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Solubility of sodium diclofenac in different solvents

Article in Fluid Phase Equilibria · December 2007

DOI: 10.1016/j.fluid.2007.07.020

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Solubility of diclofenac sodium in different solvents

L.Fele Žilnika, A. Jazbinšeka, A. Hvalab, F. Vrečerb

a
National Institute of Chemistry, Hajdrihova 19, PO Box 660, SI-1001 Ljubljana, Slovenia
Tel: +386 1 4760 220, e-mail: ljudmila.fele@ki.si, fax: +386 1 4760 300
b
New Formulations Research Department, R&D, Krka, d.d. Novo mesto, Slovenia

Abstract

The solubility of diclofenac sodium was studied in several solvents, such as acetone, ethyl
acetate and dimethyl sulfoxide, in the temperature range from 293.15 K up to 313.15 K. The
solubility of diclofenac sodium is of the same order of magnitude for acetone and ethyl
acetate. The solubility of the drug in dimethyl sulfoxide is two orders of magnitude higher and
it is of the same magnitude as in N,N-dimethylformamide, the solvent of the same class as
dimethyl sulfoxide, concerning the solubility parameter. The experimental SLE data were
modeled using the NRTL and the modified UNIQUAC model and both models were proved
to give a good representation of the experimental data.

Keywords

Solubility, Drug, SLE Modeling, Diclofenac sodium

Introduction

The thermodynamic behavior, including the solubility of a solid in a liquid, plays an

important role in drug design as well as in the design and optimization of the production
process. Micrometric and sub micrometric particles of pharmaceutical and related compounds
like hydrophobic enzymes, anti-inflammatory drugs, antibiotics and biopolymers can be
formed by employing SCF-GAS technique, where an application of an antisolvent decreases
the solubility of a material dissolved in the solution. For a successful operation, a good
solvent-antisolvent combination has to be chosen.
Diclofenac sodium is a non-steroidal active substance that acts anti-inflammatory, with
prolonged release, used in the treatment of rheumatic disorders. The substance, 2-[(2,6-
Dichlorophenyl)amino]benzene acetic acid sodium salt is a salt of a weak acid with a pKa of
4 and a partition coefficient (n-octanol/aqueous buffer, pH 7.4) of 13.4. The structure of the
diclofenac sodium is shown in Figure 1. The presence of the heteroatoms N, O, Cl and Na
causes high polarizability of the molecule and hence specific interactions with solvents that
strongly affect the solubility of the drug in different solvents. Because of the presence of the
NH group that can act either as proton donor or proton acceptor toward the solvents and the
presence of the carboxylic group, the drug possesses a Lewis acid-base character.
The solubility characteristics of diclofenac sodium in aqueous media with various ionic
strengths, ionic compositions and pH in the range of 1 to 10 were studied by Kincl et al. [1].
Their observation was that the solubility strongly depends on the ionization constant, Ka, and
on the pH of the dissolution medium. In the literature, only a few data [2] on the solubility of
the drug in solvents is available.
For the modeling, the Hansen approach [3] may be used for the determination of solubility
parameters, which divides the cohesive energy density into contributions from non-polar
interactions (van der Waals dispersion forces), dipole interactions and hydrogen bonding, with
some extensions [4,5]. Bustamante et al. [6,7] developed the expanded Hansen method,
where a direct use of the mole fraction solubility ln X2 in the three- and four parameter
models is proposed. They claim that ln X2 represents the most suitable variable for the
determination of the partial solubility parameters. The four-parameter model was used, where
the Hansen hydrogen-bonding term was split into acidic and basic partial-solubility terms to
provide better results. A set of group molar constants for sodium to calculate partial solubility
parameters of sodium salts was further proposed [8].
The concept of equilibrium thermodynamics with appropriate activity coefficient models was
used to calculate solid-liquid equilibrium (SLE) of ciprofloxacin.HCL and ciprofloxacin base
in different solvents by Melo et al. [9] and Varanda et al. [10], using the UNIQUAC and
NRTL models. Variations [11] of UNIQUAC equations have been used to correlate
experimental solubility data for polar solid organic solutes in water, e.g. sugars in water [12].
The UNIFAC group contribution approach was used recently to predict the solubilities of
solid organic compounds in solvents in order to select a suitable solvent or facilitate the
design of a crystallization process [13, 14]. In some cases more empirical approach to
correlate the solubility of the solute is used [15-17].
This contribution deals with the solubility of diclofenac sodium, anti-inflammatory drug with
prolonged release, in the following solvents: acetone, ethyl acetate and dimethyl sulfoxide
(DMSO) at temperatures 293.15 K, 298.15 K, 303.15 K, 308.15 K and 313.15 K. The
experimental data can be well correlated by using expressions for the excess Gibbs energy,
like NRTL model and modified UNIQUAC model.

Experimental

Materials and procedure

Diclofenac sodium was supplied by KRKA (Pharmaceutical Company, Novo mesto,

Slovenia) and it was used as received. The water content of the original powder of the drug
was determined in triplicate using Karl Fischer titration method. The water content was
0.487%. The solvents acetone, ethyl acetate, dichloromethane, dimethyl sulfoxide were all
analytical or chromatographic grade, supplied by Merck. Water content in the solvents was
determined in triplicates as well.

Figure 1. Molecular structure of diclofenac sodium

Solubility measurements

The solubility of diclofenac sodium in three different solvents was measured, namely acetone,
ethyl acetate and dimethyl sulfoxide. Our experimental procedure was checked on the
solubility of the drug in water at 298.15 K, measured by Barra et al. [8], and good agreement
with the data was obtained. Our measured solubility of the drug in water 20.4 mg/g is close
enough to the value of 19.4 mg/g given in the literature. When diclofenac sodium was
exposed for a longer period to a mixture of dichloromethane-dimethyl sulfoxide as solvent of
interest, a change of color of the solution with time was observed, what suggested instability
of diclofenac sodium in the mixed solvent. Therefore, further experiments with the mixed
solvent were omitted. The stability of the drug in the used solvents during the experiment was
examined by an analysis of DSC traces of the drug after the solvent treatment.

A slight excess of powder was introduced into the flasks containing pure solvents.
Suspensions sealed in the flasks were first agitated in an ultrasonic bath and then transferred
to the shaking bath at appropriate temperature (from 293.15 K to 313.15 K). After phase
equilibrium was reached (minimum 48 hours), the excess solid was removed by filtration
through a PTFE membrane of 0.2 μm pore size. The composition of the liquid phase was
determined by using an UV-Vis Agilent 8453 spectrophotometer with a wavelength accuracy
of ± 0.02 nm. Maximum wavelength absorption previously selected for the drug, 285 nm, was
used. In the case of higher volatility of the solvent or lower response as in the case of
acetone, the solvent was removed by the vacuum evaporation technique and the residual was
dissolved in solvent (dimethyl sulfoxide) and further diluted for spectrophotometric
measurements with absorbance in the linear calibration range. All the measurements were the
average of at least three independent measurements, each of them in minimum of six
replicates.

Thermal analysis

Differential scanning calorimetry was performed on a Mettler DSC 30 scanning calorimeter to

determine the molar heat and temperature of fusion of the drug and the stability of the drug in
the solvents used. DSC traces for diclofenac sodium were recorded under a flux of dry
nitrogen between 25°C and 300°C at 10K/min.

Modeling

Models

The phase equilibrium equation for a pure solid solute, which partly dissolves in a liquid
solvent, at temperature T and pressure P, given in terms of fugacities is as follows:

f 2L (T , P, x2 ) = f 2S, p (T , P ) (1)

where subscript 2 denotes solute and subscript p denotes pure. Superscripts L and S stand for
liquid and solid phase; f denotes fugacity, x is the liquid mole fraction.
By introducing the activity coefficient γ 2 of the solute and the fugacity of the solute in the
liquid phase, the equilibrium equation is:

f 2S, p
x2γ 2 = (2)
f 2L, p
The Gibbs free energy of fusion is related to the ratio of fugacities as :
ΔG fus f 2L, p
= ln S (3)
RT f2
where R is a gas constant. The Gibbs free energy of fusion can be further expressed by the
enthalpy and entropy of fusion, ΔH fus (T ) and ΔS fus (T ) . Taking the standard state of a solute
as the pure sub cooled liquid at the system temperature and assuming that the difference of the
isobaric heat capacity between the pure solid and pure liquid solute, ΔC p , is temperature
independent from T up to the melting temperature Tm, the basic solubility equation of a solute
can be written as:
ΔH fus (Tm ) ⎛ T ⎞ ΔC p ⎛ Tm − T ⎞ ΔC p Tm
ln γ 2 x 2 = − ⎜⎜1 − ⎟⎟ + ⎜ ⎟− ln (4)
RT ⎝ Tm ⎠ R ⎝ T ⎠ R T

Often the first term on the right-hand side is much more important [11,18] than the remaining
two terms, especially if T is close to the melting temperature Tm. Diclofenac sodium has a
high melting temperature, but since no data for ΔC p was available, the simplified form of the
equation was used for modeling:
ΔH fus (Tm ) ⎛ T ⎞
ln x 2 = − ln γ 2 − ⎜⎜1 − ⎟⎟ (5)
RT ⎝ Tm ⎠

To describe γ 2 , two expressions for the excess Gibbs energy were used: the NRTL model and
the modified form of UNIQUAC. In the NRTL model, the liquid phase activity coefficient is
given by the following expression:

⎡ ⎛ G12 ⎞
2
τ 21⋅G21 ⎤
ln γ 2 = x ⎢τ 12 ⎜⎜
2
⎟⎟ + ⎥ (6)
1
⎢⎣ ⎝ x 2 + x1 ⋅ G12 ⎠ (x1 + x2 ⋅ G21 )2 ⎥⎦

G12 = exp(− α 12 ⋅ τ 12 )
where (7)
G21 = exp(− α 12 ⋅ τ 21 )

For the non-randomness factor α 12 values between 0.25 and 0.40 were used in our
calculations. The temperature dependent interaction parameter τ ij was expressed as:
bij
τ ij = aij + (8)
T
with two adjustable parameters a ij and bij .

In modified form of UNIQUAC [12], the liquid phase activity coefficient is divided into
combinatorial part and a residual part:

ln γ i = ln γ iC + ln γ iR (i = 1,2) (9)

For the combinatorial part, the expression used by Peres and Macedo [12] for solubilities of
sugars was applied:

⎛ϕ ⎞ ϕ
ln γ iC = ln⎜⎜ i ⎟⎟ + 1 − i (10)
⎝ xi ⎠ xi
where xi denotes mole fraction of component i and ϕ i denotes the volume fraction of
component i, defined as:

xi ri 2 / 3
ϕi = 2
(11)
∑x r
j =1
2/3
j j

where ri is the UNIQUAC volume parameter for component i.

The original expression by Abrams and Prausnitz [19] for the residual part of activity
coefficient was used:

⎡ ⎛ ⎞⎤
⎢ ⎜ ⎟
⎛ 2 ⎞ 2
⎜ θ jτ ij ⎟⎥
ln γ i = q i ⎢1 − ln⎜⎜ ∑ θ jτ ji ⎟⎟ − ∑ 2
R ⎥ (12)
⎢ ⎜ ⎟⎥
⎝ j = 1 ⎠ j = 1
⎜ ∑ θ kτ kj ⎟⎥
⎢
⎣ ⎝ k =1 ⎠⎦
where qi is the UNIQUAC surface parameter for component i, θ j the molecular surface
fraction and τ ij the interaction parameters, given by the temperature dependence:

⎛ bij ⎞
τ ij = exp⎜⎜ aij + ⎟ (13)
⎝ T ⎟⎠
The volume and surface parameters for solvents were taken from the Dortmund Databank. To
calculate the structural parameters of diclofenac sodium the Bondi group contribution method
was used, where 0.3 nm [20] was chosen as a diameter for sodium. The molecular weight,
volume and surface parameters for all components are given in Table 1.

Table 1. Structural parameters of the components

Compound MW UNIQUAC
g/mol r q
Acetone 58.08 2.5735 2.336
Ethyl acetate 88.11 3.4786 3.116
Dimethyl sulfoxide 78.13 2.8266 2.472
Diclofenac sodium 318.13 10.4376 7.9652

Thermal analysis

Since the solubility of a solid in a liquid is determined not only by the intermolecular forces
between solute and solvent [11], but also by the melting point and the enthalpy of fusion,
DSC analysis for diclofenac sodium under a flux of dry nitrogen between 298.15 K and
573.15 K at 10K/min was performed. DSC traces recorded are in agreement with previously
published data by Bettini et al. [21]. Anhydrous diclofenac sodium melted with followed
decomposition at around 560 K.
An approximate value of the enthalpy of fusion may be calculated, as suggested by Gupta and
Heidemann [15], by:
ΔH fus
= Tm ΔS fus (14)

where the entropy of fusion, ΔS fus , can be taken as a constant value of 56.51 J mol-1 K-1.

The melting temperature of the drug, as well as both approximations for the enthalpy of
fusion of diclofenac sodium is reported in Table 2.

Table 2. Thermal properties of diclofenac sodium

Tm* (K) ΔH fus * (J/g) ΔH fus calc (J/g)

560.65 125 100
* calc
DSC analysis; from Eq. 14

Results and Discussion

The measured solubility data of diclofenac sodium in several solvents, namely, acetone, ethyl
acetate and dimethyl sulfoxide in the temperature range from 293.15 to 313.15 K are reported
in the Table 3. The solubility of the drug in dimethyl sulfoxide is two orders of magnitude
higher in comparison to acetone and ethyl acetate. As expected, the solubility of the drug is
increasing with temperature for all solvents, but this effect is more pronounced in the case of
dimethyl sulfoxide. The variation of solubility of the drug in different solvents is mainly a
result of dipole and hydrogen-bonding interactions. The presence of sodium in the drug, that
replaced the proton of the carboxylic group of diclofenac in acid form, reduces the Lewis-acid
properties of the drug. The solubility performance of diclofenac sodium from our experiments
is as follows: DMSO > acetone > ethyl acetate. Due to its high polarity, the solubility of the
salt is higher in dimethyl sulfoxide, with a total solubility parameter of 26.6 and a high polar
and hydrogen-bonding contribution.

Table 3. Solubility, S, of diclofenac sodium in mg/g of the solution

Temperature 293.15 K 298.15 K 303.15 K 308.15 K 313.15 K

Solvent S sd S sd S sd S sd S sd
Acetone 4.485 0.135 4.450 0.178 4.666 0.168 4.880 0.099 5.245 0.152
Ethyl 1.193 0.066 1.255 0.063 1.404 0.033 1.596 0.068
acetate
DMSO 111.65 2.68 135.2 6.7 150.8 9.0 182.28 2.55 212.14 2.97

The first approximation of the molar heat and temperature of fusion can be used to calculate
ideal solubility of the drug at different temperatures that depends only on the properties of the
solute. In our calculation, the thermal data from DSC analysis, given in the Table 2, were used
with the assumption that ΔC p is zero for diclofenac sodium. The effect of intermolecular
forces between solute and solvent is reflected by the activity coefficient of the solute in the
liquid phase; hence an appropriate activity coefficient model for the description should be
used.

The solubility data were modeled using the NRTL and the modified UNIQUAC model. The
binary interaction parameters of the models were obtained by regression of the measured data,
solving Equation 5, with the objective function in terms of activity coefficients, based on the
maximum likelihood principle.
Table 4 reports the values of the binary interaction parameters along with the average relative
deviations (ARD) of both models. As can be seen in Figures 2 to 4, both models give a good
representation of the experimental data. The data were regressed using the NRTL model with
4 adjustable parameters, while α was set to 0.25, 0.30, 0.35, 0.40. The best results were
obtained in the case of α = 0.25 ; therefore only these results are reported in our contribution.
The solubility of diclofenac sodium in acetone was better described by the modified
UNIQUAC model using 2 temperature independent interaction parameters. Nearly no
difference is observed between the NRTL model with 4 adjustable parameters and the
modified UNIQUAC model for the solubility of the drug in ethyl acetate and dimethyl
sulfoxide. It has to be mentioned that in the case of ethyl acetate and dimethyl sulfoxide, 2
UNIQUAC interaction parameters and 4 UNIQUAC parameters, respectively, were used.

Table 4. Values of the binary interaction parameters for the UNIQUAC and the NRTL model
and average relative deviations for solubility of diclofenac sodium (2) in several solvents (1)

Solvent NRTL model, α =0.25 Modified UNIQUAC model

a12 (/) a21 (/) ARD a12 (/) a21 (/) ARD
b12 (K) b21 (K) (%) b12 (K) b21 (K) (%)

Acetone 9.521 0.263 1.86 0 0 0.93

-1490.864 -849.741 -751.171 370.397
Ethyl acetate 9.092 0.777 2.08 0 0 1.62
-3013.099 732.298 -662.662 339.052
DMSO -0.709 0.436 1.30 0.666 12.564 1.30
-1367.789 329.616 242.381 -4641.388

Figure 2. Measured and calculated solubility data for diclofenac sodium in acetone; the
dashed line represents the NRTL model with α = 0.25 ; the solid line represents the modified
UNIQUAC model

5,6

5,4 Acetone, exp

5,2

5,0
S / mg/g

4,8

4,6

4,4

4,2

4,0
290 295 300 305 310 315
T/K
Figure 3. Measured and calculated solubility data for diclofenac sodium in ethyl acetate; the
dashed line represents the NRTL model with α = 0.25 ; the solid line represents the modified
UNIQUAC model

1,7
Ethyl acetate, exp

1,6

1,5
S / (mg/g)

1,4

1,3

1,2

1,1

292 294 296 298 300 302 304 306 308 310
T/K

Figure 4. Measured and calculated solubility data for diclofenac sodium in dimethyl
sulfoxide; the dashed line represents the NRTL model with α = 0.25 ; the solid line represents
the modified UNIQUAC model

220
Dimethyl sulfoxide, exp

200

180
S / (mg/g)

160

140

120

100
290 295 300 305 310 315
T/K

Conclusions

Solubility of diclofenac sodium in acetone, ethyl acetate and dimethyl sulfoxide in the
temperature range from 293.15 K up to 313.15 K was measured. As expected, the solubility of
the drug is increasing with temperature for all solvents, but this effect is more pronounced in
the case of dimethyl sulfoxide. The solubility of the drug strongly depends on the solvent
used, thus on the intermolecular forces between diclofenac sodium and the solvent. The
 solubility of the drug in dimethyl sulfoxide is two orders of magnitude higher in comparison
to acetone and ethyl acetate. The variation of solubility of the drug in different solvents may
be due to dipole and hydrogen-bonding interactions. The presence of sodium in diclofenac
sodium reduces the Lewis-acid properties of the drug. Due to the high polarity of the drug, the
solubility of the salt is higher in dimethyl sulfoxide, with a total solubility parameter of 26.6
and a high polar and hydrogen-bonding contribution.
The experimental SLE data were modeled using the NRTL and the modified UNIQUAC
model, and both models gave a good representation of the experimental data. The solubility
of diclofenac sodium in acetone was better described by modified UNIQUAC model using 2
temperature independent interaction parameters. Nearly no difference was observed between
NRTL and UNIQUAC models for the other two solvents.

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