J. Chem.

Thermodynamics 135 (2019) 35–44

Contents lists available at ScienceDirect

J. Chem. Thermodynamics
journal homepage: www.elsevier.com/locate/jct

Solubility and vapor pressure data of bioactive 6-(acetylamino)-

N-(5-ethyl-1,3,4-thiadiazol-2-yl) hexanamide
Angelica Sharapova ⇑, Marina Ol’khovich, Svetlana Blokhina, German Perlovich
Institute of Solution Chemistry, Russian Academy of Sciences, 1 Akademicheskaya Street, 153045 Ivanovo, Russia

a r t i c l e i n f o a b s t r a c t

Article history: This paper presents new experimental data on some key physicochemical properties of original bioactive
Received 28 June 2018 6-(acetylamino)-N-(5-ethyl-1,3,4-thiadiazol-2-yl) hexanamide (AETH). Thermal analysis of the com-
Received in revised form 19 February 2019 pound under study has been carried out using differential scanning calorimetry and thermogravimetric
Accepted 11 March 2019
techniques. AETH solubility data in five pharmaceutically relevant solvents in the temperature range
Available online 13 March 2019
from 288.15 to 318.15 K have been obtained by the classic saturation shake-flask method. The bioactive
compound has poor solubility in hexane and buffer solutions, while it is slightly soluble in selected alco-
Keywords:
hols. The experimental solubility results have been correlated by means of modified Apelblat and van’t
Bioactive 1,3,4-thiadiazole derivative
Melting parameters
Hoff equations. The selected thermodynamic models produced acceptable results. The Hansen solubility
Solubility temperature dependences parameters and their components for AETH and solvents have been evaluated by using the van Krevelen–
Hansen solubility parameter Hoftyzer atomic group contribution method. The ideal solubility and the solution activity coefficient at
Sublimation enthalpy equilibrium in the selected solvents have been quantified based on experimental values of melting
enthalpy and temperature. All the investigated solutions exhibit a positive deviation from ideality with
the maximal solubility in alcohols. The equilibrium vapor pressure of the compound studied has been
determined as a function of temperature in the range of 433.15–454.15 K by the transpiration method.
The standard thermodynamic parameters of AETH sublimation have been calculated. It has been con-
cluded that the high crystal lattice energy value equal to 131.5 kJ/mol is the dominant factor determining
the poor solubility of the bioactive compound.
Ó 2019 Elsevier Ltd.

1. Introduction mino)-N-(5-ethyl-1,3,4-thiadiazol-2-yl) hexanamide (AETH)

Thiadiazole is a prevalent and important five-membered hete-
rocyclic system containing two nitrogen atoms and a sulfur atom.
Among several isomers of thiadiazole, 1,3,4-thiadiazole has been
investigated more than the others [1]. Thiadiazole derivatives have
a wide spectrum of biological activity due to the strong aromaticity
of the cyclic system, which ensures their high in vivo stability [2].
The sulfur atom makes these compounds lipophilic and, thus,
enables them to easily permeate through biological membranes
[3]. Besides, the derivatives of this series produce a low toxic effect
on the human body. Bonding different functional groups, capable
of reacting with various receptors, to the thiadiazole ring allows
obtaining drug compounds with unique pharmacological proper-
ties [4]. This fact stimulates scientists to search for new chemical
substances with a high anti-inflammatory, analgesic activities
and relative safety of application among the new thiadiazole
derivatives [5]. The object of the present study was 6-(acetyla
containing a thiadiazole fragment as the pharmacophore (Fig. 1).
This compound has anaesthetic, anti-inflammatory, antiallergic
and analgesic activity, and in its preventive enteroprotective
effect it excels the commercially available drug deanol
aceglumate [6].
Studying physicochemical properties of new bioactive com-
pounds as potential drugs is one of the main problems of pharma-
ceutical chemistry. Knowing these properties allows not only
evaluating the characteristics that affect bioavailability of drug-
like compounds at the in vitro stage but also predicting the ways
and methods of improving their pharmacological profile. In the
present study, we provide a circumstantial summary of some
physicochemical properties of original bioactive 6-(acetylamino)-
N-(5-ethyl-1,3,4-thiadiazol-2-yl) hexanamide focusing primarily
on an overview of the solubility data especially in pharmaceuti-
cally relevant solvents as well as thermophysical and sublimation
parameters.

⇑ Corresponding author.
E-mail address: avs@isc-ras.ru (A. Sharapova).

https://doi.org/10.1016/j.jct.2019.03.015
0021-9614/Ó 2019 Elsevier Ltd.
36 A. Sharapova et al. / J. Chem. Thermodynamics 135 (2019) 35–44

water-methanol (42/58, v/v). The flow-rate was 0.4 ml/min. The

detector was operated at 257 nm. The injection volume was 10 ll.

Fig. 1. Chemical structure of 6-(acetylamino)-N-(5-ethyl-1,3,4-thiadiazol-2-yl) 2.2. Materials

hexanamide (AETH).
2. Experimental
2.1. Synthesis and identification
We placed 100 ml of acetonitrile, 12.91 g (0.1 mol/dm3) of 2-
amino-5-ethyl-1,3,4-thiadiazole into a three-neck flask equipped
with an agitator, a thermometer and a fridge; stirred the mass
and gradually added 16.65 g (0.1 mol/dm3) of N-acetylamino hex-
anoic acid chloride. Then we heated the obtained mixture to the
boiling point, 3 h later removed the acetonitrile, added 150 ml of
distilled water and mixed carefully. The obtained solution was
heated to 80 °C, and 15–20 min later the residue was filtered and
washed on a filter with distilled water. The washing continued till
the backwash water reached pH 6–7. Then the residue was dried
till it reached a constant weight at 100–105 °C. As a result, we
obtained 26.48 g of white crystalline powder representing 6-(acet
ylamino)-N-(5-ethyl-1,3,4-thiadiazol-2-yl) hexanamide.
The elemental analysis of the compound obtained was per-
formed on a CHN analyzer Carbo Erba (Czech Republic). Anal.
Calcd. for C12 H20 N4 O2 S: C 50.68%, H 7.09%, N 19.71%, O
11.25%, S 11.27%. Found: C 50.91%, H 7.23%, N 19.56%, S 11.23%.
The FT-IR spectrum of the compound synthesized was recorded
by using a Bruker Vertex 80v spectrometer (Bruker Optik GmbH,
Ettlingen, Germany) with the spectral resolution of 2 cm
1 in the
spectral range 4000 – 400 cm
1 at room temperature. The mea-
sured vibrations (m, cm
1) were 3310 and 3169 cm
1(NH); 2988,
2959, 2940 and 2860 (CH); 1669 (CO), 1560 (CONH), 1030 (C@S).
In addition, nuclear magnetic resonance spectra of the compound
isolated were recorded in a Bruker Advance III HD 400 (400 MHz
to 1H and 100 MHz to 13C analysis) (Bruker, Germany) in deuter-
ated chloroform (CDCl3, 99.9%). Graphical 1H NMR spectra of AETH
have been provided in Fig. S1 (Supporting Information). The mass
fraction purity of AETH after recrystallization was determined by
high performance liquid chromatography on an Agilent 1100 series
apparatus with a Kinetex C18, 2.6 lm, 3  100 mm (Phenomenex,
USA) (Table 1). The mobile phase consisted of a mixture of
Detailed information about all the chemicals used in this study
is listed in Table 1. Buffer solutions were prepared by using bidis-
tilled water with the electrical conductivity of 2.1 lS cm
1. The
phosphate buffer pH 7.4 (I = 0.15 mol/dm3) was made by mixing
KH2PO4 (9.1 g in 1 l) and Na2HPO412H2O (23.6 g in 1 l) salts. In
order to prepare the buffer solution pH 2.0 (I = 0.10 mol/dm3)
6.57 g of KCl was dissolved in water, 119.0 ml of 0.1 mol/dm3
hydrochloric acid was added and the volume of the solution was
adjusted to 1 l with water. The pH values were measured by using
a pH meter FG2-Kit (Mettler Toledo, Switzerland) standardized
with pH 1.68, 6.86 and 9.22 solutions.
2.3. Apparatus and procedure
2.3.1. Differential scanning calorimetry (DSC)
The melting temperatures and enthalpies of the compounds
under investigation have been determined using a Perkin-Elmer
Pyris 1 DSC differential scanning calorimeter (Perkin-Elmer Analyt-
ical Instruments, Norwalk, Connecticut, USA) with Pyris software
for Windows NT. The DSC runs were performed in an atmosphere
of 20 cm3min
1 of flowing dry helium gas of high purity (0.99996
mass fraction) using standard aluminum sample pans at the heat-
ing rate of 2 K∙min
1 Sealed and holed aluminum pans were used
for the experiment. An empty pan sealed in the same manner
was used as the reference. The accuracy of weight measurements
was 0.005 mg.
The DSC was calibrated using a two-point calibration, measur-
ing the onset temperatures of indium and bismuth standards.
The onset of melting was used for calibration because it is almost
independent of the scan rate. The melting temperatures of indium
and bismuth were 429.7 K and 544.5 K, respectively (determined
by at least five measurements). The enthalpy scale was calibrated
using the indium fusion heat. The measured fusion enthalpy value
equaled 28.69 J∙g
1 (the reference value 28.66 J∙g
1) [7]. The
expanded uncertainty (0.95 level of confidence) on the melting
temperature was determined as twice the standard deviation of
five independent measurements.

Table 1
Description of the materials used in the experiments.

Chemical name CAS Formula M/g Source Initial mass Method of Final mass Analysis
register mol
1 fraction purity purification fraction purity method
No.
6-(acetylamino)-N-(5-ethyl-1,3,4- 2184830- C12 H20 N4 O2 S 284.38 synthesis 0.95 recrystallization 0.98 HPLCa
thiadiazol-2-yl) hexanamide 56-4
Ethanol 64-17-5 C2H6O 46.07 Sigma- 0.99b – – –
Aldrich
1-Octanol 111-87-5 C8H18O 130.2 Sigma- 0.99b – – –
Aldrich
b
n-Hexane 110-54-3 C6H14 86.18 Sigma- 0.97 – – –
Aldrich
b
Potassium dihydrogen phosphate 7778-77- KH2PO4 136.08 Merck 0.99 – – –
0
Disodium hydrogen phosphate 10039- Na2HPO412H2O 358.14 Merck 0.99b – – –
dodecahydrate 32-4
Potassium chloride 7447-40- KCl 74.55 Sigma- 0.99b – – –
7 Aldrich
b
Benzoic acid 65-85-0 C7H6O2 122.12 Sigma- 0.995 – – –
Aldrich
a
High performance liquid chromatography.
b
As stated by the supplier.
 A. Sharapova et al. / J. Chem. Thermodynamics 135 (2019) 35–44
2.3.2. Thermogravimetry (TG)
Thermogravimetric analysis was performed on a TG 209 F1
thermo-microbalance (Netzsch Gerätebau GmbH, Germany) using
platinum crucibles in an atmosphere of dry argon at a flow rate of
30 cm3∙min
1 and a heating rate of 10 Kmin
1. The sample weight
was 3–5 mg. The accuracy of the mass measurement was 110
7 g.
The thermal curve reproducibility was monitored by performing
up to three replicated experiments.
2.3.3. Solubility determination
The saturated equilibrium solubility of AETH was determined
by the classical shake flask method at atmospheric pressure and
in the temperature range from 288.15 K to 318.15 K. The essence
of the above mentioned method consists in determination of the
compound concentration in the saturated solution. The indepen-
dent experiments were carried out in parallel in triplicate. The
solid sample was added carefully using a spatula to 5–10 ml of
the solvents in a glass vial, while stirring until a heterogeneous sys-
tem (solid sample and liquid) was obtained. The concentrated sus-
pensions of the compound in each solvent were shaken
continuously in an air thermostat containing a stirring device.
The point of the solution thermodynamic equilibrium was deter-
mined based on the solubility kinetic dependences and averaged
72 h. The sedimentation time of solid phase after stirring was
4 h. After saturation was achieved, the solution aliquot was taken
and centrifuged in a centrifuge Biofuge stratus (Germany) for
5 min at a fixed temperature. Then, the supernatant solutions were
filtered through a 0.20 lm filter MILLEXÒHA (Ireland). The satu-
rated solution was diluted with the corresponding solvent to the
required concentration.
The AETH concentration in molarity was determined by mea-
suring the absorbance at the wavelength of 253 nm using a UV–
vis spectrophotometer (Cary-50, USA) at room temperature. The
experimental results are reported as an average value of at least
three replicated experiments and presented in Table S1 (Support-
ing Information).
The calibration was made at room temperature using the solu-
tions with known concentrations of each substance in each inves-
tigated solvent. The solutions were prepared by adding a substance
of an appropriate mass and a certain volume of solvent (buffer pH
2.0, buffer pH 7.4, 1-octanol, ethanol, n-hexane) to the flask and
mixing until the substance was totally dissolved. The absorbance
of the solutions was measured and calibration curves were con-
structed. The calibration curve was found to be linear in the con-
centration range of 0.2–1.0 lgml
1 with a correlation coefficient
of 0.9995.
The conversion of molarity to the mole fraction concentration
scale was produced by the following equation:
M2 S
x¼ ; ð1Þ
SðM2
M 1 Þ þ 1000q
where S is the molarity (mol/dm3), q is the density of solution
(g/cm3), M1 and M2 are the molar masses of AETH and solvent,
respectively. The mole fractions for buffer solutions were calculated
with molar mass of water (without account of the buffer composi-
tions). The molarity values of compound studied have been pre-
sented in Table S1 (Supporting Information). The densities of the
solutions were measured at 288.15–318.15 K and atmospheric pres-
sure using an oscillation U-tube density meter DMA 4500 (Anton
Paar, Austria). The experimental values of the densities for the inves-
tigated solutions are given in Table S2 (Supporting Information).
Standard uncertainty for density values was 0.004 g∙cm
3.
The experimental setup and its accuracy were validated by
comparing the solubility data of benzoic acid in water with those
in literature [8–10] (Fig. 2 and Table S3). As shown in Fig. 2, the
37
0.32
0.28
-1
m/mol kg
0.24
0.20
0.16
0.12
0.08
0.04
280 290 300 310 320 330 340 350 360
T/K
Fig. 2. Plot of solubility (m) of benzoic acid in water as a function of temperature
(T). j – Reference [8]; ▲ – reference [9]; d – reference [10]; r – this work.
benzoic acid solubility measured by us is in good agreement with
literature data. The deviation of the measured solubilities from the
literature values did not exceed 2%, so it was perform that this
experimental technique was reliable.
The chemical nature of the AETH solid phase in equilibrium
with the selected solvents after the solubility experiment was
characterized by the DSC technique. No variation has been found
in the DSC profile of the samples, indicating that neither salts nor
solvates were formed.
2.3.4. Vapor pressure measurements
The temperature dependence of AETH vapor pressure was mea-
sured by the gas saturation method, also known as the transpira-
tion method. A detailed description of the apparatus had been
presented previously [11]. The equipment was tested using ben-
zoic acid. The verification experiment details and the comparison
of the obtained results with the literature data had been described
previously [12]. The standard value of the sublimation enthalpy at
T = 298.15 K obtained in our experiments was
Dgcr Hom = 90.5 ± 0.3 kJ∙mol
1. This was in good agreement with the
value recommended by IUPAC (Dgcr Hom =89.7 ± 0.5 kJ∙mol
1) [13].
The procedure in brief was as follows: approximately 0.5 g of
the investigated compound was blended with pyrex balls and
placed into a thermostated tube. At a constant temperature, the
flow of inert gas (N2) transported the saturated vapor of the sample
under investigation through the tube until it was completely con-
densed at some point downstream. The vapor pressure of the sam-
ple at this temperature was calculated from the amount of the
sublimated sample and the volume of the inert gas used. The sta-
bility of the gas flow was supported by a mass flow controller
MKS type 2179A. It is a prerequisite of the method that within
the temperature interval used and during the whole experiment
the compound does not get chemically decomposed in the measur-
ing cell and in the sublimated products, and the stripping gas vapor
pressure does not depend on the temperature. From the experi-
mentally determined pressure – flow rate relationship, the optimal
flow rate of 1.69 dm3∙h
1 was found. At this flow rate, the satu-
rated vapor pressure was independent of the flow rate and, thus,
the thermodynamic equilibrium was reached.
The sublimed substance amount is determined by the following
procedure. The condensed substance is dissolved in a definite vol-
ume of solvent Vsol. The mass of the substance is determined based
on the measuring of absorbance A of its solution with a spec-
trophotometer (Cary, USA). Knowing the value of the extinction
38 A. Sharapova et al. / J. Chem. Thermodynamics 135 (2019) 35–44
coefficient e (dm3mol
1cm
1) of the studied compound dissolved
in the solvent one can express the concentration of the solution c
(moldm
3) according to the Lambert-Beer law, by the following
relation:
A ¼ ecl
whereas the mass of the sublimed substance is calculated from:
m ¼ cV sol M
where l is the absorbing path length; M is the molar mass of the
studied substance.
The absolute vapor pressure p at each temperature T was calcu-
lated from the amount of the sublimed product within a definite
period. Considering that the vapor pressure of the substance was
very low, we were able to apply the ideal gas rule to the nitrogen
stream saturated with the substance, the values of p were calcu-
lated with Eq. (4):
p ¼ m  R  T a =V  M
where R is the universal gas constant, M is the molar mass of the
compound; Ta is the ambient temperature, V = VN2 + Vi (VN2 >> Vi)
is the total volume of the gas phase consisting of the carrier gas
and the gaseous compound under study at the atmospheric pres-
sure. The gas volume VN2 (dm3) is calculated by the equation:
V N2 ¼ v  t
where m (dm /h) is the gas flow velocity; t (h) is the sublimation
3
time period.
The saturated vapor pressure values were measured five times
at each temperature with the standard deviation of no more than
5%. Because the saturated vapor pressure of the investigated com-
pounds was low, we could assume that the change in the vapor
heat capacity with temperature was so small that it could be
neglected.
The data of vapor pressure were obtained as a function of tem-
perature and were fitted using the following equation:
lnðp=PaÞ ¼ A þ B=T
The value of the sublimation enthalpy at the mean temperature
T was calculated by the Clausius–Clapeyron equation:


@ðlnpÞ
Dcrg Hom ðTÞ ¼
R
@ð1=TÞ
whereas the sublimation entropy at the given temperature T was
calculated from the following relation:
ðDcrg Hom ðTÞ
Dcrg Gom ðTÞÞ
Dcrg Som ðTÞ ¼
T
with Dcrg Gom ðTÞ = -RT ln(p/p0), where p0 = 105 Pa.
3. Results and discussion
3.1. Thermal analysis
Fig. 3 shows the results of the thermal analysis of the studied
compound as TG (a) and DSC (b) curves. As it can be seen, AETH
shows good thermal stability in the temperature range 30–
230 °C. No AETH mass loss is observed in this range, which indi-
cates that this compound does not contain low-molecular volatile
components. The main decomposition occurs between the temper-
atures of approximately 250 and 300 °C.
The DSC curve of sample heating at the temperature 190 °C has
a sharp exothermic peak that is evidently caused by compound
melting. The onset and maximum temperatures of the melting
peak are Tonset = 205.2 ± 0.2 °C and Tmax = 208.5 ± 0.2 °C, respec-
ð2Þ
ð3Þ
Fig. 3. TG (a) and DSC (b) curves of AETH.
ð4Þ
tively. The subsequent exothermic peak at the temperature of
275 °C corresponds to AETH decomposition, which agrees with
the thermogravimetric data. The melting enthalpy was determined
by integrating the melting curve with the straight baseline and
equaled 35.2 ± 0.5 kJmol
1. Uncertainties for melting parameters
correspond to expanded uncertainties of the mean (0.95 confi-
ð5Þ
dence level). The melting entropy of AETH was calculated by equa-
tion DSm = DHm/Tm. The value of DSm was found to be equal to
127.9 ± 4.2 J∙mol
1K
1.
3.2. Solubility experimental data
For the study, we selected five pharmaceutically relevant sol-
vents: buffer pH 2.0 simulating the gastric fluid, buffer pH 7.4 –
the blood system plasma, 1-octanol as the model of the properties
of biological membranes phospholipids; hexane a component of
the blood–brain barrier media. Ethanol is a typical medium used
ð6Þ for delivering drugs in the pharmaceutical industry and is also
employed as a preservative, an extraction agent and a co-solvent.
The measured mole fraction solubilities of AETH in five selected
solvents in the temperature ranging from 288.15 to 318.15 K are
listed in Table 2, and graphically presented in Fig. 4A. As these data
ð7Þ
show, the solubility of the compound studied monotonically
increases with the rising temperature for all the studied solvents,
which is characteristic of most organic substances. Ethanol has
the highest temperature gradient of solubility facilitating the
solute–solvent interaction and enhancing dissolution power.
ð8Þ Fig. 4B further shows that the mole fraction solubilities
decrease in the following order in different solvents: ethanol >
1-octanol > buffer pH 7.4 > buffer pH 2.0 > n-hexane at the temper-
ature below about 298.15 K, it is smaller in ethanol than in
1-octanol. In order to qualitatively evaluate the solubility of the
bioactive compound studied in accordance with United States
Pharmacopeia, we expressed the molarity of AETH (Table S1) at
T = 298.15 K in mg∙ml
1 units and obtained the following values:
buffer pH 2.0–0.54, buffer pH 7.4–0.46 n- hexane
0.04, ethanol
– 4.6, 1-octanol – 1.7. As can be seen from the data, AETH was con-
sidered essentially insoluble n-hexane (S < 0.1 mg∙ml
1), very
slightly soluble in buffer solutions (0.1 < S < 1 mg∙ml
1) and
slightly soluble in 1-octanol and ethanol (S > 1 mg∙ml
1). At a fixed
temperature, the solubilities are highest in ethanol, and lowest in
n-hexane. The solubility of AETH in ethanol at the temperatures
above 298.15 R is better than in 1-octanol. This is consistent with
the observation that lower molecular weight solvents are often
‘‘stronger” than higher molecular weight solvents of the same
class. The drug solubility of the compound studied in muriatic buf-
 A. Sharapova et al. / J. Chem. Thermodynamics 135 (2019) 35–44 39

Table 2
Experimental (xexp) and correlated (xcal) AETH solubility values (in mole fractions) in the organic solvents at different temperatures and pressure p = 0.1 MPa.

T/R xexp Modified Apelblat equation van’t Hoff equation

a
xcal RD xcal RD
Buffer pH 2.0b
288.15 2.4910
5 2.4910
5 0.0003 2.3010
5 0.0752
293.15 2.9510
5 2.9310
5 0.0067 2.7110
5 0.0824
298.15 3.4010
5 3.4310
5
0.0085 3.1610
5 0.0692
303.15 3.9410
5 3.9910
5
0.0124 3.6810
5 0.0657
308.15 4.6710
5 4.6210
5 0.0117 4.2610
5 0.0877
313.15 5.3710
5 5.3110
5 0.0107 4.9110
5 0.0860
318.15 6.0310
5 6.0810
5
0.0091 5.6310
5 0.0664
Buffer pH 7.4c
288.15 2.0810
5 2.0810
5 0.0043 2.0410
5 0.0185
293.15 2.4610
5 2.4610
5
0.0002 2.4610
5
0.0004
298.15 2.9010
5 2.9010
5
0.0081 2.9510
5
0.0166
303.15 3.4110
5 3.4110
5
0.0189 3.5110
5
0.0296
308.15 4.2310
5 4.2310
5 0.0243 4.1610
5 0.0171
313.15 4.9110
5 4.9310
5 0.0057 4.9010
5 0.0068
318.15 5.7610
5 5.7610
5
0.0106 5.7410
5 0.0039
n-Hexane
288.15 1.5410
5 1.5310
5 0.0028 1.5110
5 0.0162
293.15 1.8110
5 1.8110
5
0.002 1.8110
5
0.0026
298.15 2.1510
5 2.1410
5 0.0037 2.1610
5
0.0048
303.15 2.4710
5 2.5310
5
0.0243 2.5610
5
0.0353
308.15 3.0510
5 2.9910
5 0.0204 3.0110
5 0.013
313.15 3.5510
5 3.5310
5 0.0062 3.5310
5 0.0069
318.15 4.1310
5 4.1610
5
0.0084 4.1110
5 0.0053
Ethanol
288.15 5.7810
4 5.7410
4 0.0067 5.6210
4 0.0281
293.15 7.3310
4 7.4010
4
0.0097 7.4110
4
0.0104
298.15 9.6510
4 9.5510
4 0.0108 9.6710
4
0.0025
303.15 1.1810
3 1.2310
3
0.0350 1.2510
3
0.0526
308.15 1.6210
3 1.5910
3 0.0188 1.6010
3 0.0072
313.15 2.1010
3 2.0610
3 0.0232 2.0510
3 0.0244
318.15 2.6010
3 2.6510
3
0.0182 2.5910
3 0.0039
1-Octanol
288.15 6.8510
4 6.8210
4 0.0047 6.7310
4 0.0172
293.15 8.1410
4 8.1310
4 0.0011 8.1510
4
0.0018
298.15 9.6110
4 9.7010
4
0.0093 9.8210
4
0.0214
303.15 1.1310
3 1.1610
3
0.0244 1.1710
3
0.0392
308.15 1.4210
3 1.3810
3 0.0269 1.4010
3 0.0164
313.15 1.6710
3 1.6510
3 0.0123 1.6510
3 0.0108
318.15 1.9410
3 1.9710
3
0.0151 1.9410
3
0.0019

Standard uncertainties: u(T) = 0.15 K and u(p) = 3 kPa.

Relative standard uncertainties for solubility: ur(x) = 0.045 for buffer solutions and ur(x) = 0.04 for n-hexane, ethanol and 1-octanol.
a
RD is the relative deviation: RD = (xexp – xcal)/xexp.
b
Composition of aqueous buffer pH 2.0: KCl (6.57 g in 1 l) and 0.1 mol/dm3 hydrochloric acid (119.0 ml in 1 l).
c
Composition of aqueous buffer pH 7.4: KH2PO4 (9.1 g in 1 l) and Na2HPO412H2O (23.6 g in 1 l).

fer (pH 2.0) and phosphate buffer (pH 7.4) is the same, which
allows us to make a conclusion that the hydrogen index of aqueous
solutions does not affect the dissolution process. The dissociation
constant values pKa = 9.52 ± 0.50 calculated using Advanced
Chemistry Development (ACD/Labs) Software V11.02 show that
the studied compound is a weak acid, which is caused by the pres-
ence of two secondary groups in the molecule structure. So, we can
conclude that AETH is in an almost totally nonionized form in the
selected buffer solutions.
3.3. Modeling of solubility data
In order to more quantitatively describe the solid–liquid equi-
librium, the relationship between the experimental solubility and
the temperature was modeled by the modified Apelblat and van’t
Hoff equations. The modified Apelblat equation [14,15] has been
extensively used in correlation and determination of solubility
data of different substances because of its simplicity and is
expressed as:
B
ln x ¼ A þ þ ClnðT=K Þ ð9Þ
T=K
where x is the experimental saturated mole fraction solubility of the
solute, T is the absolute temperature, A, B and C are the empirical
model parameters. Values A and B represent the variation in the
solution behavior resulting from the non-ideality of the solute sol-
ubility, whereas the value of C represents the association between
the temperatures and the enthalpy of fusion [16].
According to the van’t Hoff model, the mole fraction solubility
of a compound in the solvents studied is calculated using equation
[17]:
B
ln x ¼ A þ ð10Þ
ðT=K Þ
where x is the mole fraction solubility of the solute, A and B are the
model constants calculated using the least square analysis.
The relative average deviation (RAD) and root-mean-square
deviation (RMSD) were used to evaluate the applicability and accu-
racy of the models:
40 A. Sharapova et al. / J. Chem. Thermodynamics 135 (2019) 35–44

-6
buffer pH 2.0
buffer pH 7.4
2.0x10
-3 n-hexane
ethanol
-8

slightly soluble
soluble
1-octanol

lnx
-3
1.0x10

slightly
x

-5 -10
6.0x10

very slightly soluble

oc .4 very slightly soluble

insoluble
-5
4.0x10
-12

-5
2.0x10

l
bu r p e
r p .0

no

l
7
ffe ah

no
290 295 300 305 310 315 320

ffe H 2

ta
H
bu hex

ha
et
T/K

1-
n -
A B
Fig. 4. Solubility data of AETH in selected solvents: A
mole fraction solubility (x) of AETH at different temperatures, B – solubility histogram at 308.15 K.

N  
1X 
xexp
xcal 
organic substances is played by three types of interactions (disper-
RAD ¼  ð11Þ
N i¼1 xexp  sion interaction caused by interatomic forces of attraction; inter-
molecular dipole–dipole interaction; intermolecular hydrogen
 1=2 interaction that is seen as electrostatic interaction enhanced by
1 XN
 2 
 small hydrogen size) Hansen divided the solubility parameter into
RMSD ¼  xexp
xcal  ð12Þ
N i¼1  three components – dispersion (dd), polar (dp) and hydrogen bond-
ing interaction (dh). The total solubility value is then determined by
where N represents the number of experimental points, xexp and xcal the following equation:
are the experimental and calculated mole fraction solubility values
of the compound, respectively. d2t ¼ d2d þ d2p þ d2h ð13Þ
The mole fraction solubilities of the studied compound calcu-
lated by Eqs. (9), (10) are reported in Table 2. The calculated model The partial solubility parameters for AETH and selected solvents
parameters with the values of deviations are presented in Table 3. have been estimated using the combined group contribution meth-
As can be seen from the presented data, the modeling results ods of Van Krevelen–Hoftyzer and Fedors [21,22]. The group con-
obtained by the modified Apelblat and van’t Hoff equations show tribution parameters for the respective molecular forces and the
good consistency with the experimental solubility with RAD values associated molar volumes with the number of the corresponding
less than 2% and these models are all suitable for correlating the group for the compound studied are listed in Table 4. The HSP
solubility of AETH in the selected solvents. Obviously, the modified parameters of AETH and selected solvents as well as the calculated
Apelblat equation has the smallest values of deviations for the molar volume at 298.15 K are summarized in Table 5.
investigated systems. It is known that the similarity of HSP values of two substances
determines the degree of their interaction: the closer are the solute
3.4. Hansen solubility parameter and solvent parameters, the more effective is the dissolution pro-
cess. The calculated HSP values agree well with the experimental
The solubility behavior of AETH has been illustrated by using solubility values obtained by us. According to the data from Table 5,
the Hansen solubility parameter (HSP). HSP help to quantify the the best solvents for AETH are alcohols as their common dt param-
statements ‘like dissolves like’, and has been widely used to predict eters are closest to each other. It should be said that higher values
materials’ compatibilities, including in pharmaceutical drug devel- of all the HSP components in ethanol in comparison with those in
opment [18–20]. Taking into account the fact that the main role in 1-octanol lead to a three-time difference in the Dd value, which

Table 3
Parameters of modified Apelblat and van’t Hoff equations for AETH in the selected solvents.

Solvents A B C 105RMSD RAD

Modified Apelblat equation
Buffer pH 2.0 12.77
3357.8
20.69 0.043 0.0085
Buffer pH 7.4
137.65
3055.1 20.53 0.053 0.0103
n-Hexane
133.61 2951.9 19.83 0.035 0.0097
Ethanol
203.79 4910.5 31.66 1.309 0.0175
1-Octanol
144.90 3469.1 22.17 1.265 0.0134
van’t Hoff equation
Buffer pH 2.0
1.12
2731.6 – 0.033 0.0761
Buffer pH 7.4 0.16
3157.8 – 0.055 0.0133
n-Hexane
0.52
3048.3 – 0.149 0.0120
Ethanol 8.72
4670.3 – 0.971 0.0184
1-Octanol 3.94
3240.1 – 2.204 0.0155
 A. Sharapova et al. / J. Chem. Thermodynamics 135 (2019) 35–44 41

Table 4
Group contribution parameters and associated molar volumes of AETH.

Individual functional group Frequency Fdi, (Jm3)0.5∙mol
1 Fpi, (Jm3)0.5∙mol
1 Ehi, J/mol Vi, cm3/mol
ACH3 2 336.6 0 0 33.5
ACH2A 6 234.6 0 0 16.1
>C< 2
214.2 0 0
19.2
ACOA 2 105.0 600 9500 10.8
NHA 2 122.4 700.7 1500 4.5
ASA 1 815.9 196.0 297.5 12.0
AN@ 2 380.0 100 250 5.0
Ring(5) 1 142.8 0 0 16.0

Table 5
Molar volumes and Hansen solubility parameters for AETH and selected solvents.

Compound V, cm3∙mol
1 a
dd, MPa0.5 b
dp, MPa0.5 c
dh, MPa0.5 dt, MPa0.5 Dd
d
dv, MPa0.5
AETH 193.8 19.7 4.9 10.9 23.0 – 19.7
Buffer solutions 18.0 15.5 16.0 42.3 47.8 29.1 4.0
n-Hexane 131.6 14.9 0.0 0.0 14.9 12.9 14.9
Ethanol 58.5 15.8 8.8 19.4 26.5 10.1 13.1
1-Octanol 157.7 17.0 3.3 11.9 21.0 3.3 16.7
a
dd = RFdi/RVi.
b
dp = (RF2pi)0.5/RVi.
c
dh = (RFhi/RVi)0.5.
0:5
d
Dd ¼ ððdd1
dd2 Þ2 þ ðdp1
dp2 Þ2 þ ðdh1
dh2 Þ2 Þ .

should correspond to a significant difference in AETH solubility in
these solvents. However, the solubility of the considered com-
pound in alcohols is almost equal. The situation may be due not
only to solute–solvent interactions, but solvent–solvent interac-
tions and molecular shapes and sizes. Hexane, only capable of dis-
persion interactions (dt = dd = 14.9), behaves as a very weak
solvent, which results in very low solubility values (x = 10
5 mol.
frac.).. The poor solubility of the studied compound in buffer solu-
tions is due to its highest dt value in water, with the maximum dif-
ference in hydrogen bonding parameters, which confirms the
hydrophobic character of AETH.
The results of the HSP calculations have been illustrated by
using the Bagley diagram (Fig. 5). Based on the thermodynamic
considerations that dd and dp show similar values, whereas the
effect of dh is of quite different nature, Bagley et al. [23] introduced
a combined solubility parameter dv, which is defined as:
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
dv ¼ d2d þ d2p
20
1-Octanol
0.5
The relation of dv versus dh, enables a projection of the three-
dimensional solubility parameter into a two dimensional plot.
The bioactive AETH is placed in the center of the circle with coor-
dinates dv = 19.7 MPa0.5 and dh = 10.9 MPa0.5. Earlier, using the poor
soluble drugs data set, Albers [24] has shown that two substances
are miscible if their interaction radius in the Bagley
plot  5.6 MPa0.5. It is shown that only the point corresponding
to ethanol lies inside the solubility sphere, indicating that this alco-
hol can be a good solvent for AETH. As the presented diagram indi-
cates, the values of the other studied solvents lie beyond the area
of optimal solubility parameters, with buffer solutions and hexane
being the farthest from the center. Thus, the Bagley’s plot provides
a good approximation of the AETH behavior in the investigated sol-
vents with the measured solubility data.
The approach based on solubility parameters has been used as
an effective method to estimate the absorption behavior of new
substances in drug research and development [20]. By analysing
ð14Þ 32 known drug substances of different chemical nature, the author
found a region for optimal absorption with the centre coordinates
dv = 20.3.MPa0.5 and dh = 11.3 MPa0.5.. The bioactive compound that
we have studied has almost the same solubility parameters, which
allows us to make a conclusion that AETH can be absorbed along
the whole gastrointenstinal tract with maximal absorption
duration.
3.5. Ideal solubility and activity coefficients of AETH

16 n-Hexane
, MPa

Ideal solubility is defined as the solubility of a solute in the per-

Ethanol fect solvent, for which there is no energy contribution associated
12 R with the dissolution process. Ideal solubility depends only on the
v

AETH
energy needed to break the crystalline structure of the compound
8 and does not take into account the solvent properties. If the ther-
Buffer mophysical parameters of the solute are known, the ideal solubility
solutions can be accurately calculated by the equation:
4 

DH m T m
lnxid ¼ ð15Þ
0 10 20 30 40 RT m T
0.5
h
, MPa where xid is the ideal mole fraction solubility, Tm and DHm are the
temperature and enthalpy change of melting for the pure solute.
Fig. 5. Bagley diagram of AETH solubility (R = 5.6 – interaction radius). This approach has been especially frequently used by many
42 A. Sharapova et al. / J. Chem. Thermodynamics 135 (2019) 35–44

Table 6
Activity coefficients (c) of AETH in selected solvents at different temperatures and pressure p = 0.1 MPa.

Solvent c
288.15 K 293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Buffer pH 2.0 467.27 464.47 462.81 461.18 459.67 457.17 455.50
Buffer pH 7.4 555.24 545.66 537.03 529.38 521.07 516.92 505.68
n-Hexane 749.94 742.48 735.09 727.78 720.54 713.37 706.27
Ethanol 20.00 18.30 16.14 15.17 13.52 12.02 11.14
1-Octanol 16.85 16.50 16.21 15.97 15.53 15.20 15.03

The standard uncertainties: u(T) = 0.15 K, u(p) = 3 kPa.

Relative standard uncertainty: ur(c) = 0.04.

Table 7
Transpiration experiment parameters, vapor pressure of AETH at different temperatures and sublimation thermodynamic functions.

T/K m/mg V(N2)/dm3 Ta/K m/dm3h
1 p/Pa

433.15 0.0144 9.700 299.15 1.69 0.0130
435.15 0.0193 10.917 297.15 1.69 0.0153
437.15 0.0215 10.478 297.15 1.69 0.0179
439.15 0.0207 8.653 298.15 1.69 0.0208
441.15 0.0282 10.275 298.15 1.69 0.0239
443.15 0.0235 7.520 299.15 1.69 0.0273
445.15 0.0336 8.957 297.65 1.69 0.0327
446.65 0.0396 9.413 299.15 1.69 0.0368
446.65 0.0428 9.413 299.15 1.69 0.0398
450.15 0.0454 8.196 298.15 1.69 0.0483
452.15 0.0549 8.653 299.15 1.69 0.0554
454.15 0.0269 3.634 298.15 1.69 0.0644
p(298.15 K)/Pa 2.2110
9
Dcrg Gom ð298:15 KÞ/kJ∙mol
1 77.9 ± 1.6
Dcrg Hom ðT Þ/kJmol
1 124.0 ± 1.2
C p (298.15 K)/J∙mol
1K
1 342.8
Dcrg Hom ð298:15 KÞ/kJ∙mol
1 131.5 ± 1.2
T Dcrg Som ð298:15 KÞ/kJ∙mol
1 53.6
Dcrg Som ð298:15 KÞ/J∙mol
1∙K
1 179.8 ± 5.1

The standard uncertainties: u(T) = 0.15 K, u(Ta) = 0.15 K, u(m) = 0.00001 g.

Relative standard uncertainty: ur(p) = 0.05.

researchers in the pharmaceutical field [25–27] and has been
shown by Grant [28] to provide a better fit with respect to available
experimental solubility data.
The ideal solubilities of AETH calculated by means of Eq. (15)
from the Hm and Tm values obtained by us from the DSC experi-
ment are presented graphically in Fig. S2 (Supporting Information).
As this data shows, the ideal solubility of the studied substance
increases with temperature growth. In this temperature range,
the xid values vary from 1.1510
2 to 2.9210
2, which is three
orders of magnitude greater than the experimental solubility in
buffer solutions and hexane and one order of magnitude higher
than in the selected alcohols. This phenomenon is typical, when
the solubility predicted based on the model of an ideal solution
is normally much higher than the solubility that is actually mea-
sured for a non-ideal solution.
The activity coefficients (c) for AETH in the studied solvents
were determined using the following equation:
xid
c¼
xexp
The calculated c values in each solvent in the studied tempera-
ture interval are listed in Table 6.
By analysing the obtained data, we have found the following
regularities: a) all the investigated solutions have a positive devia-
tion from the ideality (c > 1); b) the biggest deviation from the ide-
ality is observed for buffer solutions and hexane with the
maximum values of the activity coefficients; c) the minimum c
value for AETH was obtained in ethanol and 1-octanol and is due
to stronger interactions between the bioactive compound and
these organic solvents; d) the activity coefficients decrease with
the temperature growth, which indicates a strengthening
solute–solvent molecular interaction; e) the c values of AETH
corresponded to its solubility data: the lower was the activity coef-
ficient, the higher was the compound solubility in this solvent.
3.6. Crystal lattice energy
According to the thermodynamic cycle, sublimation and solva-
tion parameters are the key properties connected with the under-
standing of the fundamental aspects of dissolution process [29].
The enthalpy of sublimation characterizing lattice energy is an
important property of the solid state as it represents a quantitative
assessment of the intermolecular interactions in solid phase. It can
be directly measured by vapor–pressure measurements. In our
study, we used the transpiration method that is especially success-
fully applied at low vapor pressure values. Among its merits are:
sufficiently high accuracy, low sensitivity to impurities and short
ð16Þ duration to reach equilibrium [30].
The vapor pressure experimental values of AETH in the temper-
ature range 433.15–454.15 K are summarized in Table 7 and
graphically presented in Fig. 6. The obtained data are well approx-
imated by the linear dependence: ln(p/Pa) = (30.08 ± 0.32) –
(1491.0 ± 14.1)/T (R = 0.9996). The sublimation parameters of
AETH calculated by Eqs. (7)–(8) are also represented in Table 7
along with their standard deviation. The sublimation enthalpy
obtained by the integrated form of the Clausius-Clapeyron equa-
tion corresponds to the average value over the experimental tem-
perature range studied.
 A. Sharapova et al. / J. Chem. Thermodynamics 135 (2019) 35–44
-2.5
-3.0
ln(p/Pa)
-3.5
-4.0
-4.5
2.18 2.20 2.22 2.24 2.26 2.28 2.30
3 -1 -1
10 T /K
Fig. 6. Plot of vapor pressure ln(p/Pa) against reciprocal temperature for AETH.
The standard molar enthalpies of sublimation Dcrg Hom ð298:15 KÞ
have been determined from the experimental data Dcrg Hom ðT Þ using
the heat capacity differences of both solid (C pc ) and gaseous (C pg )
phases at constant pressure:
Dcrg Hom ð298:15 KÞ ¼ Dcrg Hom ðT Þ
C pcr
C pg ð298:15
T Þ
¼ Dcrg Hom ðT Þ
Dcrg C p ð298:15
T Þ

1  
where Dcrg C p ð298:15Þ=J  K
1 mol ¼ 0:75 þ 0:15C pcr was derived
by Chickos et al. [31] on the basis of statistical results and C pcr
was estimated using a group additivity approach (Table 7). The
uncertainty associated with the value of C pcr was comparable to that
assigned by Chickos [32].
As the represented data show, AETH has a high value of subli-
mation enthalpy Dcrg Hom ð298:15KÞ = 131.5 ± 1.2 kJmol
1. We can
assume that the presence of 2 donor (secondary amine
groups > NH) and 4 acceptor (2 nitrogen atoms in the thiadiazole
ring and 2 carbonyl COH groups) centers in the molecule structure
will lead to the formation of a diverse system of hydrogen bonding
in the crystal lattice of the compound and, as a result, to a rather
strong molecular packing. That is why we can quite reasonably
conclude that the thermodynamic cause of the low solubility of
AETH is the high standard sublimation enthalpy, i.e. the energy
contribution of the solvation process cannot compensate for the
energy required to break the crystal lattice sufficiently.
4. Conclusions
The data on the original bioactive 6-(acetylamino)-N-(5-ethyl-
1,3,4-thiadiazol-2-yl) hexanamide solubility in five pharmaceuti-
cally relevant solvents has been determined as a function of tem-
perature by the shake-flask method. The mole fraction
solubilities of AETH at 298.15 decreased in the order: 1-octanol
(9.6110
4) > ethanol (9.5510
4) > buffer pH 2.0 (3.4310
5) > buf-
fer pH 7.4 (2.9010
5) > hexane (2.1410
5). The experimental sol-
ubilities of AETH in mole fraction were correlated well with the
van’t Hoff and modified Apelblat models. To assess the solubilizing
properties of the selected solvents a Hansen solubility parameter
based on van Krevelen–Hoftyzer contributions was used. The
results of predicting the behavior of solvents in this approach are
in a reasonable agreement with the experimental AETH solubility
values. The ideal solubility has been obtained from melting param-
eters, measured by the DSC technique. The solution activity coeffi-
cients at equilibrium in the selected solvents have been quantified.
43
The solutions in all the solvents exhibit a positive deviation from
the ideality, with the highest solubility in alcohols. Moreover, the
temperature dependence of vapor pressure for the studied com-
pound has been measured by the transpiration method. The crystal
lattice energy of AETH equal to 131.5 kJmol
1 has been evaluated
from the experimental vapor pressure values. We have concluded
that the thermodynamic reason for the low solubility of AETH is
the high value of energy required to break the crystal lattice.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jct.2019.03.015.
2.32
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JCT 2018-549