Solubility and thermodynamics of 6-phenyl-4,5-dihydropyridazin-3(2H)-one in various neat solvents at different temperatures

Article abstract of DOI:10.1016/j.molliq.2017.05.032

Pyridazinone derivatives have been investigated either pre-clinically or clinically in the treatment of various cardiovascular diseases. The main problems associated with these drugs are the poor aqueous solubility and toxicity. Therefore, in the current study, the solubility of pyridazinone derivative i.e. 6-phenyl-4,5-dihydropyridazin-3(2H)-one [coded as PDP-6] was determined in eleven different neat solvents at temperatures “T?=?293.2?K to 313.2?K” and “atmospheric pressure p?=?0.1?MPa”. Experimental mole fraction solubilities of PDP-6 were correlated well with van't Hoff and Apelblat models with mean percent deviation of ??1) followed by 2-(2-ethoxyethoxy) ethanol (Transcutol) (5.24?×?10^??1), polyethylene glycol-400 [PEG-400] (8.47?×?10^??2), ethyl acetate [EA] (1.45?×?10^??2), ethylene glycol [EG] (1.09?×?10^??2), propylene glycol [PG] (1.03?×?10^??2), 2-butanol (7.78?×?10^??3), 1-butanol (7.68?×?10^??3), ethanol (6.96?×?10^??3), isopropyl alcohol [IPA] (6.51?×?10^??3) and water (1.61?×?10^??6) and similar trend was also recorded at all five different temperatures investigated. “Apparent thermodynamic analysis” on mole fraction solubilities of PDP-6 indicated an endothermic dissolution of PDP-6 in all neat solvents studied. Based on these data, PDP-6 has been proposed as practically insoluble in water, sparingly soluble in ethanol, IPA, EG, PG, EA, 1-butanol and 2-butanol, soluble in PEG-400 and very soluble in DMSO and Transcutol.

Full text of DOI:10.1016/j.molliq.2017.05.032

Accepted Manuscript
Solubility
and
thermodynamics
of
6-phenyl-4,5-dihydropyridazin-3(2H)-one in various neat
solvents at different temperatures
Mohd Imran, Nazrul Haq, Abida, Fars K. Alanazi, Ibrahim A.
Alsarra, Faiyaz Shakeel
PII:
DOI:
Reference:
S0167-7322(17)31506-4
doi: 10.1016/j.molliq.2017.05.032
MOLLIQ 7324
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
7 April 2017
2 May 2017
8 May 2017
Please cite this article as: Mohd Imran, Nazrul Haq, Abida, Fars K. Alanazi, Ibrahim
A. Alsarra, Faiyaz Shakeel Solubility and thermodynamics of
,
6-phenyl-4,5-dihydropyridazin-3(2H)-one in various neat solvents at different
temperatures, Journal of Molecular Liquids (2017), doi: 10.1016/j.molliq.2017.05.032
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ACCEPTED MANUSCRIPT
Solubility and thermodynamics of 6-phenyl-4,5-dihydropyridazin-3(2H)-one in various neat
solvents at different temperatures
Mohd. Imranb, Nazrul Haqa, Abidab, Fars K. Alanazia, Ibrahim A. Alsarraa, Faiyaz Shakeela*
aKayyali Chair for Pharmaceutical Industries, Department of Pharmaceutics, College of
Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
bDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University,
P.O. Box 840, Rafha 919111, Saudi Arabia
*Author for correspondence
Dr. Faiyaz Shakeel, Associate Professor,
Kayyali Chair for Pharmaceutical Industries,
Department of Pharmaceutics,
College of Pharmacy, King Saud University,
P.O. Box 2457, Riyadh 11451, Saudi Arabia
Email: faiyazs@fastmail.fm

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ABSTRACT
Pyridazinone derivatives have been investigated either pre-clinically or clinically in the treatment
of various cardiovascular diseases. The main problems associated with these drugs are the poor
aqueous solubility and toxicity. Therefore, in the current study, the solubility of pyridazinone
derivative i.e. 6-phenyl-4,5-dihydropyridazin-3(2H)-one [coded as PDP-6] was determined in
eleven different neat solvents at temperatures “T = 293.2 K to 313.2 K” and “atmospheric
pressure p = 0.1 MPa”. Experimental mole fraction solubilities of PDP-6 were correlated well
with van’t Hoff and Apelblat models with mean percent deviation of < 6.0 %. The mole fraction
solubilities of PDP-6 at “T = 313.2 K” were recorded highest in dimethyl sulfoxide [DMSO]
(6.77 x 10-1) followed by 2-(2-ethoxyethoxy) ethanol (Transcutol®) (5.24 x 10-1), polyethylene
glycol-400 [PEG-400] (8.47 x 10-2), ethyl acetate [EA] (1.45 x 10-2), ethylene glycol [EG] (1.09
x 10-2), propylene glycol [PG] (1.03 x 10-2), 2-butanol (7.78 x 10-3), 1-butanol (7.68 x 10-3),
ethanol (6.96 x 10-3), isopropyl alcohol [IPA] (6.51 x 10-3) and water (1.61 x 10-6) and similar
trend was also recorded at all five different temperatures investigated. “Apparent thermodynamic
analysis” on mole fraction solubilities of PDP-6 indicated an endothermic dissolution of PDP-6
in all neat solvents studied. Based on these data, PDP-6 has been proposed as practically
insoluble in water, sparingly soluble in ethanol, IPA, EG, PG, EA, 1-butanol and 2-butanol,
soluble in PEG-400 and very soluble in DMSO and Transcutol®.
Keywords: Antihypertensive drug; Pyridazinone derivative; PDP-6; Dissolution
thermodynamics; Solubility.

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1. Introduction
Cardiovascular diseases including hypertension are the common disorders of Saudi Arabia [1].
Pyridazinone derivatives have great potential in the treatment of cardiovascular disorders [1, 2].
Many of the cardio-protective pyridazinone derivatives are either under clinical trials or clinical
use such as “imazodan [3, 4], CI-930 [4, 5] pimobendan [4, 6], indolidan [4, 7], levosimendan [4,
8], SK&F-93741 [4, 9], Y-590 [4, 10], Meribendan [11], NSP-804 [12], NSP-805 [12],
bemoradan [13, 14], senazodan [15], amipizone [4, 14], prinoxodan [16], SKF 95654 [17],
siguazodan [18] and KF 15232” [18]. The main problems associated with these compounds are
their toxicity and weak solubilization power in an aqueous media [1]. Weak solubilization power
of these compounds in water creates plenty of problems in their formulation development. The
IUPAC name of pyridazinone derivative evaluated in this work is 6-phenyl-4,5-dihydropydazin-
3(2H)-one [coded as PDP-6]. This novel antihypertensive compound was obtained as a white
crystalline powder with the molecular formula and molar mass of C10H10N2O and 174.19 g mol-1,
respectively (Figure 1) [1, 2].
This compound (PDP-6) has been investigated as a potential antihypertensive agent in literature
[1]. The solubility data of newly synthesized compounds and existing drugs in different neat
solvents are important in “their purification, recrystallization, drug discovery processes and
formulation development” [19-24]. Therefore, it is of utmost importance to measure the
solubility of PDP-6 in various neat solvents including “aqueous and organic solvents”. The most
commonly used neat solvents for solubility enhancement of weakly soluble drugs are “ethanol,
propylene glycol (PG) and polyethylene glycol-400 (PEG-400)” [25-27]. Recently, the potential
of 2-(2-ethoxyethoxy) ethanol (Transcutol®) has also been investigated for solubility
enhancement of several weakly soluble drug molecules [28-30]. The solubility data of

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pyridazinone derivatives are poorly reported in literature. Recently, we reported the solubility
data of PDP-6 in various “Transcutol + water” mixtures at temperatures “T = 293.2 K to 313.2
K” and pressure “p = 0.1 MPa” [31]. However, the solubilities and “apparent thermodynamic
function” of PDP-6 in other neat solvents have not been reported. Therefore, in the current
study, the mole fraction solubilities of PDP-6 in eleven different neat solvents including “water,
ethanol, Transcutol®, PEG-400, PG, ethylene glycol (EG), isopropanol (IPA), ethyl acetate (EA),
1-butanol, 2-butanol and dimethyl sulfoxide (DMSO)” were measured at “T = 293.2 K to 313.2
K and “p = 0.1 MPa”. Neat solvents are also known as pure solvents which are being used
without any solvent and they have high purities [19, 20]. Temperature ranges were selected
randomly at the interval of 5 K in order to obtain good data. This temperature range was
selected in such a manner that the higher temperature should not exceed the melting point
of drug. “Apparent thermodynamic analysis” on solubilities of PDP-6 was also performed using
“van’t Hoff and Krug et al. analysis”. The solubility data of PDP-6 obtained in this study could
be useful in “recrystallization, purification, pre-formulation studies and formulation
development” of PDP-6.
2. Experimental
2.1. Materials
PDP-6 was synthesized and characterized in the “Laboratory of Pharmaceutical Chemistry,
Northern Border University, Rafha, Saudi Arabia”. Ethyl alcohol (IUPAC name: ethanol), 1-
butyl alcohol (IUPAC name: 1-butanol), 2-butyl alcohol (IUPAC name: 2-butanol) and IPA
(IUPAC name: isopropanol) were obtained from “Sigma Aldrich (St. Louis, MO)”. Transcutol®
[IUPAC name: 2-(2-ethoxyethoxy)ethanol] was obtained from “Gattefosse (Lyon, France)”.
PEG-400 (IUPAC name: polyethylene glycol-400), PG (IUPAC name: 1,2-propanediol), EA

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(IUPAC name: ethyl acetate), DMSO (IUPAC name: dimethyl sulfoxide) and EG (IUPAC name:
1,2-ethanediol) were obtained from “Fluka Chemica (Buchs, Switzerland)”. Water was obtained
from “Milli-Q unit in the laboratory”. The details of all these materials are listed in
supplementary Table 1 (Table S1).
2.2. Synthesis, characterization and identification of compound PDP-6
The synthesis of compound PDP-6 was performed in a two steps. In the first step, anhydrous
aluminium chloride (0.125 M) was reacted with a solution of succinic anhydride (0.1 M)
prepared in benzene (50 mL) to produce 3-benzoylpropionic acid which was purified by
recrystallization with methanol. In the second step, 3-benzoylpropionic acid (0.01 M) was
reacted with a solution of hydrazine hydrate (0.015 M) in ethanol to produce PDP-6 which was
purified by recrystallization with ethanol. The detail procedure about synthesis of various
pyridazinone derivatives including PDP-6 is presented in our previously published article [1].
The scheme for the synthesis of PDP-6 in two different steps is given in supplementary Figure 1
(Figure S1). The synthesized compound PDP-6 was characterized in terms of yield, purity,
1
13
melting point, FT-IR spectra, H-NMR spectra, C-NMR spectra and elemental analyses. The
melting point of PDP-6 was determined using an open capillary tube method. The melting point
of PDP-6 has been reported as (152 to 154) 0C in literature [1]. In this work, the melting point of
PDP-6 by an open capillary tube method was also recorded as (152 to 154) 0C. The melting point
of PDP-6 in this work was similar to its reported value. The yield of synthesized compound was
recorded as 80 %. The purity of PDP-6 was confirmed by elemental analysis and thin layer
1
chromatography [1]. The structure elucidation of PDP-6 was based on FT-IR spectra, H-NMR
spectra, 13C-NMR spectra and elemental analysis. FT-IR spectra of PDP-6 are presented in
Figure S2. The characteristics FT-IR peaks of PDP-6 were appeared at 3220 cm-1 (N-H), 3100

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cm-1 (C-H), 1680 cm-1 (C=O), 1610 cm-1 (C=N) and 1510 cm-1 (C=C). 1H-NMR spectra of PDP-6
1
are presented in Figure S3. H NMR spectra of PDP-6 were identified on the basis of
1
“multiplicity, chemical shifts and coupling constant”. The characteristics H NMR peaks of
13
compound were observed at 2.44, 2.89, 7.40, 7.74 and 10.99 ppm. C-NMR spectra of PDP-6
13
are presented in Figure S4. The characteristics C-NMR peaks of compound were observed at
167.02, 149.34, 135.90, 129.19, 128.42, 125.56, 125.31, 25.94 and 21.85 ppm. The results of
elemental analysis of PDP-6 are presented in Table S2. The mass fractions (%) in terms of C, H
and N were very close with their calculated mass fractions. Analytical and spectral
characterization of the compound PDP-6 was in good agreement with the composition of the
synthesized compound.
2.3.Analysis of compound PDP-6
The quantification of PDP-6 was carried out with the help of “reversed phase high performance
liquid chromatography (RP-HPLC)” equipped with ultra-violet (UV) detector at 310 nm. All
analysis was performed at 298.15 K using “HPLC system (Waters, USA)”. The analysis of PDP-
6 was performed using “Nucleodur (150 × 4.6 mm) RP C8 column with 5 μm particle size”. The
binary mixture of ethanol and methanol (1:1 %) was used as the mobile phase. The elution of
PDP-6 was carried out at a flow rate of 1.0 mL min-1 at 310 nm. The volume of injection was 10
µL. The calibration curve was constructed between the concentration of PDP-6 and measured
peak area. The calibration curve of PDP-6 was recorded linear in the concentration range of (1–
100) µg g-1 with coefficient of determination (R2) value of 0.9995. The equation of regression
was recorded as y = 22058x + 3172.8; in which x is the concentration of PDP-6 and y is the
measured peak area of PDP-6.
2.4.Determination of PDP-6 solubility

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The solubility of PDP-6 in eleven different neat solvents was determined by shake flask method
reported by Higuchi and Connors [32]. The experiments were carried out at “T = 293.2 to 313.2
K” and “p = 0.1 MPa”. The excess amount of PDP-6 was added in known quantities of each neat
solvent in triplicates. The obtained samples were transferred to biological shaker (Julabo, PA) at
100 rpm for the period of 72 h. In order to optimize equilibrium time for PDP-6, preliminary
solubility studies were performed at 24, 48, 72, 96 and 120 h and solubility of PDP-6 was
measured at each time internal. It was observed that the change in the solubility of PDP-6 was
negligible after 72 h. Therefore, 72 h was selected as an optimized equilibrium time for PDP-6.
After 72 h, each sample was taken out from the biological shaker and allowed to settle PDP-6
particles for 24 h [33]. Centrifugation and filtration were avoided in this process because both
processes could change the solubility data of PDP-6 at different temperatures. Moreover, all
solid particles were settled completely after 24 h. Around 0.10 g of supernatants from each neat
solvent were carefully withdrawn, diluted 100 times (dilution ratio was 1:100) with mobile phase
(except in case of water, DMSO and Transcutol). No dilution was performed in case of water and
supernatants were diluted 10000 times (dilution ratio was 1:10000) in case of DMSO and
Transcutol. The samples were subjected for the analysis of PDP-6 content by HPLC-UV method
at 310 nm. The experimental mole fraction solubilities of PDP-6 (xe) were calculated using Eq.
(1) [28]:
푚 /푀
1
1
푥e =
(1)
푚 /푀 +푚 /푀
2
1
1
2
In which, m1 and m2 are the masses of PDP-6 and respective neat solvent, respectively. M1 and
M2 are the molar masses of PDP-6 and respective neat solvent, respectively.

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The xe value of PDP-6 was also verified by the gravimetric method [34]. The solubility of PDP-6
in Transcutol and DMSO at T = 298.2 K was measured by gravimetric method. Drug-solvent
mixtures were prepared as stated above for shake flask method. Each drug-solvent mixture was
heated at T = 298.2 K with continuous stirring till equilibrium reached. The equilibrium time for
gravimetric method was optimized by the determination of the concentration of PDP-6 at 2, 4, 6,
8 and 12 h. After 6 h, the change in the concentration of PDP-6 was recorded as negligible.
Hence, 6 h was selected as an equilibrium time for this method. After 6 h of stirring, the solution
was kept at T = 298.2 K for some time in order to get settling of particles. The supernatant from
each sample was taken, filtered and the known amount of each sample was transferred in pre
weighted vial (m0). This vial was reweighted in order to determine the mass of each sample (m3).
Each vial was then kept in an oven at T = 323.2 K for the evaporation of the solvent. After the
complete dryness of the mass of the vial, the vial was reweighed (m4). When the constant value
of the mass was obtained, the final mass for each sample was determined (m4–m0). All the
weights were determined using an electronic balance (Mettler Toledo AM50, Switzerland) with
an uncertainty of ± 0.0001 g. Each measurement was carried out in triplicates manner. The xe
value of PDP-6 was determined using Eq. (2) [34, 35]:
푚 −푚 /푀
1
4
0
푥e =
(2)
푚 −푚 /푀 +푚 −푚 /푀
2
4
0
1
3
4
3. Results and discussion
3.1. Experimental solubility data of PDP-6
Experimentally determined xe values of PDP-6 in eleven different neat solvents at “T = 293.2 K
to 313.2 K” and “p = 0.1 MPa” are presented in Table 1.

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In literature, we reported the solubility data of PDP-6 in different “Transcutol + water”
cosolvent mixtures at “T = 293.2 K to 313.2 K” and “p = 0.1 MPa” [31]. However, the
solubilities of PDP-6 in other neat solvents have not been reported so far. The mole fraction
solubility of PDP-6 in neat water at “T = 298.2 K” has been reported as 9.10 x 10-7 [31]. In
this work, the mole fraction solubility of PDP-6 in neat water at “T = 298.2 K” was
obtained as 9.18 x 10-7 which was very close to its reported value. The graphical
comparison between literature and experimental solubility of PDP-6 in water at “T = 293.2
K to 313.2 K” is presented in Figure 2 which showed excellent graphical correlation at all
five temperatures investigated. The mole fraction solubility of PDP-6 in neat Transcutol at
“T = 298.2 K” has been reported as 4.53 x 10-1 [31]. In this work, the mole fraction
solubility of PDP-6 in neat Transcutol at “T = 298.2 K” was obtained as 4.51 x 10-1 which
was also very close to its reported value. The graphical comparison between literature and
experimental solubility of PDP-6 in Transcutol at “T = 293.2 K to 313.2 K” is presented in
Figure 3 which also showed excellent graphical correlation at all five temperatures
investigated. Overall, these results indicated that solubility data of PDP-6 obtained in this
work were in good agreement with literature.
From data presented in Table 1, it can be seen that the xe values of PDP-6 were increasing with
increase in temperature in each neat solvent evaluated. The xe values of PDP-6 at “T = 313.2 K”
were recorded highest in DMSO (6.77 x 10-1) followed by Transcutol® (5.24 x 10-1), PEG-400
(8.47 x 10-2), EA (1.45 x 10-2), EG (1.09 x 10-2), PG (1.03 x 10-2), 2-butanol (7.78 x 10-3), 1-
butanol (7.68 x 10-3), ethanol (6.96 x 10-3), IPA (6.51 x 10-3) and water (1.61 x 10-6) and similar
trend was also recorded at all five different temperatures investigated. It was observed that the xe
values of PDP-6 in DMSO, Transcutol® and PEG-400 were significantly higher in comparison

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with its xe values in other neat solvents including water. In general, the xe values of PDP-6 were
significantly higher in neat solvents with functional groups such as –OH, -SO2- or O-C=O
(DMSO, Transcutol, PEG-400, EA, EG, PG, 2-butanol, 1-butanol, ethanol and IPA) in
comparison with water. This observation was probably due to the fact that PDP-6 is having some
functional groups such as –NH and C=O which could have strong molecular
interaction/solvation with neat solvents with functional groups of –OH, -SO2- or O-C=O. The xe
values of PDP-6 in 1-butanol and 2-butanol were not significantly different at each temperature
investigated. It was because of their similar molecular structures, molar masses and dielectric
constants/polarities. The xe values of PDP-6 in other alcoholic solvents such as PG and EG were
also observed in similar magnitude because both of the neat solvents have two –OH groups with
similar dielectric constants/polarities. The xe values of PDP-6 in other neat solvents such as
ethanol and IPA were also obtained in similar magnitude due to the presence of single –OH
group in both neat solvents and their polarities are also similar. However, the xe values of PDP-6
in “DMSO, Transcutol and PEG-400” were significantly higher in comparison with its xe values
in other neat solvents investigated. This observation was possible due to higher molar mass and
lower polarities of DMSO, Transcutol and PEG-400 in comparison with other neat solvents
including water [33]. Based on solubility data of current study, PDP-6 has been proposed as
practically insoluble in water, sparingly soluble in ethanol, IPA, EG, PG, EA, 1-butanol and 2-
butanol, soluble in PEG-400 and very soluble in DMSO and Transcutol [30, 33]. The solubility
data of PDP-6 could be useful in “recrystallization, purification, pre-formulation studies and
formulation development” of PDP-6.
In order to verify the solubility data of PDP-6 measured by shake flask method, the xe values of
PDP-6 in Transcutol and DMSO at T = 298.2 K were also determined by gravimetric method.

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Comparative xe values of PDP-6 in Tarnscutol and DMSO T = 298.2 K are listed in Table 2. The
xe values of PDP-6 in both solvents were in similar magnitude which indicated the shake flask
method used for the measurement of xe values of PDP-6 in Transcutol, DMSO and other neat
solvents was accurate and precise.
3.2.Hildebrand solubility parameter for PDP-6 and neat solvents
In the current study, Hildebrand solubility parameter (δ) for PDP-6 and neat solvents was
determined by “Fedors group substitution method” with the help of Eq. (3) [36]:
훿 = [(∑U0)/(∑V)]1/2
(3)
In which, U0 and V are the energy of vaporization and molar volume, respectively. With the help
of the values of U0 and V, δ values for various neat solvents have been reported in literature [37-
39]. The δ values of neat solvents investigated in this work are also reported in literature [33].
However, δ value of PDP-6 has not been reported previously in literature. Therefore, it was
determined in this work. The calculation of δ value for PDP-6 using “Fedors group substitution
method” is listed in Table 3. The calculated δ value for PDP-6 and reported δ values for different
neat solvents are presented in Table S3.
The δ value for PDP-6 was calculated as 25.71 MPa1/2. The calculated δ value of PDP-6
indicated that it had lower polarity. The xe values of PDP-6 were higher in neat solvents with
lower or medium δ values such as “DMSO, Transcutol, PEG-400, EA, EG, PG, 2-butanol, 1-
butanol, ethanol and IPA” because PDP-6 had lower polarity. However, the xe value of PDP-6
was lowest in water due to highest δ value of water.
3.3.Correlation of xe values of PDP-6

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The xe values of PDP-6 determined in the current study were correlated with two mathematical
models including “Apelblat and van’t Hoff models” [33, 40, 41]. The “Apelblat solubility
(xApl)” of compound PDP-6 was calculated and correlated using Eq. (4) [40, 41]:
ln 푥Apl = 퐴 + 퐵푇 + 퐶 ln(푇)
(4)
In which, the parameters “A, B and C” are the model parameters of “Apelblat model” presented
in Eq. (4). Apelblat parameters were determined using “nonlinear multivariate regression
analysis” of xe values of PDP-6 listed in Table 1 using MS Excel program 2010 [33]. The
correlation of xe values of PDP-6 with its xApl values was carried out in terms of the mean percent
deviations (MPD) and R2 values. The MPD values between xe and xApl of PDP-6 were
determined using Eq. (5) [42]:
Apl
100
(푥
−푥 )
e
∑
푀푃퐷 =
(5)
Apl
푁
푥
In which, N is the number of experimental data points.
The graphical correlation and curve fitting between natural logarithmic xe (ln xe) and ln xApl
values of PDP-6 in each neat solvent as a function of 1/T is presented in Figure 4. The results
presented in Figure 4 indicated excellent correlation/curve fitting between ln xe and ln xApl
values of PDP-6. The parameters of “Apelblat correlation” are presented in Table 4. The MPD
values in eleven different neat solvents were recorded as (1.17 to 5.27) %. The MPD value was
recorded highest in 2-butanol (5.27 %) followed by “1-butanol, water, EG, PG, EA, IPA,
ethanol, DMSO, PEG-400 and Transcutol”. However, the R2 values for PDP-6 were recorded as
0.9957 to 0.9998. These results indicated good correlation of xe values of PDP-6 with “Apelblat
model”.

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The “van’t Hoff model solubility (xvan’t)” of PDP-6 was calculated using Eq. (6) [33]:
ln 푥van′t = a + 푇푏
(6)
In which, the parameters “a and b” are the model parameters of “van’t Hoff model” presented
in Eq. (6). The values of “a and b” were determined by plotting ln xe values of PDP-6 as a
function of 1/T.
The correlation of xe values of PDP-6 with its xvan’t values was performed in terms of MPD and
R2
values.
The graphical correlation and curve fitting between ln xe and ln xvan’t values of PDP-6 in each
neat solvent against 1/T was found to be similar as discussed for Apelblat correlation (Figure not
shown). The parameters of van’t Hoff correlation are presented in Table 5.
The MPD values in eleven different neat solvents were recorded as (0.00 to 0.80) %. The MPD
value was recorded highest in EA (0.80 %) followed by “DMSO, water, 1-butanol, IPA,
Transcutol, PG, PEG-400, EG, ethanol and 2-butanol”. However, the R2 values for PDP-6 were
recorded as 0.9922 to 0.9998. These results again indicated good correlation of xe values of PDP-
6 with “van’t Hoff model”.
3.4.Apparent thermodynamic analysis
The dissolution thermodynamics of PDP-6 in eleven different neat solvents was studied by
“apparent thermodynamic analysis” of solubilities of PDP-6. Two different apparent
thermodynamic parameters including “apparent standard enthalpy (ΔsolH0)” and “apparent
standard Gibbs energy (ΔsolG0)” were determined by “apparent thermodynamic analysis”. The

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“ΔsolH0 values” for PDP-6 dissolution in each neat solvent were determined at “mean harmonic
temperature (Thm)” of 303 K with the help of “van’t Hoff analysis” using Eq. (7) [43, 44]:
0
휕푙푛 푥
퐻
(
) = − ∆
푃
(7)
e
sol
1
1
푅
휕( ⁄ −
)
⁄
푇
푇
hm
With the help of Eq. (7), the “ΔsolH0 values” were determined by plotting ln xe values of PDP-6
1
1
against ⁄ −
. The “van’t Hoff plots” in each neat solvent were recorded as linear with
⁄
푇
푇ℎ푚
R2 values of 0.9922 to 0.9998.
The “ΔsolG0 values” for PDP-6 dissolution were also measured at Thm of 303 K with the help of
Krug et al. analysis using Eq. (8) [45]:
∆sol퐺0 = −푅푇hm × 푖푛푡푒푟푐푒푝푡
(8)
In which, the values of intercept for each neat solvent were determined from “van’t Hoff plot”
1
1
plotted between ln xe values of PDP-6 and ⁄ −
.
⁄
푇
푇ℎ푚
The results of “apparent thermodynamic analysis” for PDP-6 dissolution in eleven different neat
solvents are presented in Table 6.
It was observed that the “ΔsolH0 values” for PDP-6 dissolution in eleven different neat solvents
were obtained as positive values in the range of (2.36 to 30.55) kJ mol-1. The “ΔsolH0 value” for
PDP-6 dissolution was obtained highest in water (30.55 kJ mol-1) followed by IPA (28.55 kJ
mol-1), ethanol (20.37 kJ mol-1), EA (19.32 kJ mol-1), 1-butanol (18.31 kJ mol-1), PG (18.08 kJ
mol-1), 2-butanol (15.99 kJ mol-1), EG (15.07 kJ mol-1), PEG-400 (14.17 kJ mol-1), Transcutol
(8.17 kJ mol-1) and DMSO (2.36 kJ mol-1). Generally, the “ΔsolH0 values” for PDP-6 dissolution
were obtained lower for neat solvents with higher xe values such as DMSO, Transcutol and

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PEG-400. However, the “ΔsolH0 values” for PDP-6 dissolution were obtained higher for neat
solvents with lower xe values such as water, IPA, ethanol, EG, PG, 1-butanol and 2-butanol.
The “ΔsolG0 values” for PDP-6 dissolution in eleven different neat solvents were also obtained
as positive values in the range of (1.05 to 34.55) kJ mol-1. The “ΔsolG0 value” for PDP-6
dissolution was also obtained highest in water (34.55 kJ mol-1) followed by IPA (13.58 kJ mol-1),
ethanol (13.19 kJ mol-1), 1-butanol (12.88 kJ mol-1), 2-butanol (12.79 kJ mol-1), PG (12.06 kJ
mol-1), EG (11.82 kJ mol-1), EA (11.29 kJ mol-1), PEG-400 (6.67 kJ mol-1), Transcutol (1.88 kJ
mol-1) and DMSO (1.05 kJ mol-1) and. The results of “ΔsolG0 values” for PDP-6 dissolution were
in good agreement with experimental solubilities of PDP-6 in eleven different neat solvents. The
positive values of “ΔsolH0 and ΔsolG0” in all neat solvents indicated an endothermic dissolution of
PDP-6 in all neat solvents studied. The lower values of “ΔsolH0 and ΔsolG0” in DMSO,
Transcutol and PEG-400 indicated that relatively lower energies are required for the
solubilization of PDP-6 in DMSO, Transcutol and PEG-400 in comparison with other neat
solvents studied. The positive values of ΔsolH0 in all eleven different neat solvents were possible
due to weak electrostatic interactions between PDP-6-solvent molecules in comparison with
strong electrostatic interactions between PDP-6-PDP-6 and solvent-solvent molecules.
4. Conclusion
In the current study, the mole fraction solubilities of a novel antihypertensive drug PDP-6 in
eleven different neat solvents were determined at “T = 293.2 K to 313.2 K and “p = 0.1 MPa”.
The experimental solubilities of PDP-6 were found to be increasing with increase in temperature
in all eleven different neat solvents studied. Experimental solubilities of PDP-6 were correlated
well with “van’t Hoff and Apelblat models” with MPD < 6.0 %. The mole fraction solubilities
of PDP-6 at “T = 313.2 K” were recorded highest in DMSO followed by Transcutol, PEG-400,

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EA, EG, PG, 2-butanol, 1-butanol, ethanol, IPA and water and similar trend was also recorded at
all five different temperatures investigated. The results of “apparent thermodynamic analysis”
indicated an “endothermic dissolution” of PDP-6 in all neat solvents studied.
Conflict of interest
“The authors state that they do not have any conflict of interest associated with this manuscript”.
Acknowledgement
“This project was financially supported by King Saud University, Vice Deanship of Research
Chairs, Kayyali Chair for Pharmaceutical industry through the grant number FN-2016”.
Supplementary information
“Supplementary materials associated with this manuscript can be found online”.
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Figure captions
Figure 1 Molecular structure of PDP-6 (molar mass: 174.19 g mol-1)
Figure 2 Comparison of experimental solubilities of PDP-6 in water with literature values
at five different temperatures; the symbol
represents the experimental solubilities of
pure PDP-6 and the symbol
reference [31]
represents the solubility values of PDP-6 taken from
Figure 3 Comparison of experimental solubilities of PDP-6 in Transcutol with literature
values at five different temperatures; the symbol represents the experimental solubilities
of PDP-6 and the symbol represents the solubility values of PDP-6 taken from reference
[31]
Figure 4 Correlation of experimental natural logarithmic solubilities (ln xe) of PDP-6 with
Apelblat model in eleven different neat solvents as a function of 1/T; symbols represent the
experimental ln xe values of PDP-6 and the solid lines represent the ln xApl values calculated
by Apelblat model

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Figure 1 Molecular structure of PDP-6 (molar mass: 174.19 g mol-1)

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Figure 2 Comparison of experimental solubilities of PDP-6 in water with literature values at five
different temperatures; the symbol
represents the experimental solubilities of pure PDP-6 and the
symbol represents the solubility values of PDP-6 taken from reference [31]

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Figure 3 Comparison of experimental solubilities of PDP-6 in Transcutol with literature values at five
different temperatures; the symbol
represents the experimental solubilities of PDP-6 and the
symbol represents the solubility values of PDP-6 taken from reference [31]

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Figure 4 Correlation of experimental natural logarithmic solubilities (ln xe) of PDP-6 with Apelblat
model in eleven different neat solvents as a function of 1/T; symbols represent the experimental ln xe
values of PDP-6 and the solid lines represent the ln xApl values calculated by Apelblat model

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Table 1 Experimental mole fraction solubilities (xe) of PDP-6 in different neat solvents (S) at “T = 293.2
K to 313.2 K and “p = 0.1 MPa”a
S
xe
T = 293.2 K
7.24 x 10-7
4.07 x 10-3
3.10 x 10-3
7.40 x 10-3
6.54 x 10-3
5.85 x 10-2
4.23 x 10-1
4.74 x 10-3
T = 298.2 K
9.18 x 10-7
4.66 x 10-3
3.78 x 10-3
8.36 x 10-3
7.32 x 10-3
6.46 x 10-2
4.51 x 10-1
5.30 x 10-3
5.55 x 10-3
9.94 x 10-3
6.47 x 10-1
T = 303.2 K
1.13 x 10-6
5.29 x 10-3
4.60 x 10-3
9.21 x 10-3
8.46 x 10-3
7.09 x 10-2
4.76 x 10-1
6.01 x 10-3
6.18 x 10-3
1.11 x 10-2
6.58 x 10-1
T = 308.2 K
1.37 x 10-6
6.07 x 10-3
5.55 x 10-3
1.01 x 10-2
9.51 x 10-3
7.80 x 10-2
5.02 x 10-1
6.70 x 10-3
6.87 x 10-3
1.28 x 10-2
6.68 x 10-1
T = 313.2 K
1.61 x 10-6
6.96 x 10-3
6.51 x 10-3
1.09 x 10-2
1.03 x 10-2
8.47 x 10-2
5.24 x 10-1
7.68 x 10-3
7.78 x 10-3
1.45 x 10-2
6.77 x 10-1
Water
Ethanol
IPA
EG
(RS)-PG
PEG-400
Transcutol
1-Butanol
(RS)-2-Butanol 5.12 x 10-3
EA
8.78 x 10-3
6.37 x 10-1
DMSO
aThe standard uncertainties u are u(T) = 0.08 K, u(p) = 0.003 MPa and ur(xe) = 1.45 %.

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Table 2 The xe values of PDP-6 in Transcutol and DMSO measured by gravimetric and shake flask
methods at T = 298.2 K
Solvent
Gravimetric method
Shake flask method
Transcutol
DMSO
4.47 x 10-1
6.44 x 10-1
4.51 x 10-1
6.47 x 10-1
1

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Table 3 Determination of internal energy (∆U0), molar volume (V) and Hildebrand solubility
parameters (δ) of PDP-6 at T = 298.2 K using Fedors method [35]
Atom or group
-CH2-
Group number
∆U0/kJ mol-1
V/cm3 mol-1
2
1
1
1
1
1
1
2 x 4.94 = 9.88
1 x 4.31 = 4.31
1 x 17.4 = 17.4
1 x 11.75 = 11.75
1 x 12.6 = 12.6
1 x 31.9 = 31.9
1 x 1.05 = 1.05
2 x 16.1 = 32.2
5.5 x -1.0 = -5.5
1 x 10.8 =10.8
1 x 5 = 5
>C=
>C=O
=N-
-NH-
1 x 4.5 = 4.5
1 x 71.4 = 71.4
1 x 16.0 = 16.0
Phenyl ring
Ring closure, 5 or more
atoms
Total
∑ ∆U0 = 88.89
∑ V = 134.4
δ = (88890/134.4)1/2 = 25.71 MPa1/2
2

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Table 4 Apelblat parameters (A, B and C), R2 and MPD (%) values for PDP-6 in different neat solvents
(S)
S
A
B
C
R2
MPD (%)
4.13
2.04
2.56
1.17
1.08
3.87
2.49
5.03
5.27
2.54
1.20
Water
Ethanol
(RS)-PG
PEG-400
Transcutol
EG
291.94
-116.58
64.70
1.31
-16930.90
2939.82
-4990.07
-1630.83
-3939.41
-8972.45
-6373.79
4875.73
11665.47
5558.70
-131.52
-43.71
17.78
-9.28
0.24
0.9998
0.9998
0.9957
0.9997
0.9995
0.9994
0.9994
0.9990
0.9994
0.9993
0.9992
67.95
159.83
70.98
-154.65
-299.74
-171.46
-2.87
-9.74
-23.61
-9.68
23.35
44.83
26.01
0.50
IPA
1-Butanol
(RS)-2-Butanol
EA
DMSO
3