Crystal Structures of New Ivermectin Pseudopolymorphs

Abstract

New pseudopolymorphs of ivermectin (IVM), a potential anti-COVID-19 drug, were prepared. The crystal structure for three pseudopolymorphic crystalline forms of IVM has been determined using single-crystal X-ray crystallographic analysis. The molecular conformation of IVM in crystals has been compared with the conformation of isolated molecules modeled by DFT calculations. In a solvent with relatively small molecules (ethanol), IVM forms monoclinic crystal structure (space group I2), which contains two types of voids. When crystallized from solvents with larger molecules, like -valerolactone (GVL) and methyl tert-butyl ether (MTBE), IVM forms orthorhombic crystal structure (space group P212121). Calculations of the lattice energy indicate that interactions between IVM and solvents play a minor role; the main contribution to energy is made by the interactions between the molecules of IVM itself, which form a framework in the crystal structure. Interactions between IVM and molecules of solvents were evaluated using Hirshfeld surface analysis. Thermal analysis of the new pseudopolymorphs of IVM was performed by differential scanning calorimetry and thermogravimetric analysis.

Full text

crystals
Article
Crystal Structures of New Ivermectin Pseudopolymorphs
Kirill Shubin 1, Agris B¯
erzin
,š2and Sergey Belyakov 1,*


Citation: Shubin, K.; B¯
erzin
,š, A.;
Belyakov, S. Crystal Structures of
New Ivermectin Pseudopolymorphs.
Crystals 2021,11, 172. https://
doi.org/10.3390/cryst11020172
Academic Editor: Alexander Pöthig
Received: 14 January 2021
Accepted: 30 January 2021
Published: 9 February 2021
Publisher’s Note: MDPI stays neutral
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iations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1Latvian Institute of Organic Synthesis, 21 Aizkraukles St., LV-1006 Riga, Latvia; kir101@osi.lv
2Faculty of Chemistry, University of Latvia, 1 Jelgavas St., LV-1004 Riga, Latvia; agris.berzins@lu.lv
*Correspondence: serg@osi.lv; Tel.: +371-67014897
Abstract:
New pseudopolymorphs of ivermectin (IVM), a potential anti-COVID-19 drug, were
prepared. The crystal structure for three pseudopolymorphic crystalline forms of IVM has been
determined using single-crystal X-ray crystallographic analysis. The molecular conformation of
IVM in crystals has been compared with the conformation of isolated molecules modeled by DFT
calculations. In a solvent with relatively small molecules (ethanol), IVM forms monoclinic crystal
structure (space group I2), which contains two types of voids. When crystallized from solvents
with larger molecules, like
γ
-valerolactone (GVL) and methyl tert-butyl ether (MTBE), IVM forms
orthorhombic crystal structure (space group P2
1
2
1
2
1
). Calculations of the lattice energy indicate that
interactions between IVM and solvents play a minor role; the main contribution to energy is made by
the interactions between the molecules of IVM itself, which form a framework in the crystal structure.
Interactions between IVM and molecules of solvents were evaluated using Hirshfeld surface analysis.
Thermal analysis of the new pseudopolymorphs of IVM was performed by differential scanning
calorimetry and thermogravimetric analysis.
Keywords: ivermectin; pseudopolymorph; crystal structure analysis; Hirshfeld surface analysis
1. Introduction
Ivermectin (IVM) is a macrocyclic lactone developed in the 1980s as an antipara-
sitic multitarget drug with nematocidal, acaricidal and insecticidal activities [
1
,
2
]. It is a
semisynthetic substance, which is used as a mixture of two components: major B
1a
(R = Et)
and minor B1b (R = Me), as shown in Figure 1.
Figure 1. Ivermectin as a mixture of two components B1a (R = Et) and B1b (R = Me).
Crystals 2021,11, 172. https://doi.org/10.3390/cryst11020172 https://www.mdpi.com/journal/crystals

Crystals 2021,11, 172 2 of 15
Currently hundreds of millions of people are using IVM for treatment of various
parasitic diseases, including onchocerciasis, lymphatic filariasis, scabies, etc. [
3
]. While at
nanomolar concentrations it is effective mostly against nematodes, at higher concentrations,
multiple new targets were identified [
4
,
5
]. Activity against various types of cancer has been
reported [
6
–
9
]. IVM is an approved drug for treatment of rosacea due to its antiparasitic
properties complemented by anti-inflammatory activity [
10
–
12
]. In addition, the activity
of IVM against various viruses [
13
], including COVID-19 [
14
,
15
], is of a special interest.
Several clinical studies are planned or have been started for this indication [16,17].
Nature and properties of a solid form of drugs is important for their production and all
relevant applications [
18
]. Analysis and understanding of the internal molecular arrange-
ments in crystalline materials bear the key to preparation of materials with controllable
and predictable solubility, hygroscopicity and mechanical properties [19,20].
Interestingly, only few crystalline structures of IVM have been reported so far. First,
two single-crystal diffraction data sets on a close analogue avermectin are deposited
in the Cambridge Crystallographic Data Centre with CCDC refcodes BASVAS [
21
] and
YOCYAT [
22
]. IVM was discussed in a context of interaction with the transmembrane
domain of certain receptors using models with low resolution [
23
,
24
]. Additionally, several
crystalline polymorphs were characterized by powder X-ray diffraction [25–28]. The only
single crystal data of IVM B
1a
published to date was reported by Seppala et al.: CSD,
Version 5.40, November 2019; CCDC refcode BIFYOF [
29
]. The IVM crystal structure
represents monoclinic modification (space group I2) of IVM as acetone-chloroform solvate.
This form is not satisfactory for drug application due to the presence of a toxic chlorinated
solvent (chloroform).
In this study, we performed crystallization of IVM from several solvents to investigate
whether other crystal structures of this compound can be obtained. It was found that
new pseudopolymorphs, isomorphic to the already reported monoclinic structure, contain
various solvent molecules in the structure cavities. Moreover, in the presence of larger
solvent molecules, orthorhombic structure can be also obtained having bigger cavities able
to accommodate larger solvent molecules. Both types of crystal structures were analyzed
and compared by characterizing intermolecular interactions and molecular conformation,
and the ability of IVM to incorporate different solvents is discussed.
2. Materials and Methods
2.1. Synthesis of Ivermectin Pseudopolymorphs
IVM was obtained from Key Organics,
γ
-valerolactone (GVL) from Carbosynth, UK.
New pseudopolymorphs of IVM were prepared by crystallization of the starting material
from an appropriate solvent. Preparation of IVM as ethanol solvate (
I
) was carried out
by dissolution of IVM (1 g) in EtOH (5 mL) at reflux. Solution was cooled to room
temperature and left for 48 h to effect the crystallization. Crystals of IVM as GVL solvate
(
II
) were prepared by brief heating of IVM (1 g) in GVL (3 mL) up to 120
◦
C, and the
obtained clear solution was left at room temperature for 72 h to effect the crystallization.
Pseudopolymorph of IVM as methyl tert-butyl ether (MTBE) solvate (
III
) was prepared
by dissolution of IVM (1 g) in MTBE (20 mL) at reflux and addition of hexanes (20 mL).
Crystals were obtained at room temperature in 24 h.
2.2. Single Crystal X-ray Diffraction
For compounds
I
(ethanol solvate),
II
(GVL solvate) and
III
(MTBE solvate) diffrac-
tion data were collected at low temperature on a Rigaku, XtaLAB Synergy, Dualflex,
HyPix (Rigaku Corporation, Tokyo, Japan) diffractometer using copper monochromated
Cu-K
α
radiation (
λ
= 1.54184 Å). The crystal structures were solved by direct methods
with the ShelXT (Version 2014/5, Georg-August Universität Göttingen, Germany) [
30
]
structure solution program using intrinsic phasing and refined with the SHELXL (ver-
sion 2016/6, Georg-August Universität Göttingen, Germany) refinement package [
31
].
All calculations were performed with the help of Olex2 software (version Olex2.refine,

Crystals 2021,11, 172 3 of 15
Durham University, UK) [
32
]. The lattice parameters for solvate
I
were determined also at
room temperature; the density of the compound was measured by the flotation method
in ethanol-chloroform system. For calculation of the density, the actual composition of
crystal
I
is 2(IVM)
×
2C
2
H
5
OH
×
1.5H
2
O (with Z= 2), where IVM = 0.8B
1a ×
0.2B
1b
,
where B1a = C48H74O14 and B1b = C47H72O14. Molecular crystals of bulky molecules with
many degrees of freedom, with disordered solvents and not containing heavy atoms (the
heaviest atom in IVM is oxygen) cannot be close to ideal, therefore, R-factors for such
crystal structures are quite high. Table 1lists the main crystal data for these compounds.
Table 1. Crystal data and structure refinement parameters for solvates I,II and III 1.
Parameter I at Low
Temperature
I at Room
Temperature II III
Empirical formula (IVM) ×
C2H5OH ×0.75H2O(IVM) ×
C2H5OH ×0.75H2O2(IVM) ×
0.5C5H8O2
2(IVM) ×
0.5C5H12O
Formula weight 931.85 931.85 1794.59 1787.605
Temperature (K) 173 293 160 160
Crystal size (mm3)0.21 ×0.11 ×0.08 0.17 ×0.09 ×0.06 0.22 ×0.16 ×0.11 0.21 ×0.17 ×0.12
Crystal system Monoclinic Monoclinic Orthorhombic Orthorhombic
Space group I2I2P212121P212121
a(Å) 14.8197(7) 14.8612(9) 16.7127(2) 16.7309(1)
b(Å) 9.1753(5) 9.1973(6) 24.5777(2) 24.5805(2)
c(Å) 39.094(2) 39.201(4) 24.5908(2) 24.5797(2)
β(◦) 94.490(5) 95.04(5) 90.0 90.0
Unit cell volume (Å3)5299.5(5) 5337.4(7) 10100.9(2) 10108.5(1)
Molecular multiplicity 4 4 4 4
Calculated density
(g/cm3)1.168 1.161 1.180 1.175
Measured density
(g/cm3)1.16
Absorption coefficient
(mm−1)0.703 0.698 0.702 0.696
F(000) 2023.5 2023.5 3887.2 3875.2
2θmax (◦) 156.0 150.0 155.0 155.0
Reflections collected 29158 5217 71647 75795
Number of
independent reflections
9710 - 20489 20330
Reflections with I>2
σ
(I)
9485 - 18694 19029
Number of refined
parameters 601 - 1143 1143
R-factors (for I>2σ(I)
and for all data) 0.0971, 0.0982 - 0.0981, 0.1051 0.0972, 0.1010
1IVM = 0.8(C48H74 O14)×0.2(C47 H72O14).
Overlay of IVM geometry was done in BIOVIA Discovery Studio 4.5 Visualizer
v4.5.0.15071 (Dassault Systèmes, France), by matching the position of atoms C3, C14
and O26.
2.3. Modeling and Quantitative Analysis of Crystal Structures
To better characterize the differences and similarities between the crystal structures
of IVM, their Hirshfeld surfaces were generated using CrystalExplorer17 (University of
Western Australia, Perth, Australia) [
33
]. They were analyzed by performing the generation
and analysis of Hirshfeld surface 2D fingerprint plots and summarizing the information
about intermolecular interactions [
34
,
35
]. Additionally, for ethanol solvate
I
, pairwise
intermolecular interaction energies for molecules, for which atoms are within 3.8 Å of
the central molecule, were estimated in CrystalExplorer17 at the B3LYP-D2/6-31G(d,p)
level [36] with electronic structure calculations performed in Gaussian09.

Crystals 2021,11, 172 4 of 15
The gas phase geometry optimizations were carried out using Schrödinger software
at the B3LYP/6-311G(d,p) level of theory [37].
2.4. Thermal Analysis
The differential scanning calorimetric/thermogravimetric (DSC/TGA) analysis was
performed on a TGA/DSC2 (Mettler Toledo, Greifensee, Switzerland) apparatus. Open
100
µ
L aluminum pans were used. Heating of the samples from 25 to 600
◦
C was performed
at a heating rate 10
◦
C
·
min
–1
. Samples of 5–10 mg mass were used, and the nitrogen flow
rate was 100 ±10 mL·min–1.
Thermal analysis (TGA and DSC) shows typical data for solid solutions (see files in
the Supplementary Materials). The peaks in the DSC patterns, which correspond to the
melting process, are quite wide: at 165
◦
C for
I
and at 172
◦
C for
II
. Their half-widths are:
17
◦
C for solvate
I
and 8
◦
C for solvate
II
. Thermal analysis data also show that solvate
II
loses the solvent (GVL) at 83
◦
C. In
I
, this process is not observed. This is due to the fact
that solvent in II is not stabilized by strong hydrogen bonds.
3. Results
3.1. Molecular Structure in the Crystal Cell
For investigation of the molecular structure of IVM by means of X-ray diffraction
method, single crystals of
I
have been grown from ethanol solution. It is well known that
the semisynthetic substance of IVM represents a mixture of two compounds—B
1a
and B
1b
in molar ratio 80:20. Thus, a solid solution of these two components as a single crystal
structure was obtained during crystallization. The formation of solid solutions, where
several chemically distinct components occupy the same position in the crystal lattice, is
not such a rare occurrence in organic and inorganic chemistry [
38
]. However, there are not
so many crystal structures of this type in crystallographic databases. This is largely due to
the technical difficulties observed during their crystallographic studies. Despite the fact
that there are two components of IVM in crystals, this paper will further focus on the main
component of IVM, namely B
1a
. Figure 2illustrates an Oak Ridge Thermal-Ellipsoid Plot
(ORTEP) diagram of solvate
I
showing the atom-labeling scheme and thermal displacement
ellipsoids for non-H atoms. For ethyl group (carbon atoms C33 and C34 and hydrogen
atoms H33a, H33b, H34a, H34b and H34c), the value of occupancy g-factor = 0.8 and, for
methyl group (carbon atom C33 and hydrogen atoms H33a, H33b and H33c), the value of
g-factor = 0.2.
The major figure of the molecular structure is the 16-membered macrocycle, which
consists of atoms C3, C10–C20, O21, C22, C4 and C9. In the crystals, the least-squares
plane of this cycle corresponds to the crystallographic plane of (0 3 2). Atoms C15 and C12
have maximal deviations (0.406(5) and –0.382(5) Å, respectively) from this plane. It should
be noted that positive and negative atomic deviations from the plane alternate. Thus, in
crystal
I
, the macrocycle has a “crown” conformation. In the fused bicyclic system, both
cycles are characterized by an envelope conformation: atom C8 deviates on 0.590(5) Å from
the plane of other atoms in the tetrahydrofuran cycle, and atom C9 deviates on 0.627(4) Å
from the plane of other five atoms in the cyclohexene cycle. All the other cycles in the
molecule have a usual chair conformation.
For the comparison of molecular structures in crystal
I
, in vacuo geometry optimiza-
tion of the molecule using density functional theory (DFT) calculations was performed. A
perspective view of the molecule in the free state and in crystals is shown in Figure 3.

Crystals 2021,11, 172 5 of 15
Figure 2.
ORTEP diagram of IVM molecule in crystal
I
showing atomic labels and 50% probability
displacement ellipsoids. Hydrogen atoms are shown as small spheres of arbitrary radii.
Figure 3.
Overlay of IVM molecules present in crystal
I
as determined in the crystal structure (colored
by elements) and after in vacuo geometry optimization (blue).

Crystals 2021,11, 172 6 of 15
As seen from the figure, the molecular conformation in the free state is close to the
one in the crystals. Main differences are associated with the presence of intramolecular
hydrogen bonds of the OH
· · ·
O type, which are formed in vacuo between the hydroxy
groups present in the molecule, whilst, in the crystals, these groups are involved in in-
termolecular hydrogen bonds. The geometrical parameters of these bonds are as follows:
angle O39−H39· · · O1 is equal to 113.5◦, H39· · · O1 length is 2.146 Å; O37−H37· · · O23 is
144.9
◦
, H37
· · ·
O23 is 1.865 Å; O57
−
H57
· · ·
O58 is 111.5
◦
and H57
· · ·
O58 is 2.278 Å. Table
S2 (Supporting Information) lists the values of selected torsion angles; for these angles, a
difference is observed in the free state and in the crystal structure.
As already mentioned, the hydroxy groups form intermolecular hydrogen bonds
in the crystal structure. The hydroxy group O39
−
H39 forms a moderate hydrogen
bond O39
−
H39
· · ·
O58 (
−
1 + x, 1 + y,z) with length 3.048(7) Å (H39
· · ·
O58 = 2.14 Å,
O39
−
H39
· · ·
O58 = 178
◦
). The hydroxy group O57
−
H57 forms bifurcated hydrogen
bonds O57
−
H57
· · ·
O37 (1+x,y,z) (O57
· · ·
O37 = 2.856(6) Å, H57
· · ·
O37 = 2.35 Å,
O57
−
H57
· · ·
O37 = 121
◦
) and O57
−
H57
· · ·
O23 (1+x,y,z) (O57
· · ·
O23 = 3.024(6) Å,
H57
· · ·
O23 = 2.25 Å, O57
−
H57
· · ·
O23 = 158
◦
). Hydrogen bond C61
−
H61c
· · ·
O39 (
−
x,
−
1+y, 1
−
z), which can be considered a moderate hydrogen bond of the CH
· · ·
O type,
should be also noted. The parameters of this bond are as follows: C61
· · ·
O39 = 3.263(7) Å,
H61c
· · ·
O39 = 2.80 Å and C61
−
H61c
· · ·
O39 = 110
◦
. By means of these intermolecular
hydrogen bonds, three-dimensional framework containing voids is formed from IVM
molecules. Figure 4shows a projection of the unit cell of crystal
I
along the monoclinic
axis. For geometric modeling of voids in crystals, solvents were removed formally and
volumes of voids were then calculated. As it can be seen, there are two types of the
voids: one of them lies in special positions (on symmetry axes of order 2), its volume is
82 Å3; the second void with volume of 221 Å3corresponds to general positions.
Figure 4. A projection of the unit cell of crystal Ialong the monoclinic axis showing the voids.
It is known that many molecules of macrocyclic compounds are characterized by
the fact that the function of distribution of the electrostatic potential has considerable
extrema [
39
]; this allows the molecules to form supramolecular adducts with ions and polar
molecules. However, for the IVM molecule, the electrostatic potential obtained from the
DFT calculation of the distribution of electron density does not contain significant extrema.
This is also the case for other macrocyclic molecules [
40
]. For this reason, molecules
of IVM can form inclusion compounds with polar molecules due to the formation of
hydrogen bonds.

Crystals 2021,11, 172 7 of 15
Disordered ethanol molecules fill the larger voids in the crystal structure and form
hydrogen bonds of the OH
· · ·
O type with oxygen atom O57. This oxygen atom and carbon,
which is attached to O57 atom, were located from a differential Fourier synthesis and
refined with g= 1.0. However, the methyl group of ethanol is disordered, and two carbon
atoms of this group were located with a differential synthesis and refined with g= 0.5. The
length of this hydrogen bond is 2.832(9) Å. The smaller voids are filled with disordered
water molecules, which form hydrogen bonds with the lengths of 2.67(1)–3.12(1) Å. It
should be noted that this crystal structure is isomorphous to the structure of avermectin
B1a, in which the voids are filled with methanol molecules [21].
The crystal structure of solvate
I
is isomorphous to the structure of IVM-acetone-
chloroform solvate (refcode BIFYOF in the Cambridge Crystallographic Database). The
void that is occupied by chloroform molecules in BIFYOF in crystal
I
is filled with disor-
dered water molecules. That is why the cell volume is by 96.3 Å
3
lower than that of the
BIFYOF structure.
We were interested in testing whether IVM can be crystallized with solvent molecules
exceeding the size of the voids (see Figure 4). It turned out that, upon crystallization of IVM
from GVL, IVM forms molecular crystals
II
of orthorhombic system (space group P2
1
2
1
2
1
)
with two independent molecules of IVM in the asymmetric unit. For both molecules, the
occupancy g-factor of IVM B
1a
is 0.8. IVM molecules form a three-dimensional framework
by means of a system of intermolecular hydrogen bonds. This framework also contains
voids; Figure 5gives a projection of the unit cell along the crystallographic parameter
ashowing their layout. The volume of voids is 552 Å
3
, and they are filled with GVL
molecules. Figure 6shows a content of the asymmetric unit of the crystal. The value of
occupation g-factor for the solvent is 0.5; this means that not all voids are filled with GVL.
It should be noted that, in the crystal structure, there molecules of (R)-enantiomer of GVL
are present despite the fact that a racemic solvent was used for the crystallization. This
suggests that IVM is suitable for the separation of racemic solvents.
The conformation changes of the IVM molecule in solvate
II
are small, but the system
of hydrogen bonds in the crystal structure differs from solvate
I
. The strongest intermolec-
ular hydrogen bonds that form the framework are as follows: O57I–H
· · ·
O43II (
−
1/2 + x,
3/2
−
y, 1
−
z) with length 2.904(5)Å (H
· · ·
O = 2.01 Å, O–H
· · ·
O = 159
◦
); O37II
−
H
· · ·
O57I
(x,y,z) with length 2.694(5)Å (H
· · ·
O = 1.82 Å, O–H
· · ·
O = 166
◦
) and O57II
−
H
· · ·
O43I (1
−
x, 1/2 + y, 1/2
−
z) with length 2.869(5)Å (H
· · ·
O = 2.11 Å, O–H
· · ·
O = 154
◦
), where I and
II are the designations of the independent molecules. Among the weak hydrogen bonds,
the contact O37I–H
· · ·
O1s (x,y,z) (O
· · ·
O = 2.494(9) Å, H
· · ·
O = 2.99Å, O–H
· · ·
O = 122
◦
)
that binds the IVM molecule with the solvent (GVL) should be distinguished.
In continuation of the study, crystallization of IVM from MTBE solution was also car-
ried out. The size of the molecule of the solvent (MTBE) is relatively large and approaches
the size of GVL. It turns out that IVM crystallizes in orthorhombic system and forms crystal
structure
III
that is isomorphous to crystal structure
II
with g= 0.8 for the B
1a
component
of IVM. The voids of crystal structure III are filled with disordered MTBE molecules.
Conformation of IVM in both isomorphous monoclinic structures (
I
and BIFYOF) and
conformation of each symmetrically unique molecule in both orthorhombic structures (
II
and
III
) are identical, as shown in Figures S1–S3 (Supplementary Materials). Meanwhile,
conformation of IVM present in monoclinic structures and in orthorhombic structures is dif-
ferent (see Figure 7). The conformation of IVM in monoclinic structures is the most differing,
while the conformation for both symmetrically independent molecules in orthorhombic
structures are also notably different.

Crystals 2021,11, 172 8 of 15
Figure 5.
A projection of the unit cell of crystal
II
on the crystallographic plane (100) showing
the voids.
Figure 6.
ORTEP diagram of two independent molecules of IVM in the asymmetric unit of crystal
II
showing thermal ellipsoids with a 50% probability level. For the sake of clarity, hydrogen atoms and
solvent have been omitted.

Crystals 2021,11, 172 9 of 15
Figure 7.
Overlay of IVM molecules present in crystal
I
(colored by elements, representing
conformation in monoclinic structures; overlay of conformation in
I
and BIFYOF is given in
Figure S1, Supplementary Materials) and crystal
II
(blue and red, representing conformation in
orthorhombic structures, overlays of conformations in
II
and
III
are given in Figures S2 and S3,
(Supplementary Materials).
3.2. Qualitative Analysis of Intermolecular Interactions: Hirshfeld Surface and 2D
Fingerprint Plots
Crystal structures of IVM solid forms were also analyzed using Hirshfeld surfaces.
This, however, was complicated by the fact that part of the structures contained disordered
solvent molecules and the fact that all three of them were actually solid solutions. Therefore,
ethanol molecules in one of its potential position was used for IVM ethanol solvate
I
in
this analysis. Hydrogen atoms were added to the solvent molecule in IVM MTBE solvate
III
in Mercury 2020.2.0. Two hydrogen atoms were removed from the acetone molecule in
BIFYOF to obtain molecule with reliable atom arrangement. In all structures of
I
,
II
and
III
,
only the geometry corresponding to B1a (R = Et) was used.
The Hirshfeld surfaces of IVM molecule in the analyzed structures are given in
Figure 8(both sides of the molecule are shown). It can be seen that, as expected, the
closest normalized distances between the atoms involved in intermolecular interactions
are present for the atoms that form conventional and also weak hydrogen bonds (most
obviously, hydroxy groups containing oxygen atoms O37, O39 and O57, carbonyl group
oxygen atom O23 and part of the ether-type oxygen atoms). As could be expected, Hirshfeld
surfaces of both monoclinic structures were quite similar and exhibited more pronounced
difference if compared to the surfaces of IVM in orthorhombic structures. Meanwhile,
Hirshfeld surfaces of both symmetrically independent molecules of the orthorhombic
structures also demonstrated notable differences showing that each of the molecule forms
different intermolecular interactions. These differences can be partially associated with the
different conformation of the molecules in monoclinic and orthorhombic structures and
each symmetrically independent molecule in orthorhombic structures.

Crystals 2021,11, 172 10 of 15
Figure 8.
Hirshfeld surfaces of IVM in the analyzed structures. All surfaces designated by 1 (on the
left) correspond to front view, whereas surfaces designated by 2 (on the right) correspond to the back
view. A and B designates each of symmetrically independent molecules.
Two-dimensional fingerprint plots of these Hirshfeld surfaces are given in Figure 9.
Again, it can be seen that plots obtained from monoclinic structures are highly similar and
there are differences to the plots obtained from the orthorhombic structures, most notably,
in the points representing H
· · ·
O contacts, showing that there are shorter contacts present in
the monoclinic structures. Meanwhile, the differences between plots for both symmetrically
independent molecules of orthorhombic structures are notably less pronounced with the
most notable difference again being the arrangement of points representing H
· · ·
O contacts
and illustrating that both symmetrically independent molecules form hydrogen bonds of
different geometric parameters.
Summary of the quantitative analysis of the contact types present in the Hirshfeld
surfaces is given in Figure 10. Using this representation, it can be seen that there were no
major differences in the relative contribution of different contact types in Hirshfeld surfaces
of IVM structures. In solvate BIFYOF containing acetone and chloroform as solvents, part
of the H
· · ·
H contacts were replaced with H
· · ·
Cl, but the sum of these two contact types
was the same as for purely H
· · ·
H contacts for the remaining surfaces. The most notable
difference among all surfaces seemed to be the larger number of H
· · ·
O contacts present
on the surface of A molecule II.

Crystals 2021,11, 172 11 of 15
Figure 9.
Two-dimensional fingerprint plots of Hirshfeld surfaces of IVM structures showing the
regions associated with the types of interatomic contacts H
· · ·
O, O
· · ·
H and H
· · ·
Cl (present only in
the structure BIFYOF).

Crystals 2021,11, 172 12 of 15
Figure 10.
Percentage contributions of individual contacts to the Hirshfeld surface area for the
analyzed IVM crystal structures.
3.3. Intermolecular Interaction Energy of IVM Ethanol Solvate I
In order to get an additional quantitative picture of the intermolecular interactions
of the crystal structure of solvate
I
, calculation of interaction energies was performed in
CrystalExplorer17 by assessing the electrostatic (E
ele
), polarization (E
pol
), dispersion (E
dis
)
and exchange-repulsion (E
rep
) terms that together form the total interaction energy (E
tot
)
(see Table 2) [
36
,
41
]. However, as water molecules exhibit partial occupancy factors and are
not a critical part of the hydrogen bonding network, they were excluded from the structure
prior to these calculations.
As can be seen from Table 2, the greatest contribution to stabilization of this structure
is made by the interactions between neighboring IVM molecules and, in most cases,
these interactions are dominated by dispersion energy component. Additionally, even
for the hydrogen-bonded molecule pairs the dispersion energy component is dominant
or comparable to the electrostatic components (the highest importance of electrostatic
components is observed in a pair having E
ele
= –43.3 kJ mol
–1
, E
pol
= –13.6 kJ mol
–1
and
E
disp
= –56.2 kJ mol
–1
). This can be easily understood considering the size of the molecule
and the relatively small amount of hydrogen bonds present in this structure (compared to
the weak and dispersion interactions). Notably lower contribution in the stabilization of this
IVM crystal structure is provided by interaction between IVM and ethanol molecules, and
even here electrostatic interactions and dispersion interactions provide similar contribution,
and only in the pair connected by a hydrogen bond the electrostatic components are the
dominant ones.
It follows from the calculations that the energy of the crystal lattice consists mainly
of the energies of interactions between IVM molecules, which form the framework of the
structure. This means that substance
I
is an exemplary compound of the host-guest type. In
this crystal structure, the voids can be filled with molecules of other solvents if the size of
these solvent molecules corresponds to these voids. This is observed in the crystal structure
of BIFYOF, where the structure and symmetry of the IVM framework are preserved.

Crystals 2021,11, 172 13 of 15
Table 2.
The pairwise total interaction energy (E
tot
) and its components (electrostatic (E
ele
), polarization (E
pol
), dispersion
(E
dis
) and exchange-repulsion (E
rep
) energy terms) for the closest molecule pairs (having atoms within 3.8 Å radius from the
central molecule) for IVM-ethanol solvate Icalculated in CrystalExplorer17.
Symmetry R/Å Eele
kJ/mol
Epol
kJ/mol
Edis
kJ/mol
Erep
kJ/mol
Etot
kJ/mol Contact 1
x, y, z 9.18 −4.4 −1.7 −46.8 23.4 −32.3 IVM-IVM
−x + 1/2, y + 1/2, −z + 1/2 10.42 −12.5 −1.9 −87.1 50.1 −59.5 IVM-IVM
−x + 1/2, y + 1/2, −z + 1/2 17.43 −3.3 −0.4 −18.5 10.4 −13.4 IVM-IVM
x, y, z 14.82 −43.3 −13.6 −56.2 57 −69.6 IVM-IVM
HBS
−x, y, −z 11.35 −8.8 −4.6 −77.2 62.4 −41.3 IVM-IVM
−x, y, −z 14.60 −5−1.4 −8.7 4.1 −11.5 IVM-IVM
−x, y, −z 22.32 0 −0.1 −6.3 3.2 −3.6 IVM-IVM
- 2.65 −14.5 −3−40.6 27.9 −35.7 IVM-EtOH
x, y, z 17.43 −1−4.3 −47.9 29.7 −27.7 IVM-IVM
- 7.28 −1.7 −0.6 −13.3 7.7 −9.1 IVM-EtOH
- 12.39 0.5 −0.1 −1.9 0.1 −1.2 IVM-EtOH
−x, y, −z 14.10 −0.6 −0.8 −22 3.8 −18 IVM-IVM
- 13.5 −35.4 −7.8 −12.2 37.8 −30.5 IVM-EtOH
HB
- 14.9 −1.1 −0.1 −2.9 1.6 −2.8 IVM-EtOH
1
IVM-IVM denotes that this is an interaction between two IVM molecules, while IVM-EtOH is an interaction between IVM and ethanol.
HB and HBS indicate that there are one or multiple hydrogen bonds connecting the respective molecules.
4. Conclusions
In summary, three new pseudopolymorphs of IVM were prepared:
I
as the ethanol
solvate,
II
as the GVL solvate and
III
as the MTBE solvate. In all cases, crystallization of
the commercially available IVM provided a solid solution of two components B
1a
and B
1b
with the retaining of the natural 80:20 ratio.
The major feature of the molecular structure is the crown-conformation of the main
macrocyclic ring. Propensity of IVM to crystallize together with solvent molecules is
associated with the molecule being bulky and, as other similar compounds, IVM cannot
pack efficiently without leaving voids in the crystal structure, which are filled with solvent
molecules. In a solvent with relatively small molecules (ethanol), IVM forms monoclinic
crystal structure (space group I2), which contains two types of voids with volumes of
82 and 221 A
3
. The largest void contains one disordered solvent molecule, while the
small one contains disordered water molecules. When crystallized from solvents with
larger molecules (GVL and MTBE), IVM forms orthorhombic crystal structure (space group
P2
1
2
1
2
1
). In case of solvates
II
and
III
, only one type of void is formed with a much bigger
volume: 552 A3.
Conformation of IVM found in crystals is generally retained through all obtained
forms
I
,
II
and
III
and also in solvate BIFYOF, data for which has been previously deposited
in the Cambridge Crystallographic Data Centre. Conformation determined for a molecule,
modeled by DFT calculations, is near to the conformation found in crystals. The Hirshfeld
surface analysis indicated the dominant role of dispersive contacts for H
· · ·
H (80% on
average), O· · · H (10% on average) and H· · · O (10% on average).
The energy of crystal lattice was calculated for model crystal system
I
, which con-
tains IVM molecule and one ethanol molecule. The interaction between IVM molecules
themselves provides the biggest contribution to the crystal energy. By means of these
interactions between IVM molecules, the molecular framework in the crystal structure
is formed.
Thermal analysis shows wide peaks in DSC patterns, typical for solid solutions see
Figures S4 and S5 (Supplementary Materials). The peak of the melting process is observed
at 165
◦
C for pseudopolymorph
I
and at 172
◦
C for
II
. Additionally, the thermal analysis

Crystals 2021,11, 172 14 of 15
data show that, in solvate
II
, the substance loses the solvent (GVL) at 83
◦
C. In crystal
I
,
this process is not observed.
Supplementary Materials:
The following are available online at https://www.mdpi.com/2073-435
2/11/2/172/s1, Table S1: Atomic Cartesian coordinates for IVM B
1a
from DFT, Table S2: Selected
torsion angles for
I
, Figure S1: Overlay of IVM molecules present in
I
and BIFYOF, Figure S2: Overlay
of the first kind of symmetrically unique IVM molecules present in
II
and
III
, Figure S3: Overlay of
the second kind of symmetrically unique IVM molecules present in
II
and
III
, Figure S4: Processed
DSC and TGA data for I, Figure S5: Processed DSC and TGA data for II.
Author Contributions:
K.S. conceived and designed the experiments, conceptualized the work
and prepared the manuscript for publication; A.B. provided crystal structure analysis, reviewed
and edited the manuscript; S.B. provided acquisition of funding and supervision of the research,
conducted the X-ray analysis, reviewed and edited the manuscript. All authors discussed the contents
of the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding:
This research was funded by project “Development of innovative face cosmetics with
controlled release of active ingredients by use of Metal Organic Frameworks or Cocrystals” (ERAF
project number 1.1.1.1/18/A/176).
Conflicts of Interest: The authors declare no conflict of interest.
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