Synthesis, Characterization and Solubility Determination of 6-Phenyl-pyridazin-3(2H)-one in Different Pharmaceutical Solvents

Article abstract of DOI:10.3390/molecules24183404

The current research work proposed the solubility data and solution thermodynamic properties of the cardiovascular agent 6-phenylpyridazin-3(2H)-one [PPD] in twelve pharmaceutical solvents at “T = 298.2 K to 318.2 K” and “p = 0.1 MPa”. The measured solubilities of PPD were regressed well with “van’t Hoff and Apelblat models”. The solid phases of pure and equilibrated PPD were characterized using differential scanning calorimetry and powder X-ray differactometry, and the results suggested no transformation of PPD into solvates/hydrates/polymorphs after equilibrium. The solubilities of PPD in a mole fraction at “T = 318.2 K” were noted at a maximum in dimethyl sulfoxide (DMSO, 4.73 × 10^?1), followed by polyethylene glycol-400 (PEG-400, 4.12 × 10^?1), Transcutol (3.46 × 10^?1), ethyl acetate (EA, 81 × 10^?2), 2-butanol (2.18 × 10^?2), 1-butanol (2.11 × 10^?2), propylene glycol (PG, 1.50 × 10^?2), isopropyl alcohol (IPA, 1.44 × 10^?2), ethylene glycol (EG, 1.27 × 10^?2), ethanol (8.22 × 10^?3), methanol (5.18 × 10^?3) and water (1.26 × 10^?5). Similar tendencies were also noted at other studied temperatures. The results of the “apparent thermodynamic analysis” showed an endothermic and entropy-driven dissolution of PPD in all pharmaceutical solvents. The results of the activity coefficients suggested a maximum interaction at the molecular level in PPD-DMSO, PPD-PEG-400 and PPD-Transcutol, compared with other combination of the solute and solvents.

Full text of DOI:10.3390/molecules24183404

molecules
Article
Synthesis, Characterization and Solubility
Determination of 6-Phenyl-pyridazin-3(2H)-one in
Different Pharmaceutical Solvents
1
,
2
1
1
and Md. Khalid Anwer 3
Faiyaz Shakeel * , Mohd Imran , Nazrul Haq , Sultan Alshehri
1
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457,
Riyadh 11451, Saudi Arabia; nazrulhaq59@gmail.com (N.H.); salshehri1@ksu.edu.sa (S.A.)
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, P.O. Box 840,
Rafha 91911, Saudi Arabia; imran_inderlok@yahoo.co.in
Department of Pharmaceutics, College of Pharmacy, Prince Sattam bin Abdulaziz University,
Al-Kharj 11942, Saudi Arabia; mkanwer2002@yahoo.co.in
2
3
*
Correspondence: faiyazs@fastmail.fm
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 25 August 2019; Accepted: 17 September 2019; Published: 19 September 2019
Abstract: The current research work proposed the solubility data and solution thermodynamic
properties of the cardiovascular agent 6-phenylpyridazin-3(2H)-one [PPD] in twelve pharmaceutical
solvents at “T = 298.2 K to 318.2 K” and “p = 0.1 MPa”. The measured solubilities of PPD were
regressed well with “van’t Hoff and Apelblat models”. The solid phases of pure and equilibrated PPD
were characterized using differential scanning calorimetry and powder X-ray differactometry, and the
results suggested no transformation of PPD into solvates/hydrates/polymorphs after equilibrium. The
solubilities of PPD in a mole fraction at “T = 318.2 K” were noted at a maximum in dimethyl sulfoxide
−
1
−1
®
(
(
DMSO, 4.73
×
10 ), followed by polyethylene glycol-400 (PEG-400, 4.12
×
10 ), Transcutol
−
1
−2
−2
−2
3.46
×
10 ), ethyl acetate (EA, 81
×
10 ), 2-butanol (2.18
×
10 ), 1-butanol (2.11
×
10 ), propylene
−
2
−2
−2
glycol (PG, 1.50
(
×
10 ), isopropyl alcohol (IPA, 1.44
×
10 ), ethylene glycol (EG, 1.27
×
10 ), ethanol
−
3
−3
−5
8.22
×
10 ), methanol (5.18
×
10 ) and water (1.26
×
10 ). Similar tendencies were also noted
at other studied temperatures. The results of the “apparent thermodynamic analysis” showed an
endothermic and entropy-driven dissolution of PPD in all pharmaceutical solvents. The results
of the activity coefficients suggested a maximum interaction at the molecular level in PPD-DMSO,
PPD-PEG-400 and PPD-Transcutol, compared with other combination of the solute and solvents.
Keywords: 6-phenylpyridazin-3(2H)-one; activity coefficient; cardiovascular drug; dissolution
thermodynamics; solubility
1
. Introduction
The derivatives of pyridazinone have been investigated extensively in the control and
management of various cardiovascular diseases [
under various phases of clinical trials while some have been approved for clinical use [
compound 6-phenylpyridazin-3(2H)-one (PPD) (molecular structure: Figure 1; chemical name:
1,
2]. Some of the pyridazinone derivatives are
3–7]. The
−1
6
-phenylpyridazin-3(2H)-one; molecular formula: C H N O; molar mass: 172.18 g
·
mol and
]. This compound has been
]. Various derivatives of PPD have also been
10], analgesics [11 12], anti-inflammatory [12 13],
], antiulcer [14] and antimicrobial agents [15] in the literature. In spite of various
therapeutic activities of PPD derivatives, these compounds have a high toxicity and poor solubility
10
8
2
CAS registry number: 2166-31-6) occurs as a white crystalline solid [
studied as a potent cardiotonic agent in the literature [
investigated as insecticidal [ ], cardioprotective [
antinociceptive [
8
6,8
9
7
,
,
,
6
Molecules 2019, 24, 3404; doi:10.3390/molecules24183404
www.mdpi.com/journal/molecules

Molecules 2019, 24, 3404
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in water and aqueous buffers [
1,6
]. The poor water solubility of PPD could be a major hurdle for its
dosage form design.
Figure 1. The molecular structure of PPD (molar mass: 172.18 g·mol−1).
The solubility values and other physico-chemical data of newly established compounds and
existing ones in various neat pharmaceutical solvents are important in “their synthesis, purification,
recrystallization, drug discovery processes and dosage form design” [16–19]. Hence, it is very
important to determine the solubility of PPD in various pharmaceutical solvents in order to get its
physicochemical information. In general, the solubility values and solution thermodynamic properties
of pyridazinone derivatives have rarely been reported so far. However, the solubilities of a similar
compound, 6-phenyl-4,5-dihydropyridazin-3(2H)-one, have been recently reported by our research
group in eleven different neat solvents including water, ethanol, isopropanol (IPA), ethylene glycol
(
(
EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), 1-butanol, 2-butanol, ethyl acetate
EA), Transcutol and dimethyl sulfoxide (DMSO) at “T = 293.2 K to 313.2 K” and “p = 0.1 MPa” [20].
The solubilities and solution thermodynamic properties of 6-phenyl-4,5-dihydropyridazin-3(2H)-one
in different “Transcutol + water” and “PEG-400 + water” binary solvent systems at “T = 293.2 K to
3
13.2 K” and “p = 0.1 MPa” have also been reported [21,22].
Nevertheless, the solubilities and solution thermodynamic properties of the synthesized compound
PPD in any of the investigated pharmaceutical solvents have not been reported so far. Hence, the
proposed research work was undertaken to determine the solubilities of PPD (expressed in mole
fraction) in twelve different pharmaceutical solvents, including “water, methanol, ethanol, IPA,
1
“
-butanol, 2-butanol, Transcutol, PEG-400, EG, PG, EA and DMSO” at “T = 298.2 K to 318.2 K” and
p = 0.1 MPa”. The temperature range “T = 298.2 K to 318.2 K” was maintained in such a way that
the maximum studied temperature, i.e., “T = 318.2 K”, should not exceed the melting temperature of
PPD (i.e., 474.2 K to 477.2 K) [ ]. The maximum studied temperature (i.e., 318.2 K) was lower than the
8
melting temperature of PPD; therefore, this temperature range was maintained in this study. Unlike
the temperature, the effect of the pressure on the solubility of PPD was not studied, and hence all these
studies were performed at an ambient pressure, i.e., “p = 0.1 MPa”. The activity coefficients of PPD in all
these pharmaceutical solvents were also determined in order to investigate the interaction of PPD with
the respective pharmaceutical solvent at a molecular level. An “apparent thermodynamic analysis”
was also conducted for the evaluation of the dissolution behavior of PPD in these pharmaceutical
solvents. The results recorded in the proposed research work would be applicable in the “synthesis,
recrystallization, purification, pre-formulation studies and dosage form design” of PPD.
2
. Results and Discussion
2
.1. Characterization and Identification of PPD
The % yield of PPD was obtained as 77.3 %. The purity of PPD was found to be > 97% (HPLC). The
1
13
structure elucidation of PPD was confirmed on the basis of “FT-IR spectra, H-NMR spectra, C-NMR
spectra, mass spectra and elemental analysis”. The recorded FT-IR spectra of PPD are furnished in
−
1
the Supplementary Figure S1 (Figure S1). The main FT-IR peaks of PPD were noted at 2854.32 cm ,
− −1 −1 −1
1
1
1
529.37 cm , 1282.13 cm , 1007.12 cm and 587.67 cm . The H-NMR spectra of PPD are furnished
1
13
in Figure S2. The main H NMR peaks of PPD were noted at different
δ values. The C-NMR spectra

Molecules 2019, 24, 3404
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of PPD are furnished in Figure S3, which also showed the characteristics peaks of PPD at different
δ
values. The mass spectra of PPD are furnished in Figure S4, which suggested the identification of the
molar mass of PPD. The resulting data of the elemental analysis of PPD are furnished in Table S1. The
mass fractions (%) of C, H and N were found to be 69.75, 4.66 and 16.25 %, respectively, which were
very close to the calculated values of C, H and N.
2
.2. Characterization of Solid Phases of PPD
The characterization of the solid phases of PPD in the pure and equilibrated samples was carried
out for the evaluation of the physical form and possible transformation of PPD after equilibrium.
“
Differential Scanning Calorimetry (DSC) and “Powder X-ray Diffractometry (PXRD)” techniques
were applied for this characterization. The recorded DSC spectra of the pure and equilibrated PPD
are furnished in Figure 2A,B, respectively. The DSC thermogram of the pure PPD presented a sharp
endothermic peak at the fusion temperature (Tfus) = 476.43 K, suggesting the fusion temperature
and crystallinity of the pure PPD. The fusion enthalpy (
∆
Hfus) of the pure PPD was estimated as
mol (Figure 2A). The DSC spectra of the equilibrated PPD also presented a sharp endothermic
peak at T = 478.85 K, suggesting the fusion temperature and crystallinity of the equilibrated PPD. The
−
1
2
4.51 kJ
·
fus
−
1
∆
Hfus = 23.72 kJ mol was recorded for the equilibrated PPD (Figure 2B). There were no significant
changes in the DSC profiles of the pure and equilibrated PPD that were noted, which suggested that PPD
·
exists in a pure crystalline form and did not transform into amorphous/polymorphic/hydrates/solvates
after equilibrium. The Tfus value of PPD has been proposed as (474.2 to 477.2) K elsewhere [8]. The
Tfus value of PPD was recorded as 476.43 K in our study. The Tfus value of the pure PPD recorded in
our work was in accordance with the literature value.
The PXRD patterns of the pure and equilibrated PPD are shown in Figure 3A,B, respectively. The
PXRD spectra of both samples, i.e., the pure and equilibrated PPD, presented sharp crystalline peaks at
various 2
θ values, suggesting the crystalline nature of pure and equilibrated PPD (Figure 3). There
were no significant changes in the PXRD patterns of both samples that were noted, suggesting that
PPD exists in a pure crystalline form and remained unchanged after equilibrium.
Figure 2. The DSC spectra of (A) pure PPD and (B) equilibrated PPD; equilibrated PPD was recovered
from methanol after slow evaporation.

Molecules 2019, 24, 3404
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Figure 3. The PXRD spectra of (A) pure PPD and (B) equilibrated PPD; equilibrated PPD was recovered
from methanol after slow evaporation.
2
.3. Measured Solubilities of PPD
e
The measured experimental solubilities of PPD in a mole fraction (x ) in twelve different
pharmaceutical solvents at “T = 298.2 K to 318.2 K” and “p = 0.1 MPa” are tabulated in Table 1. The
solubility values of a similar pyridazinone derivative, i.e., 6-phenyl-4,5-dihydropyridazin-3(2H)-one,
in eleven different pure solvents, namely “water, ethanol, IPA, EG, PG, PEG-400, 1-butanol, 2-butanol,
EA, Transcutol and DMSO” at “T = 293.2 K to 313.2 K” and “p = 0.1 MPa”, have been reported
elsewhere [20]. The solubilities of 6-phenyl-4,5-dihydropyridazin-3(2H)-one in various “Transcutol +
water” and “PEG-400 + water” binary solvent systems at “T = 293.2 K to 313.2 K” and “p = 0.1 MPa”
were also reported [21
,22]. Nevertheless, the solubilities of the investigated compound PPD in any of
the neat solvent or binary solvent mixtures have not been reported.
Table 1. The experimental solubilities (x
and “p = 0.1 MPa” a.
e
) of PPD in various neat solvents (S) at “T = 298.2 K to 318.2 K
xe
S
T = 298.2 K
T = 303.2 K
T = 308.2 K
T = 313.2 K
T = 318.2 K
−
−
−
−
−
−
−
−
−
−
−
−
6
3
3
3
3
3
2
2
2
1
1
1
−6
−6
−5
−5
Water
Methanol
Ethanol
EG
5.75 × 10
2.59 × 10
4.75 × 10
6.43 × 10
8.15 × 10
8.74 × 10
1.19 × 10
1.23 × 10
4.37 × 10
2.76 × 10
3.19 × 10
4.03 × 10
5.50 × 10
6.91 × 10
8.37 × 10
1.00 × 10
1.26 × 10
−3
−3
−3
−3
3.00 × 10
3.57 × 10
4.29 × 10
5.18 × 10
−3
−3
−3
−3
5.42 × 10
6.19 × 10
7.22 × 10
8.22 × 10
−3
−3
−2
−2
7.51 × 10
8.96 × 10
1.05 × 10
1.27 × 10
−3
−2
−2
−2
IPA
PG
9.13 × 10
1.06 × 10
1.23 × 10
1.44 × 10
−3
−2
−2
−2
9.93 × 10
1.13 × 10
1.27 × 10
1.50 × 10
−2
−2
−2
−2
1
2
-Butanol
-Butanol
EA
1.36 × 10
1.59 × 10
1.84 × 10
2.11 × 10
−2
−2
−2
−2
1.41 × 10
1.61 × 10
1.88 × 10
2.18 × 10
−2
−2
−2
−2
4.79 × 10
5.42 × 10
6.01 × 10
6.81 × 10
−1
−1
−1
−1
Transcutol
PEG-400
DMSO
2.90 × 10
3.06 × 10
3.25 × 10
3.46 × 10
−1
−1
−1
−1
3.38 × 10
3.62 × 10
3.89 × 10
4.12 × 10
−1
−1
−1
−1
4.19 × 10
4.38 × 10
4.55 × 10
4.73 × 10
idl
−2
−2
−2
−2
−1
x
6.10 × 10
6.75 × 10
7.45 × 10
8.22 × 10
a
The standard uncertainties u are u(T) = 0.20 K, u(p) = 0.003 MPa and ur(xe) = 1.61%.
From the measured solubility data of PPD, it was noted that the x
e
values of PPD were enhanced
significantly with respect to the absolute temperature in each pharmaceutical solvent that was studied.
−
1
The x
PEG-400 (4.12
e
values of PPD at “T = 318.2 K” were obtained at a maximum in DMSO (4.73
×
10 ), followed by
×
−
1
®
−1
−2
−2
−3
×
10 ), Transcutol (3.46
×
10 ), EA (6.81
×
10 ), 2-butanol (2.18
10 ), 1-butanol
10 ), methanol
−
2
−2
−2
−2
(
(
2.11
5.18
×
×
10 ), PG (1.50
10 ) and water (1.26
×
10 ), IPA (1.44
×
10 ), EG (1.27
×
10 ), ethanol (8.22
×
−
3
−5
×
10 ). Similar tendencies were also recorded at other temperatures
values of PPD in three pharmaceutical solvents, including “DMSO, PEG-400
that were studied. The x
e
and Transcutol”, were much higher when compared with other pharmaceutical solvents that were
investigated. Generally, the x values of PPD were recorded as having a similar trend as that reported
e

Molecules 2019, 24, 3404
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for the solubility of 6-phenyl-4,5-dihydropyridazin-3(2H)-one in eleven different neat solvents. Based
on the results recorded in this study, PPD is found to be weakly soluble in water, sparingly soluble in
methanol, ethanol, IPA, EG, PG, 1-butanol and 2-butanol, soluble in EA and freely soluble in DMSO,
PEG-400 and Transcutol [20
,21]. The data recorded in this work could be utilized for the “synthesis,
recrystallization, purification, pre-formulation studies and dosage form design” of PPD.
2
.4. Solubility Parameters for PPD and Various Pharmaceutical Solvents
The recorded solubility values of PPD were also correlated based on the solubility parameters of
the solute and solvent. For this correlation, the “Hansen solubility parameter (
pharmaceutical solvents was obtained with the help of Equation (1) [23–25]:
δ
)” for PPD and various
2
2
2
2
δ = δ + δ + δ ,
(1)
d
p
h
Here,
δ = dispersion solubility parameter; δp = polar solubility parameter and δ = hydrogen-bonded
d h
solubility parameter. The quantitative values of
version 4.1.07)”. The resulting data is tabulated in Table S2.
The
value for PPD was calculated as 24.70 MPa1/2, suggesting that PPD is a compound with a
lower polarity. The solubilities of PPD were also found to be higher in pharmaceutical solvents having
δ, δd, δp and δ were obtained using “HSPiP software
h
(
δ
lower
δ
values (Table S2). The solubilities of PPD were obtained at their highest in DMSO, which was
value of DMSO (23.60 MPa1 ) with PPD. Meanwhile, the solubilities of
/2
possibly due to the closed
δ
PPD were recorded at their lowest in water, which could possibly be due to the highest
δ value of
water (47.80 MPa1 ). Overall, the results of the Hansen solubility parameters were in accordance with
/2
the recorded solubility data of PPD.
2
.5. Theoretical/Ideal Solubilities of PPD
The theoretical/ideal solubility of pure PPD (xidl) was calculated using Equation (2) [26]:
!
!
−
∆Hfus(Tfus − T)
∆Cp Tfus − T
T
Tfus
ln xidl
=
+
[
+ ln
] ,
(2)
RTfus
T
R
T
p
Here, R = universal gas constant and ∆C = difference in the molar heat capacity of the solid state with
that of the liquid state [27,28].
The ∆Cp value for PPD was calculated using Equation (3) [26]:
∆
Tfus
Hfus
∆
Cp =
,
(3)
−
1
The quantitative values of Tfus and
respectively, by thermal analysis of pure PPD. The
∆
Hfus for pure PPD were obtained as 476.43 K and 24.51 kJ mol ,
·
−
1
−1
∆
C
p
value for PPD was calculated as 51.44 J·mol ·K
idl
using Equation (3). With the help of Equation (2), the x values for PPD were calculated, and the
results are tabulated in Table 1.
idl
−2
−1
10 at “T = 298.2 K
The x values for PPD were recorded in the range of 5.50
×
10 to 8.22
×
idl
to 318.2 K”. The recorded x values of PPD were found to be slightly lower than the mole fraction
solubilities of PPD in DMSO, PEG-400 and Transcutol at every temperature point. However, these
values of PPD were found to be slightly higher than its mole fraction solubilities in EA, 1-butanol and
2
-butanol at each of the studied temperatures. On the other hand, the xidl values of PPD were found to
be much higher than the mole fraction solubilities of PPD in other pharmaceutical solvents such as
water, methanol, ethanol, EG, IPA and PG at each of the studied temperatures. Based on these results,
DMSO, PEG-400 and Transcutol could be used as the ideal pharmaceutical solvents for the solubility
enhancement of PPD.

Molecules 2019, 24, 3404
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2
.6. Activity Coefficients and Solute-Solvent Molecular Interactions
The quantitative values of the activity coefficients (γi) for PPD in twelve different pharmaceutical
solvents were calculated using Equation (4) [26,29]:
xidl
xe
γ =
i
,
(4)
The quantitative values of
γ for PPD in twelve different pharmaceutical solvents at “T = 298.2 K,
i
3
03.2 K, 308.2 K, 313.2 K and 318.2 K” are tabulated in Table 2.
Through the quantitative values of for PPD, the solute-solvent interactions at the molecular level
γ
i
can be described. The activity coefficients of PPD were found to be much higher in water compared
with other pharmaceutical solvents that were studied. Meanwhile, these values for PPD were noted
as being much lower in DMSO, PEG-400 and Transcutol (Table 2) at each investigated temperature.
Generally, the values of
γ for PPD in most of the pharmaceutical solvents were found to be decreased
i
with a rise in temperature. Based on the estimated values of the activity coefficients, the highest
interactions at the molecular level were noted in PPD-DMSO, PPD-PEG-400 and PPD-Transcutol, when
compared with other combination of solute and solvent at the molecular level.
Table 2. The values of γ for PPD in various neat solvents (S) at “T = 298.2 K to 318.2 K” calculated
i
using xidl and xe values.
γ
i
S
T = 298.2 K
T = 303.2 K
T = 308.2 K
T = 313.2 K
T = 318.2 K
Water
Methanol
Ethanol
EG
9570.00
21.23
11.58
8.55
8840.00
20.30
11.24
8.12
8070.00
18.86
10.90
7.53
7430.00
17.35
10.32
7.08
6550.00
15.87
10.00
6.45
IPA
6.75
6.68
6.34
6.06
5.70
PG
6.29
6.14
5.94
5.85
5.47
1
2
-Butanol
-Butanol
EA
4.59
4.44
1.27
4.46
4.30
1.25
4.23
4.17
1.24
4.04
3.95
1.23
3.89
3.77
1.20
Transcutol
PEG-400
DMSO
0.19
0.17
0.13
0.21
0.18
0.14
0.22
0.18
0.15
0.22
0.19
0.16
0.23
0.19
0.17
2
.7. Thermodynamic Models for Solubility Correlation
Various thermodynamic-based mathematical models have been proposed for the correlation of
the experimental solubility data of solutes [25 31]. The most widely applied models for the correlation
of the solubility data of solutes in pure/neat solvents are Apelblat and van’t Hoff models [27 31].
Hence, the x values of PPD were correlated with “Apelblat and van’t Hoff models” in the proposed
–
–
e
Apl
study [25,30,31]. The “Apelblat solubility (x )” of PPD was estimated using Equation (5) [30,31]:
B
T
ln xApl = A + + C ln(T),
(5)
Here, A, B and C = model parameters of the “Apelblat model”. The values of A, B and C were
e
estimated by applying a “nonlinear multivariate regression analysis” of the x values of PPD, tabulated
Apl
in Table 1 [22]. The correlation between the x
e
and x
values of PPD was conducted in terms of “root
2
mean square deviations (RMSD) and the coefficient of determination (R )”. The RMSD values of PPD
were estimated by applying its standard equation, as reported in the literature [31,32].
The representative graph for the graphical correlation between the natural logarithmic x
e e
(ln x )
and ln xApl values of PPD in each pharmaceutical solvent against 1/T is furnished in Figure 4, suggesting

Molecules 2019, 24, 3404
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a good correlation between the ln x
e
and ln xApl values of PPD. The estimated values of the “Apelblat
correlation” are furnished in Table 3. The RMSD values of PPD in twelve different pharmaceutical
solvents were obtained as (0.16 to 0.95)%. The overall RMSD value for this correlation was recorded as
0
.62%. The maximum value of RMSD was noted in PG (0.95%). However, the minimum value was
2
noted in DMSO (0.16%). The R values for PPD were noted as 0.9980 to 0.9998. The estimated values
of RMSD and R suggested a good correlation of the xe values of PPD with the “Apelblat model”.
2
van’t
The “van’t Hoff model solubility (x
)” of PPD was estimated using Equation (6) [25]:
0
b
T
van t
ln x
= a +
,
(6)
Here, a and b = parameters of “van’t Hoff model”. The values of “a and b” were estimated from graphs
constructed between ln xe and 1/T.
2
Table 3. The Apelblat parameters (A, B and C), R and RMSD (%) for PPD in different neat solvents (S).
S
A
B
C
R2
RMSD (%)
Overall RMSD (%)
Water
Methanol
Ethanol
EG
−203.37
−521.60
−160.38
−411.70
−494.39
−382.75
−131.04
−269.06
−320.51
−203.37
−49.63
8364.17
20,859.30
4887.72
15,922.29
20,155.48
15,208.33
3505.05
9860.43
12,771.75
8364.17
1173.90
488.77
30.54
78.22
24.33
62.00
74.06
57.39
20.15
40.65
48.18
30.54
7.81
0.9994
0.9997
0.9992
0.9998
0.9995
0.9986
0.9993
0.9995
0.9995
0.9994
0.9980
0.9992
0.91
0.74
0.57
0.76
0.87
0.95
0.62
0.42
0.63
0.27
0.56
0.16
IPA
PG
0.62
1
2
-Butanol
-Butanol
EA
Transcutol
PEG-400
DMSO
−25.60
4.04
The correlation between the x
and R . The representative graph for the graphical correlation between the ln x
e
and xvan’t values of PPD was conducted again in terms of RMSD
2
van’t
e
and ln x
values of
PPD in each pharmaceutical solvent against 1/T is furnished in Figure S5, suggesting a good correlation
van’t
between the ln x
e
and ln x
values of PPD. The estimated values of the “van’t Hoff correlation”
are furnished in Table 4. The RMSD values of PPD in twelve different pharmaceutical solvents were
obtained as (0.70 to 1.70)%. The overall RMSD value for this correlation was recorded as 1.16%. The
maximum value of RMSD was noted in methanol (1.70%) with the minimum one in PEG-400 (0.70%).
2
2
The R values for PPD were noted as 0.9940 to 0.9991. The estimated values of RMSD and R again
suggested a good correlation of the xe values of PPD with the “van’t Hoff model”.
2
Table 4. The van’t Hoff model parameters (a and b), R and RMSD (%) for PPD in various neat
solvents (S).
S
a
b
R2
RMSD (%) Overall RMSD (%)
Water
Methanol
Ethanol
EG
0.22
5.10
3.44
5.76
4.30
3.70
4.67
4.62
3.94
2.30
3.00
1.63
−3669.00
−3304.80
−2623.30
−3228.70
−2724.80
−2521.30
−2715.70
−2693.10
−2113.70
−1072.50
−1238.00
−759.30
0.9970
0.9960
0.9985
0.9974
0.9947
0.9953
0.9990
0.9979
0.9961
0.9940
0.9977
0.9991
1.54
1.70
0.74
1.44
1.69
1.45
0.82
1.29
1.14
0.75
0.70
0.77
IPA
PG
1.16
1
2
-Butanol
-Butanol
EA
Transcutol
PEG-400
DMSO

Molecules 2019, 24, 3404
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Figure 4. The correlation of the experimental natural logarithmic solubilities (ln x
e
) of PPD with the
“
ln x
Apelblat model” in various neat solvents as a function of 1/T; the symbols represent the experimental
Apl
e
values of PPD, and the solid lines represent the ln x
values calculated by the “Apelblat model”.
2
.8. Thermodynamic Parameters for PPD Dissolution
The dissolution behavior of PPD in twelve different pharmaceutical solvents was investigated
using an “apparent thermodynamic analysis”. Various thermodynamic parameters, namely “apparent
0
0
standard enthalpy (∆solH ), apparent standard Gibbs free energy (∆solG ) and apparent standard
entropy (∆solS )”, were estimated via the “apparent thermodynamic analysis”. The “∆solH values” for
0
0
the PPD dissolution in each pharmaceutical solvent were estimated at the “mean harmonic temperature
(Thm)” of 308 K by applying “van’t Hoff analysis” using Equation (7) [26,33]:




∆solH0

∂ln xe






ꢀ
ꢁ = −
,
(7)




1
1
hm
R
∂
− T
T
P
0
values of PPD against 1
1
hm
The “∆solH values” for PPD were obtained by plotting the ln x
e
−
. The
T
T
2
“
van’t Hoff plots” in each pharmaceutical solvent were found to be linear with R values of 0.9942
to 0.9992.
The ∆solG and ∆solS0 values for the PPD dissolution were obtained using Equations (8) and (9),
0
respectively [26,33,34]:
0
∆solG = −RT × intercept,
(8)
(9)
hm
0
0
∆solH − ∆solG
∆solS0 =
,
T
hm
The results of the “apparent thermodynamic analysis” for the PPD dissolution are tabulated in Table 5.
0
The “∆solH values” for the PPD dissolution in twelve different pharmaceutical solvents
−
1
0
were estimated as positive values in the range of (6.32 to 30.54) kJ mol . The “∆solH value”
·
−1
for the PPD dissolution was estimated at a maximum in water (30.54 kJ
·
mol ), followed by
−
1
−1
−1
−1
methanol (27.51 kJ
-butanol (22.42 kJ
·
mol ), EG (26.88 kJ
·
mol ), IPA (22.68 kJ
·
mol ), 1
−
butanol (22.60 kJ
mol ), EA (17.59 kJ
mol ). It was noted that the “∆sol
·
mol ),
−
1
−1
−1
−1
2
·
mol ), ethanol (21.84 kJ
·
mol ), PG (20.99 kJ
·
·
mol ), PEG-400
−
1
−1
−1
0
(
10.31 kJ
·
mol ), Transcutol (8.93 kJ
·
mol ) and DMSO (6.32 kJ
·
H

Molecules 2019, 24, 3404
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values” for the PPD dissolution were estimated to be lower for pharmaceutical solvents having
0
higher solubility values (DMSO, Transcutol and PEG-400). However, the “∆solH values” for the PPD
dissolution were estimated to be higher for pharmaceutical solvents having lower solubility values
0
(
water, methanol and ethanol, etc.). The mean “∆solH value” for the PPD dissolution was determined
as 19.88 kJ·mol− , with a relative uncertainty of 0.38.
1
0
0
0
2
Table 5. Thermodynamic quantities (∆solH , ∆solG and ∆solS ) and R values for the PPD dissolution
in various neat solvents (S)b.
0
−1
0
−1
0
S /J·mol−1·K−1
R2
S
∆
H /kJ·mol
∆
G /kJ·mol
∆
sol
sol
sol
Water
Methanol
Ethanol
EG
30.54
27.51
21.84
26.88
22.68
20.99
22.60
22.42
17.59
8.93
29.92
14.39
12.99
12.06
11.61
11.46
10.60
10.53
7.46
2.00
42.59
28.70
48.08
35.93
30.92
38.97
38.59
32.89
19.20
25.04
13.64
−1
0.9971
0.9962
0.9986
0.9975
0.9949
0.9954
0.9990
0.9980
0.9962
0.9942
0.9978
0.9992
IPA
PG
1
2
-Butanol
-Butanol
EA
Transcutol
PEG-400
DMSO
3.01
2.59
2.11
10.31
6.32
b
0
−1
0
mol and u(∆solS0) = 0.43 J
mol−1·
−1
The relative uncertainties are u(∆solH ) = 0.38 kJ
·
mol , u(∆solG ) = 0.68 kJ
·
·
K .
0
The “∆solG values” for the PPD dissolution in twelve different pharmaceutical solvents were
−
1
0
also estimated as positive values in the range of (2.11 to 29.92) kJ
PPD dissolution was also estimated at a maximum in water (29.92 kJ
·
mol . The “∆solG value” for the
−
1
·
mol ), followed by methanol
−
1
−1
−1
−1
−1
(
1
14.39 kJ
−
·
mol ), ethanol (12.99 kJ
·
mol ), EG (12.06 kJ
·
mol ), IPA (11.61 kJ
·
mol ), PG (11.46 kJ
·
mol ),
−
1
−1
−1
−1
butanol (10.60 kJ
PEG-400 (2.59 kJ
·
mol ), 2-butanol (10.53 kJ
mol ) and DMSO (2.11 kJ
·
mol ), EA (7.46 kJ
mol ). The mean “
·
mol ), Transcutol (3.01 kJ
·
mol ),
−1
−1
0
·
·
∆
G value” for the PPD dissolution
sol
−
1
was determined as 10.73 kJ·mol , with a relative uncertainty of 0.68.
0
The “
∆
G values” of PPD in various pharmaceutical solvents were found to decrease with an
increase in the solubility of PPD. The results of the “∆solG values” for the PPD dissolution were in
accordance with the recorded solubility data of PPD. The estimated positive values of “∆solH and
∆solG ” in twelve pharmaceutical solvents suggested an “endothermic dissolution” of PPD in all of the
sol
0
0
0
studied pharmaceutical solvents [32].
0
The “∆solS values” for the PPD dissolution in twelve different pharmaceutical solvents were also
− −1
1
0
recorded as positive values in the range of (2.00 to 48.08) J
·
mol
·
K . The mean value of ∆solS for the
−1
−1
PDP dissolution was recorded as 29.71 J
·
mol
·
K , with a relative uncertainty of 0.43. The recorded
positive “∆solS values” for the PPD dissolution suggested an “entropy-driven dissolution” of PPD in
0
all of the studied pharmaceutical solvents [25]. Finally, the dissolution of PPD was obtained as being
“
endothermic and entropy-driven” in all of the studied pharmaceutical solvents [25,32].
3
. Materials and Methods
3
.1. Materials
The compound PPD was synthesized, recrystallized with ethanol, characterized and identified
in the “Laboratory of Pharmaceutical Chemistry, Northern Border University, Rafha, Saudi Arabia”.
Methanol, ethanol, IPA, 1-butanol and 2-butanol were procured from “Sigma Aldrich (St. Louis, MO,
®
USA)”. Transcutol was procured as a kind gift sample from “Gattefosse (Lyon, France)”. PEG-400, PG,
EA, DMSO and EG were procured from “Fluka Chemica (Buchs, Switzerland)”. Water was acquired
from “Milli-Q unit”. The detailed properties of these materials are tabulated in Table S3.

Molecules 2019, 24, 3404
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3
.2. Synthesis of Compound PPD
For the synthesis of PPD, a mixture of 3-benzoylpropionic acid (0.01 mole) and hydrazine hydrate
0.02 moles) was refluxed in ethanol for about 6 h. The mixture was cooled, and the solid was filtered,
(
washed with water and dried. The solid was then dissolved in acetic acid, and a bromine solution in
acetic acid was slowly added to it at T = 353.2 K. The resulting mixture was stirred for about 15 min.
The obtained solid was filtered, washed with water several times and recrystallized with ethanol in
order to obtain the title compound [8]. The scheme for its synthesis is furnished in Figure S6.
3
.3. Characterization and Identification of PPD
The synthesized product PPD was characterized for the “yield, purity, FT-IR spectra, H-NMR
spectra, 13C-NMR spectra, mass spectra and elemental analyses” [35
37]. The standard protocols,
1
–
as reported in the literature, were used for the characterization and identification of the compound
PPD [19,35–37].
3
.4. Quantification of PPD in Solubility Samples
The synthesized compound PPD was quantified in solubility samples by applying a “high
performance liquid chromatography (HPLC) connected with ultra-violet (UV)” detector at the
wavelength of 254 nm. The entire quantifications were carried out at “T = 298.2 K” using “HPLC
system (Waters, Milford, MA, USA)”. The column used for this quantification was the “Nucleodur
(
150
×
4.6mm) RP C18 column with 5 µm particle size”. The mixture of methanol and acetic acid
(99:1%) was utilized as the mobile phase. The proposed mobile phase was flowed with a flow
−1
rate of 1.0 mL
·
min at 254 nm for the elution of PPD. The injection volume was 10
µL for all
samples. The standard plot was made between the concentration of PPD and the obtained HPLC area.
The standard plot of PPD was noted as linear with a linearity range of (1–100)
of 0.9987. The regressed equation for PPD was recorded as y = 82,609x + 10,384, where x represents the
concentration of PPD and y represents the obtained HPLC area of PPD.
−
1
2
µg
·
g
with an R value
3
.5. Characterization of Solid Phases of Pure and Equilibrated PPD
The solid phases of PPD in pure and equilibrated solids were studied using DSC and PXRD.
The equilibrated PPD was recovered from methanol by slow evaporation. This characterization
was carried out for the evaluation of the physical form and the possible transformation of PPD into
polymorphs/solvates/hydrates after equilibrium. The DSC spectra for both samples were obtained
using “DSC-8000 Instrument (Perkin Elmer, Milford, MA, USA)”, which was calibrated and equipped
with a chiller and autosampler. Accurately weighed amounts of pure PPD (4.80 mg) and equilibrated
PPD (5.10) were taken into the DSC pan and sealed hermetically. The temperature range of “T = 298.2 K
to 673.2 K” was applied for the analysis of both samples. The heating and flow rates were set at
−
1
−1
1
0.0 K·min and 20 mL·min , respectively.
The PXRD patterns of both samples (pure and equilibrated PPD) were obtained with the help of
an “Ultima IV Diffractometer (Rigaku Inc. Tokyo, Japan)”. The 2
θ
range for obtaining these patterns
80 , with a scan speed of 0.5 min . The rest of the conditions and procedures were the
same as those reported for the PXRD analysis of luteolin and thymoquinone in the literature [31,32].
◦
◦
−1
was set at 3
−
3
.6. Measurement of PPD Solubility in Pharmaceutical Solvents
The solubility of PPD in the investigated pharmaceutical solvents was measured using the
equilibrium shake flask method, as reported previously in the literature [38]. The solubility of PPD in
each pharmaceutical solvent was estimated at “T = 298.2 to 318.2 K” and “p = 0.1 MPa”. For these
experiments, the excess quantity of PPD was added in known amounts of each pharmaceutical solvent,
and each experiment was performed in triplicates. The resultant mixtures were kept for continuous
®
shaking into a “WiseBath WSB Shaking Water Bath (Model WSB-18/30/-45, Daihan Scientific Co. Ltd.,

Molecules 2019, 24, 3404
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Seoul, Korea)”. The shaking speed and equilibrium time were set at 100 rpm and 3 days, respectively.
After 3 days, each sample was taken out from the shaker, and the PPD particles were allowed to settle
for about 24 h [22
,39]. After settling, the required amounts of supernatants from each sample matrix
were withdrawn and diluted with the mobile phase (wherever applicable). The obtained samples were
quantified for the PPD contents via the proposed HPLC-UV method at 254 nm. The x
were obtained using Equation (10) [32,39]:
e
values of PPD
(10)
m /M1
1
xe =
,
m /M + m /M
2
1
1
2
Here, m = mass of PPD (g); m = mass of respective pharmaceutical solvent (g); M = molar mass of
1
2
1
−1
−1
PPD (g·mol ); and M = molar mass of respective pharmaceutical solvent (g·mol ).
2
4
. Conclusions
The present studies were undertaken to determine the solubility of PPD in twelve different
pharmaceutical solvents at “T = 298.2 K to 318.2 K” and “p = 0.1 MPa”. The measured solubilities
of PPD were recorded as increasing with a rise in temperature in all pharmaceutical solvents. The
measured solubilities of PPD regressed well with the “van’t Hoff and Apelblat models”, with overall
RMSD values of 1.16% and 0.62%, respectively. The solubilities of PPD in the mole fraction at
“
1
T = 318.2 K” were obtained at a maximum in DMSO, followed by PEG-400, Transcutol, EA, 2-butanol,
-butanol, PG, IPA, EG, ethanol, methanol and water, and similar tendencies were also recorded
at other evaluated temperatures. The values of the activity coefficients that were calculated using
ideal solubilities of PPD suggested maximum interactions at the molecular level in PPD-DMSO,
PPD-PEG-400 and PPD-Transcutol, compared with other combinations of solute and solvents. The
“apparent thermodynamic analysis” showed an “endothermic and entropy-derived dissolution” of
PPD in all pharmaceutical solvents that were evaluated.
Supplementary Materials: The FT-IR, H NMR, 13C NMR and mass spectra of the synthesized compound PPD
are presented in Figures S1–S4, respectively. Figure S5 represents the correlation of the experimental solubilities of
PPD with the van’t Hoff model. The scheme for the synthesis of the compound PPD is presented in Figure S6. The
elemental analysis of the synthesized compound PPD is tabulated in Table S1. The Hansen solubility parameters
for the synthesized compound PPD and various pharmaceutical solvents are tabulated in Table S2. The information
about materials is furnished in Table S3.
1
Author Contributions:
Conceptualization, supervision—F.S.; Methodology—M.I., N.H. and S.A.;
Validation—M.K.A. and S.A.; Writing original draft—F.S. and S.A.; Writing-review and editing—N.H. and
M.K.A.; Software—F.S. and S.A.
Funding: This research was funded by the Deanship of Scientific Research at King Saud University via grant
number RGP-1438-013 and APC was also the supported by the Deanship of Scientific Research.
Acknowledgments: The authors would like to extend their sincere appreciation to the Deanship of Scientific
Research at King Saud University for funding the work through the research group project number RGP-1438-013.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
4.
Imran, M.; Nayeem, N. Synthesis and antihypertensive activity of some novel pyridazinones. Orient. J. Chem.
016, 32, 267–274. [CrossRef]
Imran, M.; Abida, A. 6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone-an important chemical moiety for
development of cardioactive agents: A review. Trop. J. Pharm. Sci. 2016, 15, 1579–1590. [CrossRef]
Asif, M.; Anita, S. Synthesis of new derivative of 2-[2-(1H-indol-1-yl)ethyl]-6-phenyl-4,5-dihydropyridazin-3(2H)-one.
Ovidius. Univ. Ann. Chem. 2011, 22, 98–101.
2
Dobariya, T.D.; Multani, P.J. Development and validation of methods for estimation of pimobendan in
pharmaceutical dosage form. Int. J. ChemTech. Res. 2013, 5, 2154–2164.

Molecules 2019, 24, 3404
12 of 13
5
.
Nieminen, M.S.; Fruhwald, S.; Heunks, L.M.A.; Suominen, P.K.; Gordon, A.C.; Kivikko, M.; Pollesello, P.
Levosimendan: Current data, clinical use and future development. Heart Lung Vessel 2013, 5, 227–245.
[PubMed]
6
.
.
Bansal, R.; Thota, S. Pyridazin-3(2H)-ones: The versatile pharmacophore of medicinal significance. Med. Chem.
Res. 2013, 22, 2539–2552. [CrossRef]
Wang, T.; Dong, Y.; Wang, L.; Xiang, B.; Chen, Z.; Qu, L. Design, synthesis and structure-activity relationship
studies of 6-phenyl-4,5-dihydro-3(2H)-pyridazinone derivatives as cardiotonic agents. Arzneimittelforschung
7
2
008, 58, 569–573. [PubMed]
8
9
.
.
Sircar, I. Substituted 6-Phenyl-3(2H)-Pyridazinones Useful as Cardiotonic Agents. US Patent 4404203, 13
September 1983.
Wu, J.; Kang, S.; Yuan, Q.; Luo, L.; Ma, J.; Shi, Q.; Yang, S. N-Substituted 5-chloro-6-phenylpyridazin-
3
9
(2H)-ones: Synthesis, insecticidal activity against Plutella xylostella (L.) and SAR study. Molecules 2012, 17,
413–9420. [CrossRef] [PubMed]
1
0. Siddiqui, A.A.; Mishra, R.; Shaharyar, M. Synthesis, characterization and antihypertensive activity of
pyridazinone derivatives. Eur. J. Med. Chem. 2010, 45, 2283–2290. [CrossRef]
1
1. Malinka, W.; Redzicka, A.; Jastrzebska-Wiesek, M.; Filipek, B.; Dybała, M.; Karczmarzyk, Z.; Urbanczyk-
Lipkowska, Z.; Kalicki, P. Derivatives of pyrrolo[3,4-d] pyridazinone, a new class of analgesic agents. Eur. J.
Med. Chem. 2011, 46, 4992–4999. [CrossRef]
1
1
2. Sukuroglu, M.; Ergun, B.C.; Unlu, M.; Sahin, M.F.; Kupeli, E.; Yesilada, E.; Banoglu, E. Synthesis, analgesic, and
anti-inflammatory activities of [6-(3,5-dimethyl-4-chloropyrazole-1-yl)-3(2H)-pyridazinon-2-yl] acetamides.
Arch. Pharm. Res. 2005, 5, 509–517. [CrossRef]
3. Singh, J.; Saini, V.; Kumar, A.; Bansal, R. Synthesis, molecular docking and biological evaluation of some newer
2-substituted-4-(benzo[d][1,3]dioxol-5-yl)-6-phenylpyridazin-3(2H)-ones as potential anti-inflammatory and
analgesic agents. Bioorg. Chem. 2017, 71, 201–210. [CrossRef] [PubMed]
1
1
1
4. Yamada, T.; Nobuhara, Y.; Yamaguchi, A.; Ohki, M. Pyridazinones. 1. Synthesis and antisecretory and
antiulcer activities of thioamide derivatives. J. Med. Chem. 1982, 25, 975–982. [CrossRef] [PubMed]
5. Sonmej, M.; Berber, L.; Akbas, B. Synthesis, antibacterial and antifungal activity of some new pyridazinone
metal complexes. Eur. J. Med. Chem. 2005, 41, 101–105. [CrossRef] [PubMed]
6. Shakeel, F.; Bhat, M.A.; Haq, N. Solubility of (2Z)-N-cyclohexyl-2-(3-hydroxybenzylidine) hydrazine
carbothioamide in different pure solvents at (298.15 to 338.15) K. J. Chem. Eng. Data 2014, 59, 2126–2130.
[
CrossRef]
7. Shakeel, F.; Haq, N.; Radwan, A.A.; Alanazi, F.K.; Alsarra, I.A. Solubility and solvation behavior of N -(1-(N-
methyl) benzylaminomethyl)-2-oxoindolin-3-ylidene)-2-(benzyloxy) benzohydrazide in (PEG 400 + water)
0
1
1
1
2
2
(
mixtures. J. Mol. Liq. 2016, 216, 1225–1230. [CrossRef]
8. Shakeel, F.; Bhat, M.A.; Haq, N. Solubility and dissolution thermodynamics of (2Z)-N-cyclohexyl-2-(3-
hydroxybenzylidine) hydrazine carbothioamide in 2-(2-ethoxyethoxy) ethanol + water mixtures at (298.15 to
3
38.15) K. J. Mol. Liq. 2014, 197, 381–385. [CrossRef]
9. Shakeel, F.; Bhat, M.A.; Haq, N. Solubility of N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)-
hydrazinecarbothioamide (isoniazid analogue) in Transcutol + water cosolvent mixtures at (298.15 to
3
38.15) K. J. Chem. Eng. Data 2014, 59, 1727–1732. [CrossRef]
0. Imran, M.; Haq, N.; Alanazi, F.K.; Alsarra, I.A.; Shakeel, F. Solubility and thermodynamics of 6-phenyl-4,5-
dihydropyridazin-3(2H)-one in various neat solvents at different temperatures. J. Mol. Liq. 2017, 238, 455–461.
[CrossRef]
1. Shakeel, F.; Imran, M.; Haq, N.; Alanazi, F.K.; Alsarra, I.A. Solubility and thermodynamic/solvation behavior
of 6-phenyl-4,5-dihydropyridazin-3(2H)-one in different (Transcutol + water) mixtures. J. Mol. Liq. 2017, 230,
5
11–517. [CrossRef]
2. Imran, M. Solubility and thermodynamics of 6-phenyl-4,5-dihydropyridazin-3(2H)-one in various (PEG 400
water) mixtures. Z. Phys. Chem. 2019, 233, 273–287. [CrossRef]
3. Hansen, C.M. Hansen Solubility Parameters: A Sser’s Handbook, 2nd ed.; Taylor and Francis Group; CRC Press:
Boca Raton, FL, USA, 2007; p. 544.
2
2
2
+
4. Kitak, T.; Dumicic, A.; Planinsek, O.; Sibanc, R.; Srcic, S. Determination of solubility parameters of ibuprofen
and ibuprofen lysinate. Molecules 2015, 20, 21549–21568. [CrossRef] [PubMed]

Molecules 2019, 24, 3404
13 of 13
2
2
2
2
2
5. Alshehri, S.; Haq, N.; Shakeel, F. Solubility, molecular interactions and mixing thermodynamic properties of
piperine in various pure solvents at different temperatures. J. Mol. Liq. 2018, 250, 63–70. [CrossRef]
6. Ruidiaz, M.A.; Delgado, D.R.; Mart nez, F.; Marcus, Y. Solubility and preferential solvation of indomethacin
in 1,4-dioxane + water solvent mixtures. Fluid Phase Equilibria 2010, 299, 259–265. [CrossRef]
7. Hildebrand, J.H.; Prausnitz, J.M.; Scott, R.L. Regular and Related Solutions; Van Nostrand Reinhold: New York,
NY, USA, 1970.
í
8. Manrique, Y.J.; Pacheco, D.P.; Martínez, F. Thermodynamics of mixing and solvation of ibuprofen and
naproxen in propylene glycol + water cosolvent mixtures. J. Solut. Chem. 2008, 37, 165–181. [CrossRef]
9. Apelblat, A.; Manzurola, E. Solubilities of o-acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic and p-toluic
acid and magnesium-dl-aspartate in water from T = (278–348) K. J. Chem. Thermodyn. 1999, 31, 85–91.
[CrossRef]
3
3
3
0. Manzurola, E.; Apelblat, A. Solubilities of L-glutamic acid, 3-nitrobenzoic acid, acetylsalicylic, p-toluic acid,
calcium-L-lactate, calcium gluconate, magnesium-dl-aspartate, and magnesium-l-lactate in water. J. Chem.
Thermodyn. 2002, 34, 1127–1136. [CrossRef]
1. Shakeel, F.; Haq, N.; Alshehri, S.; Ibrahim, M.A.; Elzayat, E.M.; Altamimi, M.A.; Alanazi, F.K.; Alsarra, I.A.
Solubility, thermodynamic properties and solute-solvent molecular interactions of luteolin in various pure
solvents. J. Mol. Liq. 2018, 255, 43–50. [CrossRef]
2. Ahmad, A.; Raish, M.; Alkharfy, K.M.; Alsarra, I.A.; Khan, A.; Ahad, A.; Jan, B.L.; Shakeel, F. Solubility,
solubility parameters and solution thermodynamics of thymoquinone in different mono solvents. J. Mol. Liq.
2
018, 272, 912–918. [CrossRef]
3
3
3
3. Holgu n, A.R.; Rodr guez, G.A.; Cristancho, D.M.; Delgado, D.R.; Martínez, F. Solution thermodynamics of
í
í
indomethacin in propylene glycol + water mixtures. Fluid Phase Equilibria 2012, 314, 134–139. [CrossRef]
4. Krug, R.R.; Hunter, W.G.; Grieger, R.S. Enthalpy-entropy compensation. 2. Separation of the chemical from
the statistic effect. J. Phys. Chem. 1976, 80, 2341–2351. [CrossRef]
5. Panigrahi, M.; Grabda, M.; Kozak, D.; Dorai, A.; Shibata, E.; Kawamura, J.; Nakamura, T. Liquid–liquid
extraction of neodymium ions from aqueous solutions of NdCl by phosphonium-based ionic liquids.
3
Sep. Purif. Technol. 2016, 171, 263–269. [CrossRef]
3
3
6. Arunkumar, D.; Panigrahi, M.; Kozak, D.; Grabda, M.; Shibata, E.; Nakamura, T.; Kawamura, J. Effect of
paramagnetic metal ions on 1H diffusion in tryhexyltetradecylphosphonium benzoate ionic liquid. ECS
Trans. 2016, 75, 567–573.
7. Grabda, M.; Panigrahi, M.; Oleszek, S.; Kozak, D.; Eckerte, F.; Shibata, E.; Nakamura, T. COSMO-RS screening
for efficient ionic liquid extraction solvents for NdCl and DyCl . Fluid Phase Equilibria 2014, 383, 134–143.
3
3
[CrossRef]
3
3
8. Higuchi, T.; Connors, K.A. Phase-solubility techniques. Adv. Anal. Chem. Instrum. 1965, 4, 117–122.
9. Anwer, M.K.; Muqtader, M.; Iqbal, M.; Ali, R.; Almutairy, B.K.; Alshetaili, A.; Alshahrani, S.M.;
Aldawsari, M.F.; Alalaiwe, A.; Shakeel, F. Estimating the solubility, solution thermodynamics, and molecular
interaction of aliskiren hemifumarate in alkylimidazolium based ionic liquids. Molecules 2019, 24, 2807.
[CrossRef] [PubMed]
Sample Availability: Samples of the compounds are available from the authors.
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