.003 (3)	0.001 (3)
C16	0.033 (4)	0.045 (4)	0.033 (3)	−0.002 (4)	0.000 (3)	0.013 (3)
C17	0.030 (4)	0.041 (3)	0.020 (3)	0.002 (3)	0.000 (3)	−0.009 (3)
C18	0.037 (4)	0.037 (3)	0.035 (3)	0.003 (4)	−0.007 (3)	0.003 (3)
N19	0.037 (3)	0.050 (3)	0.031 (3)	−0.001 (4)	0.005 (3)	−0.001 (3)
O20	0.059 (4)	0.054 (3)	0.033 (2)	−0.004 (3)	0.011 (2)	0.003 (2)
O21	0.067 (4)	0.052 (3)	0.040 (2)	0.008 (3)	0.004 (3)	−0.010 (2)
O22	0.064 (3)	0.048 (3)	0.041 (2)	−0.003 (3)	−0.011 (3)	−0.009 (2)
C23	0.083 (6)	0.043 (4)	0.038 (4)	0.007 (4)	0.010 (4)	−0.002 (3)

Geometric parameters (Å, º)

Cl1—C2	1.712 (7)	C12—H121	0.950
C2—C3	1.386 (9)	C13—O14	1.347 (7)
C2—C18	1.380 (8)	O14—H141	0.98 (6)
C3—N4	1.373 (7)	C15—C16	1.405 (8)
C3—C15	1.400 (8)	C15—H151	0.950
N4—C5	1.357 (8)	C16—C17	1.351 (9)
N4—H41	0.950	C16—H161	0.950
C5—O6	1.221 (7)	C17—C18	1.363 (8)
C5—C7	1.501 (8)	C17—N19	1.440 (8)
C7—C8	1.394 (8)	C18—H181	0.950
C7—C13	1.382 (8)	N19—O20	1.240 (6)
C8—C9	1.401 (8)	N19—O21	1.221 (7)
C8—H81	0.950	O22—C23	1.387 (7)
C9—Cl10	1.713 (7)	O22—H221	0.850
C9—C11	1.360 (8)	C23—H231	0.950
C11—C12	1.376 (9)	C23—H233	0.950
C11—H111	0.950	C23—H232	0.950
C12—C13	1.380 (8)
Cl1—C2—C3	120.6 (5)	C7—C13—C12	120.1 (6)
Cl1—C2—C18	117.7 (5)	C7—C13—O14	119.9 (6)
C3—C2—C18	121.7 (6)	C12—C13—O14	120.0 (6)
C2—C3—N4	117.9 (6)	C13—O14—H141	123 (4)
C2—C3—C15	118.7 (5)	C3—C15—C16	119.4 (6)
N4—C3—C15	123.4 (6)	C3—C15—H151	120.3
C3—N4—C5	128.0 (6)	C16—C15—H151	120.3
C3—N4—H41	116.0	C15—C16—C17	118.9 (6)
C5—N4—H41	116.0	C15—C16—H161	120.6
N4—C5—O6	123.1 (6)	C17—C16—H161	120.6
N4—C5—C7	116.7 (6)	C16—C17—C18	123.5 (6)
O6—C5—C7	120.2 (6)	C16—C17—N19	118.4 (6)
C5—C7—C8	115.0 (5)	C18—C17—N19	118.1 (6)
C5—C7—C13	124.8 (6)	C2—C18—C17	117.8 (6)
C8—C7—C13	120.1 (6)	C2—C18—H181	121.1
C7—C8—C9	118.3 (6)	C17—C18—H181	121.1
C7—C8—H81	120.8	C17—N19—O20	118.5 (5)
C9—C8—H81	120.8	C17—N19—O21	119.9 (5)
C8—C9—Cl10	118.8 (5)	O20—N19—O21	121.6 (6)
C8—C9—C11	121.0 (6)	C23—O22—H221	109.4
Cl10—C9—C11	120.2 (5)	O22—C23—H231	111.9
C9—C11—C12	120.3 (6)	O22—C23—H233	111.2
C9—C11—H111	119.9	H231—C23—H233	110.6
C12—C11—H111	119.9	O22—C23—H232	107.3
C11—C12—C13	120.1 (6)	H231—C23—H232	107.8
C11—C12—H121	120.0	H233—C23—H232	107.8
C13—C12—H121	120.0

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O14—H141···O22	0.98 (6)	1.56 (6)	2.520 (9)	168 (6)
N4—H41···O14	0.95	1.79	2.588 (9)	140 (1)
C15—H151···O6	0.95	2.17	2.790 (9)	122 (1)
O22—H221···N19^i	0.85	2.56	3.404 (9)	173 (1)
O22—H221···O20^i	0.85	2.32	3.098 (9)	153 (1)
O22—H221···O21^i	0.85	2.16	2.918 (9)	149 (1)

Symmetry code: (i) −x+3/2, −y+1, z+1/2.