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The dissolution behavior and apparent thermodynamic analysis of propacetamol hydrochloride in pure and mixed solvents
Journal Pre-proofs The dissolution behavior and apparent thermodynamic analysis of propacetamol hydrochloride in pure and mixed solvents Yüfang Wu, Yuancong Wu, Xiaolu Zhang PII: DOI: Reference:
S0021-9614(19)31014-6 https://doi.org/10.1016/j.jct.2019.106018 YJCHT 106018
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J. Chem. Thermodynamics
Received Date: Revised Date: Accepted Date:
9 September 2019 23 November 2019 24 November 2019
Please cite this article as: Y. Wu, Y. Wu, X. Zhang, The dissolution behavior and apparent thermodynamic analysis of propacetamol hydrochloride in pure and mixed solvents, J. Chem. Thermodynamics (2019), doi: https://doi.org/ 10.1016/j.jct.2019.106018
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The dissolution behavior and apparent thermodynamic analysis of propacetamol hydrochloride in pure and mixed solvents Yüfang Wu*, Yuancong Wu, Xiaolu Zhang Department of Biological Sciences, XinZhou Teachers University, Xinzhou, Shanxi, 034000, P. R. China.
Corresponding author Y.F. Wu. Tel: +86 350 3339210. E-mail address: [email protected]
ABSTRACT In order to study the solubility of the formed solute in the reaction solvent, the solubility of propacetamol hydrochloride (PRO) in pure and mixed solvents was experimentally determined at T = 273.15-313.15K. In all selected pure solvents, the solubility data form high to low was followed by the sequence: methanol > ethanol > acetone > n-propanol > isopropanol > acetonitrile. In mixture of (acetone + ethanol), the solubility decreased monotonically with the increasing mass fraction of acetone in mixed solvents at a certain temperature. The properties of solvents and the interaction between solvents and solutes were analyzed. All RAD values in the modified Apelblat equation are less than those in h equation. Therefore, modified Apelblat is more suitable for correlating the solubility data of PRO in selected pure solvents. In addition, satisfactory correlation results in (acetone + ethanol) were obtained by o o Jouyban-Acree model. The values of H sol and S sol
are all positive in this experiment, which
indicates the dissolution process is not only endothermic but also entropy-driving. Moreover, the values of %H are greater than those of % TS , which indicates the enthalpy is the main contributor to the change of standard Gibbs energy during the dissolution process of PRO. Key words: Propacetamol hydrochloride, Solubility data, Thermodynamic analysis.
1. Introduction
Many poorly soluble drugs having slow drug absorption leads to inadequate and variable bioavailability and gastrointestinal mucosal toxicity. [1] In the process of clinical drug preparation, solubility is the most important one rate limiting parameter. Problem of solubility is a major challenge for formulation scientist. The strong electrolyte salt forms of poorly soluble drugs that have higher dissolution rates were usually used in clinic. It is an effective method to improve the solubility and dissolution rate of poorly soluble drugs.[2,3] Paracetamol is a pain reliever and a fever reducer. It is used worldwide for the relief of mild to moderate pain associated with headache, backache, for arthritis pain and postoperative pain.[4-6] In recent years, the Bumai Squibb one kind (the USPA) pharmaceutical companies developed derivatives, propacetamol hydrochloride, (PRO, CAS Reg. No. 66532-86-3, Fig.1). In the blood, PRO, catalysed mainly by plasma esterases, is hydrolyzed efficiently to inert species paracetamol and diethylglycine. In clinical application, PRO is used as an injectable paracetamol formulations, solves the problem of the insolubility of paracetamol. [7] Since 2000, the drug has been "British Pharmacopoeia" and "European Pharmacopoeia" continuous load, approved in 2005 the domestic production of raw materials and a market. At present, the synthetic routes of propatamol reported in the literature are mainly based on paracetamol.[8-11] Ji Aiguo and co-workers used DMF as the reaction solvent. No catalyst or acid binding agent was added. Due to the solubility of the product in DMF and the acid capacity since the attachment of DMF weak, the yield of the product was low. [8] However, others mainly use acetone or pyridine as reaction solvent, potassium carbonate as catalyst and acid binding agent for a series of reactions, and then refine by pure ethanol. The above technical reports there are many deficiencies, including solvents harm the human body, the lower the yield, purity and so difficult to control, mass production difficult or purity is difficult to control. [9-11] Therefore, the solubility data and dissolution thermodynamic properties of PRO in pure alcohols, acetone, acetonitrile and mixture of (acetone + ethanol) were studied. The relationship between solvent properties and solubility was analyzed. Moreover, the results of solubility profile were evaluated by some thermodynamic models. Studying the solubility and thermodynamic properties of PRO in reactive and
refined solvents is helpful to the synthesis and purification process.
2. Solubility correlation Two single solvent equations including modified Apelblat equation [12,13]
and h equation, [14] and
one co-solvent model, Jouyban-acree model [15-17] were applied to correlate the solubility profiles of PRO. In pure solvents, the relationship between solubility results and the temperature in Kelvin can be concluded by the Modified Apelblat Equation, as shown in Eq. (1), and A, B and C are equation parameters. [12,13] ln xm ,T A
B C ln T T
(1)
Another semi-empirical model used to correlate solubility is h equation and proposed by Buchowski and co-workers. [14] It is is expressed as Eq. (2), an excellent equation to correlate the solubility of a solid in solvent and has two parameters, and h. Tm is the melting temperature of PRO in Kelvin. 1 x 1 1 ln 1 h x T / K Tm / K
(2)
The Jouyban-Acree model is usually used to describe the solute solubility as a function of temperature and solvent composition in binary mixed solvents. [15-17]The model is described as equation (3).
ln xm ,T m1 ln x1,T m2 ln x2,T
m1m2 T
2
J m m i 0
i
1
2
i
(3)
Where xm ,T represents the mole fraction solubility of PRO in mixture solvents; m1 and m2 are the mass fraction of corresponding solvent; x1,T and x2,T are the PRO solubility in pure solvent; Ji is the model parameters.
3. Experimental 3.1. Materials
Propacetamol hydrochloride with a mass fraction of 0.995 was purchased from Shanghai Yuanye Biotechnology Co., Ltd. (China). The studied solvents were analytical grade and purchased from Sinopharm Chemical Reagent Co., Ltd., China. The source and purity information of these materials was presented in Table 1. 3.2. Measurement of DSC Curves and Infrared Spectrums The differential scanning calorimetry (DSC) (Pyris-Diamond, PerkinElmer) was used to determine the DSC curves. Indium was used as reference material to pre-calibrate before experiment under a nitrogen atmosphere. The thermal analyses were performed at a heating rate of 10 K/min under a dynamic nitrogen atmosphere. About 5 mg PRO was added into a DSC pan, and heated at the temperature range from (333.15 to 520.15) K. The standard uncertainties of the temperature were estimated to be 0.5 K, and 0.2J/g for the melting enthalpy. Infrared Spectroscopy (IR) analysis (Perkin-Elmer spectrometer) was applied to characterize solid solute before and after the experiment. The sample was prepared from 2 mg of solute and 200 mg of pure dry KBr and pelletized under pressure of about 10 bars in vacuum. The IR absorption spectrum varies from 400 to 4000 cm-1 was recorded at room temperature. 3.3. Solubility determination The solubility data in this work was determined by the isothermal saturation method, which is the same as previous research methods.[18-21] Moreover, the reliability of measured method has been verified by determining the solubility of benzoic acid in our previous work.[18] Excess solid PRO was added to a given solvent, and the temperature was kept by a thermostatic bath with an uncertainty of ±0.05 K. The solution was stirred for 24 h to ensure that the solid-liquid equilibrium was reached, followed by 2 h settling of the suspension to ensure the solid precipitated to the bottom. Then 2 mL of the clear upper saturated solution was filtered by the prepared syringes filters and moved into pre-weighted volumetric flask. The solution and flask were immediately weighted using an analytical balance. The solubility of PRO in equilibrium systems was measured by the high performance liquid phase chromatograph with a type of reverse phase column (LP-C18, 250 mm × 4.6 mm) at 303.15
K. The wavelength of UV detector was 273 nm, and chromatographic grade methanol as mobile phase with a flow rate of 1.0 ml per min. The procedure was repeated three times to minimize the deviation of the experiments and the mean values were used to calculate the mole fraction solubility.
4. Results and discussion 4.1. DSC Curves and Infrared Spectrums The DSC curves of raw material and excess solid in pure and mixed solvents were shown in Fig. 2. It could be found that all solid in solution have the same DSC characteristic curves with the raw material. In this work, onset temperature is used as melting point and it is 499.27K, and the enthalpy of fusion is175.8 J/g. As reported in CN patent 105218390,[9] the melting point of PRO is 500.15 K, in addition, according to "Drugs - Synonyms and Properties" data were obtained from Ashgate Publishing Co. (US) CAPLUS, it is 501.15 K which is very close to the experimental data in this work. As shown in Fig. 2, combined with the IR spectrum peaks of raw material, all solid of PRO in solution were also identical. Therefore, according to the DSC curves and IR spectrums of PRO in Fig. 2, it can be concluded that there was no polymorph transformation or solvate formation during the solubility determination. 4.2. Solubility data The mole solubility of PRO in methanol, ethanol, n-propanol, isopropanol, acetone and acetonitrile were tabulated in Table 2, and shown graphically in Fig. 3. In all selected pure solvents, the solubility data form high to low was followed by the sequence:
methanol > ethanol > acetone > n-propanol >
isopropanol > acetonitrile. Within the temperature range studied, the solubility of PRO increased gradually. In ethanol, it was enhanced from 1.26210-4 to 4.22010-4, it was from 4.78910-4 to 14.70610-4 in methanol, which indicated that the cooling crystallization was an effective way to obtain high purity products. As mentioned above, acetone was also used as the reaction solvent. Hence, the solubility in the mixtures of (acetone + ethanol) was further studied. The results were presented in Table 3, and the solubility against temperature and solvent composition were shown in Fig. 4. As expected, the solubility data increased with the rising temperatures. Moreover, at a certain temperature, the solubility
decreased monotonically with the increasing mass fraction of acetone in mixed solvents. At 313.15K, the solubility data in pure acetone is 1.113×10-4, while it increases to 4.22010-4 in pure ethanol, an increase of 3.79 fold. It could be found that temperature and the addition of co-solvent were important for crystallization purification. By analyzing the properties of solvent including hydrogen bond acidity ( hydrogen bond basicity (), dipolarity/polarizability (*) and Hildebrand solubility parameter ( H2 ) (tabulated in Table 4), [22] we could find that solubility order from high to low in alcoholic solvents was consistent with the sequence of hydrogen bond acidity ( dipolarity/polarizability (*) and Hildebrand solubility parameter ( H2 ), except for hydrogen bond basicity (). Moreover, the maximum value was obtained in methanol, which is much larger than the data in acetone and acetonitrile. The possible reason is that the carbonyl group on the solute molecule forms hydrogen bond with the hydroxyl group on the methanol solvent molecule. However, the solubility in acetone is higher than that in n-propanol and isopropanol, probably because the hydrogen bonding ability between alcohol solvents and solute molecules decreases with the increase of carbon chain. Besides the similarity of carbonyl structure between acetone and solute molecules helps to improve the solubility according to the rule of “like dissolves like”. Compared with pure ethanol and acetone, the interaction force between solute and solvent molecules gradually decreased with the increasing mass fraction of acetone. It can be found that there are more than one factor affecting the solubility, and other factors need to be considered at the same time. 4.3. Correlation evaluation The relative average deviation (RAD) was used to evaluate the correlation results, which is described as equation (4). xie and xic are the experimental and calculated results of PRO. N is the number of experimental points. RAD
1 N
N
i 1
xie xic xie
(4)
In pure solvent, model parameters of the modified Apelblat equation and h equation along with the RAD values were listed in Table 5, and the calculated solubility data was tabulated in Table 2 as well. The
maximum of RAD (1.7310-2) was obtained from the modified Apelblat equation in acetonitrile, and it is 3.6010-2 in h equation. Moreover, all RAD values in the modified Apelblat equation are less than those in h equation. Therefore, modified Apelblat is more suitable for correlating the solubility data of PRO in selected pure solvents. While in mixtures of (acetone + ethanol), the calculated values by the Jouyban-Acree model were also listed in Table 3, and the values of model parameters together with RAD and linear correlation coefficient were shown in Table 6. The value of RAD is 1.3210-2, and the linear correlation coefficient is very close to 1, satisfactory correlation results can be obtained by Jouyban-Acree model. 4.4. Thermodynamic analysis o o The apparent dissolution standard enthalpy ( H sol ), apparent molar standard Gibbs energy ( Gsol ) and
o o of PRO dissolution process are described as the following Eqs. (5)-(8) [23-25]. The H sol and S sol o can be acquired from the slope and intercept of the solubility curves of lnxw,T versus 1/T. Moreover, Gsol
the curves of lnxw,T versus 1/T are shown in Fig. 5.
ln xw,T ln xw,T o H sol R R (1 / T ) p (1/ T ) (1/ Thm ) p o Gsol RThm intercept
o Ssol
(5)
(6)
o o H sol Gsol Thm
(7)
where R is the universal gas constant. Ti is the experiment temperature. Thm refers to the mean harmonic temperature and can be computed with Eq. (8). n is the number of temperature points. Thm
n 1 i 1 T i n
(8)
In order to illustrate the contribution of dissolution entropy and enthalpy to the change of dissolution Gibbs energy in the dissolution process, % H and %TS are employed and expressed as Eqs. (9) and (10), respectively.[26]
% H
% TS
o H sol o o H sol Thm Ssol
100
(9)
100
(10)
o Thm Ssol o o H sol Thm Ssol
o o o The calculated values of H sol , S sol and Gsol are presented in Table 7. It shows that apparent o o o dissolution standard enthalpy ( H sol ), apparent molar standard Gibbs energy ( Gsol ) and S sol of PRO
o dissolution process are all positive. The positive Gsol values of PRO dissolution in selected solvents are o obtained from 17.112 to 28.391 kJ·mol−1. The maximum Gsol
value for dissolution of PRO in
acetonitrile indicates that relative high energy is required in comparison with other solvents investigated. o The positive values of H sol demonstrate that the dissolution process of PRO is endothermic in the
studied solvents. Compared with the powerful interactions between solute and solute molecules, the newly formed bond energy is too weak between PRO molecule and solvent molecule, it cannot make up for the energy needed for destroying the primary bond, and subsequently the system requires absorbing extra heat from circumstances. It gives a good reason to explain the increasing PRO solubility with o increasing temperature. The S sol values for dissolution behavior of PRO are all positive in this
experiment, which indicates the dissolution process is not only endothermic but also entropy-driving. The calculated %H and % TS values are also listed in Table 7. The values of %H are greater than those of % TS , the enthalpy is the main contributor to the change of standard Gibbs energy during the dissolution process of PRO.
5. Conclusions The solubility of PRO in pure alcohols, acetone, acetonitrile and mixture of (acetone + ethanol) was experimentally determined at T = 273.15-313.15K. In all selected pure solvents, the solubility data form high to low was followed by the sequence: methanol > ethanol > acetone > n-propanol > isopropanol > acetonitrile. In mixture of (acetone + ethanol), the solubility decreased monotonically with the increasing
mass fraction of acetone in mixed solvents at a certain temperature. All RAD values in the modified Apelblat equation are less than those in h equation. Therefore, modified Apelblat is more suitable for correlating the solubility data of PRO in selected pure solvents. In addition, satisfactory correlation results o o in (acetone + ethanol) were obtained by Jouyban-Acree model. The values of H sol and S sol
are all
positive in this experiment, which indicates the dissolution process is not only endothermic but also entropy-driving. Moreover, the values of %H are greater than those of % TS , which indicates the enthalpy is the main contributor to the change of standard Gibbs energy during the dissolution process of PRO.
Acknowledgment The project was supported by Scientific and Technologial Innovation Programs of Higher Education Institutions in Shanxi, STIP. No. 2019L0846.
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O
O
N O
HN
HCl
DSC mW/mg
Fig. 1. The chemical structure of propacetamol hydrochloride
raw acetone + ethanol, w=0.2 acetone + ethanol, w=0.4 acetone + ethanol, w=0.6
acetonitrile
acetone + ethanol, w=0.8
isopropanol
acetone
ethanol acetone
raw n-propanol
acetonitrile n-propanol
methanol
ethanol
w=0.2 w=0.4 w=0.6
methanol isopropanol
Tm =499.27K
w=0.8
fus H 175.8 J g 330
360
390
420
450
480
510
4000 3500 3000 2500 2000 1500 1000 500
540
Wavenumber(cm-1)
T/K
Fig. 2. DSC curves and infrared spectrums of propacetamol hydrochloride in different solvents.
1.5E-3
1.2E-4
methanol ethanol n-propanol
isopropanol acetonitrile acetone
1.0E-3
x
x
8.0E-5
5.0E-4
0.0
4.0E-5
280
290
300
310
0.0
280
T/K
290
300
310
T/K
Fig. 3. Experimental solubility data of propacetamol hydrochloride in pure solvents over the temperature range
from 273.15K to 313.15K.
calculated values
0.0002 R2=0.999
0.0001
0.0001 0.0002 experimental values
.
Fig. 4. Experimental solubility data of propacetamol hydrochloride in mixture of acetone (w) + ethanol (1-w) over
the temperature range from 273.15K to 313.15K in 3d-plot, and the comparison between experimental and
ln(x)
calculated values is shown in 2d-plot, w, is the mass fraction of acetone in mixed solvents.
-0.0002 -0.0001 0.0000 0.0001 0.0002 (1/T-1/Thm)/K-1
Fig.5. The van’t Hoff plots of ln(x) versus 1/T in pure solvents and mixture of acetone (w) + ethanol (1-w), w, is the mass fraction of acetone in mixtures , █,methanol; ●, ethanol; ▲, n-propanol; ▼, isopropanol; ◆, acetonitrile; ○, acetone;△, w=0.20; □, w=0.40; ★, w=0.60; ☆, w=0.80.
Table 1 The source and purity of the materials used in this work.
Chemicals
CAS NO.
Molar mass
Source
g·mol−1
Propacetamol hydrochloride
300.7 8
Analytical method
0.995
HPLCa
67-56-1
32.04
0.998b
Ethanol
64-17-5
46.07
0.998 b
Isopropanol
67-63-0
60.1
Methanol
a
66532-86 -3
Shanghai Yuanye Biotechnology Co., Ltd. (China)
mass fraction purity
Sinopharm Chemical Reagent Co., Ltd.,China
0.995 b
None
0.996 b
n-Propanol
71-23-8
60.1
Acetone
67-64-1
58.08
0.995 b
Acetonitrile
75-05-8
41.05
0.996 b
High-performance liquid phase chromatograph. b the purity was provided by supplier.
Table 2 Experimentaland calculated mole solubility of propacetamol hydrochloride in pure solvents at the temperature range from T = (273.15 To 313.15) K under 101.3kPa.a 104xcal Modified Apelblat equation
104xe
T/K
λh equation
Methanol
273.15
4.789
4.838
4.967
278.15
5.763
5.759
5.791
283.15
6.800
6.776
6.719
288.15
7.940
7.889
7.761
293.15
9.138
9.093
8.926
298.15
10.322
10.383
10.226
303.15
11.711
11.749
11.673
308.15
13.180
13.185
13.278
313.15
14.706
14.679
15.056
Ethanol
273.15
1.262
1.258
1.306
278.15
1.540
1.53
1.544
283.15
1.822
1.833
1.816
288.15
2.156
2.169
2.124
293.15
2.532
2.533
2.474
298.15
2.947
2.925
2.867
303.15
3.325
3.341
3.31
308.15
3.787
3.775
3.806
313.15
4.220
4.226
4.361
273.15
0.154
0.156
0.162
278.15
0.204
0.21
0.211
283.15
0.283
0.277
0.273
288.15
0.366
0.358
0.349
293.15
0.453
0.456
0.443
298.15
0.563
0.571
0.557
303.15
0.704
0.704
0.697
308.15
0.861
0.856
0.865
313.15
1.024
1.026
1.067
n-Propanol
Isopropanol
273.15
0.116
0.12
0.125
278.15
0.161
0.162
0.163
283.15
0.219
0.214
0.21
288.15
0.281
0.277
0.269
293.15
0.350
0.353
0.342
298.15
0.439
0.442
0.43
303.15
0.542
0.544
0.538
308.15
0.664
0.659
0.667
313.15
0.785
0.787
0.823
Acetone
273.15
0.285
0.289
0.299
278.15
0.360
0.358
0.361
283.15
0.437
0.438
0.432
288.15
0.528
0.527
0.515
293.15
0.631
0.627
0.611
298.15
0.736
0.735
0.72
303.15
0.848
0.853
0.845
308.15
0.977
0.979
0.988
313.15
1.113
1.111
1.149
273.15
0.029
0.031
0.032
278.15
0.042
0.042
0.042
283.15
0.057
0.055
0.054
288.15
0.072
0.071
0.069
293.15
0.091
0.09
0.087
298.15
0.112
0.113
0.11
303.15
0.137
0.139
0.138
308.15
0.169
0.168
0.171
313.15
0.201
0.201
0.21
Acetonitrile
a
Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45kPa; Relative standard uncertainty ur is ur (x) = 0.043.
Table 3 Experimentaland calculate mole solubility of propacetamol hydrochloride in mixture of acetone (w) + ethanol (1-w) at the temperature range from T = (273.15 To 313.15) K under 101.3kPa.a w w=0.200
T/K
104xexp
a
104xJ-A
w=0.400 104xexp
104xJ-A
w=0.600 104xexp
104xJ-A
w=0.800 104xexp
104xJ-A
273.15
0.918
0.903
0.725
0.692
0.458
0.495
0.342
0.342
278.15
1.084
1.109
0.862
0.856
0.589
0.616
0.428
0.430
283.15
1.302
1.320
1.020
1.023
0.729
0.741
0.519
0.521
288.15
1.537
1.570
1.207
1.221
0.892
0.888
0.629
0.627
293.15
1.803
1.851
1.409
1.444
1.043
1.055
0.738
0.749
298.15
2.109
2.157
1.654
1.683
1.240
1.231
0.870
0.875
303.15
2.486
2.445
1.906
1.915
1.445
1.407
1.016
1.005
308.15
2.856
2.792
2.195
2.191
1.682
1.615
1.171
1.157
313.15
3.262
3.127
2.530
2.463
1.941
1.825
1.338
1.315
Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45kPa; Relative standard uncertainty ur is ur (x) = 0.048. Solvent mixtures were prepared by
mixing different masses of the solvents with relative standard uncertainty ur (w) = 0.002. w represents the mass fraction of acetone in mixed solvents.
Table 4 Hildebrand solubility parameters (δH) and solvatochromic parameters , and * for the selected solvents.a Solvent
a
α
β
δ2 H/1000
π*
(J/cm3)
methanol
0.98
0.66
0.60
0.8797
ethanol
0.86
0.75
0.54
0.5630
n-propanol
0.84
0.9
0.52
0.6025
isopropanol
0.76
0.84
0.48
0.563
acetone
0.08
0.43
0.71
0.3994
acetonitrile
0.19
0.4
0.75
0.5806
taken from ref.21
Table 5 Parameters of the modified Apelblat equation and h equation for propacetamol hydrochloride in different solvents.
h equation
Modified Apelblat equation Solvent A
B
102
C
RAD
h
102 RAD
Methanol
110.556
-7163.871
-16.393
0.41
0.021
107644.103
1.59
Ethanol
151.814
-9210.039
-22.652
0.43
0.008
307655.875
1.65
n-Propanol
195.258
-12410.691
-28.679
1.25
0.013
318897.251
2.89
Isopropanol
224.438
-13698.080
-33.088
1.11
0.010
413040.666
3.09
Acetone
159.700
-9864.747
-23.893
0.42
0.003
883860.022
2.04
Acetonitrile
198.459
-12580.088
-29.426
1.73
0.002
1632016.13
3.60
Table 6 Values of parameters of Jouyban-acree model along with RAD and linear correlation coefficient.
Parameter Values
J0
J1
J2
102RAD
R2
-16.136
-109.219
-317.474
1.32
0.999
Table 7 18
Standard dissolution enthalpy of propacetamol hydrochloride in pure and mixture of acetone (w) + ethanol (1-w) solvents at mean harmonic temperature (292.58 K). o Gsol
o H sol
o Ssol
kJ·mol-1
kJ·mol-1
J·mol-1
Methanol
17.112
19.780
Ethanol
20.238
n-Propanol
%H
% TS
9.120
88.11
11.89
21.501
4.316
94.45
5.55
24.450
33.643
31.418
78.54
21.46
Isopropanol
25.082
33.673
29.362
79.67
20.33
Acetonitrile
28.391
33.557
17.657
86.66
13.34
Acetone
23.645
24.018
1.275
98.47
1.53
solvents
Acetone (w) +ethanol (1-w) w=0.2
21.008
22.753
5.965
92.88
7.12
w=0.4
21.609
22.224
2.104
97.30
2.70
w=0.6
22.386
25.260
9.825
89.78
10.22
w=0.8
23.220
24.107
3.031
96.45
3.55
19
Abstract Graphic
20
1. The solubility of propacetamol hydrochloride in pure and binary solvents; 2. The solubility data were correlated by some thermodynamic models; 3. The effect of solvent properties on the solubility was analyzed; 4. Some thermodynamic properties of dissolution process were evaluated.
21
S0021-9614(19)31014-6 https://doi.org/10.1016/j.jct.2019.106018 YJCHT 106018
To appear in:
J. Chem. Thermodynamics
Received Date: Revised Date: Accepted Date:
9 September 2019 23 November 2019 24 November 2019
Please cite this article as: Y. Wu, Y. Wu, X. Zhang, The dissolution behavior and apparent thermodynamic analysis of propacetamol hydrochloride in pure and mixed solvents, J. Chem. Thermodynamics (2019), doi: https://doi.org/ 10.1016/j.jct.2019.106018
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The dissolution behavior and apparent thermodynamic analysis of propacetamol hydrochloride in pure and mixed solvents Yüfang Wu*, Yuancong Wu, Xiaolu Zhang Department of Biological Sciences, XinZhou Teachers University, Xinzhou, Shanxi, 034000, P. R. China.
Corresponding author Y.F. Wu. Tel: +86 350 3339210. E-mail address: [email protected]
ABSTRACT In order to study the solubility of the formed solute in the reaction solvent, the solubility of propacetamol hydrochloride (PRO) in pure and mixed solvents was experimentally determined at T = 273.15-313.15K. In all selected pure solvents, the solubility data form high to low was followed by the sequence: methanol > ethanol > acetone > n-propanol > isopropanol > acetonitrile. In mixture of (acetone + ethanol), the solubility decreased monotonically with the increasing mass fraction of acetone in mixed solvents at a certain temperature. The properties of solvents and the interaction between solvents and solutes were analyzed. All RAD values in the modified Apelblat equation are less than those in h equation. Therefore, modified Apelblat is more suitable for correlating the solubility data of PRO in selected pure solvents. In addition, satisfactory correlation results in (acetone + ethanol) were obtained by o o Jouyban-Acree model. The values of H sol and S sol
are all positive in this experiment, which
indicates the dissolution process is not only endothermic but also entropy-driving. Moreover, the values of %H are greater than those of % TS , which indicates the enthalpy is the main contributor to the change of standard Gibbs energy during the dissolution process of PRO. Key words: Propacetamol hydrochloride, Solubility data, Thermodynamic analysis.
1. Introduction
Many poorly soluble drugs having slow drug absorption leads to inadequate and variable bioavailability and gastrointestinal mucosal toxicity. [1] In the process of clinical drug preparation, solubility is the most important one rate limiting parameter. Problem of solubility is a major challenge for formulation scientist. The strong electrolyte salt forms of poorly soluble drugs that have higher dissolution rates were usually used in clinic. It is an effective method to improve the solubility and dissolution rate of poorly soluble drugs.[2,3] Paracetamol is a pain reliever and a fever reducer. It is used worldwide for the relief of mild to moderate pain associated with headache, backache, for arthritis pain and postoperative pain.[4-6] In recent years, the Bumai Squibb one kind (the USPA) pharmaceutical companies developed derivatives, propacetamol hydrochloride, (PRO, CAS Reg. No. 66532-86-3, Fig.1). In the blood, PRO, catalysed mainly by plasma esterases, is hydrolyzed efficiently to inert species paracetamol and diethylglycine. In clinical application, PRO is used as an injectable paracetamol formulations, solves the problem of the insolubility of paracetamol. [7] Since 2000, the drug has been "British Pharmacopoeia" and "European Pharmacopoeia" continuous load, approved in 2005 the domestic production of raw materials and a market. At present, the synthetic routes of propatamol reported in the literature are mainly based on paracetamol.[8-11] Ji Aiguo and co-workers used DMF as the reaction solvent. No catalyst or acid binding agent was added. Due to the solubility of the product in DMF and the acid capacity since the attachment of DMF weak, the yield of the product was low. [8] However, others mainly use acetone or pyridine as reaction solvent, potassium carbonate as catalyst and acid binding agent for a series of reactions, and then refine by pure ethanol. The above technical reports there are many deficiencies, including solvents harm the human body, the lower the yield, purity and so difficult to control, mass production difficult or purity is difficult to control. [9-11] Therefore, the solubility data and dissolution thermodynamic properties of PRO in pure alcohols, acetone, acetonitrile and mixture of (acetone + ethanol) were studied. The relationship between solvent properties and solubility was analyzed. Moreover, the results of solubility profile were evaluated by some thermodynamic models. Studying the solubility and thermodynamic properties of PRO in reactive and
refined solvents is helpful to the synthesis and purification process.
2. Solubility correlation Two single solvent equations including modified Apelblat equation [12,13]
and h equation, [14] and
one co-solvent model, Jouyban-acree model [15-17] were applied to correlate the solubility profiles of PRO. In pure solvents, the relationship between solubility results and the temperature in Kelvin can be concluded by the Modified Apelblat Equation, as shown in Eq. (1), and A, B and C are equation parameters. [12,13] ln xm ,T A
B C ln T T
(1)
Another semi-empirical model used to correlate solubility is h equation and proposed by Buchowski and co-workers. [14] It is is expressed as Eq. (2), an excellent equation to correlate the solubility of a solid in solvent and has two parameters, and h. Tm is the melting temperature of PRO in Kelvin. 1 x 1 1 ln 1 h x T / K Tm / K
(2)
The Jouyban-Acree model is usually used to describe the solute solubility as a function of temperature and solvent composition in binary mixed solvents. [15-17]The model is described as equation (3).
ln xm ,T m1 ln x1,T m2 ln x2,T
m1m2 T
2
J m m i 0
i
1
2
i
(3)
Where xm ,T represents the mole fraction solubility of PRO in mixture solvents; m1 and m2 are the mass fraction of corresponding solvent; x1,T and x2,T are the PRO solubility in pure solvent; Ji is the model parameters.
3. Experimental 3.1. Materials
Propacetamol hydrochloride with a mass fraction of 0.995 was purchased from Shanghai Yuanye Biotechnology Co., Ltd. (China). The studied solvents were analytical grade and purchased from Sinopharm Chemical Reagent Co., Ltd., China. The source and purity information of these materials was presented in Table 1. 3.2. Measurement of DSC Curves and Infrared Spectrums The differential scanning calorimetry (DSC) (Pyris-Diamond, PerkinElmer) was used to determine the DSC curves. Indium was used as reference material to pre-calibrate before experiment under a nitrogen atmosphere. The thermal analyses were performed at a heating rate of 10 K/min under a dynamic nitrogen atmosphere. About 5 mg PRO was added into a DSC pan, and heated at the temperature range from (333.15 to 520.15) K. The standard uncertainties of the temperature were estimated to be 0.5 K, and 0.2J/g for the melting enthalpy. Infrared Spectroscopy (IR) analysis (Perkin-Elmer spectrometer) was applied to characterize solid solute before and after the experiment. The sample was prepared from 2 mg of solute and 200 mg of pure dry KBr and pelletized under pressure of about 10 bars in vacuum. The IR absorption spectrum varies from 400 to 4000 cm-1 was recorded at room temperature. 3.3. Solubility determination The solubility data in this work was determined by the isothermal saturation method, which is the same as previous research methods.[18-21] Moreover, the reliability of measured method has been verified by determining the solubility of benzoic acid in our previous work.[18] Excess solid PRO was added to a given solvent, and the temperature was kept by a thermostatic bath with an uncertainty of ±0.05 K. The solution was stirred for 24 h to ensure that the solid-liquid equilibrium was reached, followed by 2 h settling of the suspension to ensure the solid precipitated to the bottom. Then 2 mL of the clear upper saturated solution was filtered by the prepared syringes filters and moved into pre-weighted volumetric flask. The solution and flask were immediately weighted using an analytical balance. The solubility of PRO in equilibrium systems was measured by the high performance liquid phase chromatograph with a type of reverse phase column (LP-C18, 250 mm × 4.6 mm) at 303.15
K. The wavelength of UV detector was 273 nm, and chromatographic grade methanol as mobile phase with a flow rate of 1.0 ml per min. The procedure was repeated three times to minimize the deviation of the experiments and the mean values were used to calculate the mole fraction solubility.
4. Results and discussion 4.1. DSC Curves and Infrared Spectrums The DSC curves of raw material and excess solid in pure and mixed solvents were shown in Fig. 2. It could be found that all solid in solution have the same DSC characteristic curves with the raw material. In this work, onset temperature is used as melting point and it is 499.27K, and the enthalpy of fusion is175.8 J/g. As reported in CN patent 105218390,[9] the melting point of PRO is 500.15 K, in addition, according to "Drugs - Synonyms and Properties" data were obtained from Ashgate Publishing Co. (US) CAPLUS, it is 501.15 K which is very close to the experimental data in this work. As shown in Fig. 2, combined with the IR spectrum peaks of raw material, all solid of PRO in solution were also identical. Therefore, according to the DSC curves and IR spectrums of PRO in Fig. 2, it can be concluded that there was no polymorph transformation or solvate formation during the solubility determination. 4.2. Solubility data The mole solubility of PRO in methanol, ethanol, n-propanol, isopropanol, acetone and acetonitrile were tabulated in Table 2, and shown graphically in Fig. 3. In all selected pure solvents, the solubility data form high to low was followed by the sequence:
methanol > ethanol > acetone > n-propanol >
isopropanol > acetonitrile. Within the temperature range studied, the solubility of PRO increased gradually. In ethanol, it was enhanced from 1.26210-4 to 4.22010-4, it was from 4.78910-4 to 14.70610-4 in methanol, which indicated that the cooling crystallization was an effective way to obtain high purity products. As mentioned above, acetone was also used as the reaction solvent. Hence, the solubility in the mixtures of (acetone + ethanol) was further studied. The results were presented in Table 3, and the solubility against temperature and solvent composition were shown in Fig. 4. As expected, the solubility data increased with the rising temperatures. Moreover, at a certain temperature, the solubility
decreased monotonically with the increasing mass fraction of acetone in mixed solvents. At 313.15K, the solubility data in pure acetone is 1.113×10-4, while it increases to 4.22010-4 in pure ethanol, an increase of 3.79 fold. It could be found that temperature and the addition of co-solvent were important for crystallization purification. By analyzing the properties of solvent including hydrogen bond acidity ( hydrogen bond basicity (), dipolarity/polarizability (*) and Hildebrand solubility parameter ( H2 ) (tabulated in Table 4), [22] we could find that solubility order from high to low in alcoholic solvents was consistent with the sequence of hydrogen bond acidity ( dipolarity/polarizability (*) and Hildebrand solubility parameter ( H2 ), except for hydrogen bond basicity (). Moreover, the maximum value was obtained in methanol, which is much larger than the data in acetone and acetonitrile. The possible reason is that the carbonyl group on the solute molecule forms hydrogen bond with the hydroxyl group on the methanol solvent molecule. However, the solubility in acetone is higher than that in n-propanol and isopropanol, probably because the hydrogen bonding ability between alcohol solvents and solute molecules decreases with the increase of carbon chain. Besides the similarity of carbonyl structure between acetone and solute molecules helps to improve the solubility according to the rule of “like dissolves like”. Compared with pure ethanol and acetone, the interaction force between solute and solvent molecules gradually decreased with the increasing mass fraction of acetone. It can be found that there are more than one factor affecting the solubility, and other factors need to be considered at the same time. 4.3. Correlation evaluation The relative average deviation (RAD) was used to evaluate the correlation results, which is described as equation (4). xie and xic are the experimental and calculated results of PRO. N is the number of experimental points. RAD
1 N
N
i 1
xie xic xie
(4)
In pure solvent, model parameters of the modified Apelblat equation and h equation along with the RAD values were listed in Table 5, and the calculated solubility data was tabulated in Table 2 as well. The
maximum of RAD (1.7310-2) was obtained from the modified Apelblat equation in acetonitrile, and it is 3.6010-2 in h equation. Moreover, all RAD values in the modified Apelblat equation are less than those in h equation. Therefore, modified Apelblat is more suitable for correlating the solubility data of PRO in selected pure solvents. While in mixtures of (acetone + ethanol), the calculated values by the Jouyban-Acree model were also listed in Table 3, and the values of model parameters together with RAD and linear correlation coefficient were shown in Table 6. The value of RAD is 1.3210-2, and the linear correlation coefficient is very close to 1, satisfactory correlation results can be obtained by Jouyban-Acree model. 4.4. Thermodynamic analysis o o The apparent dissolution standard enthalpy ( H sol ), apparent molar standard Gibbs energy ( Gsol ) and
o o of PRO dissolution process are described as the following Eqs. (5)-(8) [23-25]. The H sol and S sol o can be acquired from the slope and intercept of the solubility curves of lnxw,T versus 1/T. Moreover, Gsol
the curves of lnxw,T versus 1/T are shown in Fig. 5.
ln xw,T ln xw,T o H sol R R (1 / T ) p (1/ T ) (1/ Thm ) p o Gsol RThm intercept
o Ssol
(5)
(6)
o o H sol Gsol Thm
(7)
where R is the universal gas constant. Ti is the experiment temperature. Thm refers to the mean harmonic temperature and can be computed with Eq. (8). n is the number of temperature points. Thm
n 1 i 1 T i n
(8)
In order to illustrate the contribution of dissolution entropy and enthalpy to the change of dissolution Gibbs energy in the dissolution process, % H and %TS are employed and expressed as Eqs. (9) and (10), respectively.[26]
% H
% TS
o H sol o o H sol Thm Ssol
100
(9)
100
(10)
o Thm Ssol o o H sol Thm Ssol
o o o The calculated values of H sol , S sol and Gsol are presented in Table 7. It shows that apparent o o o dissolution standard enthalpy ( H sol ), apparent molar standard Gibbs energy ( Gsol ) and S sol of PRO
o dissolution process are all positive. The positive Gsol values of PRO dissolution in selected solvents are o obtained from 17.112 to 28.391 kJ·mol−1. The maximum Gsol
value for dissolution of PRO in
acetonitrile indicates that relative high energy is required in comparison with other solvents investigated. o The positive values of H sol demonstrate that the dissolution process of PRO is endothermic in the
studied solvents. Compared with the powerful interactions between solute and solute molecules, the newly formed bond energy is too weak between PRO molecule and solvent molecule, it cannot make up for the energy needed for destroying the primary bond, and subsequently the system requires absorbing extra heat from circumstances. It gives a good reason to explain the increasing PRO solubility with o increasing temperature. The S sol values for dissolution behavior of PRO are all positive in this
experiment, which indicates the dissolution process is not only endothermic but also entropy-driving. The calculated %H and % TS values are also listed in Table 7. The values of %H are greater than those of % TS , the enthalpy is the main contributor to the change of standard Gibbs energy during the dissolution process of PRO.
5. Conclusions The solubility of PRO in pure alcohols, acetone, acetonitrile and mixture of (acetone + ethanol) was experimentally determined at T = 273.15-313.15K. In all selected pure solvents, the solubility data form high to low was followed by the sequence: methanol > ethanol > acetone > n-propanol > isopropanol > acetonitrile. In mixture of (acetone + ethanol), the solubility decreased monotonically with the increasing
mass fraction of acetone in mixed solvents at a certain temperature. All RAD values in the modified Apelblat equation are less than those in h equation. Therefore, modified Apelblat is more suitable for correlating the solubility data of PRO in selected pure solvents. In addition, satisfactory correlation results o o in (acetone + ethanol) were obtained by Jouyban-Acree model. The values of H sol and S sol
are all
positive in this experiment, which indicates the dissolution process is not only endothermic but also entropy-driving. Moreover, the values of %H are greater than those of % TS , which indicates the enthalpy is the main contributor to the change of standard Gibbs energy during the dissolution process of PRO.
Acknowledgment The project was supported by Scientific and Technologial Innovation Programs of Higher Education Institutions in Shanxi, STIP. No. 2019L0846.
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O
O
N O
HN
HCl
DSC mW/mg
Fig. 1. The chemical structure of propacetamol hydrochloride
raw acetone + ethanol, w=0.2 acetone + ethanol, w=0.4 acetone + ethanol, w=0.6
acetonitrile
acetone + ethanol, w=0.8
isopropanol
acetone
ethanol acetone
raw n-propanol
acetonitrile n-propanol
methanol
ethanol
w=0.2 w=0.4 w=0.6
methanol isopropanol
Tm =499.27K
w=0.8
fus H 175.8 J g 330
360
390
420
450
480
510
4000 3500 3000 2500 2000 1500 1000 500
540
Wavenumber(cm-1)
T/K
Fig. 2. DSC curves and infrared spectrums of propacetamol hydrochloride in different solvents.
1.5E-3
1.2E-4
methanol ethanol n-propanol
isopropanol acetonitrile acetone
1.0E-3
x
x
8.0E-5
5.0E-4
0.0
4.0E-5
280
290
300
310
0.0
280
T/K
290
300
310
T/K
Fig. 3. Experimental solubility data of propacetamol hydrochloride in pure solvents over the temperature range
from 273.15K to 313.15K.
calculated values
0.0002 R2=0.999
0.0001
0.0001 0.0002 experimental values
.
Fig. 4. Experimental solubility data of propacetamol hydrochloride in mixture of acetone (w) + ethanol (1-w) over
the temperature range from 273.15K to 313.15K in 3d-plot, and the comparison between experimental and
ln(x)
calculated values is shown in 2d-plot, w, is the mass fraction of acetone in mixed solvents.
-0.0002 -0.0001 0.0000 0.0001 0.0002 (1/T-1/Thm)/K-1
Fig.5. The van’t Hoff plots of ln(x) versus 1/T in pure solvents and mixture of acetone (w) + ethanol (1-w), w, is the mass fraction of acetone in mixtures , █,methanol; ●, ethanol; ▲, n-propanol; ▼, isopropanol; ◆, acetonitrile; ○, acetone;△, w=0.20; □, w=0.40; ★, w=0.60; ☆, w=0.80.
Table 1 The source and purity of the materials used in this work.
Chemicals
CAS NO.
Molar mass
Source
g·mol−1
Propacetamol hydrochloride
300.7 8
Analytical method
0.995
HPLCa
67-56-1
32.04
0.998b
Ethanol
64-17-5
46.07
0.998 b
Isopropanol
67-63-0
60.1
Methanol
a
66532-86 -3
Shanghai Yuanye Biotechnology Co., Ltd. (China)
mass fraction purity
Sinopharm Chemical Reagent Co., Ltd.,China
0.995 b
None
0.996 b
n-Propanol
71-23-8
60.1
Acetone
67-64-1
58.08
0.995 b
Acetonitrile
75-05-8
41.05
0.996 b
High-performance liquid phase chromatograph. b the purity was provided by supplier.
Table 2 Experimentaland calculated mole solubility of propacetamol hydrochloride in pure solvents at the temperature range from T = (273.15 To 313.15) K under 101.3kPa.a 104xcal Modified Apelblat equation
104xe
T/K
λh equation
Methanol
273.15
4.789
4.838
4.967
278.15
5.763
5.759
5.791
283.15
6.800
6.776
6.719
288.15
7.940
7.889
7.761
293.15
9.138
9.093
8.926
298.15
10.322
10.383
10.226
303.15
11.711
11.749
11.673
308.15
13.180
13.185
13.278
313.15
14.706
14.679
15.056
Ethanol
273.15
1.262
1.258
1.306
278.15
1.540
1.53
1.544
283.15
1.822
1.833
1.816
288.15
2.156
2.169
2.124
293.15
2.532
2.533
2.474
298.15
2.947
2.925
2.867
303.15
3.325
3.341
3.31
308.15
3.787
3.775
3.806
313.15
4.220
4.226
4.361
273.15
0.154
0.156
0.162
278.15
0.204
0.21
0.211
283.15
0.283
0.277
0.273
288.15
0.366
0.358
0.349
293.15
0.453
0.456
0.443
298.15
0.563
0.571
0.557
303.15
0.704
0.704
0.697
308.15
0.861
0.856
0.865
313.15
1.024
1.026
1.067
n-Propanol
Isopropanol
273.15
0.116
0.12
0.125
278.15
0.161
0.162
0.163
283.15
0.219
0.214
0.21
288.15
0.281
0.277
0.269
293.15
0.350
0.353
0.342
298.15
0.439
0.442
0.43
303.15
0.542
0.544
0.538
308.15
0.664
0.659
0.667
313.15
0.785
0.787
0.823
Acetone
273.15
0.285
0.289
0.299
278.15
0.360
0.358
0.361
283.15
0.437
0.438
0.432
288.15
0.528
0.527
0.515
293.15
0.631
0.627
0.611
298.15
0.736
0.735
0.72
303.15
0.848
0.853
0.845
308.15
0.977
0.979
0.988
313.15
1.113
1.111
1.149
273.15
0.029
0.031
0.032
278.15
0.042
0.042
0.042
283.15
0.057
0.055
0.054
288.15
0.072
0.071
0.069
293.15
0.091
0.09
0.087
298.15
0.112
0.113
0.11
303.15
0.137
0.139
0.138
308.15
0.169
0.168
0.171
313.15
0.201
0.201
0.21
Acetonitrile
a
Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45kPa; Relative standard uncertainty ur is ur (x) = 0.043.
Table 3 Experimentaland calculate mole solubility of propacetamol hydrochloride in mixture of acetone (w) + ethanol (1-w) at the temperature range from T = (273.15 To 313.15) K under 101.3kPa.a w w=0.200
T/K
104xexp
a
104xJ-A
w=0.400 104xexp
104xJ-A
w=0.600 104xexp
104xJ-A
w=0.800 104xexp
104xJ-A
273.15
0.918
0.903
0.725
0.692
0.458
0.495
0.342
0.342
278.15
1.084
1.109
0.862
0.856
0.589
0.616
0.428
0.430
283.15
1.302
1.320
1.020
1.023
0.729
0.741
0.519
0.521
288.15
1.537
1.570
1.207
1.221
0.892
0.888
0.629
0.627
293.15
1.803
1.851
1.409
1.444
1.043
1.055
0.738
0.749
298.15
2.109
2.157
1.654
1.683
1.240
1.231
0.870
0.875
303.15
2.486
2.445
1.906
1.915
1.445
1.407
1.016
1.005
308.15
2.856
2.792
2.195
2.191
1.682
1.615
1.171
1.157
313.15
3.262
3.127
2.530
2.463
1.941
1.825
1.338
1.315
Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45kPa; Relative standard uncertainty ur is ur (x) = 0.048. Solvent mixtures were prepared by
mixing different masses of the solvents with relative standard uncertainty ur (w) = 0.002. w represents the mass fraction of acetone in mixed solvents.
Table 4 Hildebrand solubility parameters (δH) and solvatochromic parameters , and * for the selected solvents.a Solvent
a
α
β
δ2 H/1000
π*
(J/cm3)
methanol
0.98
0.66
0.60
0.8797
ethanol
0.86
0.75
0.54
0.5630
n-propanol
0.84
0.9
0.52
0.6025
isopropanol
0.76
0.84
0.48
0.563
acetone
0.08
0.43
0.71
0.3994
acetonitrile
0.19
0.4
0.75
0.5806
taken from ref.21
Table 5 Parameters of the modified Apelblat equation and h equation for propacetamol hydrochloride in different solvents.
h equation
Modified Apelblat equation Solvent A
B
102
C
RAD
h
102 RAD
Methanol
110.556
-7163.871
-16.393
0.41
0.021
107644.103
1.59
Ethanol
151.814
-9210.039
-22.652
0.43
0.008
307655.875
1.65
n-Propanol
195.258
-12410.691
-28.679
1.25
0.013
318897.251
2.89
Isopropanol
224.438
-13698.080
-33.088
1.11
0.010
413040.666
3.09
Acetone
159.700
-9864.747
-23.893
0.42
0.003
883860.022
2.04
Acetonitrile
198.459
-12580.088
-29.426
1.73
0.002
1632016.13
3.60
Table 6 Values of parameters of Jouyban-acree model along with RAD and linear correlation coefficient.
Parameter Values
J0
J1
J2
102RAD
R2
-16.136
-109.219
-317.474
1.32
0.999
Table 7 18
Standard dissolution enthalpy of propacetamol hydrochloride in pure and mixture of acetone (w) + ethanol (1-w) solvents at mean harmonic temperature (292.58 K). o Gsol
o H sol
o Ssol
kJ·mol-1
kJ·mol-1
J·mol-1
Methanol
17.112
19.780
Ethanol
20.238
n-Propanol
%H
% TS
9.120
88.11
11.89
21.501
4.316
94.45
5.55
24.450
33.643
31.418
78.54
21.46
Isopropanol
25.082
33.673
29.362
79.67
20.33
Acetonitrile
28.391
33.557
17.657
86.66
13.34
Acetone
23.645
24.018
1.275
98.47
1.53
solvents
Acetone (w) +ethanol (1-w) w=0.2
21.008
22.753
5.965
92.88
7.12
w=0.4
21.609
22.224
2.104
97.30
2.70
w=0.6
22.386
25.260
9.825
89.78
10.22
w=0.8
23.220
24.107
3.031
96.45
3.55
19
Abstract Graphic
20
1. The solubility of propacetamol hydrochloride in pure and binary solvents; 2. The solubility data were correlated by some thermodynamic models; 3. The effect of solvent properties on the solubility was analyzed; 4. Some thermodynamic properties of dissolution process were evaluated.
21