Experimental and Modeling Studies on the Solubility of 2-Chloro-N-(4-methylphenyl)propanamide (S1) in Binary Ethyl Acetate + Hexane, Toluene + Hexane, Acetone + Hexane, and Butanone + Hexane Solvent Mixtures Using Polythermal Method

Article abstract of DOI:10.1021/acs.jced.7b00288

The solubility of 2-chloro-N-(4-methylphenyl)propanamide (S1) in ethyl acetate + hexane mixtures between the temperatures of 273.43 to 327.67 K, in toluene + hexane mixtures from 273.24 to 331.62 K, in acetone + hexane mixtures from 269.81 to 318.8 butano

Full text of DOI:10.1021/acs.jced.7b00288

Article
pubs.acs.org/jced
Experimental and Modeling Studies on the Solubility of
2‑Chloro-N-(4-methylphenyl)propanamide (S1) in Binary Ethyl
Acetate + Hexane, Toluene + Hexane, Acetone + Hexane, and
Butanone + Hexane Solvent Mixtures Using Polythermal Method
Gladys Kate Pascual,† Philip Donnellan,† Brian Glennon,† Vamsi Krishna Kamaraju,‡
and Roderick C. Jones*,†
†Synthesis and Solid State Pharmaceutical Centre (SSPC), School of Chemical and Bioprocess Engineering,
University College Dublin, Belfield, Dublin 4, Ireland
‡APC Ltd, Cherrywood Business Park, Loughlinstown, Co Dublin, Ireland
S
* Supporting Information
ABSTRACT: The solubility of 2-chloro-N-(4-methylphenyl)-
propanamide (S1) in ethyl acetate + hexane mixtures between
the temperatures of 273.43 to 327.67 K, in toluene + hexane
mixtures from 273.24 to 331.62 K, in acetone + hexane mix-
tures from 269.81 to 318.8 butanone + hexane mixtures between
267.10 and 322.92 were determined using the polythermal
method. In situ focused beam reflectance measurement
(FBRM) was used to characterize the dissolution properties
and to provide S1’s saturation temperature profile as a function
of concentration. It was demonstrated that the solubility of
S1 increases with increasing temperature at constant solvent
composition. The experimental solubility data were correlated
using Apelblat, λh, and phase equilibria with NRTL (nonrandom
two liquid) model equations, and the predicted solubility data obtained agree sufficiently with the experimental data based on the
relative deviation (RD%) and average relative deviation (ARD%) values. The Apelblat and λh model equation provides a conve-
nient operational model of engineering interest to calculate the solubility of S1 quickly and easily, although it does not take the
solvent composition into account, therefore needing separate parameters for each different solvent compositions. Therefore, the
phase equilibria with NRTL model equation is used to provide a more comprehensive model that illustrates the effect of solvent
composition on the solubility more apparently. One general set of NRTL parameters has the capability of describing all solvent
compositions. Additionally, the melting temperature, Tm and the molar fusion enthalpy, ΔfusH, (394.83 K and 26.77 kJ mol−1
respectively) of S1 were determined by differential scanning calorimetry (DSC).
such as reactIR and reactNMR.2 Such work has shown that due
to the complex cascade nature of the overall reaction pathway,
desired product purity profiles are highly dependent on starting
INTRODUCTION
■
Functionalized α-thio-β-chloroacrylamides derivatives are gain-
ing increasing interest in the literature as synthetically viable
material purity.1−3 Consequently, 2-chloro-N-(4-methylphenyl)
propanamide (S1), a precursor in the multistep synthesis of
(Z)-3-chloro-2-(phenylthio)-N-(p-tolyl)acrylamide (P1, an API
of interest to this group, Scheme 1), requires extensive
purification via crystallization before use in order to obtain
clean product profiles.
advanced pharmaceutical intermediates1−3 (API) that can
undergo transformations, such as Diels−Alder cycloadditions,4
1,3-dipolar cycloadditions,5 and sulfide group6,7 and nucleophilic
substitutions (Figure 1).8
The solubility characteristics of a particular solute−solvent
pair have considerable influence upon the design and optimi-
zation of any crystallization9−11 and therefore a detailed under-
standing of this solubility behavior based upon comprehensive
Figure 1. Generalized structure of α-thio-β-chloroacrylamides.
β-chloroacrylamides have complex synthetic pathways which
have provided unique opportunities for developing novel mecha-
nistic elucidation methods using real time monitoring techniques,
Received: March 22, 2017
Accepted: August 25, 2017
© XXXX American Chemical Society
A
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134.4, 134.0, 129.1, 119.7, 55.9, 22.4, 20.5. MS (EI) m/z 197 [M]+,
[12C10H1235Cl14N16O 197]. HRMS (EI) m/z [M]+ 197.0604-
[C10H12ClNO]+ requires 197.0607.
Scheme 1. Synthesis of (Z)-3-Chloro-2-(phenylthio)-N-(p-tolyl)
acrylamide
Materials used in this study with corresponding sources, purity
(determined by chemical supplier), and analysis method are
shown in Table 1.
Experimental Methods. Melting Properties Measurements.
The molar enthalpy of fusion (ΔfusH) and the melting temper-
ature (Tm) of S1 were measured using differential scanning
calorimetry (DCS 200 F3Maia, Netsch) under a nitrogen atmo-
sphere, with a heating rate of 10 K·min−1 and temperature
accuracy of 0.1 K. Approximately 7 mg of sample were weighed
using an electronic analytic balance (type AX205, Mettler Toledo
instrument Co. Ltd., uncertainty of 0.01 mg) and placed on
aluminum crucible pan. To ensure accuracy, measurement was
conducted five times and the average result was taken.
Solubility Measurements. The polythermal method, a widely
used method to determine the metastable zone width,13−17 was
used to measure the solubility of S1 in various solvent compo-
sitions. It has been reported in the literature that various factors
such as cooling rate, initial composition, stirring rate and seed
particles can affect the metastable zone width.18 This article
examines only the effect of temperature upon S1’s solubility and
therefore all other variables were kept constant.
experimental data is required. In this study, the polythermal
method was used to obtain the solubility data, which involves
cooling a saturated solution until nucleation occurs, and then
subsequently heating the solution until it dissolves. This work
quantifies the solubility behavior of the molecule S1 in ethyl
acetate + hexane, toluene + hexane, acetone + hexane, and
butanone + hexane solutions, as no such data is currently
available in the literature. The experimental data were correlated
with Apelblat, λh, and the phase equilibria with NRTL (non-
random two liquid) model equations to enable both inter-
polation and extrapolation of the measured data.
EXPERIMENTAL SECTION
Materials. As seen from Scheme 2, a modified procedure
developed by Li,12 α-chloropropionyl chloride(1.16 mL, 12mmol,
The experiments were conducted in an EasyMax (102, Mettler
Toledo) reactor and in situ focused Beam reflectance measurement
(FBRM ParticleTrack G400 series, Mettler Toledo) was used to
characterize the nucleation and dissolution properties of S1.19
■
Scheme 2. Synthesis of 2-Chloro-N-(4-
methylphenyl)propanamide (S1)
1.2equiv)wasadded dropwise (with extremecaution) toa suspen-
sion of p-toluidine (1.07 g, 10 mmol) in toluene (20 mL) at 0 °C
and theresulting solution was heated torefluxfor 1 h withvigorous
stirring. After cooling, the solvent was removed under vacuum and
the resulting off white solid was collected by filtration and washed
thoroughly with cold cyclohexane (1.89 g). Spectral data of the
obtained product matched that reported in the literature.1
1HNMR (300 MHz, CDCl3): δ 8.21 (s, 1H), 7.42 (d, J = 8.2 Hz,
2H), 7.15 (d, J = 8.2 Hz, 2H), 4.54 (q, J = 7.1 Hz, 1H) 2.13 (s, 3H),
1.83 (d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.9,
Figure 2. Schematic diagram of the experimental setup for solubility
measurements.
Table 1. Sources and Mass Fraction Purity of Materials with Corresponding Analysis Method
chemical name
CAS registry number
source
mass fraction purity
further purification method
analysis method
S1
147372-41-6
141-78-6
108-88-3
67-64-1
synthesized
99%
none
none
none
none
none
none
none
none
none
none
none
HNMR
HPLC
HPLC
HPLC
HPLC
HPLC
HPLC
HPLC
HPLC
HPLC
ethyl acetate
toluene
Sigma-Aldrich
Sigma-Aldrich
Sigma-Aldrich
Sigma-Aldrich
Sigma-Aldrich
Sigma-Aldrich
Sigma-Aldrich
Sigma-Aldrich
Acros Organics
Sigma-Aldrich
≥99.5%
99.90%
≥99.8%
≥99.7%
≥97%
99%
acetone
butanone
78-93-3
hexane
110-54-3
106-49-0
7623-09-8
110-82-7
103-90-2
7732-18-5
p-toluidine
α-chloropropionyl chloride
cyclohexane
4-acetaminophenol
water
99%
99%
98%
B
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a
Table 2. Solubility of 4-Acetamidophenol in Water at Different Temperatures and p = 101.3 kPa
T/K
103 xpara
102RDtemp
102RDA
102RDB
102RDC
102RDD
102RDE
288.24
293.62
298.66
302.88
307.94
312.88
318.20
322.99
1.32
1.53
1.81
2.10
2.47
2.93
3.45
4.08
−0.03
−0.16
−0.17
0.09
−3.91
−5.47
−1.28
−1.44
0.01
−1.45
−0.86
−1.82
−1.27
−1.63
−3.06
−5.17
−4.89
−5.53
−5.83
−4.48
−3.03
−1.96
−2.08
−0.56
−0.58
−0.89
−0.19
0.09
−12.84
−10.26
−7.53
−8.63
−4.51
−1.94
0.07
0.09
0.30
−0.02
0.05
a
Standard uncertainties u are u(T) = 2 K, ur(p) = 0.05, ur(xpara) = 6 × 10−7. xpara is the measured mole fraction solubility of 4-acetaminophenol in
water; RDA, RDB, RDC, RDD, and RDE are the relative deviations of the determined solubility with the literature data from Hojjati,30 Granberg,31
Fujiwara,32 Grant,33 and Shakeel,34 respectively, while RDtemp is relative deviation between the experimentally determined saturation temperatures
using polythermal method and the saturation temperatures from the literatures.30−34
FBRM uses a focused beam of laser light that scans in
a circular path to measure the chord length distribution (CLD)
of a particle. For this study, total counts in the size range of
1−1000 μm were used to track the point of nucleation and
saturation temperature of S1.
The experimental set up is shown in Figure 2, and its operating
procedure is as follows: (i) The solute and solvent mixture was
dispensed from an electronic analytic balance (PA124, Ohaus
Pioneer series) to the reactor. (ii) The solution was agitated at a
constant rate of 200 rpm and temperature controlled at 60 °C
(50 °C for acetone−hexane mixture) for at least 30 min to ensure
full dissolution. (iii) To determine the temperature at which
nucleation occurs, the solution was cooled at a constant rate of
0.5 K·min−1 until an excess of 1000 particles was detected in the
Figure 3. Comparison between experimental solubility of 4-acetamino-
size range 0−1000 μm. The solution would turn cloudy when
□
phenol in water with that reported in literature: , literature data from
this occurs. (iv) The saturation temperature (the temperature at
which the particles dissolve once more) was determined by
heating the solution at constant rate until the number of particles
in the size range 0−1000 μm decreases below 50 counts and the
solution becomes clear. It has been demonstrated in the litera-
ture20 that the rate at which the solution is heated to reach disso-
lution should be considerably slower than the cooling rate.
Hence, the heating rate in this paper was maintained at a constant
rate of 0.1 K·min−1. The procedure was repeated at different
concentrations by using a dosing unit with 50 mL syringe (SP-50,
Mettler Toledo), where a known amount of solvent mixture was
added to the reactor to dilute the solution. To ensure accuracy,
the saturation temperature at a specific concentration was mea-
sured twice, and the uncertainty of each saturated temperature
was within 0.05 K.
31
Hojjati;30 , literature data from Granberg; Δ, literature data from
◇
Fujiwara;32 × , literature data from Grant;33 + , literature data from
Shakeel;34 , experimental data.
●
Apelblat Equation. The Apelblat equation is a commonly
used semiempirical equation to correlate experimental solubility
for mixed solvents.21−23 It is given as
B
T
ln x1 = A +
+ Cln T
(2)
where x1 is the mole fraction solubility of S1, T is absolute
temperature in Kelvin (K), and A, B, and C are empirical model
parameters.
λh Equation. Buchowski et al.24 introduced a semiempirical
equation to report the relationship between the solubility data
and temperature, which is given as
The mole fraction solubility (x1) of S1 is defined as
⎡
⎤
⎛
⎞
m1/M1
x1 =
λ(1 − x1)
1
T
1
Tm
ln 1 +
= λh
−
⎢
⎥
⎦
⎜
⎟
⎠
m1/M1 + m2/M2 + m3/M3
(1)
x1
⎣
⎝
(3)
where m1 and M1 represents the mass and molecular weight of
S1, m2, and M2 represents the mass and molecular weight of ethyl
acetate in ethyl acetate + hexane solution, toluene in toluene +
hexane solution, acetone in acetone + hexane solution, or butanone
in butanone + hexane solution while m3 and M3 represents the
mass and molecular weight of hexane, respectively.
where x1 is the mole fraction solubility of S1, T and Tm are the
absolute temperature and melting temperature of S1 in Kelvin
(K), and λ and h are the model parameters representing the
nonideal properties of the system and excess mixture enthalpy of
solution.
Phase Equilibria Equations with Nonrandom Two
Liquid Model (NRTL) Equation. Phase equilibria equations
can also be used to predict the solubility of a solute in a solvent,
which are derived based on the fact that the fugacities of all
species must be equal in each phase at equilibrium. The ratio of a
liquid’s fugacity to a stable solid’s fugacity (both at the same
temperature) can be determined using eq 4 once the solid’s
molar fusion enthalpy and melting point are known.25
THERMODYNAMIC MODELS
■
Modeling the experimental solubility data enables a more general
quantification of the mixtures’ solubility profiles and hence a
broader understanding of their behaviors. Moreover, such
developed models enable both interpolation and extrapolation
of the measured data.
C
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Figure 4. DSC curve for S1.
a
Table 3. Thermodynamic Properties of S1 at p = 101.3 kPa
Tm/K
Δ
fusH/kJ·mol−1
394.75
394.65
394.75
395.15
394.85
394.83
0.192
27.11
26.64
27.47
26.60
26.05
26.77
0.542
average
STD
a
Standard uncertainty u is ur(p) = 0.05.
⎡
⎢
⎡
⎢
⎛
⎞
1
⎢RT
T
Tm
L
S
f1 (T, P) = f1 (T, P)exp
Δ H(T) 1 −
⎜
⎟
⎠
fus
⎢
⎣
⎝
⎣
⎤
⎥
⎤
T
T ΔC dT − T
dT
ΔCp
⎥
+
∫
∫
p
⎥
⎦
Tm
Tm
T
⎥
⎦
(4)
Figure 6. Three dimensional plot showing the relationship between
number of particle counts and chord length distribution through a period
of time, during an experimental run at x1exp = 0.00998 at w2 = 0.8, where
w2 is the mass fraction of toluene in binary toluene + hexane mixtures.
Eq 4 is simplified to predict the saturation mole fraction of any
solid in a liquid, which is given as
ln x1γ = −
1 −
−
T ΔCpdT
⎡
⎤
ΔfusH
R
T
Tm
1
⎢
⎣
⎥
⎦
∫
1
RT Tm
If heat capacity data is unavailable for both the solid and liquid, it is
possible to assume that both values are approximately equal to each
other, meaning that ΔCp ≈ 0. Therefore, eq 5 can be simplified to
+
T ΔCpdT
1
∫
R
Tm
(5)
Figure 5. FBRM trend during experimental run at x1exp =9.98×10−3 when w2 =0.8, wherew2 is the mass fraction of toluene in binary toluene + hexane mixtures.
D
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3
⎧
⎨
⎩
⎫
⎬
⎭
⎡
⎢
3
⎡
⎤
ΔfusH
RT
∑
j=1 τjiGjixj
T
Tm
xjGij
ln x1 = −ln γ −
1 −
⎢
⎥
⎦
ln γ =
+ ∑
1
i
3
3
⎣
⎢
(6)
∑
k=1 Gkixk
∑
k=1 Gkjxk
j=1
⎣
where γ1, ΔfusH, and Tm are the activity coefficient, molar fusion
3
⎤
⎛
⎞
∑
k=1 xkτkjGkj
enthalpy, and melting temperature of S1, respectively.
⎥
⎜
⎟
⎟
× τ −
ij
3
k=1
⎜
Several thermodynamic models have been developed in the
literature which attempt to predict or correlate activity coef-
ficients.26 The nonrandom-two-liquid (NRTL) model is one
such model and it is derived based on the assumption that a local
composition exists around each molecule which is different to the
bulk composition. In this article, the NRTL model is used to
calculate the solute’s activity coefficient which enables the phase
equilibria model to be used to estimate the solubility, given by
eqs 7 and 8.27
⎥
⎦
∑
Gkjxk ⎠
⎝
(7)
b
ij
τ = aij + Gij = exp(−αijτij)αij = αjiτij ≠ τjiτii = 0
ij
(8)
T
Subscript 1 represents S1, while subscript 2 represents ethyl
acetate in ethyl acetate + hexane mixture, toluene in toluene +
hexane mixture, acetone in acetone + hexane mixture, and
Table 4. Experimental and Predicted Mole Fraction Solubility of S1 (1) in Ethyl Acetate (2) + Hexane (3) at Different
a,b,c,d,e
Temperatures and p = 101.3 kPa
Apelblat
λh
NRTL
103 x1
103 x1
102RD
103 x1
102RD
103 x1
102RD
exp
cal
cal
cal
w2
T/K
0.8
273.43
280.55
284.51
289.90
295.86
302.06
307.80
311.78
316.97
321.82
275.08
282.86
291.34
298.87
303.81
306.38
315.00
320.32
324.32
327.67
278.92
282.01
288.62
291.49
300.20
305.25
312.30
318.43
325.13
327.67
275.79
280.71
286.57
292.96
302.07
309.19
314.89
318.71
321.54
327.67
26.87
32.71
35.29
41.08
49.12
61.09
69.24
80.02
94.77
116.20
16.77
20.45
26.21
33.47
39.98
44.92
54.79
65.42
85.45
100.71
10.47
12.74
13.68
16.66
17.90
23.30
30.01
40.80
50.84
59.71
2.77
27.60
32.32
35.62
41.04
48.61
58.67
70.57
80.62
96.50
−2.72
1.18
23.23
30.01
34.49
41.41
50.39
61.29
73.52
82.83
96.62
13.53
8.25
27.37
33.20
35.41
40.95
48.77
60.74
68.68
79.71
94.90
−1.85
−1.52
−0.33
0.30
−0.92
0.08
2.28
−0.81
−2.58
−0.33
−6.18
−3.52
−1.94
4.85
1.04
0.71
3.96
0.57
−1.92
−0.76
−1.83
1.19
0.80
0.39
−0.13
−0.17
1.62
114.82
18.36
21.09
25.82
32.15
37.80
41.34
57.25
71.21
84.61
98.23
11.30
11.99
13.95
15.05
19.58
23.30
30.39
39.09
52.49
58.97
3.17
110.57
12.39
17.39
24.71
33.29
40.19
44.20
60.92
73.67
83.83
93.52
8.55
116.40
16.50
20.29
26.26
33.74
40.44
45.63
54.99
65.67
85.92
100.58
10.28
12.62
13.32
16.53
17.55
23.17
29.96
41.04
50.40
59.15
3.32
0.6
0.4
0.2
−9.49
−3.13
1.50
26.15
14.99
5.72
0.78
−0.20
−0.78
−1.14
−1.58
−0.37
−0.37
−0.55
0.13
3.96
0.54
5.47
−0.52
1.59
7.96
−4.50
−8.84
0.98
−11.20
−12.60
1.89
2.45
7.13
−7.93
5.90
18.33
23.36
5.44
1.80
9.77
0.99
−2.03
9.66
12.93
14.53
20.66
25.07
32.70
40.84
52.06
56.75
2.43
2.61
12.79
−15.40
−7.58
−8.95
−0.10
−2.39
4.96
0.80
−9.39
0.03
1.94
0.57
−1.26
4.19
0.18
−0.59
0.87
−3.23
1.24
0.95
−14.32
−2.41
3.38
12.29
13.39
10.58
8.83
−19.78
−7.92
−1.13
2.59
3.51
3.60
3.04
3.79
4.40
4.26
3.94
4.45
5.68
5.22
8.07
5.17
5.53
7.85
7.20
8.20
7.52
4.10
7.62
2.84
9.07
9.48
−4.60
−9.84
3.34
9.99
−10.22
−14.41
1.10
9.12
−0.56
−1.96
−0.30
−0.66
−0.65
10.91
14.59
16.23
20.98
11.98
14.10
15.95
21.01
12.48
14.42
16.07
20.25
11.12
14.63
16.34
21.11
1.75
1.03
−0.15
3.44
a
b
Standard uncertainties u are u(T) = 2 K, ur(p) = 0.05, ur(x1) = 7 × 10−7, ur(w2) = 1 × 10−6. w2 is the mass fraction of ethyl acetate (2) in binary
c
d
ethyl acetate (2) + hexane (3) mixture. x1exp is the mole fraction solubility of S1 (1) in ethyl acetate (2) + hexane (3) mixture. x1cal represents the
e
calculated solubility data using Apelblat, λh, and phase equilibria with NRTL model equations. RD refers to the corresponding relative deviation.
E
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butanone in butanone + hexane mixture, and subscript 3 repre-
sents hexane.
experimental data. This function is based on the Levenberg−
Marquardt algorithm, and uses the least-squares method to solve
nonlinear curve-fitting problems.
To evaluate the goodness of fit between the experimental and
predicted solubility from the models, their relative deviation
(RDi %) and average relative deviation (ARD %) were deter-
mined as
In these equations, τ reflects the segment−segment interaction
energies and α represents a predetermined nonrandomness fac-
tor. As recommendedbyRenon and Prausnitz,28 the selected value
for αij is 0.3 during the optimization. The segment−segment
interaction parameters are unique for each particular pair of
species and are independent of composition and temperature.
A detailed description of these parameters is provided by Tung
et al.29
Modeling. Matlab (Mathwork, MA) was used to model the
apelblat, λh and phase equilibria with NRTL equations and to
provide a general quantification of the solute’s solubility pro-
file. The function lsqcurvefit in Matlab’s optimization toolbox
was used to estimate the required model parameters for the
exp
cal
1,i
x
− x
1,i
RD =
i
exp
x
(9)
1,i
exp
cal
1,i
N
x
− x
100
N
1,i
ARD% =
∑
exp
x
1,i
i=1
(10)
Table 5. Experimental and Predicted Mole Fraction Solubility of S1 (1) in Toluene (2) + Hexane (3) at Different Temperatures
a,b,c,d,e
and p = 101.3 kPa
Apelblat
λh
NRTL
103 x1
103 x1
102RD
103 x1
102RD
103 x1
102RD
exp
cal
cal
cal
w2
T/K
1
273.24
278.33
285.50
290.93
297.29
301.24
307.73
312.06
315.66
321.66
278.26
286.03
292.31
297.02
302.36
308.95
313.74
316.55
321.18
326.46
278.51
281.86
285.78
289.67
296.39
308.14
311.71
315.29
320.67
324.07
285.35
293.53
297.25
304.24
307.91
313.39
318.25
321.77
326.94
331.62
5.17
7.19
9.29
5.54
6.89
9.51
−7.18
4.08
4.12
5.65
8.68
20.36
21.37
6.63
4.87
6.27
8.71
5.85
12.80
6.32
−2.28
2.12
12.51
16.75
20.00
27.85
35.58
41.30
57.94
4.07
12.24
16.61
20.18
27.96
34.92
42.10
57.75
3.92
11.83
16.79
20.72
28.91
35.81
42.66
56.41
2.94
5.39
11.37
15.48
18.82
26.63
34.41
41.81
61.88
4.27
9.08
0.83
−0.19
−3.60
−3.81
−0.65
−3.30
2.63
7.58
−0.92
−0.41
1.84
5.89
4.39
3.28
−1.92
0.32
−1.22
−6.81
−4.89
−11.07
−15.56
1.90
0.8
0.6
0.4
3.64
27.77
10.58
−4.43
7.25
5.39
5.60
−3.98
−12.02
4.63
4.82
5.98
6.75
7.56
7.04
7.80
9.98
9.52
9.26
9.79
12.97
17.98
21.75
26.24
33.05
44.68
2.50
12.45
17.47
22.45
26.06
33.40
44.47
2.94
4.03
12.52
17.93
23.10
26.67
33.70
43.60
2.46
3.47
12.45
16.89
20.96
24.50
31.17
42.54
2.90
4.05
2.85
0.28
6.06
−3.21
0.68
−6.20
−1.66
−1.95
2.41
3.65
6.62
−1.04
0.47
5.69
4.78
−17.67
−10.30
−1.65
9.22
1.40
−16.12
−13.72
−9.30
−1.12
−0.87
−12.07
−12.49
−10.99
−13.37
−2.22
−60.64
−20.47
−4.43
6.47
2.95
3.25
2.88
2.15
3.35
3.63
3.69
3.46
4.71
3.96
4.63
4.21
4.12
11.17
9.72
4.69
6.12
5.38
12.22
0.71
5.53
6.18
8.69
8.63
9.06
−4.33
−5.37
−4.01
−6.96
7.28
9.74
9.95
10.06
11.78
15.06
17.67
2.16
−1.11
−1.26
−7.43
4.24
10.48
12.10
14.99
17.10
2.16
11.19
12.92
15.89
18.86
2.51
11.64
14.02
18.45
1.56
−38.19
−8.85
4.13
−38.37
−8.10
5.11
2.92
3.18
3.16
3.52
3.92
3.76
3.72
4.10
5.79
5.12
11.54
10.23
2.22
5.05
12.79
11.55
3.50
5.41
6.67
5.99
5.90
6.22
6.68
7.69
7.52
7.42
7.59
1.29
8.40
9.15
−8.98
−6.76
2.19
9.07
−8.03
−6.26
1.83
8.98
−6.90
−4.06
3.94
9.85
10.52
12.84
15.31
10.47
12.89
15.56
10.25
12.61
15.01
13.13
15.50
1.23
−0.36
3.21
a
b
Standard uncertainties u are u(T) = 2 K, ur(p) = 0.05, ur(x1) = 7 × 10−7, ur(w2) = 1 × 10−6. w2 is the mass fraction of toluene (2) in binary
c
d
toluene (2) + hexane (3) mixture. x1exp is the mole fraction solubility of S1 (1) in toluene (2) + hexane (3) mixture. x1cal represents the calculated
e
solubility data using Apelblat, λh, and phase equilibria with NRTL model equations. RD refers to the corresponding relative deviation.
F
DOI: 10.1021/acs.jced.7b00288
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Journal of Chemical & Engineering Data
Article
where N is the total amount of experimental values, xexp and
and literature data.30−34 Moreover, Figure 3 graphically shows
the comparison between the experimental and literature data.
From Table 2 and Figure 3 it can be seen that the measured
experimental data is closely aligned with the published data, thus
ensuring the assumption that the developed experimental
method is sufficiently accurate.
DSC Results. The thermal analysis of S1 is shown in Figure 4.
The area under the curve represents the enthalpy of fusion, in
J·g−1. To convert the value in J·mol−1, it was multiplied to the
molecular mass of S1 (197.5 g·mol−1). ΔfusH and Tm are
determined as 26.77 0.542 kJ·mol−1 and 394.83 0.192 K,
respectively. These values are used to calculate the predicted
mole fraction (x1cal) using the phase equilibria with NRTL model
equations. The summary of results is listed in Table 3.
1,i
xcal are the ith experimental and predicted solubility mole
1,i
fractions.
RESULTS AND DISCUSSION
■
Validation of Experimental Technique. To confirm the
accuracy of the polythermal method using in situ FBRM, the
solubility of 4-acetamenophenol (paracetamol) in pure water
were measured. Since the solubility data for S1 is not widely
available in the literature, it was decided to use 4-acetamino-
phenol as its chemical structure is similar to S1 and its solubility
data has been widely published in the literature. The experi-
mental solubility data of 4-acetaminophenol in pure water is listed
in Table 2, along with the relative deviation between experimental
Table 6. Experimental and Predicted Mole Fraction Solubility of S1 (1) in Acetone (2) + Hexane (3) at Different Temperatures
a,b,c,d,e
and p = 101.3 kPa
Apelblat
λh
NRTL
103 x1
103 x1
102RD
103 x1
102RD
103 x1
102RD
exp
cal
cal
cal
w2
T/K
1
271.96
283.37
287.02
290.81
294.37
300.04
302.89
307.95
310.94
315.55
269.81
279.02
285.52
287.18
292.69
300.27
306.06
308.65
313.31
318.18
276.51
284.73
286.58
290.72
294.67
298.49
302.48
307.52
313.50
318.38
276.47
279.77
282.54
292.79
299.00
300.62
306.58
312.23
315.07
318.80
61.58
76.73
81.13
86.08
91.66
105.33
113.81
135.68
150.09
155.07
50.17
61.04
68.45
77.93
81.92
101.98
122.72
135.06
142.53
172.03
42.51
55.89
57.83
64.59
73.15
84.31
99.49
121.35
155.14
191.87
19.51
20.43
26.92
37.29
45.85
54.31
63.29
75.82
87.35
103.02
61.07
74.90
80.63
87.39
94.59
0.82
54.94
73.83
81.00
89.07
97.24
10.78
3.78
64.57
76.13
80.32
85.44
91.47
−4.87
0.78
2.39
0.62
0.16
1.00
−1.53
−3.20
−2.56
−1.73
3.01
−3.48
−6.08
−5.51
−4.19
2.68
0.74
0.21
108.03
115.79
131.59
142.24
160.98
49.90
60.95
70.99
73.90
84.82
103.37
120.99
129.99
148.29
170.63
43.37
54.06
57.14
65.10
74.38
85.23
98.96
120.79
155.06
192.03
19.86
22.55
25.08
37.24
47.33
50.37
63.38
78.79
87.88
101.39
111.14
118.58
132.05
140.42
157.66
44.48
58.89
71.34
74.25
87.21
106.66
123.40
131.17
148.93
165.75
33.55
49.31
53.70
64.57
76.55
89.62
104.89
127.04
157.05
183.83
18.54
21.56
24.27
37.53
48.23
51.08
64.42
79.57
87.85
99.86
105.65
114.40
135.11
148.44
160.29
51.76
60.16
67.02
75.36
80.43
101.00
121.99
133.74
145.60
173.11
41.10
54.10
56.15
63.31
72.53
84.53
100.55
122.96
154.50
183.77
19.27
20.03
26.07
36.12
44.81
54.43
63.78
77.38
90.64
108.47
−0.30
−0.52
0.42
5.23
6.44
1.10
−3.81
0.53
−1.67
11.34
3.52
−3.37
−3.17
1.45
0.8
0.6
0.4
0.16
−3.71
5.16
−4.23
4.72
2.09
3.29
−3.54
−1.37
1.41
−6.46
−4.59
−0.55
2.88
1.81
0.96
0.59
3.75
0.98
−4.04
0.82
−4.49
3.65
−2.15
−0.63
3.32
−2.02
3.26
21.07
11.77
7.14
3.19
1.19
2.91
−0.78
−1.69
−1.09
0.53
0.03
1.98
−4.65
−6.30
−5.42
−4.69
−1.23
4.19
0.85
−0.27
−1.06
−1.33
0.41
0.46
0.06
−0.08
−1.80
−10.35
6.82
4.22
4.98
1.21
−5.50
9.85
1.95
3.18
0.12
−0.65
−5.18
5.94
3.12
−3.22
7.25
2.27
−0.23
−0.78
−2.05
−3.76
−5.29
−0.15
−3.92
−0.61
1.58
−1.79
−4.95
−0.58
3.07
a
b
Standard uncertainties u are u(T) = 2 K, ur(p) = 0.05, ur(x1) = 7 × 10−7, ur(w2) = 1 × 10−6. w2 is the mass fraction of acetone (2) in binary
c
d
acetone (2) + hexane (3) mixture. x1exp is the mole fraction solubility of S1 (1) in acetone (2) + hexane (3) mixture. x1cal represents the calculated
e
solubility data using Apelblat, λh, and phase equilibria with NRTL model equations. RD refers to the corresponding relative deviation.
G
DOI: 10.1021/acs.jced.7b00288
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Solubility Data. The polythermal method with in situ FBRM
was used to determine the saturation temperatures (T) at a
specific mole fractions (x1exp). Figure 5 illustrates the FBRM
trend obtained from the experimental run at a mole fraction
Table 7. Experimental and Predicted Mole Fraction Solubility of S1 (1) in Butanone (2) + Hexane (3) at Different Temperatures
a,b,c,d,e
and p = 101.3 kPa
Apelblat
λh
NRTL
103 x1
103 x1
102RD
103 x1
102RD
103 x1
102RD
exp
cal
cal
cal
w2
T/K
1
271.23
275.52
280.90
285.45
291.46
296.73
302.41
307.63
313.15
319.11
267.10
275.61
282.71
288.74
294.84
296.95
303.07
309.04
316.09
321.41
274.60
281.33
286.43
291.08
294.49
300.32
306.78
311.37
315.91
322.92
274.95
284.12
294.62
302.86
305.01
306.80
309.25
312.40
315.87
320.50
77.41
82.87
89.16
105.12
115.45
128.04
130.38
148.88
173.49
207.85
46.39
57.33
69.11
78.46
88.51
95.89
110.11
129.29
162.63
195.35
35.05
44.19
51.76
56.89
70.79
82.25
98.15
112.66
132.22
159.98
18.55
22.44
31.82
50.01
55.26
61.74
69.94
80.66
95.26
116.30
79.91
84.58
91.65
98.80
−3.22
−2.06
−2.79
6.02
73.24
80.70
91.05
99.54
5.39
80.88
84.95
91.56
96.76
−4.48
−2.51
−2.69
7.95
2.62
−2.11
5.31
110.13
122.12
137.58
154.50
175.80
203.41
49.01
57.18
66.42
76.42
89.08
94.16
111.31
132.21
163.63
193.51
34.80
43.81
51.94
60.49
67.52
81.22
99.21
114.02
130.60
160.32
16.14
22.83
35.28
50.85
56.11
60.97
68.40
79.43
93.93
117.94
4.61
113.21
126.17
143.66
158.91
175.91
194.63
39.28
51.90
64.73
77.72
93.10
98.59
117.11
137.45
163.72
185.02
33.96
43.31
51.76
60.78
67.51
81.57
99.85
114.62
130.50
159.64
11.39
19.44
34.37
51.87
57.55
62.55
70.08
80.89
94.24
114.92
1.94
107.67
119.19
137.18
154.05
175.29
202.41
45.31
58.42
70.19
80.97
93.39
97.71
113.97
134.16
164.53
192.58
36.18
43.03
50.00
57.91
64.01
77.46
96.02
111.76
129.22
163.02
19.10
22.00
33.46
50.95
56.93
62.27
70.25
81.57
95.03
114.95
6.74
4.62
1.46
6.91
−5.52
−3.77
−1.33
2.14
−10.18
−6.74
−1.40
6.36
−5.214
−3.48
−1.04
2.62
0.8
0.6
0.4
−5.65
0.25
15.34
9.47
2.33
−1.91
−1.56
−3.20
−5.51
−1.90
−3.50
−3.77
−1.17
1.41
3.90
6.33
2.60
0.94
−0.64
1.80
−5.18
−2.82
−6.36
−6.31
−0.67
5.29
−1.08
−2.26
−0.62
0.94
0.71
3.11
−3.23
2.62
0.86
1.98
−0.36
−6.33
4.62
−0.01
−6.84
4.64
3.40
−1.80
9.58
1.26
0.83
5.83
−1.08
−1.21
1.23
−1.74
−1.74
1.30
2.17
0.80
2.27
−0.21
13.01
−1.75
−10.87
−1.67
−1.54
1.26
0.22
−1.90
−2.96
1.98
38.62
13.37
−8.01
−3.73
−4.14
−1.31
−0.20
−0.28
1.07
−5.13
−1.87
−3.02
−0.85
−0.44
−1.12
0.24
2.21
1.52
1.40
−1.41
1.19
1.16
a
b
Standard uncertainties u are u(T) = 2 K, ur(p) = 0.05, ur(x1) = 7 × 10−7, ur(w2) = 1 × 10−6. w2 is the mass fraction of butanone (2) in binary
butanone (2) + hexane (3) mixture. x1 is the mole fraction solubility of S1 (1) in butanone (2) + hexane (3) mixture. x1 represents the
calculated solubility data using Apelblat, λh, and phase equilibria with NRTL model equations. RD refers to the corresponding relative deviation.
c
d
cal
exp
e
Table 9. Optimized Values for the Parameters of Apelblat and
λh for Solubility of S1 (1) in Toluene (2) + Hexane (3)
Table 8. Optimized Values for the Parameters of Apelblat and
λh for Solubility of S1 (1) in Ethyl Acetate (2) + Hexane (3)
a
a
model
parameter
w2 = 1
w2 = 0.8
w2 = 0.6
w2 = 0.4
model
parameter
w2 = 0.8
w2 = 0.6
w2 = 0.4
w2 = 0.2
Apelbat
A
B
C
λ
−315.699
10170.1
48.7106
0.85744
5524.05
−318.364
10196.7
49.0674
0.61397
8200.47
−391.296
14266.7
59.3736
0.11221
32341.1
−14.4476
−2983.89
3.31950
0.08089
46382.3
Apelblat
A
B
C
λ
−302.363 −470.904 −487.622 −389.956
11051.2
46.0442
0.45224
5885.05
18466.2
71.1718
0.48080
6919.00
19133.6
73.6184
0.28081
11881.5
14434.7
59.0538
0.10321
33408.6
λh
λh
h
h
a
a
w2 is the mass fraction of ethyl acetate (2) in binary ethyl acetate (2)
+ hexane (3) mixture
w2 is the mass fraction of toluene (2) in binary toluene (2) +
hexane (3) mixture
H
DOI: 10.1021/acs.jced.7b00288
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(x1exp) of 0.00998 for binary toluene + hexane mixtures at a
composition of w2 = 0.8. The trend shows the steps involved to
determine the saturation temperature where initially the solution
is aged at 60 °C to ensure full dissolution, then cooled at a
constant rate of 0.5 K·min−1 until the crystals start to crash out at
the nucleation temperature, and finally heated at a constant rate
of 0.1 K·min−1 to determine the saturation temperature (the
temperature at which crystals are dissolved into the solution).
Figure 6 illustrates the same trend while representing the rela-
tionship between the number of particle counts and the chord
length distribution of the crystals throughout theexperimental run.
The measured saturation temperatures at various mole frac-
tions of S1 in various solvent mixtures and the relative devia-
tion between experimental and predicted solubility are listed in
Tables 4, 5, 6, and 7, where x1 is the mole fraction solubility of S1
in the solvent mixtures and w2 is the mass fraction ethyl acetate in
the binary ethyl acetate + hexane mixtures, toluene in binary
toluene + hexane mixtures, acetone in binary acetone + hexane
mixtures, and butanone in binary butanone + hexane mixtures.
The experimental solubility data were correlated using Apelblat,
λh, and phase equilibria with NRTL (nonrandom two liquid)
model equations and the optimized parameter values for all the
equations were obtained using Matlab’s lsqcurvefit function.
It should be noted that the Apelblat and λh model equation does
not take the solvent composition into consideration, and thus
Table 13. Optimized Values for Parameters of Phase
Equilibria with NRTL Model Equations for Solubility of S1
a
(1) in Toluene (2) + Hexane (3)
model
NRTL
parameter
values
a12
a13
a21
a23
a31
a32
b12
b13
b21
b23
b31
b32
−1.42222
1.09929
3.96221
0.41662
2.96684
0.01718
0.12828
−19.8879
2.77062
19.6612
10.7332
−3.23033
a
w2 is the mass fraction of toluene (2) in binary toluene (2) + hexane
Table 10. Optimized Values for the Parameters of Apelblat
a
(3) mixture
and λh for Solubility of S1 (1) in Acetone (2) + Hexane (3)
model
parameter
w2 = 1
w2 = 0.8
w2 = 0.6
w2 = 0.4
Table 14. Optimized Values for the Parameters of Phase
Equilibria with NRTL Model Equations for Solubility of S1
(1) in Acetone (2) + Hexane (3)
Apelblat
A
B
C
λ
−230.722
8382.98
35.1612
0.39822
4508.12
−195.042
6583.05
29.9488
0.55460
3922.13
−420.481
15854.8
64.0321
1.98605
1883.76
−143.827
3347.95
22.7314
0.79282
4373.39
a
model
NRTL
parameter
values
λh
a12
a13
a21
a23
a31
a32
b12
b13
b21
b23
b31
b32
2.62402
13.5277
−3.58803
20.8426
3.39349
−12.4812
−1387.01
−4765.35
2614.35
−6770.75
1267.73
4057.14
h
a
w2 is the mass fraction of acetone (2) in binary acetone (2) +
hexane (3) mixture
Table 11. Optimized Values for the Parameters of Apelblat
and λh for Solubility of S1 (1) in Butanone (2) + Hexane (3)
a
model
parameter
w2 = 1
w2 = 0.8
w2 = 0.6
w2 = 0.4
Apelblat
A
B
C
λ
−224.424
8337.06
34.1174
0.33571
4268.89
−257.651
9333.04
39.3178
0.66155
3540.49
−48.5390
−343.620
8.26880
0.70405
3899.82
−340.136
11655.3
52.2771
1.75288
2595.60
λh
h
a
w2 is the mass fraction of acetone (2) in binary acetone (2) + hexane
a
w2 is the mass fraction of butanone (2) in binary butanone (2) +
hexane (3) mixture
(3) mixture
Table 15. Optimized Values for the Parameters of Phase
Equilibria with NRTL Model Equations for Solubility of S1
(1) in Butanone (2) + Hexane (3)
Table 12. Optimized Values for Parameters of Phase
Equilibria with NRTL Model Equations for Solubility of S1
a
a
(1) in Ethyl Acetate (2) + Hexane (3)
model
NRTL
parameter
values
model
NRTL
parameter
values
a12
a13
a21
a23
a31
a32
b12
b13
b21
b23
b31
b32
−8.31736
12.3799
a12
a13
a21
a23
a31
a32
b12
b13
b21
b23
b31
b32
3.4999
2.79327
15.2292
−6.18745
−20.9361
−6.21239
26.8731
58.7989
−34.5934
44.3644
2257.48
−1631.48
−1550.07
3507.13
−2863.69
−4495.72
−17738.7
11795.9
5540.44
4502.81
−12449.5
−7325.74
a
a
w2 is the mass fraction of ethyl acetate (2) in binary ethyl acetate (2)
+ hexane (3) mixture
w2 is the mass fraction of butanone (2) in binary butanone (2) +
hexane (3) mixture
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require separate parameters for each different solvent composi-
tions, which are shown in Tables 8, 9, 10, and 11. The use of
Apelblat and λh model equation provide a convenient opera-
tional model of engineering interest to calculate the solubility of
S1 quickly and easily. The Phase Equilibria with NRTL model
equation is used to provide a more comprehensive model that
illustrates the effect of solvent composition on the solubility
more apparently. One general set of NRTL parameters has
the capability of describing all solvent compositions, which are
listed in Tables 12, 13, 14, and 15. Moreover, the average rela-
tive deviations for various mixture compositions are shown in
Tables 16, 17, 18, and 19. Figures 7, 8, 9, 10, 11, 12, 13, and 14
present the model equations that give the best ARD% in each
solvent mixture (graphs for the remaining models can be found in
the Supporting Information). The general trend in Figures 7 to 10
is that the solubility of S1 increases significantly with an increase
in temperature.
Table 16. ARD% of Various Models in Ethyl Acetate (2) +
a
Hexane (3)
To further illustrate the effect of solvent composition on the
solubility of S1, the experimental solubility data of ethyl acetate +
hexane between 280 and 320 K, toluene + hexane between 300
model
w2 = 0.8
w2 = 0.6
w2 = 0.4
w2 = 0.2
Apelblat
λh
0.06965
1.35524
0.12226
0.36539
3.36917
0.24689
0.28333
3.04558
1.01189
0.65907
3.01381
2.75246
NRTL
a
w2 is the mass fraction of ethyl acetate (2) in binary ethyl acetate (2)
+ hexane (3) mixture
Table 17. ARD% of Various Models in Toluene (2) +
a
Hexane (3)
model
w2 = 1
w2 = 0.8
w2 = 0.6
w2 = 0.4
Apelbat
λh
0.35242
4.48437
4.71545
0.39533
3.75347
0.12447
1.30175
1.57710
9.22668
3.12349
2.63524
7.49120
NRTL
a
w2 is the mass fraction of toluene (2) in binary toluene (2) +
hexane (3) mixture
Figure 8. Solubility data of S1 (1) in toluene (2) + hexane (3) mixtures:
◇
□
*, w2 = 1; + , w2 = 0.8; , w2 = 0.6; , w2 = 0.4; −, apelblat equation
calculated. w2 is the mass fraction of toluene (2) in binary toluene (2) +
hexane (3) mixtures.
Table 18. ARD% of Various Models in Acetone (2) +
a
Hexane (3)
model
w2 = 1
w2 = 0.8
w2 = 0.6
w2 = 0.4
Apelblat
λh
0.07655
0.29049
0.48095
0.08331
0.57776
0.52205
0.01619
2.19151
1.42412
0.42694
0.52111
0.03861
NRTL
a
w2 is the mass fraction of acetone (2) in binary acetone (2) +
hexane (3) mixture
Table 19. ARD% of Various Models in Butanone (2) +
a
Hexane (3)
model
w2 = 1
w2 = 0.8
w2 = 0.6
w2 = 0.4
Apelblat
λh
0.13099
0.26558
0.48160
0.07493
1.60388
1.87610
0.05066
0.17478
1.97470
0.21541
3.65769
1.20150
Figure 9. Solubility data of S1 (1) in acetone (2) + hexane mixtures (3):
NRTL
◇
□
*, w2 = 1; + , w2 = 0.8; , w2 = 0.6; , w2 = 0.4; −, apelblat equation
calculated. w2 is the mass fraction of acetone (2) in binary acetone (2) +
hexane (3) mixtures.
a
w2 is the mass fraction of butanone (2) in binary butanone (2) +
hexane (3) mixture
Figure 7. Solubility data of S1 (1) in ethyl acetate (2) + hexane (3)
Figure 10. Solubility data of S1 (1) in butanone (2) + hexane (3)
◇
□
◇
□
mixtures: *, w2 = 0.8; + , w2 = 0.6; , w2 = 0.4; , w2 = 0.2; −, apelblat
equation calculated. w2 is the mass fraction of ethyl acetate (2) in binary
ethyl acetate (2) + hexane (2) mixtures.
mixtures: *, w2 = 1; + , w2 = 0.8; , w2 = 0.6; , w2 = 0.4; −, apelblat
equation calculated. w2 is the mass fraction of butanone (2) in binary
butanone (2) + hexane (3) mixtures.
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and 320 K, acetone + hexane between 285 and 305 K, and
butanone + hexane between 275 and 315 K were correlated using
the regressed model parameters for apelblat, λh, and phase
equilibria with NRTL model equations listed in Tables 8 to 15.
It can be clearly seen from Figures 11 to 14 that the change of
solvent composition has a great effect on the solubility of S1, as
the presence of hexane in the solvent mixtures decreases the
solubility of S1.
CONCLUSION
■
The polythermal method using in situ focused beam reflectance
measurement (FBRM) was used to characterize the solubility
Figure 14. Solubility data of S1 (1) in butanone (2) + hexane
◇
○
(3) mixtures: , T = 275 K; *, T = 285 K; + , T = 295 K;
T = 305 K; , T = 315 K; −, apelblat equation calculated. w2 is the mass
,
□
fraction of butanone (2) in binary butanone (2) + hexane (3) mixtures.
properties of 2-chloro-N-(4-methylphenyl)propanamide (S1) in
ethyl acetate + hexane, toluene + hexane, acetone + hexane and
butanone + hexane mixtures in various temperatures. To provide
a general quantification of the solubility profiles, the experi-
mental data was correlated using the Apelblat, λh, and phase
equilibria with NRTL model equations. The Apelblat and
λh model equation provides a convenient operational model of
engineering interest to calculate the solubility of S1 quickly and
easily, although it does not take the solvent composition into
account, therefore needing separate parameters for each different
solvent compositions. Therefore, the phase equilibria with NRTL
model equation is used to provide a more comprehensive model
that illustrates the effect of solvent composition on the solubility
more apparently. One general set of NRTL parameters has the
capability of describing all solvent compositions. The predicted
solubility data obtained using the Apelblat, λh, and phase equi-
libria with NRTL model equations agrees well with the experi-
mental solubility data, as shown by the RD% and ARD% values.
Figure 11. Solubility data of S1 (1) in ethyl acetate (2) + hexane
(3) mixtures: , T = 280 K; *, T = 290 K; + , T = 300 K; , T = 310 K;
◇
○
□
, T = 320 K; −, apelblat equation calculated. w2 is the mass fraction of
ethyl acetate (2) in binary ethyl acetate (2) + hexane (3) mixtures.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jced.7b00288.
■
S
Graphs showing the solubility data of S1 in ethyl acetate +
hexane, toluene + hexane, acetone + hexane, and butanone +
hexane solvent mixtures, correlated using the Apelblat, λh,
and phase equilibria with NRTL model equations (PDF)
Figure 12. Solubility data of S1 (1) in toluene (2) + hexane
◇
○
(3) mixtures: , T = 300 K; *, T = 305 K; + , T = 310 K;
T = 315 K; , T = 320 K; −, λh equation calculated. w2 is the mass
,
□
AUTHOR INFORMATION
Corresponding Author
*Tel.: +353 1 7162815; Fax: +353 1 7161177; E-mail:
roderick.jones@ucd.ie.
■
fraction of toluene (2) in binary toluene (2) + hexane (3) mixtures.
ORCID
Philip Donnellan: 0000-0001-8576-7857
Roderick C. Jones: 0000-0002-2884-4884
Funding
The financial support of the Synthesis and Solid State
Pharmaceutical center (SSPC) and Science Foundation Ireland
(SFI, 12/RC/2275) are gratefully acknowledged.
Notes
The authors declare no competing financial interest.
Figure 13. Solubility data of S1 (1) in acetone (2) + hexane
NOMENCLATURE
A, B, C empirical model parameters for Apelblat equation
API advanced pharmaceutical intermediates
◇
■
○
(3) mixtures: , T = 285 K; *, T = 290 K; + , T = 295 K;
T = 300 K; , T = 305 K; −, apelblat equation calculated. w2 is the mass
,
□
fraction of acetone (2) in binary acetone (2) + hexane (3) mixtures.
K
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(7) Kissane, M.; Murphy, M.; Lawrence, S. E.; Maguire, A. R. Synthesis
and stereoselective oxidation of α-thio-β-chloropropenyloxazolidin-2-
ones. Tetrahedron: Asymmetry 2010, 21, 2550−2558.
(8) Kissane, M.; Murphy, M.; O’Brien, E.; Chopra, J.; Murphy, L.;
Collins, S. G.; Lawrence, S. E.; Maguire, A. R. Addition-substitution
reactions of 2-thio-3-chloroacrylamides with carbon, nitrogen, oxygen,
sulfur and selenium nucleophiles. Org. Biomol. Chem. 2011, 9, 2452−
2472.
(9) Hou, G.; Power, G.; Barrett, M.; Glennon, B.; Morris, G.; Zhao, Y.
Development and Characterization of a Single Stage Mixed-Suspension,
Mixed-Product-Removal Crystallization Process with a Novel Transfer
Unit. Cryst. Growth Des. 2014, 14, 1782−1793.
(10) Power, G.; Hou, G.; Kamaraju, V. K.; Morris, G.; Zhao, Y.;
Glennon, B. Design and optimization of a multistage continuous cooling
mixed suspension, mixed product removal crystallizer. Chem. Eng. Sci.
2015, 133, 125−139.
ARD average relative deviation
CLD chord length distribution
CSD crystal size distribution
DSC differential scanning calorimetry
FBRM focused beam reflectance measurement
h model parameter for λh equation representing excess
mixture enthalpy of solution
m mass (g)
M molecular mass (g mol−1)
NRTL nonrandom two liquid model
R universal gas constant (J mol−1K−1)
RD relative deviation
S1 2-chloro-N-(4-methylphenyl)propanamide
STD standard deviation
T absolute temperature (K)
(11) Morris, G.; Power, G.; Ferguson, S.; Barrett, M.; Hou, G.;
Glennon, B. Estimation of Nucleation and Growth Kinetics of Benzoic
Acid by Population Balance Modeling of a Continuous Cooling Mixed
Suspension, Mixed Product Removal Crystallizer. Org. Process Res. Dev.
2015, 19, 1891−1902.
Tm melting temperature of S1 (K)
w solvent mixture compositions
x1 mole fraction solubility of S1 (mol)
x1cal predicted mole fraction solubility of S1 (mol)
x
para mole fraction solubility of 4-acetaminophenol (paracetamol)
(12) Li, X.; Wang, D.; Wu, J.; Xu, W. Novel Approach to 3-Methyl-1H-
quinoxalin-2-ones. Synth. Commun. 2005, 35, 2553−2560.
(13) Barrett, P.; Smith, B.; Worlitschek, J.; Bracken, V.; O’Sullivan, B.;
O’Grady, D. A Review of the Use of Process Analytical Technology for
the Understanding and Optimization of Production Batch Crystal-
lization Processes. Org. Process Res. Dev. 2005, 9, 348−355.
(mol)
Greek Symbols
ΔCp change of heat capacity at constant pressure
ΔfusH molar fusion enthalpy
ΔHd dissolution enthalpy
ΔSd dissolution entropy
́
̈
́
(14) Nyvlt, J.; Sohnel, O.; Matuchova, M.; Broul, M. The Kinetics of
industrial crystallization; Elsevier: New York, 1985.
ΔHfus molar enthalpy of fusion
ΔSfus molar entropy of fusion
λ model parameter for λh equation representing nonideal
properties of the system
γ1 activity coefficient of S1
τ segment−segment interaction energies
α nonrandomness factor
(15) Sangwal, K. Novel Approach to Analyze Metastable Zone Width
Determined by the Polythermal Method: Physical Interpretation of
Various Parameters. Cryst. Growth Des. 2009, 9, 942−950.
(16) Sayan, P.; Ulrich, J. Effect of Various Impurities on the Metastable
Zone Width of Boric Acid. Cryst. Res. Technol. 2001, 36, 411−417.
(17) Sahin, O.; Dolas, H.; Demir, H. Determination of nucleation
kinetics of potassium tetraborate tetrahydrate. Cryst. Res. Technol. 2007,
42, 766−772.
Subscripts
1 S1
(18) Wang, L.; Peng, J.; Li, L.; Feng, H.; Dong, Y.; Li, W.; Liang, J.;
Zheng, Z. Solubility and Metastable Zone Width of Sodium Chromate
Tetrahydrate. J. Chem. Eng. Data 2013, 58, 3165−3169.
(19) Barrett, P.; Glennon, B. Characterizing the Metastable Zone
Width and Solubility Curve Using Lasentec FBRM and PVM. Chem.
Eng. Res. Des. 2002, 80, 799−805.
2 ethyl acetate, toluene, acetone, or butanone
3 hexane
REFERENCES
(20) Correia, P.; Lopes, C.; Piedade, M. E. M.; Lourenco̧ , J. A. A.;
■
Serrano, M. L. Solubility and Metastable Zone Width of 1-Keto-1,2,3,4-
tetrahydro-6-methylcarbazole in Acetone. J. Chem. Eng. Data 2006, 51,
1306−1309.
(1) Murphy, M.; Lynch, D.; Schaeffer, M.; Kissane, M.; Chopra, J.;
O’Brien, E.; Ford, A.; Ferguson, G.; Maguire, A. R. Investigation of the
synthetic and mechanistic aspects of the highly stereoselective
transformation of [small alpha]-thioamides to [small alpha]-thio-
[small beta]-chloroacrylamides. Org. Biomol. Chem. 2007, 5, 1228−
1241.
(21) Zhang, J.; Dang, L.; Wei, H. Solubility of 5-(Dithiolan-3-
yl)pentanoic Acid in the Mixed Solvents of Cyclohexane + Ethyl
Acetate, Heptane + Ethyl Acetate, and Hexane + Ethyl Acetate. J. Chem.
Eng. Data 2010, 55, 4025−4028.
(2) Foley, D. A.; Doecke, C. W.; Buser, J. Y.; Merritt, J. M.; Murphy, L.;
Kissane, M.; Collins, S. G.; Maguire, A. R.; Kaerner, A. ReactNMR and
ReactIR as Reaction Monitoring and Mechanistic Elucidation Tools:
The NCS Mediated Cascade Reaction of α-Thioamides to α-Thio-β-
chloroacrylamides. J. Org. Chem. 2011, 76, 9630−9640.
(3) Kissane, M.; Maguire, A. R. Stereoselective Synthesis of 2-Thio-3-
Chloroacrylamides and Investigation of their Reactivity. Synlett 2011,
2011, 1212−1232.
(4) Kissane, M.; Lynch, D.; Chopra, J.; Lawrence, S. E.; Maguire, A. R.
The influence of reaction conditions on the Diels-Alder cycloadditions
of 2-thio-3-chloroacrylamides; investigation of thermal, catalytic and
microwave conditions. Org. Biomol. Chem. 2010, 8, 5602−5613.
(5) Kissane, M.; Lawrence, S. E.; Maguire, A. R. 1,3-Dipolar
cycloadditions of 2-thio-3-chloroacrylamides with nitrile oxides and
nitrones. Tetrahedron 2010, 66, 4564−4572.
(6) Kissane, M.; Lawrence, S. E.; Maguire, A. R. Diastereoselective
sulfur oxidation of 2-thio-3-chloroacrylamides. Tetrahedron: Asymmetry
2010, 21, 871−884.
(22) Su, M.; Wang, J.; Hou, Y. Solubility of 6-Aminopenicillanic Acid in
Aqueous Salt Solutions from 273.15 to 303.15 K. J. Chem. Eng. Data
2007, 52, 2266−2268.
(23) Wang, J.; Wang, J.; Liu, J.; Wang, S.; Pei, J. Solubility of d-Aspartic
Acid and l-Aspartic Acid in Aqueous Salt Solutions from (293 to 343) K.
J. Chem. Eng. Data 2010, 55, 1735−1738.
(24) Buchowski, H.; Ksiazczak, A.; Pietrzyk, S. Solvent activity along a
saturation line and solubility of hydrogen-bonding solids. J. Phys. Chem.
1980, 84, 975−979.
(25) Sandler, S. I. Chemical, Biochemical, and Engineering Thermody-
namics, 4th ed.; John Wiley & Sons, Inc: New York, 2006.
(26) Prausnitz, J. M.; Tavares, F. W. Thermodynamics of fluid-phase
equilibria for standard chemical engineering operations. AIChE J. 2004,
50, 739−761.
(27) Wang, H.; Wang, Q.; Xiong, Z.; Chen, C.; Shen, B. Solubilities of
Benzoic Acid in Binary Methylbenzene + Benzyl Alcohol and
Methylbenzene + Benzaldehyde Solvent Mixtures. J. Chem. Eng. Data
2015, 60, 643−652.
L
DOI: 10.1021/acs.jced.7b00288
J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data
Article
(28) Renon, H.; Prausnitz, J. M. Estimation of Parameters for NRTL
Equation for Excess Gibbs Energy of Strongly Non-ideal Liquid
Mixtures. Ind. Eng. Chem. Process Des. Dev. 1969, 8, 413−419.
(29) Tung, H.-H.; Tabora, J.; Variankaval, N.; Bakken, D.; Chen, C.-C.
Prediction of pharmaceutical solubility Via NRTL-SAC and COSMO-
SAC. J. Pharm. Sci. 2008, 97, 1813−1820.
(30) Hojjati, H.; Rohani, S. Measurement and Prediction of Solubility
of Paracetamol in Water−Isopropanol Solution. Part 1. Measurement
and Data Analysis. Org. Process Res. Dev. 2006, 10, 1101−1109.
(31) Granberg, R. A.; Rasmuson, Å. C. Solubility of Paracetamol in
Pure Solvents. J. Chem. Eng. Data 1999, 44, 1391−1395.
(32) Fujiwara, M.; Chow, P. S.; Ma, D. L.; Braatz, R. D. Paracetamol
Crystallization Using Laser Backscattering and ATR-FTIR Spectrosco-
py: Metastability, Agglomeration, and Control. Cryst. Growth Des. 2002,
2, 363−370.
(33) Grant, D. J. W.; Mehdizadeh, M.; Chow, A. H. L.; Fairbrother, J. E.
Non-linear van’t Hoff solubility-temperature plots and their pharma-
ceutical interpretation. Int. J. Pharm. 1984, 18, 25−38.
(34) Shakeel, F.; Alanazi, F. K.; Alsarra, I. A.; Haq, N. Solubilization
Behavior of Paracetamol in Transcutol−Water Mixtures at (298.15 to
333.15) K. J. Chem. Eng. Data 2013, 58, 3551−3556.
M
DOI: 10.1021/acs.jced.7b00288
J. Chem. Eng. Data XXXX, XXX, XXX−XXX