The solid-state structure of the β-blocker metoprolol: a combined experimental and in silico investigation

Article abstract of DOI:10.1107/S2053229618017084

Metoprolol {systematic name: (RS)-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol}, C₁₅H₂₅NO₃, is a cardioselective β₁-adrenergic blocking agent that shares part of its molecular skeleton with a large number of other β-blockers. Results from its solid-state characterization by single-crystal and variable-temperature powder X-ray diffraction and differential scanning calorimetry are presented. Its molecular and crystal arrangements have been further investigated by molecular modelling, by a Cambridge Structural Database (CSD) survey and by Hirshfeld surface analysis. In the crystal, the side arm bearing the isopropyl group, which is common to other β-blockers, adopts an all-trans conformation, which is the most stable arrangement from modelling data. The crystal packing of metoprolol is dominated by an O—H…N/N…H—O pair of hydrogen bonds (as also confirmed by a Hirshfeld surface analysis), which gives rise to chains containing alternating R and S metoprolol molecules extending along the b axis, supplemented by a weaker O…H—N/N—H…O pair of interactions. In addition, within the same stack of molecules, a C—H…O contact, partially oriented along the b and c axes, links homochiral molecules. Amongst the solid-state structures of molecules structurally related to metoprolol deposited in the CSD, the β-blocker drug betaxolol shows the closest analogy in terms of three-dimensional arrangement and interactions. Notwithstanding their close similarity, the crystal lattices of the two drugs respond differently on increasing temperature: metoprolol expands anisotropically, while for betaxolol, an isotropic thermal expansion is observed.

Full text of DOI:10.1107/S2053229618017084

research papers
The solid-state structure of the b-blocker meto-
prolol: a combined experimental and in silico
investigation
ISSN 2053-2296
Patrizia Rossi,a Paola Paoli,a* Laura Chelazzi,b Luca Contic and Andrea Bencinic
aDepartment of Industrial Engineering, University of Florence, Via di S. Marta 3, Florence, I-50139, Italy, bCentro di
Cristallografia Strutturale, University of Florence, Via della Lastruccia 3, Sesto Fiorentino-FI, I-50019, Italy, and
cDepartment of Chemistry ‘Ugo Schiff’, University of Florence, Via della Lastruccia 3, Sesto Fiorentino-FI, I-50019, Italy.
*Correspondence e-mail: paola.paoli@unifi.it
Received 12 October 2018
Accepted 30 November 2018
Edited by A. R. Kennedy, University of Strath-
clyde, Scotland
Metoprolol {systematic name: (RS)-1-isopropylamino-3-[4-(2-methoxyethyl)-
phenoxy]propan-2-ol}, C15H25NO3, is a cardioselective ꢀ1-adrenergic blocking
agent that shares part of its molecular skeleton with a large number of other
ꢀ-blockers. Results from its solid-state characterization by single-crystal and
variable-temperature powder X-ray diffraction and differential scanning
calorimetry are presented. Its molecular and crystal arrangements have been
further investigated by molecular modelling, by a Cambridge Structural
Database (CSD) survey and by Hirshfeld surface analysis. In the crystal, the
side arm bearing the isopropyl group, which is common to other ꢀ-blockers,
adopts an all-trans conformation, which is the most stable arrangement from
modelling data. The crystal packing of metoprolol is dominated by an O—
Hꢀ ꢀ ꢀN/Nꢀ ꢀ ꢀH—O pair of hydrogen bonds (as also confirmed by a Hirshfeld
surface analysis), which gives rise to chains containing alternating R and S
metoprolol molecules extending along the b axis, supplemented by a weaker
Oꢀ ꢀ ꢀH—N/N—Hꢀ ꢀ ꢀO pair of interactions. In addition, within the same stack of
molecules, a C—Hꢀ ꢀ ꢀO contact, partially oriented along the b and c axes, links
homochiral molecules. Amongst the solid-state structures of molecules
structurally related to metoprolol deposited in the CSD, the ꢀ-blocker drug
betaxolol shows the closest analogy in terms of three-dimensional arrangement
and interactions. Notwithstanding their close similarity, the crystal lattices of the
two drugs respond differently on increasing temperature: metoprolol expands
anisotropically, while for betaxolol, an isotropic thermal expansion is observed.
Keywords: metoprolol; beta-blocker; in silico;
crystal structure; Hirshfeld surface; anisotropic
lattice expansion.
CCDC reference: 1882466
Supporting information: this article has
supporting information at journals.iucr.org/c
1. Introduction
Metoprolol, or (RS)-1-isopropylamino-3-[4-(2-methoxyethyl)-
phenoxy]propan-2-ol (see a in Scheme 1), is a cardioselective
ꢀ1-adrenergic blocking agent that has numerous medical
applications, such as the treatment of acute myocardial
infarction, heart failure, angina pectoris and hypertension
(Benfield et al., 1986; Brogden et al., 1977). The drug is usually
manufactured as a racemic mixture, notwithstanding the fact
that the ꢀ1-blocking activity resides in the S enatiomer
(Dasbiswas et al., 2008). In addition, given its quite low melting
point (323 K) (Ionescu et al., 2006), metoprolol is always
marketed in salt-based formulations (i.e. tartrate, succinate
and fumarate) that differ in the drug-release mechanism
(Wikstrand et al., 2003). According to the Biopharmaceutics
Classification Scheme, metoprolol belongs to the class I
substances (Amidon et al., 1995), meaning that it has both high
aqueous solubility and intestinal permeability, which makes
this API (active pharmaceutical ingredient) suitable for
Extended Release (ER) formulations.
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Recently, we have reported on the solid-state structure and
thermal behaviour of the tartrate (Paoli et al., 2016) and
fumarate salts (Rossi et al., 2018) studied by in silico and
experimental techniques. In both cases, comparisons with the
crystal structure of the closely related succinate salt (Barto-
lucci et al., 2009) were made and, where possible, the results
were rationalized on the basis of their respective crystal
arrangements.
been used to characterize time-controlled metoprolol tartrate
delivery systems using acrylic resins (Eudragit RL and
Eudragit RS) for the coating. Systems containing the drug salt
were compared to systems containing only the neutral meto-
prolol or only the tartaric acid to enable a better under-
standing of the interactions between the metoprolol salt and
the film, which can strongly affect the release of the drug
(Glaessl et al., 2009).
Although the literature reports (Ionescu et al., 2006) the
analysis by single-crystal X-ray diffraction of MB at 173 K
(MB-173; monoclinic crystal system, space group P21/n, one
independent molecule in the asymmetric unit), neither the
atomic coordinates nor the crystal data have been deposited in
the Cambridge Structural Database (CSD; Version 5.39 of
November 2017; Groom et al., 2016). For this reason, the solid-
state structure of metoprolol has been redetermined by a
single-crystal X-ray structure analysis.
The molecular structure of the metoprolol molecule has
been compared to those of metoprolol-like molecules depos-
ited in the CSD and the conformational space accessible to the
2-hydroxy-3-(isopropylamino)propoxy side arm has been
investigated by molecular dynamics simulations and density
functional theory (DFT) calculations.
The crystal structure has been analysed with the programs
Mercury CSD (Macrae et al., 2008) and Crystal Explorer17
(Turner et al., 2017) in order to identify the contributions to
the intermolecular contacts between the metoprolol molecules
and the results have been compared to those of structurally
related ꢀ-blocker molecules. Finally, variable-temperature
PXRD (VT-PXRD) and DSC measurements were carried out
in order to study thermally-induced changes, and the results
are discussed.
In this article, we have turned our attention to the meto-
prolol free base (MB hereafter). The interest in the solid-state
investigation of MB is due to two main reasons. Firstly,
metoprolol shares with a large number of ꢀ-blocker drugs the
2-hydroxy-3-(isopropylamino)propoxy side arm. Therefore, it
would be interesting to gain information about the molecular
structure of MB, in particular, the conformational preferences
due to the freedom of rotation of such a side arm, and the
intermolecular interactions and hydrogen-bond patterns
which originate from this side arm in order to find correlations
between structural parameters and physicochemical proper-
ties, such as melting point and solubility (Datta & Grant,
2004), and possibly to extend these findings to closely related
APIs, such as propanolol and betaxolol. Secondly, there is a
great deal of interest by the pharmaceutical industry in the
investigation of solids containing APIs with improved physi-
cochemical properties. In this context, the assessment of the
phase stability and of the thermal behaviour of compounds of
pharmaceutical interest (such as temperature-related phase
transformations, anisotropic lattice expansion/contraction and
thermal stability) provide valuable information (Rossi et al.,
2014; Paoli et al., 2016). For example, powder X-ray diffraction
(PXRD) and differential scanning calorimetry (DSC) have
2. Experimental
Metoprolol tartrate and betaxolol hydrochloride were
purchased from Sigma–Aldrich (product codes M5391-10G
and B5683-50MG, respectively) and used without further
purification.
2.1. Synthesis and crystallization
The metoprolol and betaxolol salts (350 and 100 mg,
respectively) were dissolved in a minimal amount of Milli-Q
water (0.5 and 2 ml, respectively) and passed through an anion
exchange resin (Dowex Marathon 11 chloride form; Sigma–
Aldrich CAS 69011-19-4) in order to obtain the free base
forms of metoprolol (MB) and betaxolol (BE hereafter)
directly in water. Concerning BE, water was completely
removed by evaporation under reduced pressure and the
resulting solid was dissolved in 3 ml of methanol–water
(20:80%, v/v). Slow evaporation of the organic phase at low
temperature (277–278 K) gave colourless crystals of BE
suitable for single-crystal X-ray diffraction analysis after two
weeks. In the case of MB, complete removal of the tartrate
1
anion was confirmed by H NMR analysis of solutions of the
compound in D2O at pD 11.10 (pH 10.70) before and after
ꢁ
88 Rossi et al.
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Table 1
Experimental details.
Table 2
Selected torsion angles (ꢃ) (S enantiomer) for MB and MB-173.
Crystal data
Chemical formula
Mr
Torsion angle
MB
MB-173a
C15H25NO3
267.36
Monoclinic, P21/n
100
16.0344 (3), 5.4375 (1), 17.8512 (3)
100.731 (2)
1529.18 (5)
4
Cu Kꢁ
0.64
C2—C1—O1—C7
C1—O1—C7—C8
O1—C7—C8—C9
C7–C8—C9—N1
C8—C9—N1—C10
C9—N1—C10—C11
C9—N1—C10—C12
C3—C4—C13—C14
C4—C13—C14—O3
C13—C14—O3—C15
4.7 (3)
4.5
177.6
177.8 (2)
ꢄ162.4 (2)
ꢄ176.0 (2)
ꢄ163.4 (2)
76.0 (2)
Crystal system, space group
Temperature (K)
ꢄ162.9
˚
a, b, c (A)
ꢄ176.0
ꢄ163.4
76.7
ꢀ (ꢃ)
3
˚
V (A )
ꢄ161.4 (2)
ꢄ161.2
Z
Radiation type
97.3 (2)
ꢄ74.1 (2)
177.4 (2)
98.1
ꢄ73.2
177.6
ꢃ (mmꢄ1
Crystal size (mm)
)
0.25 ꢂ 0.20 ꢂ 0.14
Reference: (a) Ionescu et al. (2006).
Data collection
Diffractometer
Absorption correction
Rigaku Excalibur Onyx
Multi-scan (CrysAlis PRO; Rigaku
OD, 2018)
0.923, 1.000
6999, 2915, 2070
1.5Ueq(C). Table 2 lists a selection of the torsion angles. The
hydrogen-bond parameters are listed in Table 3.
Tmin, Tmax
No. of measured, independent and
observed [I > 2ꢄ(I)] reflections
Rint
0.059
0.618
2.3. Variable-temperature unit-cell parameter determination
ꢄ1
˚
(sin ꢂ/ꢅ)max (A
)
The crystal lattice parameters of MB in the 130–300 K range
were determined from powder X-ray diffraction patterns
measured in a vacuum using a Bruker Advance diffractometer
(Cu Kꢁ radiation, 40 kV ꢂ 40 mA), equipped with a Bruker
LYNXEYE-XE detector, scanning range 2ꢂ = 7–35ꢃ, 0.02ꢃ
increments of 2ꢂ and a counting time of 0.8 s/step. The
temperature variation rate was 10 K minꢄ1 and, after the
target temperature had been reached, the sample was kept for
10 min at that temperature before proceeding with data
collection. The patterns underwent a Pawley fit with the
software TOPAS (Coelho, 2012). A shifted Chebyshev poly-
nomial with eight coefficients and a pseudo-Voigt function
were used to fit the background and peak shape, respectively.
The unit-cell parameters, volume and R factor for MB are
summarized in Table 4. The unit-cell parameters for BE were
determined by single-crystal diffraction analysis. Data were
measured at 100, 130, 170, 210, 230, 260 and 300 K using an
Rigaku Excalibur Onyx diffractometer. The unit-cell para-
meters are reported in Table S4 of the supporting information.
Refinement
R[F2 > 2ꢄ(F2)], wR(F2), S
No. of reflections
No. of parameters
0.050, 0.121, 1.04
2915
247
Only H-atom coordinates refined
H-atom treatment
˚
ꢄ3
Áꢆmax, Áꢆmin (e A
)
0.23, ꢄ0.22
Computer programs: CrysAlis PRO (Rigaku OD, 2018), SIR2004 (Burla et al., 2005),
SHELXL2014 (Sheldrick, 2015), ORTEP-3 (Farrugia, 2012), Mercury (Macrae et al.,
2008), Discovery Studio Visualizer (Accelrys, 2018) and PARST97 (Nardelli, 1995).
treatment with the anion-exchange resin. On purification on a
column, the singlet at 4.36 ppm attributed to protons b and b0
(Qiao et al., 2011) of the tartrate anion (Table S1 and Fig. S1 in
the supporting information) disappears, indicating the
complete absence of that anion in the final product. Removal
of the solvent was performed by evaporation under reduced
pressure to a final volume of ca 3 ml. The sample was divided
into two aliquots in order to test different crystallization
conditions. The first aliquot was allowed to evaporate at room
temperature (298 K), resulting in the formation of a micro-
crystalline powder of MB, after 3 d, suitable for PXRD
measurements. In the case of the second aliquot, a slower
evaporation of the solvent, performed at 277–278 K, afforded
the formation of colourless crystals of MB suitable for single-
crystal X-ray diffraction analysis after three weeks.
2.4. Differential scanning calorimetry
Differential scanning calorimetry (DSC) experiments on
MB samples were performed on a Mettler Toledo DSC1
Excellence. Measurements were run in aluminium pans with
pinhole lids (mass samples range from 1.5 to 3.5 mg).
Temperature and enthalpy calibrations were done using
indium as a standard. Melting point and heat of fusion (ÁH)
were determined by measurements in the 298!343!298 K
2.2. X-ray data collection and structure resolution
The crystal structure of MB was investigated by means of
single-crystal X-ray diffraction. Measurements were carried
out at 100 K with an Rigaku Excalibur Onyx diffractometer
using Cu Kꢁ radiation.
Table 3
Hydrogen-bond geometry (A, ).
ꢃ
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
O2—H2Oꢀ ꢀ ꢀN1i
N1–H1Nꢀ ꢀ ꢀO2ii
C5—H5ꢀ ꢀ ꢀO3iii
0.89 (3)
0.93 (3)
1.01 (3)
1.011 (3)
0.934 (4)
1.92 (3)
2.39 (3)
2.56 (3)
2.910 (4)
3.11 (1)
2.808 (3)
3.167 (3)
3.526 (3)
3.730 (4)
3.93 (1)
178 (3)
142 (2)
160 (2)
138.7 (2)
147 (3)
Crystal data, data collection and structure refinement
details are summarised in Table 1. All H atoms were located
from difference electron-density maps and their coordinates
were refined freely, while their displacement parameters were
linked to those of their parent atoms, i.e. Uiso(H) =
1.2Ueq(C,N,O), except for methyl groups, where Uiso(H) =
C13—H13Aꢀ ꢀ ꢀO3iii
C15—H15Aꢀ ꢀ ꢀO3iv
Symmetry codes: (i) ꢄx + 1, ꢄy + 2, ꢄz + 1; (ii) ꢄx + 1, ꢄy + 1, ꢄz + 1; (iii) x, y + 1, z; (iv)
ꢄx + 1, ꢄy + 1, ꢄz.
ꢁ
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The ꢀ-blocker metoprolol 89

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Table 4
Unit-cell parameters, volume (V) and R factor for MB at different
temperatures from XRPD data.
3
V (A )
ꢀ (ꢃ)
Rwp
˚
T (K) a (A)
˚
b (A)
˚
c (A)
˚
130
170
190
230
260
300
16.103 (2)
16.202 (1)
16.258 (3)
5.459 (1)
17.858 (6) 100.588 (7) 1543.1 (6) 5.77
5.4581 (8) 17.865 (3) 100.521 (7) 1553.3 (4) 5.87
5.453 (1) 17.862 (6) 100.471 (8) 1557.3 (6) 5.75
16.3816 (7) 5.4477 (6) 17.875 (2) 100.408 (7) 1568.9 (3) 6.27
16.4789 (6) 5.4394 (6) 17.892 (2) 100.349 (6) 1577.6 (3) 5.92
16.5703 (9) 5.4259 (8) 17.889 (8) 100.226 (8) 1582.8 (3) 6.32
Figure 1
Mercury (Macrae et al., 2008) view of the S enantiomer of metoprolol in
MB (50% probability displacement ellipsoids).
range. A linear heating rate of 10 K minꢄ1 was used. Experi-
ments were performed in air. DSC peaks were analyzed using
STARe software (Mettler–Toledo, 2018). All measurements
were performed in triplicate and standard errors were ꢅ0.1 K
for temperature and ꢅ0.3 kJ molꢄ1 for enthalpy.
phenoxy]-2-hydroxy-3-(isopropylamino)propane (IA) mole-
cules (details in Section 3.2). Total interaction energies for a
˚
cluster of molecules (molecules within a radius of 3.8 A with
respect to the reference molecule) of MB and BE at the
B3LYP/6-31G** level of theory were also calculated. The
corresponding energy frameworks were then constructed and
visualized using the default values (the radii of the cylinders
that make up the framework represent the relative strengths
of the molecular packing in different directions). In BE, the
cyclopropylmethoxy group is disordered over two positions
and the model having the highest occupancy factor was used to
generate the HS and for energy calculations.
2.5. Computational methods
Geometry optimizations (MM) and molecular dynamics
(MD) simulations were made using the CHARMm Force
Field (Brooks et al., 1983). MM calculations were performed
on each species using the Smart Minimizer energy minimiza-
tion procedure implemented in Discovery Studio (Version 2.1;
Accelrys, 2018) and before starting the MD simulations the
geometry of each compound was further optimized using the
steepest descent and conjugate gradient algorithms. MD
simulations were carried out at 100 and 300 K, both in vacuum
and in an implicit water model; water calculations were
performed mimicking the solvent by using a distance-depen-
dent dielectric constant of 80. In the MD simulations, the time
step was 1 fs for all runs, the equilibration time was 100 ps and
the production time was 1000 ps, and snapshot conformations
were sampled every 10 ps. The Minimization, the Standard
Dynamics Cascade and Analyze Trajectory, all implemented in
Discovery Studio, were the protocols used for energy mini-
mization, MD simulations and analysis of MD trajectories,
respectively.
GAUSSIAN09 (Frisch et al., 2010) was used for quantum
chemical (QC) calculations using the following functionals:
B3LYP (Becke, 1993; Stephens et al., 1994) and B97-D
(Grimme, 2006). The basis set was 6-311G(d,p) (Frisch et al.,
1984). The Berny algorithm was used (Peng et al., 1996). The
reliability of the stationary points was assessed by evaluation
of the vibrational frequencies.
Searching on motifs (to identify interaction motifs between
molecular fragments and determine their relative abundance)
and Calculating Intermolecular Energies using the UNI inter-
molecular potentials (Gavezzotti, 1994, 1998) in order to
identify the intermolecular interactions which are most
significant from an energetic point of view, both carried out
using the CSD Materials software (Macrae et al., 2008), were
used to analyse the crystal packing arrangement.
3. Results and discussion
3.1. Molecular structure from single-crystal X-ray diffraction
and modelling studies
The metoprolol molecule crystallizes in the monoclinic
space group P21/n with one molecule in the asymmetric unit
(Fig. 1). Because the cardiac ꢀ-blocking activity especially
resides in the S enantiomer, the following discussion will be
focused on this isomer. Bond lengths and angles are within the
expected ranges (Groom et al., 2016). The side chain bearing
the isopropyl group adopts an elongated conformation, with
the side-chain atoms O1, C7, C8 and C9 trans-disposed (all
trans or aT, Table 2), with all atoms, except for O2 and C11,
being almost coplanar with the attached aromatic ring, as
indicated by the torsion angles that define its orientation. By
contrast, the 2-methoxyethyl group is perpendicularly
oriented, as indicated by the value of the torsion angle about
the C13—C14 bond.
A search of the CSD was carried out to locate structures
with the molecular fragment sketched as b of Scheme 1. This
moiety, which features the 2-hydroxy-3-(isopropylamino)-
propoxy side arm together with the phenyl ring, is quite
interesting given that it is common to a large variety of
ꢀ-blocker drugs, such as atenolol, betaxolol, practolol and
bisoprolol. The CSD survey gives six compounds [neither
solvated species nor salts have been taken into account; the
structure of a metoprolol analogue (refcode IQEPUP; Melgar-
Fernandez et al., 2004) was not taken into account given its R
configuration] which, based on the conformation adopted by
the chain bearing the isopropyl group, can be classified in four
different conformational families, as illustrated in Fig. 2. The
superimposition of the X-ray structures of the six molecules
found in the CSD highlights that three of them, identified by
CrystalExplorer17 (Turner et al., 2017) was used to compute
Hirshfeld surfaces (HS) and their associated 2D (two-dimen-
sional) fingerprint plots to further investigate the inter-
molecular interactions in the crystal packing of MB and of the
strictly related propranolol (PR), BE and 1-[4-(cyanomethyl)-
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Figure 2
Superimposition of the X-ray structures of the neutral species found in the CSD (Groom et al., 2016). Structures are superimposed as ball-and-stick
atoms. H atoms have been omitted for clarity. Upper left: aT conformation (BEMBOK = red; GAPZEE = violet; KAZPOQ = brown); upper right: tttg+
conformation (CEZVIN = black; CIDHAZ = green); lower left: ttgꢄt conformation (ROKNUB = pink); lower right: ttg+g+ conformation (CIDHAZ =
pale blue).
the refcodes BEMBOK (Laguerre et al., 1981), GAPZEE
(Hou et al., 2012) and KAZPOQ (Akisanya et al., 1998), adopt
the aT conformation (differences about the final C—N and
N—C bonds have been neglected), as found in MB and MB-
173 (Ionescu et al., 2006; see Section 1); two molecules, i.e.
CEZVIN (de Castro et al., 2007) and one of the crystal-
lographically unique molecules in CIDHAZ (de Castro et al.,
2007), show a trans–trans–trans–gauche(+) (tttg+) arrangement
conformation in vacuum, while in simulated water, ꢇ4 also
populates gauche conformations. By contrast, ꢇ2 appears
frozen in the starting trans conformation both in vacuum and
simulated solvent, but in vacuum, at least 85% of the snapshot
conformations feature an O—Hꢀ ꢀ ꢀO intramolecular contact
˚
(distance less than 2.5 A), while in simulated solvent, the
percentage drops to 18%. Similarly, intramolecular N—Hꢀ ꢀ ꢀO
˚
contacts (distance less that 2.5 A) are observed in at least 86%
of the C—O—C—C—C atoms, while
a
trans–trans–
of the sampled conformations in vacuum, while the inclusion
of a distance-dependent dielectric constant makes such an
interaction definitely less important (it is present in less than
24% of the snapshot conformations).
From each MD trajectory at 300 K both in vacuum and in
the implicitly simulated water medium, ten snapshot confor-
mations were extracted and their geometries optimized; the
all-trans rotational isomer, i.e. the same as found in the solid
gauche(ꢄ)–trans (ttgꢄt) conformation is shown by ROKNUB
(Canotilho et al.,, 2008) and, finally, a trans–trans–gauche(+)–
gauche(+) (ttg+g+) conformation is shown by the second
independent molecule in the crystal packing of CIDHAZ. This
conformational variability is not surprising given that side
chains usually have a large conformational freedom, in addi-
tion, their conformations can be biased by intermolecular
interactions (vide infra). In this context, it appears interesting
to study the conformational behaviour of such a chain by
investigating the basic structure (BS, see c of Scheme 1)
common to all the above-mentioned ꢀ-adrenoreceptor
antagonists by Molecular Dynamics (MD) and Quantum
Chemical (QC) methods.
The BS_aT, BS_TG, BS_GT and BS_GG conformational
isomers representative of the four conformational families
(aT, tttg+, ttgꢄt and ttg+g+, respectively) found in the CSD were
used as the starting geometries for MD simulations at 100 and
300 K, both in a vacuum and in an implicit water model.
MD trajectories collected at 100 K, in vacuum and with the
implicitly simulated water medium, show overall metoprolol
geometries very close to the corresponding starting rotational
isomer found in the solid state (see Figs. S2, S3, S6 and S7 in
the supporting information). As expected, during MD simu-
lations at 300 K, both in vacuum and in the simulated water
medium, the side arm of the metoprolol molecule explores a
wider portion of the conformational space. In particular, the
starting geometry of the rotational isomer does not affect the
space sampled, as shown by the distribution of the side-chain
torsion-angle values, which is very similar irrespective of the
starting geometry of metoprolol (see Figs. S4, S5, S8 and S9 in
the supporting information). In particular, in all cases, ꢇ1
accesses the entire range of values, ꢇ3 and ꢇ4 adopt a trans
Figure 3
View along the a-axis direction of the zigzag chains of MB propagating
parallel to the b axis.
ꢁ
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Figure 4
Views of the crystal lattices of (left) propranolol (PR), (centre) betaxolol (BE) and (right) a precursor of atenolol (IA), showing chains of molecules
propagating along the shortest axis direction describing an R22(10) hydrogen-bond pattern.
state of metoprolol, is always the most stable. An identical
result comes from QC geometry optimization: the BS_aT
conformational isomer which, as expected, features O—
Hꢀ ꢀ ꢀO and N—Hꢀ ꢀ ꢀO contacts, has the lowest energy content,
ꢄx + 1, ꢄy + 2, ꢄz + 1; Table 3]; by contrast, the hydroxy
group acts as a definitely weaker hydrogen-bond acceptor
toward the N—H group of an inverted neighbouring molecule
ii
ꢃ
˚
[N1—H1ꢀ ꢀ ꢀO2 = 2.39 (3) A and 142 (2) ; symmetry code: (ii)
ꢄx + 1, ꢄy + 1, ꢄz + 1; Table 3]. As a whole, these interactions
give raise to two intrachain hydrogen-bond patterns of R22(10)
type [R22(10)>a>a and R22(10)>b>b] (Bernstein et al., 1995),
which are responsible for the formation of infinite chains of
metoprolol molecules extending along the b-axis direction
(Fig. S10 of the supporting information). Finally, a relatively
while the BS_GG isomer is the highest in energy [ÁG298
=
13.19 (B3LYP) and 5.19 kJ molꢄ1 (B97-D)].
In summary, the aminohydroxy side arm appears quite
flexible, being able to change its 3D arrangement in response
to the environment, as provided by the X-ray (crystal
environment), MD (in vacuum and simulated solvent) and
QC (in vacuum) data. Modelling results identify the all-trans
conformation as the most stable, irrespective of the model
(MM versus QC) and of the medium (vacuum versus simulated
solvent), which, consistently, is the most populated in the solid
state (X-ray data of MB/MB-173, BEMBOK, GAPZEE and
KAZPOQ).
weak interaction of the C—Hꢀ ꢀ ꢀO type [C5—H5ꢀ ꢀ ꢀO3iii
=
ꢃ
˚
2.56 (3) A and 160 (2) ; symmetry code: (iii) x, y + 1, z; Fig. 3]
partially oriented along the b and c axes, exists between
homochiral molecules belonging to the same chain.
Since the most significant hydrogen-bond motif, i.e. R22(10)
involves the molecular fragment that metropolol shares with a
large number of ꢀ-blocker drugs, the CSD was searched to find
which hydrogen-bond motifs are formed most commonly by a
pair of the molecular fragments sketched as d of Scheme 1
through O—Hꢀ ꢀ ꢀN(—H) interactions and the occurrence of
the double R22(10) motif. In most of the retrieved hits (70.6%),
at least one O—Hꢀ ꢀ ꢀN(—H) interaction holds the two mol-
ecular fragments together. The most common motifs are an
infinite chain (C1, i.e. chain, one contact), with frequency
29.4% (calculated as the number of hits found/number of
structures that feature the searched fragment), followed by R2
(i.e. ring, two contacts) (27.5%), while rings with four contacts
(R4) represent about 10% of the sample (these motif
descriptors are not the same as graph-set notation). Three (see
e of Scheme 1) of the 14 structures featuring an R2 pattern
show the same motif [R22(10)>a>a and R22(10)>b>b] as found
in MB (and MB-173): two of them, propranolol [refcode
PROPRA10 (Ammon et al., 1977), PR in the following] and
betaxolol (ROKNUB, BE in the following) belong to the
3.2. Crystal structure from single-crystal X-ray diffraction
and computational studies
In the crystal lattice, alternating R and S molecules of
metoprolol related by an inversion centre give rise to zigzag
chains extending along the b axis. Aview of the crystal packing
along the a axis is presented in Fig. 3. As already reported by
Ionescu et al. (2006), within the chain, each molecule is held in
place by two pairs of intermolecular hydrogen bonds involving
the hydroxy and amine groups, which both act as hydrogen-
bond donors and acceptors (Table 3). For symmetry reasons,
each pair of hydrogen bonds consists of two identical inver-
sion-related O—Hꢀ ꢀ ꢀN/Nꢀ ꢀ ꢀH—O and Oꢀ ꢀ ꢀH—N/N—Hꢀ ꢀ ꢀO
hydrogen bonds. When the hydroxy group acts as a donor
toward the N atom of an inversion-related molecule, the
resulting hydrogen bond is strong (Desiraju & Steiner, 1999)
i
ꢃ
˚
[O2—H2ꢀ ꢀ ꢀN1 = 1.92 (3) A and 178 (3) ; symmetry code: (i)
ꢁ
92 Rossi et al.
The ꢀ-blocker metoprolol
Acta Cryst. (2019). C75, 87–96

research papers
contacts, show up as pale-red regions. The corresponding
fingerprint plots are given in Fig. S13 in the supporting
information. All the fingerprint plots feature a pair of spikes
which represent the hydrogen bonds involving the NH/OH
groups (upper left OH donor, bottom left NH acceptor) and
two well-defined lateral wings (except PR, see later) which
account for C—Hꢀ ꢀ ꢀꢈ contacts. Finally Fig. S14 in the
supporting information shows the fingerprint plots broken
down into contributions from Nꢀ ꢀ ꢀH and Cꢀ ꢀ ꢀC close contacts
for the four molecules presented here (Fig. S15 shows the
other contributions). From these data, it emerges that the
nature and contribution of the intermolecular contacts of MB
and BE, which differ with respect to the terminal group
(isopropyl instead of cyclopropyl), are very similar; thus, they
have almost identical roles in the corresponding crystal
packing. By contrast, in PR and IA, Cꢀ ꢀ ꢀC and Nꢀ ꢀ ꢀH contacts
also contribute to the crystal packing through the naphthalene
group in PR and the cyano group in IA.
Due to the close similarity between MB and BE, the
following discussion focuses on these two compounds. Results
from intermolecular interaction energy calculations (B3LYP
and HF energy models) between molecular pairs in MB and
BE confirm that the O—Hꢀ ꢀ ꢀN/Nꢀ ꢀ ꢀH—O pair of hydrogen
bonds are by far the most important interactions, followed by
the C—Hꢀ ꢀ ꢀꢈ interactions in BE, while in MB, all the other
contacts are almost isoenergetic and definitely less important
from an energetic point of view. The values of the interaction
energy calculated between the closest molecules are used to
construct the energy framework shown in Fig. 7. A comparison
of the total energy frameworks evidences the strict similarity
between MB and BE. For example, the views along the a and b
axes of MB look very similar to the views down the b and a
Figure 5
dnorm surfaces of MB (left) and AI (right). Neighbouring molecules
associated with close contacts are also shown.
ꢀ-blocker class of drugs, the third is a reaction intermediate in
an alternative route for the synthesis of atenolol (KAZPOQ,
IA in the following). As already found for MB, in all three
cases, mutually inverted molecules face each other and are
held together by hydrogen bonds between the hydroxy and
amino groups, giving rise to chains extending along the
shortest axis direction (Fig. 4 and Table S2 in the supporting
information). In other words, the number, types, geometry and
patterns of the intermolecular hydrogen bonds described by
the OH/NH groups are practically identical. Thus, the overall
packing arrangements, as well as the densities and the Kitai-
gorodskii packing index (KPI) (Kitaigorodskii, 1961; Spek,
1998), are very similar (Table S3 in the supporting informa-
tion).
As already found for MB, and also in PR, BE and IA,
hydrogen bonds are definitely stronger when OH acts as a
donor than when it acts as an acceptor. Accordingly, in all the
crystal lattices, the most significant interaction in energetic
terms, as suggested by the intermolecular potential calculated
using the empirical UNI pair potential parameters (Gavezzotti
1994, 1998), is between the pair of molecules held together by
the O—Hꢀ ꢀ ꢀN/Nꢀ ꢀ ꢀH—O pair of hydrogen bonds. The
Oꢀ ꢀ ꢀH—N/N—Hꢀ ꢀ ꢀO pair of interactions appears less
important from an energetic point of view and, in PR and BE,
it even ranks third among the strongest interactions (second in
MB and IA; Fig. S11 in the supporting information). In PR
and BE, the relative arrangement of the pair of molecules
involved in the second strongest interaction (Fig. S12 in the
supporting information) suggests that ꢈ–ꢈ parallel-displaced
interactions in PR (along b) and C—Hꢀ ꢀ ꢀꢈ contacts in BE
(along a) are at work within each chain (for geometrical
details, see Table S2 in the supporting information).
The intermolecular interactions which hold together MB,
IA, PR and BE in their respective solids were further inves-
tigated using Hirshfeld surface (HS) analysis. The corre-
sponding HSs mapped with dnorm highlighting the inter-
molecular contacts are shown in Figs. 5 and 6; in all cases, the
dominant interaction is the O—Hꢀ ꢀ ꢀN/Nꢀ ꢀ ꢀH—O pair of
hydrogen bonds (two large red spots); the weaker Oꢀ ꢀ ꢀH—N/
N—Hꢀ ꢀ ꢀO couple of interactions, as well as less prominent
Figure 6
dnorm surfaces of PR (left) and BE (right). Neighbouring molecules
associated with close contacts are also shown.
ꢁ
Acta Cryst. (2019). C75, 87–96
Rossi et al.
The ꢀ-blocker metoprolol 93

research papers
Table 5
axes of BE (the same applies when viewing down the mol-
ecular axis).
Linear (ꢁ) and volume (ꢀ) thermal expansion coefficients (TECs)
calculated for MB taking as reference the unit-cell parameter values
calculated at 130 K.
In conclusion, an analysis of the intermolecular contacts in
MB, in terms of geometry, motifs, Hirshfeld surface and
intermolecular energies, highlights the close resemblance of
the metoprolol crystal packing with that of another ꢀ-blocker
drug betaxolol. In both cases, the O—Hꢀ ꢀ ꢀN/Nꢀ ꢀ ꢀH—O
hydrogen bonds appear to drive the arrangement of the
molecules in the corresponding solid, giving rise to chains of
alternating R and S molecules which propagate along the
shortest axis direction.
T (K)
ꢁa (10ꢄ5) Cꢄ1
ꢁb (10ꢄ5) Cꢄ1
ꢁc (10ꢄ5) Cꢄ1
ꢀ (10ꢄ4) Cꢄ1
130
170
190
230
260
300
–
–
–
–
15.4
16.0
17.3
18.0
17.1
ꢄ0.4
ꢄ1.8
ꢄ2.1
ꢄ2.8
ꢄ3.6
1.0
0.4
0.9
1.5
1.0
1.6
1.5
1.7
1.7
1.5
the XRPD patterns measured in the temperature range 130–
300 K superimpose quite well (Fig. S18 in the supporting
information); there were no differences in the overall number
of peaks and in their relative intensities on heating. Thus, no
phase changes occur under these experimental conditions up
to the MB melting point. However, a closer inspection shows
that peaks shift to a different extent as the temperature is
increased; several peaks move towards lower 2ꢂ values, while
the position of others remains almost unchanged, thus
suggesting that an anisotropic thermal expansion takes place
on raising the temperature. In particular, the shift is evident
for the (h00) and (h0l) peaks; by contrast, the (0k0), (hk0) and
(0kl) peaks do not shift significantly with the increasing
3.3. Crystal structure from X-ray microcrystalline powder
diffraction and differential scanning calorimetry analysis
The correspondence between the crystal structure of
metoprolol free base, as determined by single-crystal X-ray
diffraction (MB), and that of the bulk material was checked by
comparing calculated (150 K) and measured (130 K) powder
diffraction patterns (Fig. S16 in the supporting information).
DSC measurements performed in the 298–343 K range do not
show any evidence of a thermal event (see Fig. S17 in the
supporting information), except that related to the melting at
around 324 K (peak 323.9 K, extrapolated peak 324.0 K) with
a melting enthalpy of 188.1 J gꢄ1 (50.3 kJ molꢄ1). Consistently,
Figure 7
Energy frameworks corresponding to the total interaction energy in MB and BE (views are chosen in order to highlight similarities between MB and
BE).
ꢁ
94 Rossi et al.
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Acta Cryst. (2019). C75, 87–96

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temperature. The knowledge that MB undergoes an aniso-
tropic expansion on heating could be relevant when the phase
purity of the API, as well as its phase composition in formu-
lations, is checked by a comparison of the powder diffraction
pattern of a sample with a reference powder pattern: unex-
pected differences due to anisotropic lattice expansion/
contraction could lead to wrong conclusions about phase
purity/composition. In particular, the lattice parameters
calculated from the XRPD patterns (see Section 2) listed in
Table 4 confirm this observation; the a axis expands signifi-
cantly with respect to both b (which by contrast slightly
contracts) and c (which remains almost unchanged). This
trend is well quantified by the linear thermal expansion
coefficients (TECs; Hori et al., 2007; Krishnan et al., 1979)
listed in Table 5 (and it is only partially accounted for by the
intermolecular hydrogen bonds involving the hydroxy and
amine groups that link the metoprolol molecules along the b
axis).
Due to the crystal packing similarities between MB and BE,
it appears interesting to assess the thermal behaviour of
betaxolol. In the investigated temperature range (i.e. 100–
300 K), BE does not undergo any phase transition, as shown
by the single-crystal X-ray diffraction data. Polymorph I of
betaxolol (Maria et al., 2013) is stable under the experimental
conditions adopted and, what is more, the crystal lattice
expands isotropically on raising the temperature (the linear
thermal expansion coefficient for BE is reported in Table S5 of
the supporting information).
Thus, notwithstanding the strict similiarity between the
crystal packings of MB and BE in terms of the nature of the
most significant intermolecular contacts (number, type,
geometry, motifs, interaction energies) and packing efficiency
(density, KPI), they respond differently to thermal stimulus;
the metoprolol lattice expands anisotropically, while by
contrast and quite surprisingly, an isotropic expansion is
observed for betaxolol. Besides, the latter shows, as reported
by Canotilho (Canotilho et al., 2008), a slightly higher melting
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temperature, 341 K, but
a smaller melting enthalpy
(45.9 kJ molꢄ1). In other words, crystal structure similarities
do not imply similar macroscopic properties.
Hou, X., Li, Z. & Lv, Q. (2012). Acta Cryst. E68, o359.
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Therefore, however much has been done within the
framework of structure–property/function relationships, much
remains to be done, especially when APIs are concerned, due
to the relevance of their solid-form properties in view of their
pharmaceutical development.
Acknowledgements
Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe,
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The authors thank the Centro di Cristallografia Strutturale
(CRIST) of the University of Florence for the X-ray diffrac-
tion facilities and Dr Samuele Ciattini for his valuable tech-
nical assistance.
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supporting information
supporting information
Acta Cryst. (2019). C75, 87-96 [https://doi.org/10.1107/S2053229618017084]
The solid-state structure of the β-blocker metoprolol: a combined experimental
and in silico investigation
Patrizia Rossi, Paola Paoli, Laura Chelazzi, Luca Conti and Andrea Bencini
Computing details
Data collection: CrysAlis PRO (Rigaku OD, 2018); cell refinement: CrysAlis PRO (Rigaku OD, 2018); data reduction:
CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: SIR2004 (Burla et al., 2005); program(s) used to
refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: ORTEP-3 (Farrugia, 2012), Mercury (Macrae et
al., 2008) and Discovery Studio Visualizer (Accelrys, 2018); software used to prepare material for publication: PARST97
(Nardelli, 1995).
(RS)-1-Isopropylamino-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol
Crystal data
C15H25NO3
Mr = 267.36
F(000) = 584
Dx = 1.161 Mg m−3
Cu Kα radiation, λ = 1.54184 Å
Cell parameters from 2330 reflections
θ = 5.0–71.6°
Monoclinic, P21/n
a = 16.0344 (3) Å
b = 5.4375 (1) Å
c = 17.8512 (3) Å
β = 100.731 (2)°
V = 1529.18 (5) Å3
Z = 4
µ = 0.64 mm−1
T = 100 K
Prism, colourless
0.25 × 0.20 × 0.14 mm
Data collection
Rigaku Excalibur Onyx
diffractometer
Detector resolution: 8.1241 pixels mm-1
ω–scans
2915 independent reflections
2070 reflections with I > 2σ(I)
Rint = 0.059
θ
max = 72.4°, θmin = 4.1°
Absorption correction: multi-scan
(CrysAlis PRO; Rigaku OD, 2018)
h = −16→19
k = −6→5
T
min = 0.923, Tmax = 1.000
l = −21→21
6999 measured reflections
Refinement
Refinement on F2
Least-squares matrix: full
R[F2 > 2σ(F2)] = 0.050
wR(F2) = 0.121
S = 1.04
2915 reflections
247 parameters
0 restraints
Hydrogen site location: difference Fourier map
Only H-atom coordinates refined
w = 1/[σ2(Fo2)]
where P = (Fo2 + 2Fc2)/3
(Δ/σ)max < 0.001
Δρmax = 0.23 e Å−3
Δρmin = −0.22 e Å−3
Acta Cryst. (2019). C75, 87-96
sup-1

supporting information
Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance
matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles;
correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate
(isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)
x
y
z
Uiso*/Ueq
O1
O2
H2O
O3
N1
H1N
C1
C2
H2
C3
H3
C4
C5
H5
C6
H6
C7
0.58862 (10)
0.49093 (9)
0.4649 (18)
0.62308 (10)
0.58702 (12)
0.5419 (18)
0.61709 (13)
0.66687 (13)
0.6861 (16)
0.69224 (13)
0.7276 (17)
0.66966 (13)
0.62073 (14)
0.6073 (16)
0.59397 (14)
0.5592 (17)
0.61650 (15)
0.6038 (17)
0.6786 (18)
0.57844 (13)
0.5848 (16)
0.62571 (14)
0.6279 (17)
0.6861 (18)
0.64417 (14)
0.6730 (18)
0.71156 (18)
0.751 (2)
0.9053 (3)
0.7620 (3)
0.906 (6)
0.4679 (3)
0.7743 (4)
0.666 (5)
0.8718 (4)
0.6755 (4)
0.549 (5)
0.6635 (4)
0.519 (5)
0.8443 (4)
1.0405 (4)
1.176 (5)
1.0543 (4)
1.193 (5)
0.7381 (5)
0.566 (5)
0.745 (5)
0.8244 (4)
1.024 (5)
0.7091 (4)
0.520 (5)
0.761 (5)
0.7272 (4)
0.575 (5)
0.9217 (6)
0.936 (6)
1.085 (7)
0.894 (7)
0.7176 (6)
0.578 (6)
0.700 (6)
0.878 (6)
0.8303 (4)
1.004 (5)
0.727 (5)
0.7253 (4)
0.804 (5)
0.31091 (8)
0.42778 (8)
0.4260 (14)
−0.02818 (8)
0.57732 (9)
0.5745 (14)
0.24370 (11)
0.22848 (11)
0.2658 (14)
0.15809 (11)
0.1456 (13)
0.10277 (11)
0.11998 (11)
0.0808 (14)
0.18926 (11)
0.2012 (13)
0.37205 (11)
0.3583 (14)
0.3846 (14)
0.43925 (11)
0.4429 (13)
0.51207 (11)
0.5055 (14)
0.5229 (14)
0.65126 (11)
0.6498 (14)
0.66736 (15)
0.6256 (19)
0.6686 (19)
0.714 (2)
0.0271 (4)
0.0264 (4)
0.032*
0.0284 (4)
0.0240 (4)
0.029*
0.0220 (4)
0.0229 (4)
0.027*
0.0239 (5)
0.029*
0.0226 (4)
0.0237 (4)
0.028*
0.0234 (4)
0.028*
0.0255 (5)
0.031*
0.031*
0.0229 (4)
0.027*
0.0247 (5)
0.030*
0.030*
0.0260 (5)
0.031*
0.0402 (6)
0.060*
0.060*
0.060*
0.0369 (6)
0.055*
H7A
H7B
C8
H8
C9
H9A
H9B
C10
H10
C11
H11A
H11B
H11C
C12
H12A
H12B
H12C
C13
H13A
H13B
C14
H14A
0.685 (2)
0.749 (2)
0.59151 (16)
0.547 (2)
0.626 (2)
0.71339 (13)
0.7050 (18)
0.7649 (19)
0.7124 (18)
0.02582 (12)
0.0122 (14)
0.0302 (13)
−0.03709 (12)
−0.0389 (14)
0.055*
0.055*
0.0256 (5)
0.031*
0.031*
0.560 (2)
0.69651 (14)
0.7105 (17)
0.7519 (17)
0.62961 (15)
0.5725 (18)
0.0258 (5)
0.031*
Acta Cryst. (2019). C75, 87-96
sup-2

supporting information
H14B
C15
H15A
H15B
H15C
0.6438 (17)
0.55782 (17)
0.505 (2)
0.556 (2)
0.569 (2)
0.765 (5)
0.3694 (5)
0.433 (6)
0.195 (7)
0.411 (6)
−0.0871 (15)
−0.08500 (14)
−0.0801 (17)
−0.0775 (17)
−0.1393 (18)
0.031*
0.0343 (6)
0.051*
0.051*
0.051*
Atomic displacement parameters (Å2)
U11
U22
U33
U12
U13
U23
O1
O2
O3
N1
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
0.0332 (8)
0.0217 (8)
0.0344 (9)
0.0216 (9)
0.0217 (10)
0.0232 (10)
0.0222 (10)
0.0209 (10)
0.0268 (11)
0.0240 (10)
0.0279 (12)
0.0178 (10)
0.0193 (10)
0.0248 (11)
0.0417 (15)
0.0326 (13)
0.0257 (11)
0.0317 (12)
0.0373 (14)
0.0310 (8)
0.0284 (9)
0.0220 (8)
0.0303 (10)
0.0272 (11)
0.0229 (11)
0.0250 (11)
0.0249 (11)
0.0227 (11)
0.0225 (11)
0.0277 (12)
0.0279 (12)
0.0317 (13)
0.0295 (12)
0.0447 (16)
0.0552 (17)
0.0286 (12)
0.0247 (11)
0.0272 (13)
0.0191 (7)
0.0056 (7)
−0.0005 (6)
−0.0026 (6)
0.0015 (8)
−0.0015 (8)
0.0022 (8)
0.0003 (8)
−0.0068 (8)
−0.0025 (9)
0.0029 (9)
0.0016 (9)
−0.0030 (8)
0.0009 (9)
0.0049 (9)
−0.0115 (12)
0.0086 (12)
−0.0021 (9)
−0.0017 (9)
−0.0042 (10)
0.0101 (6)
0.0062 (6)
0.0010 (6)
0.0049 (7)
0.0064 (8)
0.0032 (8)
0.0050 (8)
0.0044 (8)
0.0043 (8)
0.0036 (8)
0.0069 (8)
0.0047 (8)
0.0034 (8)
0.0034 (8)
−0.0026 (11)
0.0071 (10)
0.0084 (8)
0.0073 (9)
−0.0021 (10)
0.0038 (6)
0.0013 (6)
0.0008 (6)
0.0015 (7)
0.0000 (8)
0.0047 (8)
−0.0021 (9)
−0.0016 (8)
0.0028 (9)
−0.0001 (8)
0.0041 (9)
0.0010 (8)
−0.0020 (9)
0.0009 (9)
−0.0012 (11)
0.0030 (11)
0.0005 (9)
0.0029 (8)
0.0016 (10)
0.0295 (7)
0.0269 (7)
0.0204 (8)
0.0183 (9)
0.0222 (9)
0.0246 (10)
0.0220 (9)
0.0215 (9)
0.0236 (10)
0.0218 (10)
0.0234 (10)
0.0229 (10)
0.0234 (10)
0.0306 (12)
0.0236 (11)
0.0239 (10)
0.0219 (10)
0.0350 (13)
Geometric parameters (Å, º)
O1—C1
O1—C7
O2—C8
O2—H2O
O3—C14
O3—C15
N1—C9
N1—C10
N1—H1N
C1—C2
C1—C6
C2—C3
C2—H2
C3—C4
C3—H3
C4—C5
C4—C13
1.373 (2)
C7—H7B
C8—C9
C8—H8
C9—H9A
C9—H9B
C10—C11
C10—C12
C10—H10
C11—H11A
C11—H11B
C11—H11C
C12—H12A
C12—H12B
C12—H12C
C13—C14
C13—H13A
C13—H13B
0.98 (3)
1.427 (3)
1.421 (3)
0.88 (3)
1.415 (3)
1.420 (3)
1.462 (3)
1.482 (3)
0.93 (3)
1.390 (3)
1.390 (3)
1.393 (3)
0.97 (3)
1.393 (3)
1.02 (3)
1.514 (3)
1.09 (3)
1.04 (3)
0.99 (3)
1.501 (4)
1.515 (3)
0.95 (3)
1.06 (4)
0.99 (4)
0.94 (4)
1.03 (4)
0.98 (3)
1.00 (4)
1.513 (3)
1.01 (3)
1.04 (3)
1.392 (3)
1.516 (3)
Acta Cryst. (2019). C75, 87-96
sup-3

supporting information
C5—C6
C5—H5
C6—H6
C7—C8
C7—H7A
1.385 (3)
1.01 (3)
0.99 (3)
1.518 (3)
0.98 (3)
C14—H14A
C14—H14B
C15—H15A
C15—H15B
C15—H15C
1.00 (3)
0.99 (3)
0.94 (4)
0.96 (3)
1.04 (3)
C1—O1—C7
C8—O2—H2O
C14—O3—C15
C9—N1—C10
C9—N1—H1N
C10—N1—H1N
O1—C1—C2
O1—C1—C6
C2—C1—C6
C1—C2—C3
C1—C2—H2
C3—C2—H2
C2—C3—C4
C2—C3—H3
C4—C3—H3
C5—C4—C3
C5—C4—C13
C3—C4—C13
C6—C5—C4
C6—C5—H5
C4—C5—H5
C5—C6—C1
C5—C6—H6
C1—C6—H6
O1—C7—C8
O1—C7—H7A
C8—C7—H7A
O1—C7—H7B
C8—C7—H7B
H7A—C7—H7B
O2—C8—C9
O2—C8—C7
C9—C8—C7
O2—C8—H8
C9—C8—H8
C7—C8—H8
N1—C9—C8
N1—C9—H9A
C8—C9—H9A
118.43 (16)
103.9 (18)
110.67 (17)
112.58 (16)
104.2 (16)
106.5 (15)
124.69 (18)
115.31 (18)
119.98 (18)
119.16 (19)
122.1 (15)
118.7 (15)
121.7 (2)
120.2 (14)
118.1 (14)
117.86 (18)
120.36 (19)
121.77 (19)
121.32 (19)
121.2 (14)
117.5 (14)
119.9 (2)
121.1 (14)
118.9 (14)
107.01 (17)
113.3 (15)
113.5 (16)
108.1 (15)
110.4 (15)
104 (2)
110.35 (17)
110.11 (17)
109.87 (17)
109.0 (14)
109.6 (13)
107.9 (13)
111.40 (17)
111.1 (14)
109.6 (13)
N1—C9—H9B
C8—C9—H9B
H9A—C9—H9B
N1—C10—C11
N1—C10—C12
108.6 (14)
111.3 (14)
105 (2)
110.63 (19)
108.75 (18)
111.3 (2)
110.4 (15)
106.4 (16)
109.4 (16)
114.5 (18)
110 (2)
106 (3)
112 (2)
106 (3)
109 (3)
112.4 (19)
113 (2)
108 (3)
107.4 (19)
108 (3)
107 (3)
114.19 (18)
109.4 (14)
106.5 (14)
109.3 (14)
109.9 (13)
107 (2)
110.30 (17)
109.7 (15)
112.3 (14)
110.8 (15)
109.8 (15)
104 (2)
110.9 (19)
107.9 (18)
108 (3)
110.8 (18)
109 (3)
C11—C10—C12
N1—C10—H10
C11—C10—H10
C12—C10—H10
C10—C11—H11A
C10—C11—H11B
H11A—C11—H11B
C10—C11—H11C
H11A—C11—H11C
H11B—C11—H11C
C10—C12—H12A
C10—C12—H12B
H12A—C12—H12B
C10—C12—H12C
H12A—C12—H12C
H12B—C12—H12C
C14—C13—C4
C14—C13—H13A
C4—C13—H13A
C14—C13—H13B
C4—C13—H13B
H13A—C13—H13B
O3—C14—C13
O3—C14—H14A
C13—C14—H14A
O3—C14—H14B
C13—C14—H14B
H14A—C14—H14B
O3—C15—H15A
O3—C15—H15B
H15A—C15—H15B
O3—C15—H15C
H15A—C15—H15C
H15B—C15—H15C
111 (3)
Acta Cryst. (2019). C75, 87-96
sup-4