Ciprofloxacin salt and salt co-crystal with di­hydroxy­benzoic acids

Nugraha, Y.P.; Sugiyama, H.; Uekusa, H.

doi:10.1107/S2056989022001177

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 78| Part 3| March 2022| Pages 259-263

https://doi.org/10.1107/S2056989022001177

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Ciprofloxacin salt and salt co-crystal with dihydroxybenzoic acids

Yuda Prasetya Nugraha,^a ^* Haruki Sugiyama ^b,^c and Hidehiro Uekusa ^d

^aDepartment of Pharmaceutics, School of Pharmacy, Bandung Institute of Technology, Bandung 40132, Indonesia, ^bResearch and Education Center for Natural Sciences, Keio University, Hiyoshi, 4-1-1, Kohoku, Yokohama 223-8521, Japan, ^cDepartment of Life and Coordination-Complex Molecular Science, Institute for Molecular Science, Myodaiji, Okazaki 444-8787, Japan, and ^dDepartment of Chemistry, Tokyo Institute of Technology, 2-12-1, Ookayama, Meguro, Tokyo 152-8551, Japan
^*Correspondence e-mail: yudapn@itb.ac.id

Edited by D. Chopra, Indian Institute of Science Education and Research Bhopal, India (Received 12 January 2022; accepted 1 February 2022; online 3 February 2022)

The crystal structure of two multi-component crystals of ciprofloxacin [systematic name: 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)quinoline-3-carboxylic acid], a fluoroquinolone antibiotic, namely, ciprofloxacin 2,6-dihydroxybenzoate salt, C₁₇H₁₉FN₃O₃⁺·C₇H₅O₄⁻, (I), and ciprofloxacin hydrochloride–3,5-dihydroxybenzoic–water (1/1/1), C₁₇H₁₉FN₃O₃⁺·Cl⁻·C₇H₆O₄·H₂O, (II), were determined. In (I) and (II), the ciprofloxacin cations are connected via head-to-tail N—H⋯O hydrogen bonding. Both structures show an alternating layered arrangement between ciprofloxacin and dihydroxybenzoic acid.

Keywords: crystal structure; fluoroquinolone; ciprofloxacin; dihydroxybenzoic acid; salt co-crystal; antibiotic.

CCDC references: 2098049; 2098403

1. Chemical context

The design and exploration of multi-component crystals of active pharmaceutical ingredients (APIs) have gained increasing interest over recent decades. The formation of multi-component crystals, i.e. salts and co-crystals through a crystal-engineering approach has been continuously demonstrated as a versatile tool to improve the physicochemical properties of APIs (Kavanagh et al., 2019 ; Putra & Uekusa, 2020 ; Thakur & Thakuria, 2020 ). Recently, the co-crystallization of salt APIs or salt co-crystal formation has been increasingly studied. Salt co-crystallization has been utilized to suppress hydrate formation of salt APIs (Nugraha & Uekusa, 2018 ; Fujito et al., 2021 ). As a part of our study of salt co-crystals of APIs, we investigated multi-component crystals of ciprofloxacin. Ciprofloxacin is a Biopharmaceutics Classification System (BCS) class IV fluoroquinolone antibiotic that is widely used therapeutically as the free base and the hydrochloride salt (Olivera et al., 2011 ).

2. Structural commentary

Compound (I) was obtained as an anion-exchange product between ciprofloxacin hydrochloride and 2,6-dihydrobenzoic acid in solution. 2,6-Dihydroxybenzoic acid (2,6HBA) is a relatively strong carboxylic acid with a pK_a of 1.30 (Gdaniec et al., 1994 ; Habibi-yangjeh et al., 2005 ). Compound (I) crystallizes in the monoclinic space group P2₁/c. The asymmetric unit consists of one ciprofloxacin cation and one 2,6HBA anion (Fig. 1). The C—O distances of the ciprofloxacin carboxylic group i.e., 1.218 (3) and 1.325 (3) Å indicate that it exists as the neutral carboxylic form. However, in 2,6HBA, the C–O distances are very similar i.e., 1.263 (4) and 1.267 (3) Å due to resonance stabilization in the carboxylate anion (Childs et al., 2007 ; Aakeröy et al., 2006 ). As a result, the piperazinyl group of ciprofloxacin is protonated. Therefore, compound (I) is a salt. The formation of a salt is well-predicted by the pK_a rule (Cruz-Cabeza, 2012 ). The pK_a of ciprofloxacin are 6.18 and 8.73 for the carboxylic acid and the piperazinyl ring, respectively (Sun et al., 2002 ). Therefore, salt formation is expected because the ΔpK_a between the piperazinyl ring of ciprofloxacin and the carboxylic acid of 2,6HBA is greater than 4. Similar behaviour is observed in the salicylate salt of ciprofloxacin (Surov et al., 2019 ; Nugrahani et al., 2020 ).

Figure 1
Displacement ellipsoid (50% probability level) drawing with the atomic labelling scheme for compound (I)

showing the hydrogen bonds within the selected asymmetric unit.

Compound (II) crystallizes in the non-centrosymmetric P1 space group despite the lack of a chiral centre. The asymmetric unit comprises one ciprofloxacin cation, one chloride anion and one 3,5HBA molecule, as shown in Fig. 2. In addition, one water molecule is incorporated into the crystal lattice. An anion-exchange reaction during crystallization did not occur in this system. Compared to 2,6HBA, the coformer is a weaker acid with a pK_a of 4.04 (Habibi-yangjeh et al., 2005). Contrary to the previous structures, the coformer exists as a neutral molecule in the crystal. The carboxylic C18—O4 and C18—O5 distances of 2,6HBA are 1.320 (4) and 1.216 (4) Å, respectively, confirming its neutral state. Additionally, the carboxylic C1—O1 and C1—O2 distances of ciprofloxacin, i.e. 1.227 (4) and 1.314 (4) Å, respectively, also confirm the neutral state of this moiety. On the other hand, the piperazinyl group is protonated. Hence, compound (II) is a salt co-crystal monohydrate of ciprofloxacin.

Figure 2
Displacement ellipsoid (50% probability level) drawing with the atomic labelling scheme for compound (II)

showing the hydrogen bonds within the selected asymmetric unit.

Compounds (I) and (II) exhibit similar conformations, as shown in Fig. 3. The molecular conformation of the ciprofloxacin molecule is governed by intramolecular O2—H2⋯O3 and C14—H14A⋯F1 hydrogen bonding (Tables 1 and 2). In both structures, the piperazinium ring exhibits a chair conformation. The main difference is the relative orientation between the piperazinium moiety and the quinolone ring. The C7—N2—C14—C15 torsion angles are 97.0 (2) and −167.8 (2)°, respectively, for compounds (I) and (II).

Table 1
Hydrogen-bond geometry (Å, °) for (I)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O2—H2⋯O3	0.84	1.73	2.512 (2)	155
N3—H3A⋯O1ⁱ	0.91	2.38	2.977 (2)	123
N3—H3A⋯O6	0.91	2.09	2.890 (2)	146
N3—H3B⋯O4ⁱⁱ	0.91	2.18	2.897 (3)	136
N3—H3B⋯O5ⁱⁱ	0.91	2.24	3.090 (3)	155
C11—H11⋯O3ⁱⁱⁱ	1.00	2.46	3.239 (3)	134
C12—H12A⋯O4^iv	0.99	2.54	3.374 (3)	141
C13—H13A⋯O7^v	0.99	2.51	3.193 (3)	126
C14—H14A⋯F1	0.99	2.13	2.831 (2)	126
C15—H15B⋯O1ⁱⁱⁱ	0.99	2.33	3.282 (3)	161
C17—H17A⋯O5ⁱⁱ	0.99	2.60	3.408 (3)	139
O6—H6⋯O5	0.84	1.77	2.520 (3)	148
O7—H7⋯O4	0.84	1.85	2.508 (4)	134
C21—H21⋯O4ⁱⁱ	0.95	2.54	3.488 (3)	178
Symmetry codes: (i) x, y, z+1; (ii) ; (iii) ; (iv) $[x-1, -y+{\script{3\over 2}}, z-{\script{1\over 2}}]$ ; (v) .

Table 2
Hydrogen-bond geometry (Å, °) for (II)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O2—H2⋯O3	0.84	1.78	2.551 (3)	152
N3—H3A⋯O1ⁱ	0.91	1.75	2.652 (3)	172
N3—H3B⋯Cl1	0.91	2.30	3.106 (3)	148
C10—H10⋯F1ⁱⁱ	0.95	2.46	3.158 (4)	130
C12—H12B⋯O7ⁱⁱⁱ	0.99	2.47	3.435 (4)	166
C14—H14B⋯F1	0.99	2.27	2.927 (3)	123
C16—H16B⋯Cl1^iv	0.99	2.78	3.609 (3)	142
O4—H4⋯Cl1	0.84	2.28	3.082 (2)	160
O6—H6⋯Cl1^v	0.84	2.40	3.232 (2)	170
O7—H7⋯O8	0.84	1.96	2.769 (3)	161
O8—H8A⋯Cl1ⁱ	0.88 (6)	2.51 (6)	3.362 (3)	164 (4)
O8—H8B⋯O5^vi	0.82 (6)	2.05 (6)	2.865 (4)	170 (5)
Symmetry codes: (i) ; (ii) ; (iii) ; (iv) ; (v) x, y+1, z; (vi) .

Figure 3
Molecular overlay of ciprofloxacin cation in compounds (I)

(red) and (II)

(blue). Hydrogen atoms are omitted for clarity.

3. Supramolecular features

In compound (I), the carboxylate anion of 2,6HBA acts as a hydrogen-bond donor for intramolecular hydrogen bonds involving two hydroxyl groups, namely O6—H6⋯O5 and O7—H7⋯O4. The protonated nitrogen atom N3 of the piperazinyl ring is involved in the formation of trifurcated hydrogen bonds with O4, O5, and O6 of the coformer. These charge-assisted hydrogen bonds, i.e. N3—H3B⋯O4, N3—H3B⋯O5, and N3—H3A⋯O6, form an infinite chain structure along the a-axis direction (Table 1, Fig. 4). The chains are connected to the adjacent ciprofloxacin molecule through head-to-tail N3—H3A⋯O1 hydrogen bonding. The crystal packing of (I) is shown in Fig. 5. Along the a-axis, centrosymmetric pairs of ciprofloxacin molecules are stacked by π–π interactions. The distance between the centroids of symmetry-related C4–C9 rings is 3.4986 (11) Å. This arrangement leads to the formation of a columnar packing arrangement. Interestingly, a similar packing feature was observed in the 1.75 hydrate of ciprofloxacin salicylate (Nugrahani et al., 2020). In addition, compound (I) shows a layered structure with alternating ciprofloxacin and 2,6HBA layers along the b axis.

Figure 4
Intermolecular hydrogen-bonding motifs in (I)

showing infinite chains along the a-axis direction formed by ciprofloxacin and 2,6HBA (red). Hydrogen atoms are omitted for clarity.

Figure 5
Packing motifs of (I)

viewed along (a) the a axis and (b) the c axis highlighting the alternating layers of ciprofloxacin and the coformer.

The supramolecular features of compound (II) are similar to those observed in compound (I). Ciprofloxacin cations are interconnected through head-to-tail N3—H3A⋯O1 hydrogen bonds (Table 2), forming an infinite chain arrangement. The chloride ion and water molecule are involved in an extensive hydrogen-bond network bridging ciprofloxacin and 3,5HBA (Fig. 6a). Interestingly, compound (II) also shows a layered arrangement of ciprofloxacin and the coformer (Fig. 6b).

Figure 6
Intermolecular hydrogen-bonding motifs in (II)

highlighting the role of the chloride ion and water molecule in bridging ciprofloxacin and 3,5HBA (blue). Hydrogen atoms are omitted for clarity. (b) The crystal packing of (II)

showing the alternating layered arrangement.

4. Database survey

Several crystal structures of ciprofloxacin salts with benzoic acid derivatives have been reported, including salts with salicylic acid (Surov et al., 2019; Nagalapalli & Yaga Bheem, 2014 ; CSD refcode family DOFWUT), 4-hydroxybenzoic acid (Surov et al., 2020 ; CSD refcode PUNMUJ), 4-aminobenzoic acid (Surov et al., 2020; CSD refcode PUNMIX) and gallic acid (Surov et al., 2020; CSD refcode PUNMOD). A search for salt co-crystals of ciprofloxacin hydrochloride yielded one reported crystal structure, a co-crystal of ciprofloxacin hydrochloride with 4-hydroxybenzoic acid (Martínez-Alejo et al., 2014 ; CSD refcode XOHTUL). Compound (II) was also disclosed in a patent without any structural information (Rojas et al., 2016 ).

5. Synthesis and crystallization

Single crystals of (I) and (II) were obtained by preparing a saturated solution of equimolar ciprofloxacin hydrochloride and the respective coformer in methanol/water (1:1) at room temperature. The saturated solution was allowed to slowly evaporate at room temperature. A suitable single crystal was selected and measured for structure determination.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were refined using a riding model and their displacement parameters (U_iso) were fixed to 1.2U_eq of the parent carbon or nitrogen atom and 1.5U_eq for hydroxyl groups.

Table 3
Experimental details

	(I)	(II)
Crystal data
Chemical formula	C₁₇H₁₉FN₃O₃⁺·C₇H₅O₄⁻	C₁₇H₁₉FN₃O₃⁺·C₇H₆O₄·Cl⁻·H₂O
M_r	485.46	539.93
Crystal system, space group	Monoclinic, P2₁/c	Triclinic, P1
Temperature (K)	93	93
a, b, c (Å)	7.9722 (5), 21.2705 (11), 13.0860 (7)	7.2165 (2), 8.8298 (4), 10.1184 (3)
α, β, γ (°)	90, 101.805 (6), 90	92.997 (3), 95.219 (2), 111.557 (4)
V (Å³)	2172.1 (2)	594.60 (4)
Z	4	1
Radiation type	Cu Kα	Cu Kα
μ (mm⁻¹)	0.98	2.00
Crystal size (mm)	0.23 × 0.05 × 0.04	0.28 × 0.2 × 0.05

Data collection
Diffractometer	XtaLAB Synergy R, DW system, HyPix	XtaLAB Synergy R, DW system, HyPix
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2020 $[Rigaku OD (2020). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ )	Multi-scan (CrysAlis PRO; Rigaku OD, 2020 $[Rigaku OD (2020). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ )
T_min, T_max	0.919, 1.000	0.839, 1.000
No. of measured, independent and observed reflections	15936, 4378, 3601 (?)	16358, 4420, 4323 [I > 2σ(I)]
R_int	0.038	0.035
(sin θ/λ)_max (Å⁻¹)	0.630	0.625

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.053, 0.139, 1.04	0.034, 0.094, 1.12
No. of reflections	4378	4420
No. of parameters	319	344
No. of restraints	0	3
H-atom treatment	H-atom parameters constrained	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.34, −0.41	0.25, −0.47
Absolute structure	–	Flack x determined using 1889 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	–	0.011 (7)
Computer programs: CrysAlis PRO (Rigaku OD, 2020 $[Rigaku OD (2020). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ ), SHELXT2018/2 (Sheldrick, 2015a ), SHELXL2018/3 (Sheldrick, 2015b ), OLEX2 (Dolomanov et al., 2009 ) and Mercury (Macrae et al., 2020 ).

Supporting information

CCDC references: 2098049; 2098403

Crystal structure: contains datablocks I, II. DOI: https://doi.org/10.1107/S2056989022001177/dx2042sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989022001177/dx2042Isup2.hkl

Structure factors: contains datablock II. DOI: https://doi.org/10.1107/S2056989022001177/dx2042IIsup3.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989022001177/dx2042Isup4.cml

checkCIF report

Computing details top

For both structures, data collection: CrysAlis PRO (Rigaku OD, 2020); cell refinement: CrysAlis PRO (Rigaku OD, 2020); data reduction: CrysAlis PRO (Rigaku OD, 2020); program(s) used to solve structure: SHELXT2018/2 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: Mercury (Macrae et al., 2020).

4-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)piperazin-1-ium 2,6-dihydroxybenzoate (I) top

Crystal data top

C₁₇H₁₉FN₃O₃⁺·C₇H₅O₄⁻	F(000) = 1016
M_r = 485.46	D_x = 1.485 Mg m⁻³
Monoclinic, P2₁/c	Cu Kα radiation, λ = 1.54184 Å
a = 7.9722 (5) Å	Cell parameters from 4777 reflections
b = 21.2705 (11) Å	θ = 4.0–72.0°
c = 13.0860 (7) Å	µ = 0.98 mm⁻¹
β = 101.805 (6)°	T = 93 K
V = 2172.1 (2) Å³	Block, colourless
Z = 4	0.23 × 0.05 × 0.04 mm

Data collection top

XtaLAB Synergy R, DW system, HyPix diffractometer	15936 measured reflections
Radiation source: Rotating-anode X-ray tube, Rigaku XtaLAB Synergy-R	4378 independent reflections
Mirror monochromator	R_int = 0.038
Detector resolution: 10.0000 pixels mm^-1	θ_max = 76.3°, θ_min = 4.0°
ω scans	h = −9→9
Absorption correction: multi-scan (CrysAlisPro; Rigaku OD, 2020)	k = −17→26
T_min = 0.919, T_max = 1.000	l = −15→16

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.053	H-atom parameters constrained
wR(F²) = 0.139	w = 1/[σ²(F_o²) + (0.062P)² + 1.4432P] where P = (F_o² + 2F_c²)/3
S = 1.03	(Δ/σ)_max = 0.001
4378 reflections	Δρ_max = 0.34 e Å⁻³
319 parameters	Δρ_min = −0.41 e Å⁻³
0 restraints

Special details top

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 (Å²) top

	x	y	z	U_iso*/U_eq
F1	0.05295 (16)	0.41493 (5)	0.67770 (9)	0.0377 (3)
O1	0.4436 (2)	0.54707 (8)	0.16888 (11)	0.0432 (4)
O2	0.3833 (2)	0.44645 (7)	0.18852 (11)	0.0402 (4)
H2	0.347742	0.424196	0.232696	0.060*
O3	0.28730 (19)	0.41034 (7)	0.35014 (11)	0.0362 (3)
N1	0.3471 (2)	0.59129 (8)	0.46044 (12)	0.0314 (4)
N2	0.0934 (2)	0.53783 (8)	0.75639 (13)	0.0328 (4)
N3	0.2572 (3)	0.58568 (8)	0.95730 (14)	0.0395 (4)
H3A	0.356800	0.595565	1.002153	0.047*
H3B	0.169225	0.594851	0.989447	0.047*
C1	0.4001 (3)	0.50538 (10)	0.22173 (15)	0.0354 (5)
C2	0.3602 (3)	0.51643 (10)	0.32635 (15)	0.0327 (4)
C3	0.3006 (2)	0.46647 (10)	0.38290 (15)	0.0326 (4)
C4	0.2566 (2)	0.48427 (10)	0.48093 (15)	0.0316 (4)
C5	0.1856 (3)	0.44006 (9)	0.54010 (15)	0.0327 (4)
H5	0.172151	0.397574	0.517532	0.039*
C6	0.1363 (3)	0.45781 (9)	0.62931 (15)	0.0321 (4)
C7	0.1580 (2)	0.51970 (9)	0.67053 (15)	0.0313 (4)
C8	0.2342 (2)	0.56281 (9)	0.61296 (15)	0.0314 (4)
H8	0.256130	0.604419	0.638611	0.038*
C9	0.2786 (2)	0.54598 (9)	0.51851 (15)	0.0303 (4)
C10	0.3838 (3)	0.57567 (10)	0.36771 (15)	0.0329 (4)
H10	0.428110	0.607231	0.329187	0.040*
C11	0.3814 (3)	0.65431 (9)	0.50290 (16)	0.0338 (4)
H11	0.471754	0.657418	0.568093	0.041*
C12	0.2333 (3)	0.69888 (10)	0.49555 (18)	0.0418 (5)
H12A	0.232822	0.727421	0.555245	0.050*
H12B	0.118861	0.684208	0.459028	0.050*
C13	0.3671 (3)	0.70946 (10)	0.43140 (17)	0.0407 (5)
H13A	0.334605	0.701423	0.355393	0.049*
H13B	0.448510	0.744615	0.451562	0.049*
C14	0.1041 (3)	0.49851 (10)	0.84970 (16)	0.0357 (5)
H14A	0.115360	0.453863	0.830791	0.043*
H14B	−0.002908	0.502959	0.876377	0.043*
C15	0.2556 (3)	0.51692 (9)	0.93462 (16)	0.0340 (4)
H15A	0.250824	0.493237	0.999094	0.041*
H15B	0.363113	0.505307	0.912586	0.041*
C16	0.2411 (3)	0.62529 (10)	0.86112 (16)	0.0364 (5)
H16A	0.344474	0.620481	0.830902	0.044*
H16B	0.229875	0.670139	0.878811	0.044*
C17	0.0831 (3)	0.60408 (10)	0.78271 (15)	0.0327 (4)
H17A	−0.020076	0.611142	0.812303	0.039*
H17B	0.071566	0.629659	0.718442	0.039*
O4	1.1188 (2)	0.66620 (11)	1.0984 (2)	0.0830 (8)
O5	0.8981 (3)	0.62083 (8)	0.99400 (18)	0.0683 (6)
O6	0.5971 (2)	0.63810 (8)	1.02051 (13)	0.0476 (4)
H6	0.675991	0.625422	0.991803	0.071*
O7	1.0721 (3)	0.74339 (12)	1.23479 (19)	0.0809 (8)
H7	1.128472	0.712831	1.218955	0.121*
C18	0.9592 (3)	0.65706 (12)	1.0688 (2)	0.0531 (7)
C19	0.8411 (3)	0.68834 (9)	1.12632 (16)	0.0336 (4)
C20	0.6639 (3)	0.67641 (10)	1.10169 (16)	0.0332 (4)
C21	0.5540 (3)	0.70341 (11)	1.1582 (2)	0.0447 (5)
H21	0.434867	0.694228	1.142088	0.054*
C22	0.6208 (4)	0.74400 (12)	1.2386 (2)	0.0593 (8)
H22	0.545515	0.763145	1.277098	0.071*
C23	0.7929 (5)	0.75756 (13)	1.2647 (2)	0.0625 (8)
H23	0.835717	0.785656	1.320376	0.075*
C24	0.9025 (3)	0.72996 (12)	1.20927 (18)	0.0475 (6)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F1	0.0444 (7)	0.0350 (6)	0.0334 (6)	−0.0065 (5)	0.0070 (5)	−0.0004 (5)
O1	0.0555 (10)	0.0466 (9)	0.0264 (7)	0.0049 (7)	0.0058 (7)	0.0000 (7)
O2	0.0470 (9)	0.0437 (9)	0.0280 (7)	0.0011 (7)	0.0030 (6)	−0.0068 (6)
O3	0.0384 (8)	0.0360 (8)	0.0312 (7)	0.0019 (6)	0.0003 (6)	−0.0065 (6)
N1	0.0347 (9)	0.0338 (9)	0.0239 (8)	0.0014 (7)	0.0017 (7)	0.0003 (6)
N2	0.0370 (9)	0.0345 (9)	0.0254 (8)	−0.0019 (7)	0.0030 (7)	−0.0007 (7)
N3	0.0477 (10)	0.0353 (9)	0.0290 (9)	0.0021 (8)	−0.0074 (8)	−0.0025 (7)
C1	0.0360 (11)	0.0418 (11)	0.0255 (10)	0.0036 (9)	−0.0008 (8)	−0.0026 (9)
C2	0.0300 (10)	0.0390 (11)	0.0260 (9)	0.0034 (8)	−0.0014 (8)	−0.0031 (8)
C3	0.0288 (9)	0.0364 (10)	0.0288 (10)	0.0040 (8)	−0.0033 (8)	−0.0031 (8)
C4	0.0290 (9)	0.0370 (10)	0.0254 (9)	0.0016 (8)	−0.0022 (7)	−0.0011 (8)
C5	0.0331 (10)	0.0313 (10)	0.0298 (10)	0.0020 (8)	−0.0024 (8)	−0.0035 (8)
C6	0.0304 (10)	0.0340 (10)	0.0293 (10)	−0.0024 (8)	−0.0001 (8)	0.0016 (8)
C7	0.0300 (9)	0.0360 (10)	0.0253 (9)	0.0006 (8)	−0.0002 (7)	−0.0010 (8)
C8	0.0308 (10)	0.0337 (10)	0.0265 (9)	0.0011 (8)	−0.0017 (7)	−0.0016 (8)
C9	0.0297 (10)	0.0345 (10)	0.0242 (9)	0.0027 (8)	−0.0001 (7)	0.0005 (8)
C10	0.0332 (10)	0.0387 (11)	0.0249 (9)	0.0031 (8)	0.0014 (8)	0.0011 (8)
C11	0.0398 (11)	0.0325 (10)	0.0282 (10)	−0.0005 (8)	0.0053 (8)	−0.0009 (8)
C12	0.0457 (12)	0.0372 (11)	0.0420 (12)	0.0049 (9)	0.0074 (10)	−0.0010 (9)
C13	0.0538 (13)	0.0345 (11)	0.0328 (11)	0.0025 (9)	0.0067 (9)	0.0015 (9)
C14	0.0406 (11)	0.0380 (11)	0.0275 (10)	−0.0058 (9)	0.0047 (8)	0.0008 (8)
C15	0.0385 (11)	0.0330 (10)	0.0283 (10)	0.0013 (8)	0.0018 (8)	−0.0005 (8)
C16	0.0410 (11)	0.0326 (10)	0.0321 (10)	0.0006 (8)	−0.0011 (9)	−0.0021 (8)
C17	0.0335 (10)	0.0359 (10)	0.0269 (9)	0.0020 (8)	0.0017 (8)	−0.0010 (8)
O4	0.0390 (10)	0.0790 (14)	0.140 (2)	0.0173 (9)	0.0391 (12)	0.0559 (15)
O5	0.1042 (17)	0.0351 (9)	0.0862 (15)	0.0002 (10)	0.0675 (13)	−0.0015 (10)
O6	0.0513 (10)	0.0531 (10)	0.0356 (8)	−0.0164 (8)	0.0027 (7)	−0.0101 (7)
O7	0.0613 (12)	0.0922 (16)	0.0708 (14)	−0.0414 (11)	−0.0296 (11)	0.0281 (13)
C18	0.0488 (14)	0.0374 (13)	0.082 (2)	0.0124 (10)	0.0340 (14)	0.0259 (13)
C19	0.0320 (10)	0.0335 (10)	0.0344 (10)	−0.0010 (8)	0.0048 (8)	0.0063 (8)
C20	0.0342 (10)	0.0347 (10)	0.0296 (10)	−0.0019 (8)	0.0036 (8)	0.0007 (8)
C21	0.0394 (12)	0.0431 (12)	0.0547 (14)	0.0024 (10)	0.0172 (10)	0.0040 (11)
C22	0.096 (2)	0.0364 (13)	0.0590 (16)	−0.0030 (13)	0.0477 (16)	−0.0036 (11)
C23	0.108 (2)	0.0474 (14)	0.0343 (12)	−0.0330 (15)	0.0198 (14)	−0.0087 (11)
C24	0.0525 (14)	0.0496 (13)	0.0341 (11)	−0.0194 (11)	−0.0056 (10)	0.0104 (10)

Geometric parameters (Å, º) top

F1—C6	1.359 (2)	C12—H12A	0.9900
O1—C1	1.218 (3)	C12—H12B	0.9900
O2—H2	0.8400	C12—C13	1.503 (3)
O2—C1	1.325 (3)	C13—H13A	0.9900
O3—C3	1.265 (2)	C13—H13B	0.9900
N1—C9	1.405 (3)	C14—H14A	0.9900
N1—C10	1.347 (3)	C14—H14B	0.9900
N1—C11	1.455 (3)	C14—C15	1.516 (3)
N2—C7	1.383 (3)	C15—H15A	0.9900
N2—C14	1.468 (3)	C15—H15B	0.9900
N2—C17	1.457 (3)	C16—H16A	0.9900
N3—H3A	0.9100	C16—H16B	0.9900
N3—H3B	0.9100	C16—C17	1.521 (3)
N3—C15	1.492 (3)	C17—H17A	0.9900
N3—C16	1.498 (3)	C17—H17B	0.9900
C1—C2	1.486 (3)	O4—C18	1.267 (3)
C2—C3	1.431 (3)	O5—C18	1.263 (4)
C2—C10	1.369 (3)	O6—H6	0.8400
C3—C4	1.448 (3)	O6—C20	1.358 (3)
C4—C5	1.408 (3)	O7—H7	0.8400
C4—C9	1.400 (3)	O7—C24	1.355 (3)
C5—H5	0.9500	C18—C19	1.479 (3)
C5—C6	1.359 (3)	C19—C20	1.406 (3)
C6—C7	1.420 (3)	C19—C24	1.409 (3)
C7—C8	1.402 (3)	C20—C21	1.382 (3)
C8—H8	0.9500	C21—H21	0.9500
C8—C9	1.400 (3)	C21—C22	1.381 (4)
C10—H10	0.9500	C22—H22	0.9500
C11—H11	1.0000	C22—C23	1.375 (5)
C11—C12	1.501 (3)	C23—H23	0.9500
C11—C13	1.490 (3)	C23—C24	1.376 (4)

C1—O2—H2	109.5	C13—C12—H12B	117.8
C9—N1—C11	119.24 (16)	C11—C13—C12	60.21 (15)
C10—N1—C9	119.88 (17)	C11—C13—H13A	117.8
C10—N1—C11	120.86 (17)	C11—C13—H13B	117.8
C7—N2—C14	123.30 (17)	C12—C13—H13A	117.8
C7—N2—C17	120.67 (17)	C12—C13—H13B	117.8
C17—N2—C14	110.55 (16)	H13A—C13—H13B	114.9
H3A—N3—H3B	107.8	N2—C14—H14A	109.4
C15—N3—H3A	109.0	N2—C14—H14B	109.4
C15—N3—H3B	109.0	N2—C14—C15	111.36 (17)
C15—N3—C16	112.86 (16)	H14A—C14—H14B	108.0
C16—N3—H3A	109.0	C15—C14—H14A	109.4
C16—N3—H3B	109.0	C15—C14—H14B	109.4
O1—C1—O2	121.63 (19)	N3—C15—C14	111.86 (17)
O1—C1—C2	123.19 (19)	N3—C15—H15A	109.2
O2—C1—C2	115.18 (19)	N3—C15—H15B	109.2
C3—C2—C1	121.03 (18)	C14—C15—H15A	109.2
C10—C2—C1	118.14 (19)	C14—C15—H15B	109.2
C10—C2—C3	120.83 (19)	H15A—C15—H15B	107.9
O3—C3—C2	122.61 (19)	N3—C16—H16A	110.0
O3—C3—C4	121.90 (19)	N3—C16—H16B	110.0
C2—C3—C4	115.48 (18)	N3—C16—C17	108.50 (17)
C5—C4—C3	120.65 (18)	H16A—C16—H16B	108.4
C9—C4—C3	121.38 (19)	C17—C16—H16A	110.0
C9—C4—C5	117.95 (18)	C17—C16—H16B	110.0
C4—C5—H5	119.8	N2—C17—C16	111.57 (16)
C6—C5—C4	120.40 (19)	N2—C17—H17A	109.3
C6—C5—H5	119.8	N2—C17—H17B	109.3
F1—C6—C5	117.95 (18)	C16—C17—H17A	109.3
F1—C6—C7	118.58 (18)	C16—C17—H17B	109.3
C5—C6—C7	123.34 (19)	H17A—C17—H17B	108.0
N2—C7—C6	122.04 (18)	C20—O6—H6	109.5
N2—C7—C8	121.89 (18)	C24—O7—H7	109.5
C8—C7—C6	115.79 (18)	O4—C18—C19	118.7 (3)
C7—C8—H8	119.2	O5—C18—O4	122.3 (3)
C9—C8—C7	121.53 (19)	O5—C18—C19	119.0 (2)
C9—C8—H8	119.2	C20—C19—C18	121.1 (2)
C4—C9—N1	119.20 (18)	C20—C19—C24	117.7 (2)
C4—C9—C8	120.89 (19)	C24—C19—C18	121.2 (2)
C8—C9—N1	119.91 (18)	O6—C20—C19	120.12 (19)
N1—C10—C2	123.07 (19)	O6—C20—C21	118.6 (2)
N1—C10—H10	118.5	C21—C20—C19	121.3 (2)
C2—C10—H10	118.5	C20—C21—H21	120.7
N1—C11—H11	115.6	C22—C21—C20	118.7 (2)
N1—C11—C12	118.27 (18)	C22—C21—H21	120.7
N1—C11—C13	120.07 (17)	C21—C22—H22	119.0
C12—C11—H11	115.6	C23—C22—C21	122.0 (2)
C13—C11—H11	115.6	C23—C22—H22	119.0
C13—C11—C12	60.32 (15)	C22—C23—H23	120.4
C11—C12—H12A	117.8	C22—C23—C24	119.3 (2)
C11—C12—H12B	117.8	C24—C23—H23	120.4
C11—C12—C13	59.47 (14)	O7—C24—C19	119.6 (3)
H12A—C12—H12B	115.0	O7—C24—C23	119.3 (3)
C13—C12—H12A	117.8	C23—C24—C19	121.1 (2)

F1—C6—C7—N2	−1.6 (3)	C9—C4—C5—C6	1.8 (3)
F1—C6—C7—C8	−175.68 (16)	C10—N1—C9—C4	2.8 (3)
O1—C1—C2—C3	176.50 (19)	C10—N1—C9—C8	−177.48 (18)
O1—C1—C2—C10	−4.2 (3)	C10—N1—C11—C12	102.8 (2)
O2—C1—C2—C3	−2.7 (3)	C10—N1—C11—C13	32.6 (3)
O2—C1—C2—C10	176.59 (18)	C10—C2—C3—O3	−175.52 (18)
O3—C3—C4—C5	−4.5 (3)	C10—C2—C3—C4	4.3 (3)
O3—C3—C4—C9	177.25 (17)	C11—N1—C9—C4	−175.72 (17)
N1—C11—C12—C13	−110.4 (2)	C11—N1—C9—C8	4.0 (3)
N1—C11—C13—C12	107.5 (2)	C11—N1—C10—C2	177.41 (18)
N2—C7—C8—C9	−171.43 (18)	C14—N2—C7—C6	42.6 (3)
N2—C14—C15—N3	52.0 (2)	C14—N2—C7—C8	−143.72 (19)
N3—C16—C17—N2	−58.5 (2)	C14—N2—C17—C16	61.2 (2)
C1—C2—C3—O3	3.8 (3)	C15—N3—C16—C17	53.4 (2)
C1—C2—C3—C4	−176.44 (17)	C16—N3—C15—C14	−51.4 (2)
C1—C2—C10—N1	178.08 (18)	C17—N2—C7—C6	−166.08 (18)
C2—C3—C4—C5	175.74 (17)	C17—N2—C7—C8	7.6 (3)
C2—C3—C4—C9	−2.5 (3)	C17—N2—C14—C15	−56.9 (2)
C3—C2—C10—N1	−2.6 (3)	O4—C18—C19—C20	−175.4 (2)
C3—C4—C5—C6	−176.56 (18)	O4—C18—C19—C24	3.0 (3)
C3—C4—C9—N1	−0.9 (3)	O5—C18—C19—C20	2.6 (3)
C3—C4—C9—C8	179.39 (18)	O5—C18—C19—C24	−179.0 (2)
C4—C5—C6—F1	173.48 (16)	O6—C20—C21—C22	−177.9 (2)
C4—C5—C6—C7	−2.5 (3)	C18—C19—C20—O6	−3.4 (3)
C5—C4—C9—N1	−179.21 (17)	C18—C19—C20—C21	177.1 (2)
C5—C4—C9—C8	1.1 (3)	C18—C19—C24—O7	2.3 (3)
C5—C6—C7—N2	174.32 (18)	C18—C19—C24—C23	−178.0 (2)
C5—C6—C7—C8	0.2 (3)	C19—C20—C21—C22	1.6 (3)
C6—C7—C8—C9	2.7 (3)	C20—C19—C24—O7	−179.2 (2)
C7—N2—C14—C15	97.0 (2)	C20—C19—C24—C23	0.5 (3)
C7—N2—C17—C16	−93.5 (2)	C20—C21—C22—C23	−0.9 (4)
C7—C8—C9—N1	176.92 (17)	C21—C22—C23—C24	0.0 (4)
C7—C8—C9—C4	−3.4 (3)	C22—C23—C24—O7	179.9 (2)
C9—N1—C10—C2	−1.1 (3)	C22—C23—C24—C19	0.2 (4)
C9—N1—C11—C12	−78.7 (2)	C24—C19—C20—O6	178.08 (19)
C9—N1—C11—C13	−148.89 (19)	C24—C19—C20—C21	−1.4 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O3	0.84	1.73	2.512 (2)	155
N3—H3A···O1ⁱ	0.91	2.38	2.977 (2)	123
N3—H3A···O6	0.91	2.09	2.890 (2)	146
N3—H3B···O4ⁱⁱ	0.91	2.18	2.897 (3)	136
N3—H3B···O5ⁱⁱ	0.91	2.24	3.090 (3)	155
C11—H11···O3ⁱⁱⁱ	1.00	2.46	3.239 (3)	134
C12—H12A···O4^iv	0.99	2.54	3.374 (3)	141
C13—H13A···O7^v	0.99	2.51	3.193 (3)	126
C14—H14A···F1	0.99	2.13	2.831 (2)	126
C15—H15B···O1ⁱⁱⁱ	0.99	2.33	3.282 (3)	161
C17—H17A···O5ⁱⁱ	0.99	2.60	3.408 (3)	139
O6—H6···O5	0.84	1.77	2.520 (3)	148
O7—H7···O4	0.84	1.85	2.508 (4)	134
C21—H21···O4ⁱⁱ	0.95	2.54	3.488 (3)	178

Symmetry codes: (i) x, y, z+1; (ii) x−1, y, z; (iii) −x+1, −y+1, −z+1; (iv) x−1, −y+3/2, z−1/2; (v) x−1, y, z−1.

4-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)piperazin-1-ium chloride–3,5-hydroxybenzoic acid–water (1/1/1) (II) top

Crystal data top

C₁₇H₁₉FN₃O₃⁺·C₇H₆O₄·Cl⁻·H₂O	Z = 1
M_r = 539.93	F(000) = 282
Triclinic, P1	D_x = 1.508 Mg m⁻³
a = 7.2165 (2) Å	Cu Kα radiation, λ = 1.54184 Å
b = 8.8298 (4) Å	Cell parameters from 10041 reflections
c = 10.1184 (3) Å	θ = 4.4–75.8°
α = 92.997 (3)°	µ = 2.00 mm⁻¹
β = 95.219 (2)°	T = 93 K
γ = 111.557 (4)°	Block, colourless
V = 594.60 (4) Å³	0.28 × 0.2 × 0.05 mm

Data collection top

XtaLAB Synergy R, DW system, HyPix diffractometer	4420 independent reflections
Radiation source: Rotating-anode X-ray tube, Rigaku XtaLAB Synergy-R	4323 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.035
Detector resolution: 10.0000 pixels mm^-1	θ_max = 74.5°, θ_min = 4.4°
ω scans	h = −9→9
Absorption correction: multi-scan (CrysAlisPro; Rigaku OD, 2020)	k = −10→11
T_min = 0.839, T_max = 1.000	l = −12→12
16358 measured reflections

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.034	w = 1/[σ²(F_o²) + (0.0589P)² + 0.0709P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.094	(Δ/σ)_max < 0.001
S = 1.12	Δρ_max = 0.25 e Å⁻³
4420 reflections	Δρ_min = −0.47 e Å⁻³
344 parameters	Absolute structure: Flack x determined using 1889 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
3 restraints	Absolute structure parameter: 0.011 (7)
Primary atom site location: dual

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
Cl1	0.85144 (9)	0.46863 (8)	0.40663 (7)	0.02533 (17)
F1	0.4599 (3)	0.5185 (2)	0.98137 (17)	0.0273 (4)
O1	0.3224 (3)	−0.3703 (3)	1.2978 (2)	0.0284 (5)
O2	0.3642 (4)	−0.1499 (3)	1.4315 (2)	0.0294 (5)
H2	0.379572	−0.051835	1.423817	0.044*
O3	0.3972 (3)	0.1143 (3)	1.3272 (2)	0.0280 (5)
N1	0.2840 (4)	−0.1445 (3)	0.9603 (2)	0.0213 (5)
N2	0.3796 (4)	0.3457 (3)	0.7334 (2)	0.0210 (5)
N3	0.4407 (4)	0.4661 (3)	0.4778 (2)	0.0233 (5)
H3A	0.412202	0.525266	0.413562	0.028*
H3B	0.528778	0.423848	0.448534	0.028*
C1	0.3370 (4)	−0.2274 (4)	1.3126 (3)	0.0249 (6)
C2	0.3276 (4)	−0.1342 (4)	1.1970 (3)	0.0222 (6)
C3	0.3655 (4)	0.0366 (4)	1.2138 (3)	0.0226 (6)
C4	0.3687 (4)	0.1155 (4)	1.0907 (3)	0.0220 (6)
C5	0.4158 (4)	0.2850 (4)	1.0937 (3)	0.0227 (6)
H5	0.444144	0.349621	1.176480	0.027*
C6	0.4203 (4)	0.3556 (4)	0.9773 (3)	0.0214 (6)
C7	0.3828 (4)	0.2667 (4)	0.8503 (3)	0.0202 (6)
C8	0.3389 (4)	0.1003 (4)	0.8483 (3)	0.0212 (6)
H8	0.314618	0.036841	0.765286	0.025*
C9	0.3297 (4)	0.0241 (4)	0.9661 (3)	0.0204 (6)
C10	0.2882 (4)	−0.2168 (4)	1.0730 (3)	0.0218 (6)
H10	0.262685	−0.330555	1.066643	0.026*
C11	0.2568 (4)	−0.2397 (4)	0.8324 (3)	0.0219 (6)
H11	0.381927	−0.228926	0.791979	0.026*
C12	0.0740 (5)	−0.2667 (4)	0.7366 (3)	0.0257 (6)
H12A	0.087678	−0.270948	0.640183	0.031*
H12B	−0.021768	−0.217677	0.763308	0.031*
C13	0.0926 (5)	−0.4047 (4)	0.8124 (3)	0.0259 (6)
H13A	0.007825	−0.440061	0.885206	0.031*
H13B	0.117236	−0.493315	0.762121	0.031*
C14	0.5686 (4)	0.4771 (4)	0.7139 (3)	0.0231 (6)
H14A	0.667670	0.429259	0.691921	0.028*
H14B	0.623427	0.549862	0.797431	0.028*
C15	0.5351 (5)	0.5757 (4)	0.6022 (3)	0.0253 (6)
H15A	0.447094	0.632955	0.628102	0.030*
H15B	0.665144	0.659131	0.586453	0.030*
C16	0.2536 (5)	0.3306 (4)	0.5001 (3)	0.0240 (6)
H16A	0.198514	0.256713	0.417103	0.029*
H16B	0.152583	0.375766	0.523119	0.029*
C17	0.2940 (4)	0.2351 (4)	0.6112 (3)	0.0221 (6)
H17A	0.167365	0.147006	0.626540	0.027*
H17B	0.388812	0.184215	0.586309	0.027*
O4	0.8307 (4)	0.7243 (3)	0.2157 (2)	0.0292 (5)
H4	0.845149	0.674900	0.282288	0.044*
O5	0.8281 (4)	0.9108 (3)	0.3721 (2)	0.0338 (5)
O6	0.9253 (4)	1.4048 (3)	0.1019 (2)	0.0282 (5)
H6	0.922943	1.426566	0.183393	0.042*
O7	0.7685 (4)	0.9471 (3)	−0.2173 (2)	0.0282 (5)
H7	0.769716	1.019031	−0.268691	0.042*
C18	0.8310 (5)	0.8689 (4)	0.2561 (3)	0.0245 (6)
C19	0.8373 (4)	0.9759 (4)	0.1448 (3)	0.0233 (6)
C20	0.8753 (4)	1.1395 (4)	0.1782 (3)	0.0230 (6)
H20	0.894255	1.180995	0.269053	0.028*
C21	0.8855 (4)	1.2429 (4)	0.0771 (3)	0.0230 (6)
C22	0.8531 (4)	1.1805 (4)	−0.0565 (3)	0.0229 (6)
H22	0.860643	1.250739	−0.125512	0.028*
C23	0.8099 (4)	1.0150 (4)	−0.0877 (3)	0.0231 (6)
C24	0.8048 (4)	0.9107 (4)	0.0123 (3)	0.0243 (6)
H24	0.779908	0.798399	−0.009350	0.029*
O8	0.7775 (4)	1.1327 (3)	−0.4306 (2)	0.0309 (5)
H8A	0.799 (7)	1.230 (7)	−0.457 (5)	0.046*
H8B	0.779 (7)	1.068 (7)	−0.492 (5)	0.046*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.0315 (3)	0.0267 (3)	0.0219 (3)	0.0151 (3)	0.0052 (2)	0.0029 (2)
F1	0.0445 (10)	0.0200 (9)	0.0203 (8)	0.0152 (8)	0.0057 (7)	−0.0001 (7)
O1	0.0376 (12)	0.0253 (12)	0.0242 (11)	0.0142 (9)	0.0011 (9)	0.0058 (9)
O2	0.0419 (13)	0.0289 (12)	0.0176 (10)	0.0132 (10)	0.0032 (9)	0.0048 (8)
O3	0.0426 (13)	0.0294 (12)	0.0144 (9)	0.0160 (10)	0.0048 (9)	0.0003 (8)
N1	0.0270 (12)	0.0220 (13)	0.0168 (12)	0.0117 (10)	0.0024 (9)	−0.0002 (9)
N2	0.0255 (12)	0.0232 (13)	0.0144 (11)	0.0097 (10)	0.0009 (9)	0.0008 (9)
N3	0.0303 (12)	0.0286 (13)	0.0173 (11)	0.0174 (10)	0.0047 (9)	0.0046 (10)
C1	0.0243 (14)	0.0325 (18)	0.0202 (14)	0.0131 (12)	0.0027 (11)	0.0050 (12)
C2	0.0238 (13)	0.0266 (15)	0.0179 (13)	0.0108 (11)	0.0036 (10)	0.0041 (12)
C3	0.0262 (14)	0.0272 (15)	0.0175 (14)	0.0131 (12)	0.0044 (11)	0.0038 (11)
C4	0.0234 (13)	0.0268 (15)	0.0177 (13)	0.0117 (11)	0.0035 (10)	0.0007 (11)
C5	0.0282 (14)	0.0232 (15)	0.0182 (13)	0.0117 (12)	0.0036 (10)	−0.0011 (11)
C6	0.0267 (14)	0.0176 (13)	0.0206 (14)	0.0094 (11)	0.0032 (11)	−0.0006 (11)
C7	0.0222 (13)	0.0228 (15)	0.0171 (13)	0.0105 (11)	0.0018 (10)	0.0016 (11)
C8	0.0239 (13)	0.0230 (15)	0.0167 (13)	0.0095 (11)	0.0021 (10)	−0.0023 (11)
C9	0.0210 (13)	0.0217 (14)	0.0188 (14)	0.0084 (10)	0.0030 (10)	0.0005 (11)
C10	0.0242 (13)	0.0215 (15)	0.0225 (14)	0.0112 (11)	0.0033 (11)	0.0050 (11)
C11	0.0291 (14)	0.0213 (14)	0.0173 (13)	0.0121 (12)	0.0024 (11)	−0.0009 (11)
C12	0.0317 (15)	0.0243 (15)	0.0213 (13)	0.0117 (12)	−0.0005 (12)	0.0006 (11)
C13	0.0329 (15)	0.0211 (15)	0.0242 (14)	0.0110 (12)	0.0038 (11)	−0.0004 (11)
C14	0.0281 (14)	0.0233 (15)	0.0183 (13)	0.0103 (12)	0.0021 (11)	0.0011 (11)
C15	0.0335 (15)	0.0240 (15)	0.0198 (14)	0.0116 (12)	0.0050 (11)	0.0040 (11)
C16	0.0291 (15)	0.0241 (15)	0.0192 (13)	0.0111 (12)	0.0006 (11)	0.0012 (11)
C17	0.0264 (14)	0.0242 (16)	0.0174 (13)	0.0121 (11)	0.0006 (10)	0.0006 (11)
O4	0.0432 (13)	0.0270 (12)	0.0240 (11)	0.0194 (10)	0.0077 (9)	0.0056 (9)
O5	0.0540 (14)	0.0318 (13)	0.0216 (11)	0.0224 (11)	0.0074 (10)	0.0025 (9)
O6	0.0423 (12)	0.0214 (11)	0.0220 (10)	0.0133 (9)	0.0046 (9)	−0.0007 (8)
O7	0.0408 (12)	0.0264 (12)	0.0186 (10)	0.0140 (10)	0.0046 (9)	−0.0003 (9)
C18	0.0269 (14)	0.0271 (16)	0.0230 (14)	0.0137 (12)	0.0048 (11)	0.0025 (12)
C19	0.0240 (13)	0.0265 (16)	0.0216 (14)	0.0116 (11)	0.0039 (11)	0.0017 (12)
C20	0.0254 (13)	0.0255 (15)	0.0196 (13)	0.0117 (11)	0.0029 (11)	−0.0003 (11)
C21	0.0244 (13)	0.0205 (14)	0.0243 (14)	0.0092 (11)	0.0023 (11)	−0.0019 (11)
C22	0.0249 (14)	0.0247 (15)	0.0215 (14)	0.0115 (11)	0.0045 (11)	0.0035 (12)
C23	0.0240 (13)	0.0281 (16)	0.0187 (14)	0.0119 (12)	0.0023 (11)	−0.0010 (12)
C24	0.0261 (14)	0.0259 (15)	0.0232 (15)	0.0122 (12)	0.0058 (11)	−0.0007 (12)
O8	0.0438 (13)	0.0286 (13)	0.0212 (11)	0.0146 (10)	0.0044 (9)	0.0017 (9)

Geometric parameters (Å, º) top

F1—C6	1.357 (4)	C12—C13	1.513 (4)
O1—C1	1.227 (4)	C13—H13A	0.9900
O2—H2	0.8400	C13—H13B	0.9900
O2—C1	1.314 (4)	C14—H14A	0.9900
O3—C3	1.263 (4)	C14—H14B	0.9900
N1—C9	1.397 (4)	C14—C15	1.517 (4)
N1—C10	1.339 (4)	C15—H15A	0.9900
N1—C11	1.463 (4)	C15—H15B	0.9900
N2—C7	1.407 (4)	C16—H16A	0.9900
N2—C14	1.468 (4)	C16—H16B	0.9900
N2—C17	1.467 (4)	C16—C17	1.510 (4)
N3—H3A	0.9100	C17—H17A	0.9900
N3—H3B	0.9100	C17—H17B	0.9900
N3—C15	1.489 (4)	O4—H4	0.8400
N3—C16	1.484 (4)	O4—C18	1.320 (4)
C1—C2	1.475 (4)	O5—C18	1.216 (4)
C2—C3	1.428 (4)	O6—H6	0.8400
C2—C10	1.369 (4)	O6—C21	1.356 (4)
C3—C4	1.457 (4)	O7—H7	0.8400
C4—C5	1.406 (4)	O7—C23	1.372 (4)
C4—C9	1.407 (4)	C18—C19	1.501 (4)
C5—H5	0.9500	C19—C20	1.385 (4)
C5—C6	1.358 (4)	C19—C24	1.395 (4)
C6—C7	1.419 (4)	C20—H20	0.9500
C7—C8	1.384 (4)	C20—C21	1.395 (4)
C8—H8	0.9500	C21—C22	1.399 (4)
C8—C9	1.394 (4)	C22—H22	0.9500
C10—H10	0.9500	C22—C23	1.389 (5)
C11—H11	1.0000	C23—C24	1.398 (4)
C11—C12	1.499 (4)	C24—H24	0.9500
C11—C13	1.492 (4)	O8—H8A	0.88 (6)
C12—H12A	0.9900	O8—H8B	0.82 (6)
C12—H12B	0.9900

C1—O2—H2	109.5	C11—C13—C12	59.9 (2)
C9—N1—C11	120.6 (2)	C11—C13—H13A	117.8
C10—N1—C9	119.9 (3)	C11—C13—H13B	117.8
C10—N1—C11	119.0 (3)	C12—C13—H13A	117.8
C7—N2—C14	115.7 (2)	C12—C13—H13B	117.8
C7—N2—C17	114.7 (2)	H13A—C13—H13B	114.9
C17—N2—C14	111.0 (2)	N2—C14—H14A	109.5
H3A—N3—H3B	108.0	N2—C14—H14B	109.5
C15—N3—H3A	109.3	N2—C14—C15	110.6 (2)
C15—N3—H3B	109.3	H14A—C14—H14B	108.1
C16—N3—H3A	109.3	C15—C14—H14A	109.5
C16—N3—H3B	109.3	C15—C14—H14B	109.5
C16—N3—C15	111.4 (2)	N3—C15—C14	110.2 (2)
O1—C1—O2	121.8 (3)	N3—C15—H15A	109.6
O1—C1—C2	121.2 (3)	N3—C15—H15B	109.6
O2—C1—C2	117.0 (3)	C14—C15—H15A	109.6
C3—C2—C1	121.3 (3)	C14—C15—H15B	109.6
C10—C2—C1	117.3 (3)	H15A—C15—H15B	108.1
C10—C2—C3	121.4 (3)	N3—C16—H16A	109.5
O3—C3—C2	122.5 (3)	N3—C16—H16B	109.5
O3—C3—C4	122.3 (3)	N3—C16—C17	110.7 (2)
C2—C3—C4	115.2 (3)	H16A—C16—H16B	108.1
C5—C4—C3	120.8 (3)	C17—C16—H16A	109.5
C5—C4—C9	118.6 (3)	C17—C16—H16B	109.5
C9—C4—C3	120.6 (3)	N2—C17—C16	109.4 (2)
C4—C5—H5	120.3	N2—C17—H17A	109.8
C6—C5—C4	119.5 (3)	N2—C17—H17B	109.8
C6—C5—H5	120.3	C16—C17—H17A	109.8
F1—C6—C5	119.0 (3)	C16—C17—H17B	109.8
F1—C6—C7	117.8 (2)	H17A—C17—H17B	108.2
C5—C6—C7	123.2 (3)	C18—O4—H4	109.5
N2—C7—C6	120.4 (3)	C21—O6—H6	109.5
C8—C7—N2	122.6 (3)	C23—O7—H7	109.5
C8—C7—C6	116.9 (3)	O4—C18—C19	113.1 (3)
C7—C8—H8	119.4	O5—C18—O4	123.1 (3)
C7—C8—C9	121.1 (3)	O5—C18—C19	123.8 (3)
C9—C8—H8	119.4	C20—C19—C18	117.9 (3)
N1—C9—C4	119.8 (2)	C20—C19—C24	121.7 (3)
C8—C9—N1	119.6 (3)	C24—C19—C18	120.4 (3)
C8—C9—C4	120.7 (3)	C19—C20—H20	120.3
N1—C10—C2	123.0 (3)	C19—C20—C21	119.3 (3)
N1—C10—H10	118.5	C21—C20—H20	120.3
C2—C10—H10	118.5	O6—C21—C20	122.8 (3)
N1—C11—H11	116.2	O6—C21—C22	117.1 (3)
N1—C11—C12	118.9 (3)	C20—C21—C22	120.1 (3)
N1—C11—C13	117.2 (2)	C21—C22—H22	120.2
C12—C11—H11	116.2	C23—C22—C21	119.6 (3)
C13—C11—H11	116.2	C23—C22—H22	120.2
C13—C11—C12	60.8 (2)	O7—C23—C22	121.6 (3)
C11—C12—H12A	117.8	O7—C23—C24	117.3 (3)
C11—C12—H12B	117.8	C22—C23—C24	121.1 (3)
C11—C12—C13	59.4 (2)	C19—C24—C23	118.2 (3)
H12A—C12—H12B	115.0	C19—C24—H24	120.9
C13—C12—H12A	117.8	C23—C24—H24	120.9
C13—C12—H12B	117.8	H8A—O8—H8B	112 (5)

F1—C6—C7—N2	−2.4 (4)	C9—N1—C11—C13	−140.3 (3)
F1—C6—C7—C8	−178.8 (3)	C9—C4—C5—C6	0.7 (4)
O1—C1—C2—C3	−173.3 (3)	C10—N1—C9—C4	−3.6 (4)
O1—C1—C2—C10	4.3 (4)	C10—N1—C9—C8	175.5 (3)
O2—C1—C2—C3	5.9 (4)	C10—N1—C11—C12	117.4 (3)
O2—C1—C2—C10	−176.5 (3)	C10—N1—C11—C13	47.5 (4)
O3—C3—C4—C5	2.6 (4)	C10—C2—C3—O3	178.2 (3)
O3—C3—C4—C9	−179.1 (3)	C10—C2—C3—C4	−2.9 (4)
N1—C11—C12—C13	−106.9 (3)	C11—N1—C9—C4	−175.7 (2)
N1—C11—C13—C12	109.5 (3)	C11—N1—C9—C8	3.4 (4)
N2—C7—C8—C9	−175.5 (3)	C11—N1—C10—C2	175.1 (3)
N2—C14—C15—N3	−55.7 (3)	C14—N2—C7—C6	62.4 (4)
N3—C16—C17—N2	58.0 (3)	C14—N2—C7—C8	−121.4 (3)
C1—C2—C3—O3	−4.2 (4)	C14—N2—C17—C16	−59.9 (3)
C1—C2—C3—C4	174.7 (3)	C15—N3—C16—C17	−56.1 (3)
C1—C2—C10—N1	−177.1 (3)	C16—N3—C15—C14	54.5 (3)
C2—C3—C4—C5	−176.4 (3)	C17—N2—C7—C6	−166.4 (3)
C2—C3—C4—C9	2.0 (4)	C17—N2—C7—C8	9.8 (4)
C3—C2—C10—N1	0.5 (4)	C17—N2—C14—C15	59.2 (3)
C3—C4—C5—C6	179.1 (3)	O4—C18—C19—C20	−168.3 (3)
C3—C4—C9—N1	1.1 (4)	O4—C18—C19—C24	11.9 (4)
C3—C4—C9—C8	−178.0 (3)	O5—C18—C19—C20	11.1 (5)
C4—C5—C6—F1	178.0 (3)	O5—C18—C19—C24	−168.6 (3)
C4—C5—C6—C7	−1.1 (5)	O6—C21—C22—C23	−179.4 (3)
C5—C4—C9—N1	179.5 (3)	O7—C23—C24—C19	−177.1 (3)
C5—C4—C9—C8	0.4 (4)	C18—C19—C20—C21	178.9 (3)
C5—C6—C7—N2	176.7 (3)	C18—C19—C24—C23	179.2 (3)
C5—C6—C7—C8	0.3 (4)	C19—C20—C21—O6	−178.9 (3)
C6—C7—C8—C9	0.8 (4)	C19—C20—C21—C22	1.4 (4)
C7—N2—C14—C15	−167.8 (2)	C20—C19—C24—C23	−0.5 (4)
C7—N2—C17—C16	166.7 (2)	C20—C21—C22—C23	0.3 (4)
C7—C8—C9—N1	179.7 (3)	C21—C22—C23—O7	177.1 (3)
C7—C8—C9—C4	−1.2 (4)	C21—C22—C23—C24	−2.2 (4)
C9—N1—C10—C2	2.9 (4)	C22—C23—C24—C19	2.3 (4)
C9—N1—C11—C12	−70.4 (4)	C24—C19—C20—C21	−1.3 (4)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O3	0.84	1.78	2.551 (3)	152
N3—H3A···O1ⁱ	0.91	1.75	2.652 (3)	172
N3—H3B···Cl1	0.91	2.30	3.106 (3)	148
C10—H10···F1ⁱⁱ	0.95	2.46	3.158 (4)	130
C12—H12B···O7ⁱⁱⁱ	0.99	2.47	3.435 (4)	166
C14—H14B···F1	0.99	2.27	2.927 (3)	123
C16—H16B···Cl1^iv	0.99	2.78	3.609 (3)	142
O4—H4···Cl1	0.84	2.28	3.082 (2)	160
O6—H6···Cl1^v	0.84	2.40	3.232 (2)	170
O7—H7···O8	0.84	1.96	2.769 (3)	161
O8—H8A···Cl1ⁱ	0.88 (6)	2.51 (6)	3.362 (3)	164 (4)
O8—H8B···O5^vi	0.82 (6)	2.05 (6)	2.865 (4)	170 (5)

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

Acknowledgements

The authors thank the Materials Analysis Division of the Open Facility Center at the Tokyo Institute of Technology for the research facilities.

References

Aakeröy, C. B., Hussain, I. & Desper, J. (2006). Cryst. Growth Des. 6, 474–480. Google Scholar
Childs, S. L., Stahly, G. P. & Park, A. (2007). Mol. Pharm. 4, 323–338. Web of Science CSD CrossRef PubMed CAS Google Scholar
Cruz-Cabeza, A. J. (2012). CrystEngComm, 14, 6362–6365. CAS Google Scholar
Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339–341. Web of Science CrossRef CAS IUCr Journals Google Scholar
Fujito, T., Oshima, T., Higashi, K., Ueda, K., Ito, M., Masu, H., Noguchi, S. & Moribe, K. (2021). Cryst. Growth Des. https://doi.org/10.1021/acs.cgd.1c01050. Google Scholar
Gdaniec, M., Gilski, M. & Denisov, G. S. (1994). Acta Cryst. C50, 1622–1626. CSD CrossRef CAS Web of Science IUCr Journals Google Scholar
Habibi-yangjeh, A., Danandeh-jenagharad, M. & Nooshyar, M. (2005). Bull. Korean Chem. Soc. 26, 2007–2016. CAS Google Scholar
Kavanagh, O. N., Croker, D. M., Walker, G. M. & Zaworotko, M. J. (2019). Drug Discovery Today, 24, 796–804. Web of Science CrossRef CAS PubMed Google Scholar
Macrae, C. F., Sovago, I., Cottrell, S. J., Galek, P. T. A., McCabe, P., Pidcock, E., Platings, M., Shields, G. P., Stevens, J. S., Towler, M. & Wood, P. A. (2020). J. Appl. Cryst. 53, 226–235. Web of Science CrossRef CAS IUCr Journals Google Scholar
Martínez-Alejo, J. M., Domínguez-Chávez, J. G., Rivera-Islas, J., Herrera-Ruiz, D., Höpfl, H., Morales-Rojas, H. & Senosiain, J. P. (2014). Cryst. Growth Des. 14, 3078–3095. Google Scholar
Nagalapalli, R. & Yaga Bheem, S. (2014). J. Crystallogr. pp. 1–5. Google Scholar
Nugraha, Y. P. & Uekusa, H. (2018). CrystEngComm, 20, 2653–2662. Web of Science CSD CrossRef CAS Google Scholar
Nugrahani, I., Tjengal, B., Gusdinar, T., Horikawa, A. & Uekusa, H. (2020). Crystals, 10, 1–19. Web of Science CrossRef Google Scholar
Olivera, M. E., Manzo, R. H., Junginger, H. E., Midha, K. K., Shah, V. P., Stavchansky, S., Dressman, J. B. & Barends, D. M. (2011). J. Pharm. Sci. 100, 22–33. Web of Science CrossRef CAS PubMed Google Scholar
Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249–259. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Putra, O. D. & Uekusa, H. (2020). Advances in Organic Crystal Chemistry, pp. 153–184. Singapore: Springer Singapore. Google Scholar
Rigaku OD (2020). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England. Google Scholar
Rojas, H. M., Chávez, J. G. D., Höpfl, D. H. R., Alejo, J. M. M. & Peláez, J. P. S. (2016). Solid forms of antibiotics. United States Patent and Trademark Office. Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sun, J., Sakai, S., Tauchi, Y., Deguchi, Y., Chen, J., Zhang, R. & Morimoto, K. (2002). Eur. J. Pharm. Biopharm. 54, 51–58. Web of Science CrossRef PubMed CAS Google Scholar
Surov, A. O., Vasilev, N. A., Churakov, A. V., Stroh, J., Emmerling, F. & Perlovich, G. L. (2019). Cryst. Growth Des. 19, 2979–2990. Web of Science CSD CrossRef CAS Google Scholar
Surov, A. O., Vasilev, N. A., Voronin, A. P., Churakov, A. V., Emmerling, F. & Perlovich, G. L. (2020). CrystEngComm, 22, 4238–4249. Web of Science CSD CrossRef CAS Google Scholar
Thakur, T. S. & Thakuria, R. (2020). Cryst. Growth Des. 20, 6245–6265. Web of Science CrossRef CAS Google Scholar

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Volume 78| Part 3| March 2022| Pages 259-263

https://doi.org/10.1107/S2056989022001177

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