New diclofenac choline hydrate salt: Synthesis, characterization and solubility

Article abstract of DOI:10.1016/j.molstruc.2019.126922

A new choline hydrate salt of Diclofenac (DCF) was obtained using crystallization from a solution of DCF sodium and choline chloride in ethanol. The structure of the compound was determined by single-crystal X-ray diffraction. The DCF anions, choline cati

Full text of DOI:10.1016/j.molstruc.2019.126922

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New diclofenac choline hydrate salt: synthesis, characterization and solubility
Svetlana Blokhina, Angelica Sharapova, Marina Ol’khovich, Andrei Churakov,
German Perlovich
PII:
S0022-2860(19)31013-0
https://doi.org/10.1016/j.molstruc.2019.126922
126922
DOI:
Article Number:
Reference:
MOLSTR 126922
To appear in:
Journal of Molecular Structure
Received Date:
Accepted Date:
27 May 2019
11 August 2019
Please cite this article as: Svetlana Blokhina, Angelica Sharapova, Marina Ol’khovich, Andrei
Churakov, German Perlovich, New diclofenac choline hydrate salt: synthesis, characterization and
solubility, Journal of Molecular Structure (2019), https://doi.org/10.1016/j.molstruc.2019.126922
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New diclofenac choline hydrate salt: synthesis, characterization and solubility
a
a,
a
b
Svetlana Blokhina , Angelica Sharapova *, Marina Ol’khovich , Andrei Churakov ,
German Perlovich a
a Institute of Solution Chemistry, Russian Academy of Sciences, 1 Akademicheskaya
Street, 153045, Ivanovo, Russia
b Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 31
Leninsky Prospekt, 119991, Moscow, Russia
*
Corresponding author: Phone: 7 (4932)351545, E-mail: avs@isc-ras.ru
E-mail addresses:
Svetlana Blokhina – svb@isc-ras.ru
Marina Ol’khovich – omv@isc-ras.ru
Andrei Churakov – andrei.churakov@durham.ac.uk
German Perlovich – glp@isc-ras.ru

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Abstract
A new choline hydrate salt of Diclofenac (DCF) was obtained using crystallization
from a solution of DCF sodium and choline chloride in ethanol. The structure of the
compound was determined by single-crystal X-ray diffraction. The DCF anions,
choline cations and water molecules were arranged as a two-dimensional bridge
structure connected through hydrogen bonds. The “choline-skeleton” in the crystal is
systematically disordered, showing two propeller-like cage structures. The formation
of a new compound was confirmed by the powder X-ray diffraction method. The
thermal behavior of the salt was characterized by the DSC, DTA and HSM
techniques. The compound solubility was measured by the shake-flask method at a
temperature of 25oC in water and buffer solutions with different pH that simulated
physiological media. It has been established that the solubility of the synthesized salt
is higher than that of DCF sodium in all the aqueous solutions used.
Key words: Diclofenac salt, X-ray structure, thermal analysis, solubility
1. Introduction
Diclofenac (DCF) belongs to the group of non-steroidal anti-inflammatory
drugs and is widely used in treatment of different diseases of the musculoskeletal
system. In addition to the pronounced anti-inflammatory activity, the drug has a
powerful analgesic potential [1]. The non-salt form of DCF is a derivative of phenyl-
acetic acid and belongs to the compounds that are poorly soluble in water [2]. Using
the drug in the form of a sodium salt allows significantly increasing the solubility of
the non-salt form, which is important for lowering the dosage and reducing the
undesirable side effects on the body [3]. DCF is commercially present as sodium and
potassium salts for oral administration and is considered to be “the gold standard” in
treating inflammatory and degenerative diseases of joints [4]. However, the problem
of obtaining water-soluble drug forms of DCF remains quite urgent as the DCF
sodium solubility is only 50 mg/ml [5], and the pyrrolidone and 2-aminoethanol salts
are practically insoluble [6].
It is now known that using DCF salts with organic and inorganic bases
prevents the drug intramolecular cyclization and stabilizes the pharmacologically
active structure of the phenyl-acetic acid [7]. All this has drawn researchers’ attention
to the derivatives of choline as a base capable of accepting a proton and forming a
hydrogen bond with the acid anion [8]. Besides, choline (CL) as a physiological
compound that is already used in therapy has no drawbacks related to the system or
local toxicity [9]. It has been found that the DCF choline salt has improved physico-
chemical and pharmacological properties, such as good water solubility, stability of
aqueous solutions, lower toxicity, absence of a sodium ion, which allows using this
salt for treating patients with nephropathy and hypertension [10]. Recent studies of
the antioxidant activity of DCF choline have shown that its action increases anti-
inflammatory effects [11]. The chemical structures of DCF and сholine chloride are
displayed in Figure 1.

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There are currently several methods of synthesizing DCF choline salt through
DCF interaction with choline hydroxide [12], choline chloride [13] and choline
bicarbonate [14]. The study of the crystal structure has been done for pure DCF [15,
16] and its sodium salt [17]. In this work, we have obtained a new form of the drug –
DCF choline hydrate salt (DCF•CL•H2O), and studied its crystal structure,
thermophysical properties and solubility in water.
a)
b)
Fig. 1. Molecular structures of DCF sodium (a) and CL chloride (b).
2. Experimental
2.1. Materials
Diclofenac sodium C14H10Cl2NNAO2 (99 %,) and choline chloride C5H14ClNO
(98 %) were purchased from Acros Organics. All the solvents were available
commercially and used as received without further purification. Bidistilled water
(with electrical conductivity 2.1 μS cm-1) was used to prepare the buffer solutions.
Hydrochloric acid 9.0ꢀml was added to 1ꢀl distilled water to obtain hydrochloric acid
solution with a pH value of 1.2 to simulate gastric juice. In order to prepare the buffer
solution, pH 2.0 (I = 0.10 mol·l-1), 6.57 g of KCl was dissolved in water, 119.0 ml of
0.1 mol∙l-1 hydrochloric acid was added and the volume of the solution was adjusted
to 1 l with water. Buffer with pH 4.0 was obtained by dissolving 8.955 g of disodium
hydrogen phosphate 12H2O and 3.4023 g of potassium dihydrogen phosphate in 1
liter volume distilled water. Taking 0.2ꢀ mol·l-1 potassium dihydrogen phosphate
solution of 250ꢀml, adding 0.2ꢀ mol·l-1 sodium hydroxide of 118ꢀml and diluting it to
1ꢀl with distilled water, the phosphate buffer with pH of 6.8 was simulated as artificial
intestinal fluid. Phosphate buffer pH 7.4 (I = 0.15 mol·l-1) as model blood plasma was
prepared by combining KH2PO4 (9.1 g in 1 l) and Na2HPO4·12H2O (23.6 g in 1 l)
salts. The pH values were measured by using a pH meter FG2-Kit (Mettler Toledo,
Switzerland) standardized with pH 1.68, 6.86 and 9.22 solutions.
2.2. Preparation of DCF choline hydrate salt.

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The synthesis was carried out in ethanol at room temperature. Sodium
diclofenac (1.590 g, 5 mmol) dissolved in ethanol in a round bottom flask was added
to a solution of choline chloride (Acros Organics 99%, 0.698 g, 5 mmol). The
mixture was stirred for one hour and a white solution was formed. The ethanol and
residual water were removed on a rotary evaporator. The sodium chloride was
precipitated by adding dichloromethane and removed by filtration. The
dichloromethane was then removed on the rotary evaporator at the temperature T =
298.15 K for 48 h. The product was finally obtained as a 1.910 g solid, the reaction
yield was 96 %. The crystals were in the form of white needles suitable for single
crystal X-ray diffraction.
2.3. Single crystal structure determination
Single-crystal X-ray diffraction data were collected on a Bruker SMART
APEX II diffractometer using graphite-monochromated MoKα radiation (λ=0.71073
Å) at 150 K. Absorption corrections based on measurements of equivalent reflections
were applied [18]. The structures were solved by direct methods and refined by full
matrix least-squares on F2 with anisotropic thermal parameters for all non-hydrogen
atoms [19]. Amino hydrogen atom H1 and water hydrogen atoms H41 and H42 were
found from a difference Fourier map and their positional parameters were refined. All
other hydrogen atoms were placed in calculated positions and refined using a riding
model. Choline cation is disordered over two positions with occupancy ratio
0.68(1)/0.32(1). The solvent water position O(5) is partially occupied (0.16(2)). The
crystallographic data for DCF choline hydrate salt has been deposited with the
Cambridge Crystallographic Data Centre as supplementary publications under the
CCDC number 1912547. This information can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
The single crystal X-ray diffraction analysis was performed at the User Facilities
Center of IGIC RAS within the State Assignment on Fundamental Research to the
Kurnakov Institute of General and Inorganic Chemistry.
2.4. Powder X-ray diffraction (PXRD)
Powder X-ray diffraction patterns of the compounds were recorded under
ambient conditions in the Bragg-Brentano geometry with a Bruker D8 Advance
diffractometer with CuKɑ radiation (λ=1.5406 Å) at 40 kV and 40 mA power. The X-
ray diffraction patterns were collected over the 2θ range 5–30°, with a 0.03° step size.
2.5. Differential scanning calorimetry (DSC)
The thermal behavior of DCF choline hydrate salt was characterized using a
differential scanning calorimeter of Perkin Elmer Pyris 1 DSC (Perkin Elmer
Analytical Instruments, Norwalk, Connecticut, USA). The DSC procedure was
conducted in an atmosphere of drained argon of high purity of 99.990 % at the speed
of 20 ml/min by using standard aluminum containers for the samples. The DSC was

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calibrated by the indium melting peak onset (Perkin Elmer P/N 0319-0033). The
indium melting temperature was Tonset=156.5 ± 0.1°C (n=10). The melting enthalpy
equaled 28.48 J·g-1 and corresponded to the recommended value of 28.45 J·g-1. All
the DSC experiments were conducted at the heating rate of 10°C·min-1 in the range of
25-300oC. The samples (2-5 mg) dried before the experiment were placed into
aluminum crucibles. The weighing accuracy was ± 0.05 mg. An empty sealed
crucible was used as a reference.
2.4. Thermogravimetric analysis (TGA)
TGA was performed on a TG 209 F1 Iris thermomicrobalance (Netzsch,
Germany). Approximately 10 mg of the sample was added to a platinum crucible.
The samples were heated at a constant heating rate of 10°C·min−1.The samples were
purged with a stream of flowing dry Ar at 30 mL·min−1 throughout the experiment.
2.4. Hot-stage polarized optical microscopy (HSM)
Thermomicroscopic investigations were performed with an optical polarizing
microscope (Altami Polar 312) equipped with a hot stage and a Microstat 100
temperature controller. The obtained images were recorded with an Altami 3150R6
digital camera using Altami Studio image capture software. The samples were heated
over a temperature range of 25–180 оC at a constant heating rate of 5 оC min-1. The hot
stage was calibrated using USP melting point standards (vanillin, acetanilide,
phenacetin, and caffeine).
2.5. Solubility study
Тhe experiment was carried out by the saturation shake-flask method at 298.15
± 0.1 K. The essence of the above-mentioned method includes determination of the
compound concentration in the saturated solution. Glass ampoules containing the
tested substance and the solvent were placed into an air thermostat with a stirring
device. The time required for achieving a constant value of the solution concentration
was determined from the solubility kinetic dependences and averaged 24 hours. The
time of solid phase sedimentation after the stirring was 2 hours. The solution aliquot
was taken and centrifuged in a centrifuge (Biofuge Stratos, Germany) for 10 minutes
under a fixed temperature. The solid phase was removed by isothermal filtration with
a MILLEX®HA 0.45 µm filter (Ireland). The saturated solution was diluted with the
corresponding solvent to the required concentration. The compound solubility was
measured by a spectrophotometer Cary-50 (Varian, USA) with an accuracy of 2 – 4
%. The experimental results were reported as an average value of at least three
replicated experiments. The residue samples from the saturated solutions used for the
solubility experiments were isolated and dried. The drying procedure was performed
in the open air without heating or any drying agents. The samples were analyzed by
DSC and TGA immediately after the drying. The identity of the DSC and TGA

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curves of the residue samples and the solid salt indicates that there were no changes
in the structure of the studied compound after the solubility experiment.
3. Results and discussion
3.1. Crystal structure of DCF choline hydrate salt
The DCF choline hydrate crystallized in the monoclinic P21/c space group
with a DCF anion, a choline cation and a 1.155 water molecule in the asymmetric
unit (Fig. 2). The salt has the following stoichiometry: C14H10Cl2NO2·C5H14NO·
1.155H2O и formula weight equal 420.11 g/mol. The corresponding crystal data,
structure refinement details and geometry of the hydrogen bonds are presented in
Tables 1 and 2.
Fig. 2. View of the DCF•CL•H2O asymmetric unit
Table 1. Crystal data, data collection and structure refinement parameters of
DCF•CL•H2O.
CCDC code
crystal system
space group
crystal size, mm
a, Å
1912547
monoclinic
P21/c
0.40 x 0.35 x 0.01
21.092(3)

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b, Å
c, Å
9.1085(12)
10.4488(13)
90.201(4)
2007.3(4)
4
, 
volume, Å3
Z
Dcalc, gcm-3
, mm-1
Reflections
collected/unique
1.390
0.352
13218/3531
2567
0.0650
Reflections with I>2(I)
Rint
2Θ range for data
collection
2.44 to 25.05
-25<=h<=23, -10<=k<=10, -
12<=l<=12
0.0928
Limiting indices
R1[I>2(I)]
wR2 (all data)
0.2154
1.065
Gof on F2
Data/restraints/parameters
max / min, eÅ-3
CCDC code
crystal system
space group
crystal size, mm
a, Å
3531/18/284
0.886 / -0.690
1912547
monoclinic
P21/c
0.40 x 0.35 x 0.01
21.092(3)
b, Å
9.1085(12)
The standard deviations are presented in brackets.
Table 2. Hydrogen bond geometry in the DCF choline hydrate
Symmetry code
d(D-H)
(Å)
0.80
0.80
0.80
0.80
0.84(7)
0.81(7)
d(H...A)
(Å)
d(D...A)
(Å)
DH
A ()
DHA
O(3A)-H(3A)...O(2)
O(3B)-H(3B)...O(2)
O(5)-H(51)...O(4)
O(5)-H(52)...O(4)
O(4)-H(41)...O(1)
O(4)-H(42)...O(2)
1.77
1.89
2.34
2.22
1.97(7)
2.05(8)
2.572(12)
2.69(3)
3.14(4)
3.02(4)
2.803(8)
2.813(8)
177.1
-
-
178.9
179.7
179.6
169(10)
155(11)
-x+1, y+1/2, -z+1/2
x, -y+3/2, z+1/2
-
- x, -y+3/2, z-1/2
The DCF anions, choline cations and water molecules are arranged as a two-
dimensional bridge structure connected through hydrogen bonds. The “choline-
skeleton” in the crystal is systematically disordered, showing two propeller-like cage
structures A and B. Such type of disorder is well known for silatranes and
germatranes [20, 21]. In this case the length of the intermolecular hydrogen bond
between the DCF anion and choline cation O(3A)-H(3A)…O(2) and the dihedral

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angle corresponding to it are smaller than those of the О(3В)-Н(3В)…О(2) bond. The
water molecule forms intermolecular hydrogen bonds with the oxygen atoms of the
DCF carboxylate-ion group: О(4)-Н(41)…О(1) and О(4)-Н(42)…О(2). Besides,
weaker hydrogen bonds are formed between the individual water molecules: O(5)-
H(51)…O(4) and O(5)-H(52)…O(4). Formation of relatively short hydrogen bonds
between the CO2- group of pharmaceutical compounds and water molecules is typical
for their solvates [22, 23] and aqueous solutions [24].
Fig. 3. Two-dimensional network structure in DCF•CL•H2O salt.
3.2. PXRD analysis
The experimental PXRD pattern of the obtained salt was compared to the
initial compounds: DCF, DCF sodium and choline chloride (Fig. 4). The results show
that the position of the salt characteristic diffraction peaks at 2θ = 4.46°, 8.57°,
12.77°, 15.78°, 16.98°, 21.34° and 25.54° is absolutely different from the pure
compounds, which indicates the formation of a new crystalline phase.

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a
b
c
d
0
5
10
15
20
25
30
35
2 (o)
Fig. 4. PXRD pattern of DCF (a), DCF sodium (b), choline (c), and DCF•CL•H2O salt
(d).
3.3. Thermal characterization
The thermophysical properties of the diclofenac salt have been studied by a
combination of methods: DSC, TGA and HSM (Figures 5, 6). The thermal analysis
o
has shown the first mass loss of 7.59% (onset 25.0 C) corresponding to the broad
o
endothermic peak on the DSC curve (centered at 56.0 C). These changes are
o
connected with the sample dehydration that finishes at 90.8 C. The second
o
o
endothermic peak (Tpeak=106.6 C) and the exothermic one (Tpeak=110.7 C) are
caused by the restructuring of the salt under study which consists in its transformation
from a crystallohydrate into the non-hydrated form that is not accompanied by a mass
change. The third endothermic effect (with Tonset=162.3 oC) centered at 170.5 oC and
characterizing the sample melting agrees with the melting point observed by HSM

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and corresponds on the TGA curve to the mass loss onset temperature. At the
temperature of 202.8 oC, a sharp mass decrease starts triggered by the decomposition
of the molten sample and finishing with complete evaporation of the degradation
products at 260.6 oC.
2
0
-2
25
50
75
100
125
150
175
200
225
250
275
Temperature, oC
a)
b)
Fig. 5. DCS (a), TG and DTG (b) curves of DCF•CL•H2O salt.
Fig. 6. HSM images of DCF•CL•H2O salt at different temperatures.

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3.4. Solubility
Solubility is an essential physicochemical property that has to be evaluated in
the drug development process [25]. The solubility of DCF, DCF sodium and
DCF•CL•H2O was measured in water and buffer solutions with pH 1.2, 2.0, 4.0, 6.8
and 7.4 to mimic various physiological media of the gastrointestinal tract (Table 3). It
is established that the solubility of the synthesized salt increases significantly with a
growth pH of the buffer solution. The DCF solubility in water is known to equal 2.4
o
10-3 mg/ml at a temperature of 25 C [26]. The DCF choline hydrate salt solubility
determined in this work is equal to 19.199 mg/ml, which much higher than that
magnitude of pure DCF. The solubility of the obtained salt in water is slightly higher
than the DCF sodium solubility equal to 14.18 mg/ml, which is given in work [27],
but is lower than the value of 19.96 mg/ml given by the authors of [28]. It should be
said that the values of DCF salt solubility reported in literature differ considerably
from each other, which is associated with the existence of several polymorphic
modifications of the compound and formation of different ionic forms in solutions
[26]. The increase in the solubility of the drug salt form in comparison with the
individual compound is explained by a stronger interaction of the ionized molecules
with the solvent than that of the neutral species [29].
Table 3. Equilibrium solubility of DCF•CL•H2O salt in aqueous solvents at 25 oC
(literature data are presented in parentheses).
Solubility, mg/ml
Solvent
aDCF
-
0.002 (0.001)
0.004
bDCF sodium
0.0006
DCF•CL•H2O
3.352
Buffer pH 1.2
Buffer pH 2.0
Buffer pH 4.0
Buffer pH 6.8
Buffer pH 7.4
Water
0.0015 (0.0017)
0.0287 (0.0033)
1.1759 (0.67)
5.71 (5.15)
3.983
6.175
0.061
11.404
12.435
19.199
0.0254 (0.0178)
0.786 (0.8577)
13.34 (14.18)
a Ref. [26]
b Ref. [27]
As the data show, the solubility of the obtained salt in all the solvents used is
higher than that of DCF sodium (Fig. 7). An especially large increase in the
DCF•CL•H2O salt solubility compared to DCF sodium is observed in buffer pH 2.0
modelling the medium of the gastrointestinal tract. And the solubility of DCF salts
decrease with changing solvents in the following order: water > buffer рН 7.4 >
buffer рН 2.0.

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Fig. 7. Solubility diagram of DCF, DCF sodium and DCF•CL•H2O salt (this study) in
aqueous solvents at 25oC.
4. Conclusions
In this work, a new salt formation has been applied to achieve the enhancement
in the DCF solubility. DCF choline hydrate salt (1:1:1.155) was obtained by
crystallization from solution of DCF sodium and choline chloride in ethanol. The
compound has been characterized by single-crystal X-ray diffraction. A two-
dimensional structure of the salt has been stabilized through bridge hydrogen bonds
between the DCF anions, choline cations and water molecules. Two “choline-
skeleton” propeller-like cage structures in the crystal are systematically disordered.
The сompound obtained according to the proposed procedureis free from organic and
inorganic impurities. The PXRD method was used to confirm the formation of the
new salt. The results of studying dehydration, restructuring and melting processes
obtained by the DSC, DTA and HSM techniques agree with each other. The salt
solubility was measured by the shake-flask method at a temperature of 25 oC in water
and buffer solutions with different pH which simulate physiological media. It has
been established that the solubility of the synthesized salt in all the aqueous solutions
used is higher than that of DCF sodium applied in medicine. An especially large
increase in the DCF choline hydrate salt solubility compared to DCF sodium is
observed in buffer pH 2.0 modelling the medium of the gastrointestinal tract.
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Journal Pre-proof
• A new choline hydrate salt of Diclofenac was synthesized
• The structure of new salt was determined by single-crystal X-ray diffraction
• The thermal behavior of the salt was characterized by the DSC, DTA and HSM techniques
• The solubility of the synthesized salt is significantly higher than that of DCF sodium