The Preparation and Characterization of New Antazoline Salts with Dicarboxylic Acids

Article abstract of DOI:10.1080/15421406.2014.905041

New antazoline salts with organic acids (fumaric acid, oxalic acid, and maleic acid) were prepared. The effect of the crystallization solvent and mechanochemical treatment on the crystalline forms of these salts was studied. Two polymorphs of antazoline hydrogen maleate were identified and their relative stability was determined. The molecular structures of antazoline hydrogen oxalate and antazoline hydrogen maleate showed differences in antazoline cation conformation. In crystal structures of all salts both imidazoline nitrogens of antazoline cation are involved in hydrogen bond formation with carboxyl groups of the acid.

Full text of DOI:10.1080/15421406.2014.905041

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The Preparation and Characterization of
New Antazoline Salts with Dicarboxylic
Acids
a
a
a
Agnese Dravniece , Andris Actiņš , Kristīne Krūkle-Bērziņa & Inese
ab
Sarceviča
a
Faculty of Chemistry, University of Latvia, Riga, Latvia
b
Latvian Institute of Organic Synthesis, Riga, Latvia
Published online: 15 Jan 2015.
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To cite this article: Agnese Dravniece, Andris Actiņš, Kristīne Krūkle-Bērziņa & Inese Sarceviča (2015)
The Preparation and Characterization of New Antazoline Salts with Dicarboxylic Acids, Molecular
Crystals and Liquid Crystals, 606:1, 154-164, DOI: 10.1080/15421406.2014.905041
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Mol. Cryst. Liq. Cryst., Vol. 606: pp. 154–164, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 1542-1406 print/1563-5287 online
DOI: 10.1080/15421406.2014.905041
The Preparation and Characterization of New
Antazoline Salts with Dicarboxylic Acids
1
,∗
1
ˇ
¯
AGNESE DRAVNIECE, ANDRIS ACTI N¸ S, KRISTINE
1
1,2
¯
¯
ˇ
KRUKLE-BERZI N¸ A, AND INESE SARCEVICA
1
Faculty of Chemistry, University of Latvia, Riga, Latvia
Latvian Institute of Organic Synthesis, Riga, Latvia
2
New antazoline salts with organic acids (fumaric acid, oxalic acid, and maleic acid) were
prepared. The effect of the crystallization solvent and mechanochemical treatment on
the crystalline forms of these salts was studied. Two polymorphs of antazoline hydrogen
maleate were identified and their relative stability was determined. The molecular
structures of antazoline hydrogen oxalate and antazoline hydrogen maleate showed
differences in antazoline cation conformation. In crystal structures of all salts both
imidazoline nitrogens of antazoline cation are involved in hydrogen bond formation
with carboxyl groups of the acid.
Keywords Crystal structure; crystallization; hydrogen bonding motifs; polymorphism;
salts; X-ray diffractometry
Introduction
Active pharmaceutical ingredients (APIs) typically contain functional groups that can form
hydrogen bonds and therefore ensure the biological activity of the drugs [1, 2]. Many of
these compounds are administered in the form of salts formed by interaction of organic
bases and acids, provided that there is a sufficient difference between the acid and base pKa
values [3, 4]. For example, if the ꢀpKa > 3.75 for pyridine ring containing compounds and
+
−
carboxylic acids, then an ionic N–H ···O bond will form [5]. Such molecular complexes
as salts and cocrystals of APIs are desirable in the pharmaceutical industry because of
extended patent protection and the different physicochemical properties compared to the
parent drug [6–8]. Furthermore, the knowledge about crystalline forms of a drug compound
offers additional information about its behaviour in the presence of other molecules. This
information can be useful in the early stages of novel drug development.
Crystallization from solvents [9] and mechanical treatment [10] are some of the meth-
ods widely used in the preparation of new crystalline forms. The polymorph obtained by
crystallization is often determined by the choice of the solvent [11, 12] and by the envi-
ronmental conditions during the crystallization [13]. In addition, the crystals can contain
solvent molecules and form solvates and hydrates [12].
∗
Address correspondence to Agnese Dravniece, Faculty of Chemistry, University of Latvia,
Kr. Valdemara street 48, LV-1013, Riga, Latvia. E-mail: agnese.dravniece@lu.lv
Color versions of one or more of the figures in the article can be found online at
www.tandfonline.com/gmcl.
154

New Antazoline Salts with Dicarboxylic Acids
155
Antazoline (N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-N-(phenylmethyl)aniline) is an
imidazoline derivative with anticholinergic properties that is used as an antihistamine drug
for the treatment of nasal congestion and in eye drops [14]. It also has been proven to
be effective in the treatment of cardiac arrhythmias [15, 16], and can be administered
both intravenously and orally. Both antazoline hydrochloride and phosphate are used in
pharmaceutical practice, yet new salts may offer an opportunity to improve drug properties
as solubility, stability [17, 18]. In this study, preparation and characterization of new
antazoline salts with fumaric acid, oxalic acid, and malonic acid is reported. Features of
crystal and molecular structures of these salts are discussed.
Experimental
Materials
Antazoline base was prepared from antazoline phosphate (supplied by JSC Grindeks,
Riga, Latvia). Sodium hydroxide, fumaric acid, oxalic acid dihydrate, maleic acid, and
organic solvents were purchased from commercial sources and used as received. Water was
deionized in the laboratory to <0.1 μS.
Preparation of Antazoline Base
Antazoline base was prepared at ambient conditions by dissolving 10.00 g antazoline
phosphate in 400 mL deionized water and mixing with an equimolar amount of 3.30 g
sodium hydroxide dissolved in 25 mL deionized water. The resulting product was filtered,
allowed to dry for 24 h, and stored in an airtight container.
Preparation of Antazoline Salts
Crystallization. Antazoline salts were prepared by dissolving 0.20 g of antazoline base
in 10 mL of appropriate solvent (ethanol, 2-propanol, butanol, acetone, 2-butanone, 3-
pentanone, ethyl acetate, butyl acetate, methanol, and tetrahydrofuran) and adding the
chosen acid (0.04 g of fumaric acid, 0.10 g of oxalic acid dihydrate, or 0.09 g of maleic
◦
acid) dissolved in 10 mL of the same solvent. Experiments were conducted at 22 C,
40–60% RH. The resulting products were recovered by filtration and allowed to dry at
ambient conditions for 1 h. The dried salts were kept in airtight containers.
Neat Grinding. Salts were also prepared by grinding 0.20 g of antazoline base with 0.04 g
of fumaric acid, 0.07 g of oxalic or 0.09 g of maleic acid in a Retsch MM300 ball mill
(Retsch GmbH) for 10 min with 15 Hz frequency without solvent addition. Mixture of
starting compounds was milled in 35 mL grinding jars using one 1.5 cm stainless steel ball.
Polymorph Screening. Antazoline–dicarboxylic acid salts were suspended in various or-
ganic solvents (ethanol, 2-propanol, butanol, acetone, 2-butanone, 3-pentanone, ethyl ac-
◦
etate, butyl acetate, methanol, and tetrahydrofuran) at 22 C, 40–60% RH for 24 h, and the
suspensions were allowed to dry. The composition of the product was determined using
powder X-ray diffractometry.
Powder X-Ray Diffractometry
X-ray diffraction measurements were carried out with a Bruker D8 Advance X-ray powder
diffractometer (Bruker AXS) equipped with a LynxEye position sensitive detector. Copper

156
A. Dravniece et al.
radiation (CuKα λ = 1.5418 Å) was used. The tube voltage and current were set to 40 kV
and 40 mA. The divergence slit was 0.6 mm and the scattering slit was 8.0 mm. The samples
◦
◦
were scanned over the 2θ range of 3–35 at the rate of 0.2 s/0.02 . The diffraction patterns
plus
were analyzed with DIFFRAC EVA (ver. 2.1) software (Bruker AXS).
Single Crystal X-Ray Diffractometry
Single crystals of antazoline hydrogen oxalate (AO) and antazoline hydrogen maleate
for structure determination were obtained from ethanol and acetone, respectively. Single
crystal X-ray diffraction data were measured with a Nonius Kappa CCD diffractometer
(Bruker AXS GmbH, Germany) with MoKα radiation (0.71073 Å) at 173 K. Data reduction
was performed with the DENZO/SCALEPACK software [19]. The crystal structures were
solved by direct methods with Shelxs97 [20], refinement was performed using Shelxl97
[20].
Thermal Analysis
The thermal properties were investigated by DSC and DTA/TG.
DTA/TG analysis carried out on a SII Exstar 6000 DTA/TG6300 system. Powdered
samples (5–10 mg) were analyzed on aluminum pans under air atmosphere at the heating
◦
◦
◦
rate of 10 C/min from 30 C to 200 C.
DSC was performed on a Mettler Toledo DSC 823e instrument. Samples (2–4 mg)
◦
were heated in aluminum pans under air atmosphere at the heating rate of 10 C/min from
4
◦ ◦
0 C to 300 C.
Karl Fischer Titration
Karl Fischer titration was carried out using Metrohm Titrando 836. Approximately
300–500 mg of samples were weighed on a Precisa XB 220A balance and titrated with
Hydranal Composite 5 (Fluka).
Results and Discussion
Crystalline Forms of Antazoline Salts
The pKa values of antazoline are 7.79 and 9.74 [21, 22], while the pKa values for fumaric
acid are 3.03 and 4.44; for oxalic acid they are 1.25 and 4.14, and for maleic acid they are
1.9 and 6.07. The pKa values suggest that salt formation is expected between antazoline and
these acids. New salts of antazoline with oxalic acid, fumaric acid, and maleic acid were
prepared during this study by crystallization and mechanical treatment. The formation of
different crystalline forms of antazoline salts was investigated by suspending the salts in
different solvents and by grinding in ball mills.
Antazoline Fumarate (AF)
Crystallization of antazoline with a fumaric acid (2:1 stoichiometry of acid to base) from all
used solvents resulted in the formation of antazoline fumarate (AF) that became hydrated
at ambient conditions. The comparison of PXRD patterns of AF, the hydrate (AF·0.5H2O),
and the starting compounds is shown in Fig. 1. The stoichiometry of AF·0.5H2O according

New Antazoline Salts with Dicarboxylic Acids
157
Figure 1. The PXRD patterns of antazoline base, fumaric acid, antazoline fumarate, and its
hemihydrate.
to KF titration and DTA/TG analysis was 0.5 mol of water per 1 mol of AF. The dehydration
◦
of the AF·0.5H2O occurred at 80 C and led to the anhydrous form (AF).
The search for antazoline fumarate polymorphs via slurrying in solvents did not produce
new crystalline forms. Antazoline fumarate hemihydrate was obtained instead in all the
slurrying experiments. The preparation of AF by milling antazoline base with fumaric acid
in a ball mill without solvent addition resulted in AF.
Antazoline Hydrogen Oxalate (AO)
The crystallization of antazoline with oxalic acid from different solvents produced AO.
The PXRD patterns of AO and starting materials are shown in Fig. 2. No new polymorphs
were obtained in the experiments where AO was suspended in different solvents. Grinding
antazoline base with oxalic acid dihydrate in a ball mill also produced AO.
Figure 2. The PXRD patterns of antazoline, oxalic acid dihydrate, and AO.

158
A. Dravniece et al.
Figure 3. The PXRD patterns of antazoline, maleic acid, and AM polymorphs (AM-α and AM-β).
Antazoline Hydrogen Maleate (AM)
Crystallization from different solvents gave one nonsolvated form of antazoline hydrogen
maleate (AM-α). Another polymorph of this salt (AM-β) was obtained by suspending the
AM-α in isopropanol at ambient conditions. PXRD patterns of AM-α and AM-β are shown
in Fig. 3. Both polymorphs were stable at room temperature, whereas during the storage at
◦
1
00 C slow solid-state phase transition AM-α→AM-β was observed.
The relative thermodynamic stability of both polymorphs was established by DSC
analysis. The polymorphic system was monotropic, as the higher melting form (AM-β;
◦
−1
melting point 154 C; heat of fusion 130.1 J g ) had a higher heat of fusion compared
◦
−1
to the lower melting form (AM-α; melting point 151 C; heat of fusion 120.7 J g ). This
monotropy suggested that the transition from AM-α to AM-β was irreversible as observed
in the suspension experiment. The AM-α was the kinetic product and was prepared in the
crystallization experiments, whereas grinding of antazoline base with maleic acid produced
the thermodynamic product AM-β. An appropriate choice of the preparation method may
therefore enable a control of polymorphic composition.
Crystal structures of AO and polymorphs of antazoline hydrogen maleate.
The crystal structures of AO, AM-α, and AM-β forms were determined in this work.
AO and both polymorphs of AM crystallize in the triclinic crystal system with two formula
units of the salt in the unit cell. The most relevant crystallographic data for AO, AM-α and
AM-β are presented in Table 1.
The molecular structure of AO is shown in Fig. 4(b). Salt formation occurs by hydrogen
transfer from oxalic acid to the N2 nitrogen of the antazoline imidazoline ring (Fig. 4(b)).
A bifurcated hydrogen bond forms between the N3 nitrogen atom in the antazoline moiety
and the O4 and O2 oxygen atoms in the oxalate monoanion. The imidazoline N2 nitrogen
+
δ−
is hydrogen bonded through N−H · · ·O to the O3 oxygen in another oxalate anion
Table 2).
Oxalic moieties in AO are linked by shared H1 and H4A hydrogen atoms resulting in
(
parallel chains perpendicular to the crystallographic axis b (Fig. 4(b)).
The molecular structures of AM both polymorphs are shown in Fig. 5.

New Antazoline Salts with Dicarboxylic Acids
159
Table 1. Crystallographic data for AO and hydrogen maleate polymorphs (AM-α and
AM-β)
AO
AM-α
AM-β
Formula
Formula weight (g mol )
Crystal system
C19H21N3O4
355.35
C21H23N3O4
381.42
C21H23N3O4
381.42
−1
Triclinic
Triclinic
Triclinic
¯
P1
¯
1
¯
1
¯
P1
Space group
a (Å)
b (Å)
P
P
9.04000(10)
9.8768(2)
10.8307(2)
88.5578(6)
67.4838(6)
86.2971(10)
891.45
2
5.6341 (2)
10.1335 (2)
17.6670 (2)
102.3221(12)
90.6186(13)
90.6706 (9)
985.27 (4)
2
7.4881(2)
11.3146(2)
11.9783(2)
99.5695(12)
103.767(13)
91.9442(9)
969.08
2
c (Å)
o
α ( )
o
β ( )
o
γ ( )
V (Å )
3
Z
−3
Dcalc (g cm )
1.324
0.094
376
1.286
0.090
404
1.307
0.092
404
−1
μ, mm
F(000)
Number of parameters
245
293
262
Number of reflections (I > 2σ)
5779
2674
3529
wR
0.172
0.126
0.113
R (I > 2σ)
GOF
0.060
1.044
0.055
1.038
0.046
1.020
CCDC
975563
975562
975561
Table 2. Hydrogen bond parameters for antazoline molecular salts
D–H (Å) H···A (Å) D···A (Å) <D–H···A (◦) Symmetry code
D–H···A
AO
O1–H1···O1
N2–H2···O3
N3–H3···O2
N3–H3···O4
O4–H4A···N4
1.23
1.23
2.4543(10)
180
1–x, –y, –z
x, 1+y, z
0.931(19) 1.912(19) 2.8145(13)
163.0(16)
173.4(17)
113.6(14)
180
0.93(2)
0.93(2)
1.22
1.93(2)
2.505(19) 2.9994(13)
2.8497(14)
1+x, 1+y, z
1+x, 1+y, z
–x, –y, 1–z
1.22
2.4481(10)
AM- α
N2–H2···O1
O3–H2B···O2
N3–H3···O4
0.89(2)
1.08(3)
0.95(2)
1.94(2)
1.34(3)
1.83(2)
2.802(2)
2.416(2)
2.748(2)
161(2)
176(3)
162(2)
–1+x, –1+y, z
intra
x, y, z
AM-β
N2–H2···O1
O2–H2B···O3
N3–H3···O4
0.875(17) 1.978(17) 2.8403(15)
1.20(2) 1.20(2) 2.4001(16)
0.911(18) 1.858(18) 2.7257(17)
168.2(16)
178(2)
158.4(16)
x, y, 1+z
intra
x, y, z

160
A. Dravniece et al.
Figure 4. (a) The molecular structure of AO showing the numbering of atoms. (b) Hydrogen bonding
motifs in AO. Thermal ellipsoids are drawn at the 50% probability level.
The benzyl group in AM-α was disordered over two positions with the occupancy
factors of 0.6 (ring C8–C9–C10–C11A–C12A–C13A, black in Figure 5) and 0.4 (ring
C8–C9–C10–C11B–C12B–C13B, grey in Fig. 5). The angle between these two possible
◦
ring positions is 27.9 . The angle between the plane of the maleate monoanion and the
◦
◦
plane of the imidazoline ring in AM-α was 88.0 , while in AM-β this angle was 8.4 .

New Antazoline Salts with Dicarboxylic Acids
161
Figure 5. The molecular structures of antazoline hydrogen maleate showing the numbering of atoms
in AM-α (a) and in AM-β (b). Thermal ellipsoids are drawn at the 50% probability level.
In the crystal structures of both AM polymorphs (AM-α and AM-β) similar hydro-
gen bonding motifs were observed. One of the carboxyl groups of the maleic acid was
deprotonated. The remaining proton was involved in the formation of an intramolecular
δ−
δ−
O · · ·H· · ·O hydrogen bond with a graph set S(7) between both carboxyl groups of
the maleic acid. The protonated imidazoline nitrogen of the antazoline formed an ionic
+
δ−
N –H· · ·O bond to the carboxylate group of the maleate monoanion. A neutral N–H· · ·O
hydrogen bond connected the other N of the antazoline imidazoline to the carbonyl O of
the maleic acid carboxyl group. In both AM polymorphs, hydrogen-bonded acid and base
moieties alternated to form extended parallel chains (Fig. 6).
The imidazoline ring in antazoline is prone to involvement in hydrogen bonding. The
protonated N of antazoline in the base crystal structure acts as a proton donor for the
nonprotonated N acceptor enabling the formation of an N–H· · ·N hydrogen bond [22]. In
salt structures, both of the imidazoline N atoms are H donors and involve in N–H· · ·A
(acceptor) hydrogen bonds. Although only one of the acid groups in dicarboxylic acids
Figure 6. Packing diagrams showing hydrogen bonding motifs in the AM-α (a) and AM-β (b) crystal
structure. For AM-α, only benzyl ring positions with occupancy 0.6 are shown.

162
A. Dravniece et al.
Table 3. Torsion and dihedral angles of antazoline moiety in its crystalline forms
◦
◦
Dihedral angle ( )
Torsion angle ( )
C6–C1– N2–C15– C1–N1– C1–N1– Imidazoline/ Imidazoline/
Phenyl/
benzyl
Compound N1–C7 C14–N1 C14–C15 C7–C8
phenyl
79.5
benzyl
66.7
Antazoline −8.0(5) 19.7(5)
96.5(4) 96.0(4)
84.3
73.5
base
AO
AM-α
3.4(2) −33.3(1) −77.9(1) −75.6(1)
−5.2(3) 24.0(3) 78.0(2) 97.5(2)
87.7
86.3
22.4
∗
∗
∗
∗∗
85.1
73.9
72.7
∗
67.4
AM-β
−2.0(1) −1.8(2) −88.4(2) −75.0(2)
85.2
37.1
88.4
∗
Benzyl ring with occupancy of 0.6
∗
∗
Benzyl ring with occupancy of 0.4
(oxalic, maleic acid) is deprotonated, both of them participate in hydrogen bonding as H
acceptors. The ability of antazoline moiety to participate in H-bonding with both of its
imidazole N leads to formation of infinite hydrogen-bonded chains in AM and AO.
The relative stability of polymorphs can be influenced by hydrogen bonding, packing
forces, and other. The H· · ·A (acceptor) distances in AM-α are slightly shorter than in
AM-β (Table 2). However, there is a disorder of the benzyl ring position in AM-α probably
resulting in an energy increase of this crystal structure. Furthermore, the crystallographic
density of AM-β is larger than the density of AM-α (Table 1).
Figure 7. Conformational comparison of antazoline moiety in crystal structures of antazoline base
(
green), AO (blue), AM-α (red), and AM-β (orange).

New Antazoline Salts with Dicarboxylic Acids
163
To analyze conformation of antazoline moiety in its base [22] and salt crystal struc-
tures, torsion angles and dihedral angles between imidazoline, benzyl, and phenyl rings in
antazoline cation have been compared (Table 3).
These angles show that the conformation of antazoline moiety is different in each
crystalline form. The orientation of imidazoline and benzyl ring with regard to phenyl ring
in AM-α crystal structure is similar to their orientation in the crystal structure of antazoline
base, whereas the conformation of antazoline moiety in AM-β is more similar to that in
AO (Fig. 7).
Conclusions
The antihistamine antazoline forms salts with dicarboxylic acids: fumaric acid, oxalic
acid, and maleic acid were obtained by crystallization from solution and by grinding in ball
mills. Two polymorphs of antazoline hydrogen maleate were obtained. Crystallization from
solution produces the kinetically stable antazoline hydrogen maleate AM-α form while the
thermodynamically stable AM-β form is obtained from grinding experiments.
The conformation of antazoline moiety in each crystal structure is different. However,
similar trends can be observed between orientation of the benzyl and imidazoline rings with
respect to the phenyl ring between antazoline base and AM-α and between AO and AM-β.
As a result of imidazoline N protonation in all antazoline salt crystal structures, both
imidazole N participate in hydrogen bonding as hydrogen donors leading to characteristic
acid–base–acid chain formation.
Funding
This work was supported by the European Regional Development Fund (No.
2011/0014/2DP/2.1.1.1.0/10/APIA/VIAA/092).
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