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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)-
ꢁ
90 Rossi et al.
The ꢀ-blocker metoprolol
Acta Cryst. (2019). C75, 87–96