Anion effect on the binary and ternary phase diagrams of chiral medetomidine salts and conglomerate crystal formation

Article abstract of DOI:10.1002/chir.22299

The binary phase diagrams of hydrogen halides salts of medetomidine (Med.HX, X:Br,I) and hydrogen oxalate salt of medetomidine (Med.Ox) were determined based on thermogravimetric/differential thermal analysis (TGA/DTA) and their crystal structure behavior was confirmed by comparison of the X-ray diffractometry and FT-IR spectroscopy of the racemate and pure enantiomer. All hydrogen halide salts presented racemic compound behavior. Heat of fusion of halides salt of (rac)-medetomidine decreased with ionic radius increase. Eutectic points for Med.HCl (previously reported), Med.HBr, and Med.HI rest were unchanged approximately. The solubility of different enantiomeric mixtures of Med.HBr and Med.HI were measured at 10, 20, and 30°C in 2-propanol showing a solubility increase with ionic radius. A binary phase diagram of Med.Ox shows a racemic conglomerate behavior. The solubility of enantiomeric mixtures of Med.Ox were measured at 10, 20, 30, and 40°C. The ternary phase diagram of Med.Ox in ethanol conforms to a conglomerate crystal forming system, favoring its enantiomeric purification by preferential crystallization.

Full text of DOI:10.1002/chir.22299

CHIRALITY 26:183–188 (2014)
Anion Effect on the Binary and Ternary Phase Diagrams of Chiral
Medetomidine Salts and Conglomerate Crystal Formation
1
2
1
*
EBRAHIM CHOOBDARI, HOSSEIN FAKHRAIAN, AND MOHAMMAD HASSAN PEYROVI
1Department of Chemistry, Shahid Beheshti University, Evin, Tehran, Iran
2Department of Chemistry, Imam Hossein University, Tehran, Iran
ABSTRACT
The binary phase diagrams of hydrogen halides salts of medetomidine (Med.HX,
X:Br,I) and hydrogen oxalate salt of medetomidine (Med.Ox) were determined based on
thermogravimetric/differential thermal analysis (TGA/DTA) and their crystal structure behavior
was confirmed by comparison of the X-ray diffractometry and FT-IR spectroscopy of the racemate
and pure enantiomer. All hydrogen halide salts presented racemic compound behavior. Heat of
fusion of halides salt of (rac)-medetomidine decreased with ionic radius increase. Eutectic points
for Med.HCl (previously reported), Med.HBr, and Med.HI rest were unchanged approximately.
The solubility of different enantiomeric mixtures of Med.HBr and Med.HI were measured at 10,
20, and 30°C in 2-propanol showing a solubility increase with ionic radius. A binary phase diagram
of Med.Ox shows a racemic conglomerate behavior. The solubility of enantiomeric mixtures of
Med.Ox were measured at 10, 20, 30, and 40°C. The ternary phase diagram of Med.Ox in ethanol
conforms to a conglomerate crystal forming system, favoring its enantiomeric purification by prefer-
ential crystallization. Chirality 26:183–188, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: medetomidine; enantiomer; conglomerate; racemic compound; phase diagram;
X-ray diffractometry; thermogravimetric analysis; differential thermal analysis;
chiral resolution; preferential crystallization
INTRODUCTION
conglomerate behavior too, and there are many other cases.
Hence, finding salting reagents for conglomerate formation is
important. However, even now, the mechanism of conglomer-
ate formation is insufficiently understood and, actually, most
conglomerates have been discovered by trial-and-error rather
than by design.13
More than one-half of marketed and candidate drugs are
chiral,1–5 enantiomers of which may have different pharmaco-
logical effects.6–8 Thus, resolution of racemates is important
in order to avoid side effects caused by the presence of an
undesirable component in a chiral drug.
The effect of anions as conglomerators on the crystal
structure of racemates was studied, mostly concerning race-
mic coordination complexes14–19 and limited types of organic
racemates were investigated from this point of view.20–26
The structural and thermoanalytical investigations of the
rac-α-phenylethylammonium salts have proved that the
hydrogen phthalate and hydrogen malonate anions form
racemic compounds, while the hydrogen succinate anion forms
a conglomerate, the latter being the only one which could be
resolved by preferential crystallization.22 A comparison of the
structures has revealed that the hydrogen bonding network in
hydrogen phthalate and hydrogen malonate salts are very simi-
lar, while the hydrogen succinate salt is different. Intramolecu-
lar hydrogen bonds through acidic hydrogens were formed
only between the carboxylic groups of the racemic compounds.
X-ray crystallographic studies carried out for seven conglom-
erates, 17 racemic compounds, and four enantiomerically pure
salts of chiral primary amines with achiral monocarboxylic
acids have revealed that conglomerate salts crystals can be
regarded as an assembly of a characteristic columnar
hydrogen-bond network in which the ammonium cations and
the carboxylate anions are aligned around a 2-fold screw axis
(21-column).24
The solid phase formed from a solution of racemate can be
a racemic compound, a conglomerate, or a racemic solid
solution (i.e., pseudoracemate). While the formation of a solid
solution is rare, the formation of a racemic compound occurs
most frequently and only 5 ꢀ 10% of racemates exhibit
conglomerate behavior.9 Conglomerates form two separate
enantiomeric solid phases upon crystallization of their race-
mates and thus can be resolved by preferential crystallization,
which is one of the most frequent methods for industrial
separation of optical isomers of racemates.10,11 Comparisons
of the melting point, solubility, and IR and/or XRD spectrum
of the racemic and optical active forms are the three main
methods to determine whether a racemate is a conglomerate
or not. Usually, in the case of a conglomerate, its optically
active form has lower solubility and a higher melting point
than the corresponding racemic form, and shows the same
IR and/or XRD spectral pattern as that of the racemic form.
The modification of a drug into a salt form offers many
advantages in pharmaceutical formulation. Furthermore,
converting racemic drugs into the salt forms may lead to a
conglomerate and thus facilitate the resolution of racemates
by a preferential crystallization technique. A statistical
analysis of a set of more than 500 salts has shown that the
probability of finding conglomerate in the salts form of race-
mates is 2 or 3 times greater than in their covalent form.12
For example, alanine, leucine, and tryptophan crystallize as
racemic compounds, but their benzenesulfonate salts crystal-
lize as conglomerates; hydrochloride of histidine presents a
*Correspondence to: Hossein Fakhraian, Department of Chemistry, Imam
Hossein University, Tehran, Iran. E-mail: Fakhraian@yahoo.com
Received for publication 29 September 2013; Accepted 11 December 2013
DOI: 10.1002/chir.22299
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2014 Wiley Periodicals, Inc.

184
CHOOBDARI ET AL.
(with mass in the range from 10 to 15 mg) were sealed in Al2O3
crucibles. All TG-DTA scans were performed from 15 to 300°C at a
heating rate of 10°C/min and with nitrogen gas purging.
Recently, investigation of a set of 12 [7]helquat salts led
to identification of conglomerate behavior in only the
bis(trifluoroacetate)salt of [7]helquat.25
(rac)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole (Fig. 1),
known by the generic name of medetomidine, is a synthetic
racemic drug used as both a surgical anesthetic and analge-
sic. This drug contains equal parts of two optical enantiomers,
dexmedetomidine and levomedetomidine. Medetomidine is
used as a sedative, analgesic, and anesthetic premedication
in animals. Dexmedetomidine, as the active ingredient of
the racemic mixture, has gained more interest than the
medetomidine racemate in human anesthesiology. In our
recent study,27 the racemic compound behavior of Med.HCl
was introduced and its binary and ternary phase diagram
were determined.
Herein, we try to find an achiral anions for medetomidine
salts presenting conglomerate system crystal favorable for
preferential crystallization. Thus, the racemic species of
halide salts of medetomidine (Med.HBr, Med.HI) and oxalate
salt of medetomidine (Med.Ox) were studied using the
melting point phase diagram, the infrared spectra, and
the powder X-ray diffraction patterns. The liquidus curve
in the binary phase diagram of a chiral system was predicted
using Schröder-van Laar and Prigogine-Defay equations. The
solubility diagrams of Med.HBr in 2-propanol over the
temperature range 10–30°C and Med.Ox in ethanol over the
temperature range 10–40°C were determined.
Solubility Measurement
For solubility measurements, a classical isothermal method was
applied. Calculated amounts of racemate and pure enantiomer were
weighed, mixed, and put in a small glass double jacketed vessel of 6
mL. A known amount of solvent, not sufficient to dissolve all the solid,
was added. The suspensions were stirred at 500 rpm at constant temper-
ature ( 0.1°C) using a heating immersion circulator devices (Julabo F12,
Germany). After 20 h the suspensions were filtered. The liquid phases
(filtrates) were weighed ( 0.1 mg) in a flask (mempty) before (msolution
and after evaporation to dryness at room temperature (mdry). The mass
fraction solubility (w) is given as:
)
mdry ꢀ mempty
w ¼
msolution ꢀ mempty
HPLC analyses were performed on a Knauer EA 4300F equipped with a
UV detector (220 nm), model 2600, and an AGP stationary phase
(column: 150 mm× 4 mm, 5 μm particles, Illkirch, France) with an eluent
(1% 2-propanol in 20mM acetate buffer with pH= 5) flow rate of 0.9 mL/min.
THEORETICAL
Schröder-Van Laar and Prigogine-Defay Equation
In liquidus curve in the binary phase diagram of a chiral
system, the absolute fusion temperature can be predicted as
a function of mole fraction (x), from the enthalpy of fusion
of pure enantiomers using a classical thermodynamic
expression of the Van’t Hoff type, the so-called Shröder-van
Laar equation:9
EXPERIMENTAL
General
ꢀ
ꢁ
Racemate Med.HCl with a purity of 99.9% was purchased from GBL
Hisoar (China) without further purification. (S)-Medetomidine free base
was prepared by tartaric acid as resolving agent according to the litera-
ture.28 (S)-Med.HBr, (rac)-Med.HBr, (S)-Med.HI, and (rac)-Med.HI were
prepared by reaction of (S)-and rac-medetomidine free base with HBr and
HI using a Dean-Stark apparatus according to the literature.29 Reaction of
an equivalent molar ratio of oxalic acid and medetomidine in ethanol
afforded (S)-Med.Ox and (rac)-Med.Ox after evaporation of solvent.
High-performance liquid chromatography (HPLC) grade 2-propanol and
ethanol were purchased from Merck (Germany). The enantiomeric
mixtures of (S)-Med.HBr, (S)-Med.HI, and (S)-Med.Ox with molar
fraction between 0.5 and 1.0, used both for TGA-DTA and solubility
measurement, were prepared by mixing the corresponding molar
amounts of (rac)-Med.HBr, (rac)-Med.HI, and (rac)-Med.Ox with
(S)-Med.HBr, (S)-Med.HI, and (S)-Med.Ox, respectively, which were
accurately weighed by a Mettler Toledo AX205 balance (Greifensee,
Switzerland) with a precision of 0.01 mg.
ΔHm
R
1
Tm
1
T
ln x ¼
ꢀ
(1)
To predict the liquidus curve between the two eutectics of a
racemic compound the Prigogine-Defay equation (Eq. (2))
can be used:
ꢀ
ꢁ
2ΔHm;rac
1
1
T
ln 4xð1 ꢀ xÞ ¼
ꢀ
(2)
R
Tm;rac
RESULTS AND DISCUSSION
FT-IR spectroscopy, XRD spectrum, melting points diagram
(binary phase diagram), and ternary phase diagram of the
racemic and optical active forms of medetomidine salts were
studied as follows to determine the crystal behavior of these
salts. The 1H NMR spectrum of Med.HBr, Med.HI, and Med.
Ox showed quantitative purity of salts but does not give any in-
formation about the kind of salts (see Supporting Information).
Fourier transform infrared (FT-IR) spectra of all racemates and
optically active forms were obtained with a Bomem MB-Series FT-IR
spectrometer using KBr pellets. Measurements were carried out in the
range of 400–4000 cm–1 at ambient temperature with a resolution of 4
cm-1, and number of scans of 20.
X-ray diffraction patterns of all compounds were recorded at ambient
temperature using a Philips-PW 17C diffractometer with Cu Kα radiation.
Thermogravimetric-differential thermal analysis was conducted using an
STA 503M system from Bähr (Germany). The TG-DTA curves were
recorded and analyzed using the WinTA software v. 9.0. For quantitative
analysis, the enantiomeric mixtures with various compositions were
prepared by mechanical mixing using a mortar and pestle. Samples
Fourier Transform Infrared Spectroscopy (FT-IR)
The FT-IR spectra of the pure enantiomers and the racemic
mixture can be used to characterize a racemate. If the
racemate is a conglomerate, its spectrum is superposable on
that of the enantiomers, while it is different in the case of a
racemic compound. The FT-IR spectrum (peak positions and
shape) of racemic mixture and S-enantiomer of the hydrogen
halide salts of medetomidine (Med.HX: X = Br and I),
recrystallized from ethanol, are clearly different (Fig. 2) as
was previously reported for Med.HCl,27 suggesting hydrogen
halide salts of medetomidine as a racemic compound and
indicating that variation of the halide ionic radius does not lead
Fig. 1. Molecular structure of medetomidine.
Chirality DOI 10.1002/chir

PHASE DIAGRAMS OF CHIRAL MEDETOMIDINE SALTS
185
Fig. 2. FT-IR spectra of (a) (rac)- and (b) (S)-enantiomer of medetomidine
salts (Med.HBr, Med.HI, and Med.Ox).
to conglomerate crystal formation. The peak positions and
shape of the FT-IR spectrum for (S)-enantiomers and racemic
mixture of hydrogen oxalate salt of medetomidine are the same
(Fig. 2), suggesting Med.Ox to be a conglomerate.
For determination of ion exchange in solid state FT-IR
measurements, (rac)-medetomidine hydroiodide and (rac)-
medetomidine oxalate samples were prepared using a KBr
pellet and were pressurized at a time series of 0, 5, 10, 15, and
20 min. The FT-IR spectra of the five samples did not show
any changes in intensity ratio and shift, indicating that the ion
exchange phenomena had not occurred in these cases.
Fig. 3. X-ray diffraction data spectra of (a) (S)- enantiomer and (b) (rac)
compound of medetomidine salts (Med.HBr, Med.HI, and Med.Ox).
X-Ray Diffraction (XRD)
There are substantial differences between the diffractograms
of (S)-enantiomer and racemate of Med.HBr and Med.HI
(Fig. 3), as previously reported for Med.HCl,27 supporting the
observations considering hydrogen halide salts of
medetomidine as racemic compounds. A close match of the
2θ values of the peaks in the XRD patterns of the (S)-Med.Ox
and (rac)-Med.Ox (Fig. 3) indicates the same crystal struc-
ture, suggesting that the racemic species is a conglomerate.
Minor differences in relative intensity of the XRD patterns
may arise from differences in crystallinity and/or preferred
orientation.
Binary Phase Diagrams of Medetomidine Salts
The determination of the melting phase diagram is useful, not
only for the determination of the type of racemate, but it makes
Chirality DOI 10.1002/chir

186
CHOOBDARI ET AL.
possible measuring the optical purity of the medetomidine salts
by a simple melting point measurement.
from DTA curves are in good agreement with those calculated
from Eqs. (1) and (2). From these data and our previous
study,27 heat of fusion of S-enantiomer and racemate of hydro-
gen halide salts of medetomidine can be calculated. Heat of
fusion of the racemate decreases with an increase of ionic
radius (Table 1), while eutectic points of hydrogen halide salts
of medetomidine are nearly unchanged. All hydrogen halide
salts of medetomidine presented racemic compound behavior.
The binary phase diagram of Med.Ox shows a conglomerate
Med.HBr, Med.HI, and Med.Ox samples with enantiomeric
compositions ranging from (R/S:50/50) to (R/S: 0/100) were
prepared by weighing and mixing specific amounts of (S)-
enantiomer and racemate. DTA profiles obtained from the
solid samples of various compositions led to the construction
of the binary phase diagram of Med.HBr, Med.HI, and Med.
Ox (Fig. 4). It can be seen that the melting points determined
Fig. 4. DTA curves and binary phase diagram of medetomidine salts (Med.HBr, Med.HI, and Med.Ox) for different mole fraction of enantiomers ((S):(R)).
Chirality DOI 10.1002/chir

PHASE DIAGRAMS OF CHIRAL MEDETOMIDINE SALTS
187
TABLE 1. Heat of fusion of hydrogen halide salts of
medetomidine
forming system (Fig. 6). Perhaps the O-H/O intermolecular
hydrogen bonds between the oxalate groups of neighboring
homochiral molecules led to the formation of conglomerate.
Med.HCl27
(kJ/mol)
Med.HBr
(kJ/mol)
Med.HI
(kJ/mol)
CONCLUSIONS
Racemate
Pure enantiomer
49.0
45.0
34.0
28.0
30.0
28.5
From the melting point diagram, Med.HBr and Med.HI
racemates are identified as racemic compound-forming sys-
tems with a melting point higher than that of pure enantiomer,
presenting a eutectic point at 146°C (X(S)-Med.HBr = 0.87) and
126°C (X(S)-Med.HI = 0.82). Interestingly, The binary phase
diagram of medetomidine oxalate points out a conglomerate
behavior of this salt. The solubility of the Med.HBr system in
2-propanol was measured from 10 to 30°C and its ternary phase
diagram in 2-propanol was constructed by plotting the equilib-
rium data in an equilateral triangle area, revealing a strong
temperature dependency of the solubility. The eutectic compo-
sition of Med.HBr system was observed at XS = 0.95. Substan-
tial differences between the XRD patterns and FT-IR
spectrum of racemate and pure enantiomer of hydrogen halide
salts of medetomidine indicate that these salts are racemic com-
pounds. The peak positions and shape of the FT-IR spectrum
and XRD patterns for the racemate and pure enantiomer of
hydrogen oxalate salt of medetomidine are the same,
suggesting that Med.Ox is a conglomerate. From the four
investigated model compounds, only one, the Med.Ox, forms
conglomerate, providing the possibility of optical resolution
by preferential crystallization.
behavior. The last peak in the DTA curves for Med.Ox is
related to the decomposition of oxalate above 190oC.30
Ternary Phase Diagram of Med.HBr and Med.Ox
The measured solubility data of the (S)-Med.HBr, (rac)-Med.
HBr, and different mixtures of both in 2-propanol were used for
determination of the ternary phase diagram (Fig. 5). Three
solubility isotherms between 10 and 30°C were considered,
presenting the typical shape of the racemic compound forming
systems. The solubility increased with temperature attaining
the maximum values for the eutectic mixtures (95:5).
The ternary phase diagram of the Med.Ox enantiomers in eth-
anol at 10, 20, 30, and 40oC conforms to a conglomerate crystal
SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
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Chirality DOI 10.1002/chir