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Cosolvent action of promethazine hydrochloride in (ethyl acetate + alcohols) and thermodynamic property analysis
Journal Pre-proofs Cosolvent action of promethazine hydrochloride in (ethyl acetate + alcohols) and thermodynamic property analysis Zehui Yang, Danfeng Shao, Guoquan Zhou PII: DOI: Reference:
S0021-9614(19)31059-6 https://doi.org/10.1016/j.jct.2019.106030 YJCHT 106030
To appear in:
J. Chem. Thermodynamics
Received Date: Revised Date: Accepted Date:
8 July 2019 12 December 2019 13 December 2019
Please cite this article as: Z. Yang, D. Shao, G. Zhou, Cosolvent action of promethazine hydrochloride in (ethyl acetate + alcohols) and thermodynamic property analysis, J. Chem. Thermodynamics (2019), doi: https://doi.org/ 10.1016/j.jct.2019.106030
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Cosolvent action of promethazine hydrochloride in (ethyl acetate + alcohols) and thermodynamic property analysis Zehui Yang *, Danfeng Shao*, Guoquan Zhou, School of Materials and Chemical Engineering, Ningbo University of Technology, Ningbo City, Zhejiang Provice,315211,PRC.
Corresponding author: Zehui Yang ([email protected]); Danfeng Shao ([email protected]).
ABSTRACT This study presents the solubility profiles of promethazine hydrochloride in pure and mixed solvents. The effects of temperature and composition of mixed solvents on solubility were investigated. Maximum solubility value was obtained in n-propanol in pure solvents, and in ethyl acetate, it is the lowest. While in two mixtures of ethyl acetate (1-w) + ethanol (w, mass fraction) and ethyl acetate (1-w) + isopropanol (w), the values increased monotonically with the increasing temperature, and increased with increasing co-solvent (alcohols) mass fraction (w) to a maximum value at w = 0.4 and then decreased. The interaction between promethazine hydrochloride molecule and solvent molecules was discussed. The function of temperature and solvent composition in pure and binary mixed solvents was evaluated by some thermodynamic models. The dissolution thermodynamic properties, including enthalpy, entropy and Gibbs energy of promethazine hydrochloride in the dissolution process were evaluated using the van't Hoff equation. The results indicate that in all selected solvents the dissolution behavior were endothermic and entropy-driven. Key words: Promethazine hydrochloride; Cosolvent action; Solubility behavior; Thermodynamic properties
1. Introduction Phenothiazines form a large class of basic drugs used primarily for the treatment of moderate to severe mental disorders. They can also be used as anti-emetics, sedatives, antipuritics, antidyskinetics, analgesics
and antihistaminics. [1-4] Promethazine hydrochloride (PMT) is one of the most important amphiphilic phenothiazine drug (Fig. 1). As therapeutic agents, it is widely used to treat various mental and personality disorders. [5] It is also used to prevent and treat nausea and vomiting related to certain conditions, and treat allergy symptoms such as rash, itching, and runny nose. [6-8] PMT is usually available as a mono component in dosage forms involving injections, oral suspensions, tablets, suppositories and syrup.[1] According to Indian Patent 2010MU00613, the mixed impurity in PMT is removed by crystallization in a mixed solvent of isopropanol and toluene. [9] However, Urszula Doman´ska and his co-workers studied the equilibrium mole fraction solubility of PMT in a range of temperatures from 240 to 340 K in three important solvents for drugs: water, ethanol, and 1-octanol using the dynamic method. [10] Besides, PMT contains a structure consisting of a hydrophobic (rigid, almost planar tricyclic ring system) and a hydrophilic (short hydrocarbon chain carrying a terminal nitrogen atom) portion, therefore, it is amphipathic molecule, and temperature and pure or mixed organic solvents with medium polarity have certain effects on the dissolution behavior. This thermodynamic behavior and understanding of interaction mechanisms between drugs and solvents play a pivotal role in the design of drug compounds as well as in the development and optimization of drug manufacturing processes. The objective of this work is further to study the shape of the solubility profile and dissolution thermodynamic properties of PMT in pure and mixed solvents with a wide polarity range.
2. Experimental 2.1. Materials Promethazine hydrochloride with purity > 99% was provided by Hubei Jinshuo Biotechnology Co., Ltd. (China). In this work a commercial PMT mixture of enantiomers (R+, S-), (the composition is about 1: 1) was used. The purity of 0.996 in mass fraction was measured by high performance liquid phase chromatograph (HPLC). Ethanol, n-propanol, acetonitrile, isopropanol and ethyl acetate which were of analytical grade with purity over 99.5% were all purchased from Sinopharm Chemical Reagent Co., Ltd., China. The detailed information of these materials in the present work was presented in Table 1.
2.2. Melting properties measurement The DSC curves of PMT raw and excess solid in solution were measured, and the high purity nitrogen was used as protection gas with constant flow rate of 100 mL·min−1. Before experiment, the differential scanning calorimetric (DSC) instrument (Pyris-Diamond, PerkinElmer) was calibrated by using indium standard. About 5 mg samples powder was added into the hermetic DSC pan. After that, starting the heating program within a certain temperatures range (from 303.15K to 523.15K) at a heating rate of 5 K·min−1. 2.3. Solubility measurement The operation of the measurement is the same as our previous research methods. [11, 12] Therefore, the experimental process described simply here. The measurement was carried out in jacketed glass vessel with magnetic stirring, and the temperature was controlled by a thermostatically controlled water bath through the outer jacket. The actual temperature in the vessel was measured by a micro thermometer with a standard uncertainty of ± 0.02 K. A reflux condenser was directly connected to the vessel to prevent solvent from evaporating. During the experiment, the fluctuation range of atmospheric pressure is 400 Pa. To determine the concentration of PMT, an Agilent 1260 HPLC system coupled with a UV detector was used. All the chromatographic analysis was performed on C18 column. The detective wavelength was set at 298 nm, and chromatograph procedure was performed at 303.15K. The mobile phase was pure methanol. In order to check the repeatability of solubility determination, each experiment was repeated two times and then the average value was used to calculate the mole fraction solubility.
3. Results and discussion 3.1. Results of melting properties The thermal analyses of PMT raw and excess solid in solution are shown in Fig. 2. In this study, the onset point of the DSC curve (the intersection of the extension of the baseline with the tangent at the point of greatest slope of the DSC curve) is used as the melting point. According to the results shown in Fig. 2, the DSC curves of PMT raw and excess solid in solution are almost identical, and the onset and peak temperatures are about 500.64K, 506.30K, respectively. The enthalpy of fusion of PMT is 28.91
kJ·mol−1 in this work. The standard uncertainties of the measurement were estimated to be 0.5 K for the temperature and 400 J·mol−1 for the melting enthalpy. According to the ICTAC and GEFTA recommendations, onset temperature is used as melting temperature. In reference 10, the melting point and enthalpy of fusion of PMT are 499.0K and 28.4 kJ·mol−1, respectively. The melting point and enthalpy of melting between the experimental values and literature values have slight deviation. It may be due to the different experimental process, such as the heating rate of 10 K·min−1 in the literature. It can be seen that no polymorph transformation or solvate formation is observed during the whole experiment. 3.2. Effect of the solvent properties on solubility in pure solvents The mole fraction solubility data of PMT in ethanol, n-propanol, isopropanol, acetonitrile and acetone and two mixtures over the temperature from 273.15 to 313.15 K are presented in Tables 2 and 3, and are graphically plotted in Figs. 3 and 4, respectively. Compared with the result in ethanol reported by Urszula Doman´ska and his co-workers, it shows good agreement with the literature data. Moreover, the properties of solvents including dipolarity/polarizability (π*), hydrogen-bond donor acidity (α), hydrogen-bond acceptor basicity (β) and solubility parameters (δ2) are listed in Table 4. [13] As expected, the solubility value in pure solvents and two mixtures with a fixed composition increased with the rising temperature. In all studied pure solvents, the mole solubility are in general in the order of n-propanol > ethanol > acetonitrile > isopropanol > ethyl acetate. According to polarity index in Table 4, the result shows that the solubility of PMT decreases with decreasing solubility parameters (δ2) of the solvents except for n-propanol. As can be seen from Fig.1, PMT contains a structure consisting of a hydrophobic (rigid, almost planar tricyclic ring system) and a hydrophilic (short hydrocarbon chain carrying a terminal nitrogen atom) portion, hence it is amphipathic molecule, and has medium polarity similar with that of n-propanol. According to the empirical rule “like dissolves like”, the solubility in n-propanol is highest. However, the higher and lower polarity of solvent (such as ethanol and ethyl acetate) may increase the repulsion between the solvent molecule and the hydrophobic and hydrophilic portion, which leads to the lower solubility. The complex dissolution process is affected by various factors, such as chemical structure and properties of solute along with solvent, as well as solvating interactions, especially the
hydrogen-bond interaction. Through the analysis of hydrogen-bond donor (HBD) acidity (α) and hydrogen-bond acceptor (HBA) basicity (β) for all selected solvents, HBD acidity and HBA basicity are all contributive to the hydrogen-bond interaction between solutes and solvents. 3.3. The effect of solvent properties on solubility in mixed solvents In two mixtures of ethanol (w) + ethyl acetate (1-w) and isopropanol (w) + ethyl acetate (1-w), the solubility of PMT increases to a maximum with the increasing the concentration of alcohols, and then decreases with further increase of alcohols, the maximum data is founded at the composition of w=0.4. -2
Particularly, in mixture of isopropanol (w) + ethyl acetate (1-w), the solubility data is 0.11310 at 273.15K, and at w=0.4, it is 0.99510-2, nearly increases 9 times. As mentioned above, PMT is amphipathic molecule. With the addition of alcohols, ethanol or isopropanol participates in the solvation of the hydrophilic species by replacing some ethyl acetate molecules in the solvation of ethyl acetate shell of the solute. In addition, in pure ethyl acetate, with the increase of alcohol composition, the polarity of the mixed system increases, and the polarity difference between the system and the solute decreases firstly and then increases. According to the empirical rule “like dissolves like”, the solubility data first increases and then decreases with the increase of alcohols. Therefore, the co-solvent action is affected not only by the interaction force between solvent and solute molecule but also the polarity of solvent. 3.4. Solubility modeling The results of dissolution process of PMT in different solvents were evaluated by the modified Apelblat equation, [14-16] h equation and [15, 16]Jouyban-Acree model [17]. The connection of existence between the solubility data in selected pure solvents and the temperature in Kelvin can be concluded by the Modified Apelblat equation. It was shown in Eq. (1) [14-16]. Where A, B and C are the equation parameters.
B l nxm , T A C l n T T
(1)
Another semi-empirical equation used is h equation, which is used to describe the solid–liquid equilibrium behavior of PMT as well, and expressed as equation (2). [15,16] The h equation has two parameters and h.
1 x 1 1 ln 1 h x T Tm
(2)
Where and h are adjustable equation parameters, Tm denotes the melting temperature of PMT in Kelvin.
The Jouyban-Acree model is usually used to describe the solute solubility as a function of temperature and solvent composition in binary mixed solvents. [17] The model is described as Eq. (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 PMT in mixture solvents; m1 and m2 are the mass fraction of corresponding solvent; x1,T and x2,T are the PMT solubility in pure solvent; Ji is the model parameters. The accuracy of two thermodynamic models association is evaluated by the relative average deviation and (RAD) and root-mean-square deviation (RMSD), as shown in Eqs. (4) and (5). 1 RAD N
RMSD
N
i 1
N i 1
xie xic xie
( xic xie )2
(4)
(5)
N
xie and xic are the experimental and calculated values. N is the number of experimental points.
The calculated values and model parameters along with the RAD and RMSD values are listed in Tables 2, 3 and Tables 5, 6, respectively. Regression model parameters are particularly important in the field of medicine. Moreover, in mixed solvents, experimental and calculated values are shown graphically in 3d-plot and 2d-plot in Fig.4. In pure and mixed solvents systems, the maximum value of RMSD are all less than 2.2910-4 and 12.4110-4, respectively. The values RAD are a little larger, in pure solvent, the maximum is 2.1510-2, however, it reaches a maximum, 4.9810-2, in system of isopropanol + ethyl acetate. Compared with h equation, the modified Apelblat equation has the smaller RMSD and RAD values. Therefore, the modified Apelblat equation is more suitable to describe the solubility of PMT in selected pure solvents. As for two mixtures of alcohols + ethyl acetate, the calculation deviation of the
model is within the acceptable range of engineering application. Hence, Jouyban-Acree model could be used to describe the solubility behavior of PMT well in binary solvents at different composition ranges. Generally known, the dissolution of PMT in corresponding solvents relates to some changes of thermodynamic parameters. Thermodynamic property of a solute dissolved in solvents can provide important information for the dissolution process. Thermodynamic properties of PMT in pure and mixed o solvents including the apparent dissolution standard enthalpy ( H sol ), apparent molar standard Gibbs
o o o o energy ( Gsol ) and S sol are described as the following Eqs. (6)-(9) [18-20]. The H sol and Gsol can
be acquired from the slope and intercept of the solubility curves of lnxw,T versus 1/T. The results of van’t Hoff plots for PMT dissolution are shown in Fig. 5. ln xw,T ln xw,T o H sol R R (1/ T ) (1/ T ) (1 / T ) p hm p o Gsol RThm intercept
o Ssol
(6)
(7)
o o H sol Gsol Thm
(8)
Where n is the number of temperature points. R is the universal gas constant. Ti is the experiment temperature. Thm refers to the mean harmonic temperature and can be computed with Eq. (9).
Thm
n 1 i 1 T i
(9)
n
At Thm = 292.58K, the values of apparent thermodynamic properties are all positive and listed in Table o 7. Remarkably, the lower Gsol value for dissolution of PMT indicates that lower energies are required,
which indicates that the dissolution capacity in pure and mixed solvents is consistent with the sequence of o . As expect, the values of standard dissolution enthalpy are all positive and within the range of Gsol
(16.746 to 29.388 kJ·mol−1), the dissolution process is endothermic, which give a good reason to explain
o the increasing solubility with increasing temperature. From Table 7, the S sol values for dissolution
behavior are all positive as well, which indicate the dissolution process is apparently not only endothermic but also entropy-driving.
4. Conclusions The solubility profiles of promethazine hydrochloride in pure and mixed solvents were determined. The maximum solubility value was obtained in n-propanol in pure solvents, and in ethyl acetate, it is the lowest. In mixtures of ethyl acetate (1-w) + ethanol (w, mass fraction) and ethyl acetate (1-w) + isopropanol (w), the values increased monotonically with the increasing temperature, and increased with increasing co-solvent (alcohols) mass fraction (w) to a maximum value at w = 0.4 and then decreased. Through the analysis of hydrogen-bond donor acidity and hydrogen-bond acceptor basicity for all selected solvents, HBD acidity and HBA basicity are all contributive to the hydrogen-bond interaction between solutes and solvents. The modified Apelblat equation and Jouban-Acree model are suitable to describe the solubility of PMT in selected solvents. The calculation of dissolution thermodynamic properties indicate that in all selected solvents the dissolution process is endothermic and entropy-driven. Acknowledgment The research is supported by China National Key Research and invention program of the thirteenth Five-Year Plan (No.2017YFD0200707). And the authors also want to give thanks to the Ministry of Education Scientific Research Foundation (No.XM20131225085213994) as well as Zhejiang Province Public Technology Project (No.2013C31G2290019) and Ningbo Natural Science Foundations (No.2013A610094 and No. 2018A610411).
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Fig. 1. Chemical structure of promethazine hydrochloride.
acetonitrile ethyl acetate isopropanol
DSC mW/mg
n-propanol ethanol raw
Tm =500.64K H fus 28.91kJ/mol
Tpeak =506.30K
360
400
440
480
520
ethanol (w)+ ethyl acetate (1-w),w=0.2
isopropanol (w)+ ethyl acetate (1-w),w=0.2
ethanol (w)+ ethyl acetate (1-w),w=0.4
isopropanol(w)+ ethyl acetate (1-w), w=0.4
ethanol (w)+ ethyl acetate (1-w),w=0.6
isopropanol (w)+ ethyl acetate (1-w),w=0.6
ethanol (w)+ ethyl acetate (1-w), w=0.8
isopropanol(w)+ ethyl acetate (1-w),w=0.8
DSC mW/mg
DSC mW/mg
T/K
raw
raw
Tpeak =506.30K
360
400
440 T/K
480
Tpeak =506.30K 520
360
400
440
480
520
T/K
Fig. 2. DSC curves of promethazine hydrochloride in pure and mixed solvents during the experiment.
0.024
x
0.018
x
ethanol in this work cited from ref.10
ethanol n-propanol isopropanol ethyl acetate acetonitrile
0.012
0.006
0.000
280
290
300
280
310
290
300
310
T/K
T/K
Fig. 3. Solubility data of promethazine hydrochloride in pure solvents within the temperature range from T/K
= (273.15 to 313.15).
. 273.15K, 288.15K, 303.15K,
0.024
278.15K, 293.15K, 308.15K,
283.15K 298.15K 313.15K
278.15K, 293.15K, 308.15K,
283.15K 298.15K 313.15K
0.024
0.018
0.018
0.012
x
x
273.15K, 288.15K, 303.15K,
0.030
0.012 0.006
0.006 ethanol+ ethyl acetate
0.000
0.0
0.2
0.4
0.6 w
0.8
1.0
0.000
isopropanol+ ethyl acetate
0.0
0.2
0.4
0.6 w
0.8
1.0
Fig. 4. Experimental solubility data of promethazine hydrochloride in mixture of alcohol (w) + ethyl acetate (1-w) within the temperature range from T/K = (273.15 to 313.15) in 3d-plot, and 2d-plot is a comparison between experimental and calculated values, symbols is experimental data,w, is the mass fraction of alcohol in mixed solvents,---, calculated by Jouyban-Acree model.
-3.0 -4.0
ln(x)
ln(x)
-5.6 -6.3
-5.0
w=0.2 w=0.4 w=0.6 w=0.8
-3.6
w=0.2 w=0.4 w=0.6 w=0.8
-4.5
-4.9
isopropanol(w) + ethyl acetate (1-w)
ethanol(w) + ethyl acetate (1-w)
-4.2 ln(x)
-4.2
ethanol; n-propanol isopropanol; ethyl acetate acetonitrile
-4.8 -5.4
-5.5
-6.0
-7.0 -0.0002 -0.0001 0.0000 0.0001 0.0002 (1/T-1/Thm)/K-1
-6.0
-0.0002 -0.0001 0.0000 0.0001 0.0002 (1/T-1/Thm)/K-1
-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 alcohol (w) + ethyl acetate (1-w), w, is the mass fraction of alcohol in mixed solvents.
Table 1 Detailed information on the materials used in the work.
Chemicals
Molar mass
CAS NO.
Source
g·mol−1
a
Promethazine hydrochloride
58-33-3
320.88
Ethanol
64-17-5
46.07
Isopropanol
67-63-0
60.1
n-Propanol
71-23-8
60.1
Ethyl acetate
141-78-6
88.11
Acetonitrile
75-05-8
41.05
Hubei Jinshuo Biotechnology Co., Ltd. (China)
mass fraction purity
Analytical method
0.996
HPLCa
0.998b Sinopharm Chemical Reagent Co., Ltd.,China
0.998 b 0.995 b
None
0.996 b 0.995 b
High-performance liquid phase chromatograph. b the purity was provided by supplier.
Table 2 Experimental (xe) and calculated (xcal) mole fraction solubility of promethazine hydrochloride in different solvents at the temperature range from T = (273.15 To 313.15) K under P=101.3kPa.a
T/K
100x
273.15
0.2739
100xcal Modified Apelblat equation Ethanol 0.2677
278.15
0.3463
0.3453
0.3491
283.15
0.4322
0.4388
0.4367
288.15
0.5454
0.5498
0.542
293.15
0.6800
0.6797
0.6678
298.15
0.8363
0.8298
0.8171
303.15
0.9965
1.0012
0.9931
308.15
1.200
1.1944
1.1995
313.15
1.407
1.410
1.440
0.76
1.15
e
100 RAD n-Propanol
λh equation 0.2768
273.15
0.7236
0.7274
0.746
278.15
0.859
0.8624
0.8672
283.15
1.017
1.011
1.0033
288.15
1.180
1.173
1.1553
293.15
1.348
1.3477
1.3245
298.15
1.528
1.5342
1.5125
303.15
1.730
1.7313
1.7204
308.15
1.936
1.9378
1.9500
313.15
2.155
2.1521
2.2028
0.31
1.53
100 RAD Isopropanol 273.15
0.1130
0.1146
0.1170
278.15
0.1400
0.1396
0.1402
283.15
0.1689
0.1681
0.1669
288.15
0.2019
0.2003
0.1976
293.15
0.2354
0.2362
0.2326
298.15
0.2759
0.2760
0.2726
303.15
0.3200
0.3196
0.3179
308.15
0.3650
0.3670
0.3691
313.15
0.4193
0.4181
0.4268
0.48
1.44
100 RAD Acetonitrile 273.15
0.2229
0.2259
0.2337
278.15
0.2887
0.2882
0.2902
283.15
0.3631
0.3617
0.3577
288.15
0.4484
0.4472
0.4377
293.15
0.5451
0.5449
0.532
298.15
0.6569
0.6552
0.6424
303.15
0.7785
0.7779
0.7712
308.15
0.9059
0.9125
0.9204
313.15
1.0620
1.0580
1.0926
0.40
2.15
100 RAD Ethyl acetate
273.15
0.0885
0.088
0.0865
278.15
0.0988
0.0989
0.0985
283.15
0.1111
0.1112
0.1117
288.15
0.1247
0.1251
0.1263
293.15
0.1405
0.1408
0.1423
298.15
0.1580
0.1584
0.1599
303.15
0.1795
0.1783
0.1791
308.15
0.2008
0.2007
0.2000
313.15
0.2255
0.2259
0.2229
0.27
0.96
100 RAD a
Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45kPa; Relative standard uncertainty ur is ur (x) = 0.046.
Table 3 Experimental (xe) and calculated (xcal) mole fraction solubility of promethazine hydrochloride in two mixtures of ethanol (w) + ethyl acetate (1-w) and isopropanol (w) + ethyl acetate (1-w) at the temperature range from T = (273.15 To 313.15) K under 101.3kPa.a w w=0.200
T/K
102xexp
w=0.400 102xJ-A
102xexp
102xJ-A
w=0.800
w=0.600 102xexp
102xJ-A
102xexp
102xJ-A
ethanol (w) + ethyl acetate (1-w) 273.15
0.3486
0.5052
0.6531
0.7065
0.5424
0.5796
0.4339
0.4263
278.15
0.4355
0.5629
0.7695
0.8054
0.6454
0.6824
0.5321
0.5195
283.15
0.5488
0.6296
0.9129
0.9179
0.7854
0.8001
0.6347
0.6276
288.15
0.6682
0.7053
1.067
1.051
0.9239
0.9442
0.7702
0.7651
293.15
0.8200
0.7913
1.245
1.201
1.100
1.109
0.9269
0.9247
298.15
0.9933
0.8847
1.437
1.365
1.284
1.291
1.107
1.105
303.15
1.180
0.9917
1.635
1.542
1.487
1.482
1.303
1.292
308.15
1.379
1.101
1.842
1.735
1.722
1.703
1.519
1.518
313.15
1.603
1.221
2.109
1.937
1.956
1.930
1.754
1.748
isopropanol (w) + ethyl acetate (1-w) 273.15
0.3713
0.4149
0.9949
1.005
0.9536
1.088
0.5261
0.5106
278.15
0.4117
0.4606
1.124
1.122
1.063
1.239
0.6075
0.6025
283.15
0.4637
0.5118
1.278
1.246
1.205
1.395
0.7120
0.6976
a
288.15
0.5243
0.5673
1.442
1.379
1.373
1.563
0.8374
0.8023
293.15
0.5896
0.6282
1.669
1.517
1.561
1.731
0.9533
0.9060
298.15
0.6790
0.6958
1.908
1.673
1.759
1.923
1.087
1.028
303.15
0.7846
0.7761
2.160
1.850
2.037
2.134
1.233
1.160
308.15
0.8845
0.8527
2.430
2.015
2.322
2.333
1.380
1.288
313.15
1.004
0.9417
2.702
2.210
2.634
2.569
1.544
1.441
Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45kPa; Relative standard uncertainty ur is ur (x) = 0.052. 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 alcohols in system of alcohol(w) + ethyl acetate (1-w).
Table 4 Hildebrand solubility parameters (δH) and solvatochromic parameters , and * for the selected solvents.a 2
α
Solvent
a
β
δH/1000
π*
(J/cm3)
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
ethyl acetate
0
0.45
0.55
0.331
acetonitrile
0.19
0.4
0.75
0.5806
from ref.13.
Table 5 Parameters of the modified Apelblat equation and h equation for promethazine hydrochloride in different solvents.
h equation
Modified Apelblat equation Solvent A
B
104RMS D
C
h
104 RMSD
Ethanol
134.482
-9126.348
-19.072
0.48
0.976
3612.397
1.36
n-Propanol
110.466
-6996.197
-16.003
0.42
0.309
7281.626
2.29
Isopropanol
95.606
-6803.296
-13.809
0.12
0.105
25709.366
0.39
Ethyl acetate
-96.923
2239.55
14.561
0.05
0.019
98826.054
0.15
Acetonitrile
165.492
-10280.108
-23.877
0.28
0.549
5979.812
1.43
Table 6 Values of parameters of Jouyban-Acree model along with RAD and RMSD values. J0
J1
J2
102RAD
103RMSD
ethanol + ethyl acetate
1576.958
-1206.609
800.054
4.45
8.46
isopropanol + ethyl acetate
2679.672
86.257
-202.989
4.98
12.41
20
Table 7 Standard dissolution enthalpy of promethazine hydrochloride in pure and mixture solvents at mean harmonic temperature (292.58 K). o Gsol
o H sol
o S sol
kJ·mol-1
kJ·mol-1
J·mol-1·K-1
Ethanol
12.241
29.388
58.605
n-Propanol
10.552
19.316
29.956
Isopropanol
14.790
23.079
28.329
Acetonitrile
12.790
27.542
50.422
Ethyl acetate
15.970
16.746
2.652
ethanol (w) + ethyl acetate (1-w),w=0.2
11.779
27.295
53.031
ethanol (w) + ethyl acetate (1-w), w=0.4
10.738
20.831
34.497
ethanol (w) + ethyl acetate (1-w), w=0.6
11.044
22.988
40.823
ethanol (w) + ethyl acetate (1-w), w=0.8
11.448
25.015
46.367
isopropanol(w) + ethyl acetate (1-w),w=0.2
12.437
17.950
18.841
isopropanol (w) + ethyl acetate (1-w), w=0.4 9.977
18.113
27.807
isopropanol (w) + ethyl acetate (1-w), w=0.6 10.108
18.246
27.818
isopropanol (w) + ethyl acetate (1-w), w=0.8 11.380
19.308
27.098
solvents
21
1. Research the solubility profiles of promethazine hydrochloride in pure and mixed solvents; 2. Discuss the effect of solvent properties on the dissolution process; 3. The interaction between promethazine hydrochloride molecule and solvent molecules was analyzed. 4. Some thermodynamic properties of dissolution process are evaluated.
22
Abstract Graphic
23
S0021-9614(19)31059-6 https://doi.org/10.1016/j.jct.2019.106030 YJCHT 106030
To appear in:
J. Chem. Thermodynamics
Received Date: Revised Date: Accepted Date:
8 July 2019 12 December 2019 13 December 2019
Please cite this article as: Z. Yang, D. Shao, G. Zhou, Cosolvent action of promethazine hydrochloride in (ethyl acetate + alcohols) and thermodynamic property analysis, J. Chem. Thermodynamics (2019), doi: https://doi.org/ 10.1016/j.jct.2019.106030
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Cosolvent action of promethazine hydrochloride in (ethyl acetate + alcohols) and thermodynamic property analysis Zehui Yang *, Danfeng Shao*, Guoquan Zhou, School of Materials and Chemical Engineering, Ningbo University of Technology, Ningbo City, Zhejiang Provice,315211,PRC.
Corresponding author: Zehui Yang ([email protected]); Danfeng Shao ([email protected]).
ABSTRACT This study presents the solubility profiles of promethazine hydrochloride in pure and mixed solvents. The effects of temperature and composition of mixed solvents on solubility were investigated. Maximum solubility value was obtained in n-propanol in pure solvents, and in ethyl acetate, it is the lowest. While in two mixtures of ethyl acetate (1-w) + ethanol (w, mass fraction) and ethyl acetate (1-w) + isopropanol (w), the values increased monotonically with the increasing temperature, and increased with increasing co-solvent (alcohols) mass fraction (w) to a maximum value at w = 0.4 and then decreased. The interaction between promethazine hydrochloride molecule and solvent molecules was discussed. The function of temperature and solvent composition in pure and binary mixed solvents was evaluated by some thermodynamic models. The dissolution thermodynamic properties, including enthalpy, entropy and Gibbs energy of promethazine hydrochloride in the dissolution process were evaluated using the van't Hoff equation. The results indicate that in all selected solvents the dissolution behavior were endothermic and entropy-driven. Key words: Promethazine hydrochloride; Cosolvent action; Solubility behavior; Thermodynamic properties
1. Introduction Phenothiazines form a large class of basic drugs used primarily for the treatment of moderate to severe mental disorders. They can also be used as anti-emetics, sedatives, antipuritics, antidyskinetics, analgesics
and antihistaminics. [1-4] Promethazine hydrochloride (PMT) is one of the most important amphiphilic phenothiazine drug (Fig. 1). As therapeutic agents, it is widely used to treat various mental and personality disorders. [5] It is also used to prevent and treat nausea and vomiting related to certain conditions, and treat allergy symptoms such as rash, itching, and runny nose. [6-8] PMT is usually available as a mono component in dosage forms involving injections, oral suspensions, tablets, suppositories and syrup.[1] According to Indian Patent 2010MU00613, the mixed impurity in PMT is removed by crystallization in a mixed solvent of isopropanol and toluene. [9] However, Urszula Doman´ska and his co-workers studied the equilibrium mole fraction solubility of PMT in a range of temperatures from 240 to 340 K in three important solvents for drugs: water, ethanol, and 1-octanol using the dynamic method. [10] Besides, PMT contains a structure consisting of a hydrophobic (rigid, almost planar tricyclic ring system) and a hydrophilic (short hydrocarbon chain carrying a terminal nitrogen atom) portion, therefore, it is amphipathic molecule, and temperature and pure or mixed organic solvents with medium polarity have certain effects on the dissolution behavior. This thermodynamic behavior and understanding of interaction mechanisms between drugs and solvents play a pivotal role in the design of drug compounds as well as in the development and optimization of drug manufacturing processes. The objective of this work is further to study the shape of the solubility profile and dissolution thermodynamic properties of PMT in pure and mixed solvents with a wide polarity range.
2. Experimental 2.1. Materials Promethazine hydrochloride with purity > 99% was provided by Hubei Jinshuo Biotechnology Co., Ltd. (China). In this work a commercial PMT mixture of enantiomers (R+, S-), (the composition is about 1: 1) was used. The purity of 0.996 in mass fraction was measured by high performance liquid phase chromatograph (HPLC). Ethanol, n-propanol, acetonitrile, isopropanol and ethyl acetate which were of analytical grade with purity over 99.5% were all purchased from Sinopharm Chemical Reagent Co., Ltd., China. The detailed information of these materials in the present work was presented in Table 1.
2.2. Melting properties measurement The DSC curves of PMT raw and excess solid in solution were measured, and the high purity nitrogen was used as protection gas with constant flow rate of 100 mL·min−1. Before experiment, the differential scanning calorimetric (DSC) instrument (Pyris-Diamond, PerkinElmer) was calibrated by using indium standard. About 5 mg samples powder was added into the hermetic DSC pan. After that, starting the heating program within a certain temperatures range (from 303.15K to 523.15K) at a heating rate of 5 K·min−1. 2.3. Solubility measurement The operation of the measurement is the same as our previous research methods. [11, 12] Therefore, the experimental process described simply here. The measurement was carried out in jacketed glass vessel with magnetic stirring, and the temperature was controlled by a thermostatically controlled water bath through the outer jacket. The actual temperature in the vessel was measured by a micro thermometer with a standard uncertainty of ± 0.02 K. A reflux condenser was directly connected to the vessel to prevent solvent from evaporating. During the experiment, the fluctuation range of atmospheric pressure is 400 Pa. To determine the concentration of PMT, an Agilent 1260 HPLC system coupled with a UV detector was used. All the chromatographic analysis was performed on C18 column. The detective wavelength was set at 298 nm, and chromatograph procedure was performed at 303.15K. The mobile phase was pure methanol. In order to check the repeatability of solubility determination, each experiment was repeated two times and then the average value was used to calculate the mole fraction solubility.
3. Results and discussion 3.1. Results of melting properties The thermal analyses of PMT raw and excess solid in solution are shown in Fig. 2. In this study, the onset point of the DSC curve (the intersection of the extension of the baseline with the tangent at the point of greatest slope of the DSC curve) is used as the melting point. According to the results shown in Fig. 2, the DSC curves of PMT raw and excess solid in solution are almost identical, and the onset and peak temperatures are about 500.64K, 506.30K, respectively. The enthalpy of fusion of PMT is 28.91
kJ·mol−1 in this work. The standard uncertainties of the measurement were estimated to be 0.5 K for the temperature and 400 J·mol−1 for the melting enthalpy. According to the ICTAC and GEFTA recommendations, onset temperature is used as melting temperature. In reference 10, the melting point and enthalpy of fusion of PMT are 499.0K and 28.4 kJ·mol−1, respectively. The melting point and enthalpy of melting between the experimental values and literature values have slight deviation. It may be due to the different experimental process, such as the heating rate of 10 K·min−1 in the literature. It can be seen that no polymorph transformation or solvate formation is observed during the whole experiment. 3.2. Effect of the solvent properties on solubility in pure solvents The mole fraction solubility data of PMT in ethanol, n-propanol, isopropanol, acetonitrile and acetone and two mixtures over the temperature from 273.15 to 313.15 K are presented in Tables 2 and 3, and are graphically plotted in Figs. 3 and 4, respectively. Compared with the result in ethanol reported by Urszula Doman´ska and his co-workers, it shows good agreement with the literature data. Moreover, the properties of solvents including dipolarity/polarizability (π*), hydrogen-bond donor acidity (α), hydrogen-bond acceptor basicity (β) and solubility parameters (δ2) are listed in Table 4. [13] As expected, the solubility value in pure solvents and two mixtures with a fixed composition increased with the rising temperature. In all studied pure solvents, the mole solubility are in general in the order of n-propanol > ethanol > acetonitrile > isopropanol > ethyl acetate. According to polarity index in Table 4, the result shows that the solubility of PMT decreases with decreasing solubility parameters (δ2) of the solvents except for n-propanol. As can be seen from Fig.1, PMT contains a structure consisting of a hydrophobic (rigid, almost planar tricyclic ring system) and a hydrophilic (short hydrocarbon chain carrying a terminal nitrogen atom) portion, hence it is amphipathic molecule, and has medium polarity similar with that of n-propanol. According to the empirical rule “like dissolves like”, the solubility in n-propanol is highest. However, the higher and lower polarity of solvent (such as ethanol and ethyl acetate) may increase the repulsion between the solvent molecule and the hydrophobic and hydrophilic portion, which leads to the lower solubility. The complex dissolution process is affected by various factors, such as chemical structure and properties of solute along with solvent, as well as solvating interactions, especially the
hydrogen-bond interaction. Through the analysis of hydrogen-bond donor (HBD) acidity (α) and hydrogen-bond acceptor (HBA) basicity (β) for all selected solvents, HBD acidity and HBA basicity are all contributive to the hydrogen-bond interaction between solutes and solvents. 3.3. The effect of solvent properties on solubility in mixed solvents In two mixtures of ethanol (w) + ethyl acetate (1-w) and isopropanol (w) + ethyl acetate (1-w), the solubility of PMT increases to a maximum with the increasing the concentration of alcohols, and then decreases with further increase of alcohols, the maximum data is founded at the composition of w=0.4. -2
Particularly, in mixture of isopropanol (w) + ethyl acetate (1-w), the solubility data is 0.11310 at 273.15K, and at w=0.4, it is 0.99510-2, nearly increases 9 times. As mentioned above, PMT is amphipathic molecule. With the addition of alcohols, ethanol or isopropanol participates in the solvation of the hydrophilic species by replacing some ethyl acetate molecules in the solvation of ethyl acetate shell of the solute. In addition, in pure ethyl acetate, with the increase of alcohol composition, the polarity of the mixed system increases, and the polarity difference between the system and the solute decreases firstly and then increases. According to the empirical rule “like dissolves like”, the solubility data first increases and then decreases with the increase of alcohols. Therefore, the co-solvent action is affected not only by the interaction force between solvent and solute molecule but also the polarity of solvent. 3.4. Solubility modeling The results of dissolution process of PMT in different solvents were evaluated by the modified Apelblat equation, [14-16] h equation and [15, 16]Jouyban-Acree model [17]. The connection of existence between the solubility data in selected pure solvents and the temperature in Kelvin can be concluded by the Modified Apelblat equation. It was shown in Eq. (1) [14-16]. Where A, B and C are the equation parameters.
B l nxm , T A C l n T T
(1)
Another semi-empirical equation used is h equation, which is used to describe the solid–liquid equilibrium behavior of PMT as well, and expressed as equation (2). [15,16] The h equation has two parameters and h.
1 x 1 1 ln 1 h x T Tm
(2)
Where and h are adjustable equation parameters, Tm denotes the melting temperature of PMT in Kelvin.
The Jouyban-Acree model is usually used to describe the solute solubility as a function of temperature and solvent composition in binary mixed solvents. [17] The model is described as Eq. (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 PMT in mixture solvents; m1 and m2 are the mass fraction of corresponding solvent; x1,T and x2,T are the PMT solubility in pure solvent; Ji is the model parameters. The accuracy of two thermodynamic models association is evaluated by the relative average deviation and (RAD) and root-mean-square deviation (RMSD), as shown in Eqs. (4) and (5). 1 RAD N
RMSD
N
i 1
N i 1
xie xic xie
( xic xie )2
(4)
(5)
N
xie and xic are the experimental and calculated values. N is the number of experimental points.
The calculated values and model parameters along with the RAD and RMSD values are listed in Tables 2, 3 and Tables 5, 6, respectively. Regression model parameters are particularly important in the field of medicine. Moreover, in mixed solvents, experimental and calculated values are shown graphically in 3d-plot and 2d-plot in Fig.4. In pure and mixed solvents systems, the maximum value of RMSD are all less than 2.2910-4 and 12.4110-4, respectively. The values RAD are a little larger, in pure solvent, the maximum is 2.1510-2, however, it reaches a maximum, 4.9810-2, in system of isopropanol + ethyl acetate. Compared with h equation, the modified Apelblat equation has the smaller RMSD and RAD values. Therefore, the modified Apelblat equation is more suitable to describe the solubility of PMT in selected pure solvents. As for two mixtures of alcohols + ethyl acetate, the calculation deviation of the
model is within the acceptable range of engineering application. Hence, Jouyban-Acree model could be used to describe the solubility behavior of PMT well in binary solvents at different composition ranges. Generally known, the dissolution of PMT in corresponding solvents relates to some changes of thermodynamic parameters. Thermodynamic property of a solute dissolved in solvents can provide important information for the dissolution process. Thermodynamic properties of PMT in pure and mixed o solvents including the apparent dissolution standard enthalpy ( H sol ), apparent molar standard Gibbs
o o o o energy ( Gsol ) and S sol are described as the following Eqs. (6)-(9) [18-20]. The H sol and Gsol can
be acquired from the slope and intercept of the solubility curves of lnxw,T versus 1/T. The results of van’t Hoff plots for PMT dissolution are shown in Fig. 5. ln xw,T ln xw,T o H sol R R (1/ T ) (1/ T ) (1 / T ) p hm p o Gsol RThm intercept
o Ssol
(6)
(7)
o o H sol Gsol Thm
(8)
Where n is the number of temperature points. R is the universal gas constant. Ti is the experiment temperature. Thm refers to the mean harmonic temperature and can be computed with Eq. (9).
Thm
n 1 i 1 T i
(9)
n
At Thm = 292.58K, the values of apparent thermodynamic properties are all positive and listed in Table o 7. Remarkably, the lower Gsol value for dissolution of PMT indicates that lower energies are required,
which indicates that the dissolution capacity in pure and mixed solvents is consistent with the sequence of o . As expect, the values of standard dissolution enthalpy are all positive and within the range of Gsol
(16.746 to 29.388 kJ·mol−1), the dissolution process is endothermic, which give a good reason to explain
o the increasing solubility with increasing temperature. From Table 7, the S sol values for dissolution
behavior are all positive as well, which indicate the dissolution process is apparently not only endothermic but also entropy-driving.
4. Conclusions The solubility profiles of promethazine hydrochloride in pure and mixed solvents were determined. The maximum solubility value was obtained in n-propanol in pure solvents, and in ethyl acetate, it is the lowest. In mixtures of ethyl acetate (1-w) + ethanol (w, mass fraction) and ethyl acetate (1-w) + isopropanol (w), the values increased monotonically with the increasing temperature, and increased with increasing co-solvent (alcohols) mass fraction (w) to a maximum value at w = 0.4 and then decreased. Through the analysis of hydrogen-bond donor acidity and hydrogen-bond acceptor basicity for all selected solvents, HBD acidity and HBA basicity are all contributive to the hydrogen-bond interaction between solutes and solvents. The modified Apelblat equation and Jouban-Acree model are suitable to describe the solubility of PMT in selected solvents. The calculation of dissolution thermodynamic properties indicate that in all selected solvents the dissolution process is endothermic and entropy-driven. Acknowledgment The research is supported by China National Key Research and invention program of the thirteenth Five-Year Plan (No.2017YFD0200707). And the authors also want to give thanks to the Ministry of Education Scientific Research Foundation (No.XM20131225085213994) as well as Zhejiang Province Public Technology Project (No.2013C31G2290019) and Ningbo Natural Science Foundations (No.2013A610094 and No. 2018A610411).
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Fig. 1. Chemical structure of promethazine hydrochloride.
acetonitrile ethyl acetate isopropanol
DSC mW/mg
n-propanol ethanol raw
Tm =500.64K H fus 28.91kJ/mol
Tpeak =506.30K
360
400
440
480
520
ethanol (w)+ ethyl acetate (1-w),w=0.2
isopropanol (w)+ ethyl acetate (1-w),w=0.2
ethanol (w)+ ethyl acetate (1-w),w=0.4
isopropanol(w)+ ethyl acetate (1-w), w=0.4
ethanol (w)+ ethyl acetate (1-w),w=0.6
isopropanol (w)+ ethyl acetate (1-w),w=0.6
ethanol (w)+ ethyl acetate (1-w), w=0.8
isopropanol(w)+ ethyl acetate (1-w),w=0.8
DSC mW/mg
DSC mW/mg
T/K
raw
raw
Tpeak =506.30K
360
400
440 T/K
480
Tpeak =506.30K 520
360
400
440
480
520
T/K
Fig. 2. DSC curves of promethazine hydrochloride in pure and mixed solvents during the experiment.
0.024
x
0.018
x
ethanol in this work cited from ref.10
ethanol n-propanol isopropanol ethyl acetate acetonitrile
0.012
0.006
0.000
280
290
300
280
310
290
300
310
T/K
T/K
Fig. 3. Solubility data of promethazine hydrochloride in pure solvents within the temperature range from T/K
= (273.15 to 313.15).
. 273.15K, 288.15K, 303.15K,
0.024
278.15K, 293.15K, 308.15K,
283.15K 298.15K 313.15K
278.15K, 293.15K, 308.15K,
283.15K 298.15K 313.15K
0.024
0.018
0.018
0.012
x
x
273.15K, 288.15K, 303.15K,
0.030
0.012 0.006
0.006 ethanol+ ethyl acetate
0.000
0.0
0.2
0.4
0.6 w
0.8
1.0
0.000
isopropanol+ ethyl acetate
0.0
0.2
0.4
0.6 w
0.8
1.0
Fig. 4. Experimental solubility data of promethazine hydrochloride in mixture of alcohol (w) + ethyl acetate (1-w) within the temperature range from T/K = (273.15 to 313.15) in 3d-plot, and 2d-plot is a comparison between experimental and calculated values, symbols is experimental data,w, is the mass fraction of alcohol in mixed solvents,---, calculated by Jouyban-Acree model.
-3.0 -4.0
ln(x)
ln(x)
-5.6 -6.3
-5.0
w=0.2 w=0.4 w=0.6 w=0.8
-3.6
w=0.2 w=0.4 w=0.6 w=0.8
-4.5
-4.9
isopropanol(w) + ethyl acetate (1-w)
ethanol(w) + ethyl acetate (1-w)
-4.2 ln(x)
-4.2
ethanol; n-propanol isopropanol; ethyl acetate acetonitrile
-4.8 -5.4
-5.5
-6.0
-7.0 -0.0002 -0.0001 0.0000 0.0001 0.0002 (1/T-1/Thm)/K-1
-6.0
-0.0002 -0.0001 0.0000 0.0001 0.0002 (1/T-1/Thm)/K-1
-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 alcohol (w) + ethyl acetate (1-w), w, is the mass fraction of alcohol in mixed solvents.
Table 1 Detailed information on the materials used in the work.
Chemicals
Molar mass
CAS NO.
Source
g·mol−1
a
Promethazine hydrochloride
58-33-3
320.88
Ethanol
64-17-5
46.07
Isopropanol
67-63-0
60.1
n-Propanol
71-23-8
60.1
Ethyl acetate
141-78-6
88.11
Acetonitrile
75-05-8
41.05
Hubei Jinshuo Biotechnology Co., Ltd. (China)
mass fraction purity
Analytical method
0.996
HPLCa
0.998b Sinopharm Chemical Reagent Co., Ltd.,China
0.998 b 0.995 b
None
0.996 b 0.995 b
High-performance liquid phase chromatograph. b the purity was provided by supplier.
Table 2 Experimental (xe) and calculated (xcal) mole fraction solubility of promethazine hydrochloride in different solvents at the temperature range from T = (273.15 To 313.15) K under P=101.3kPa.a
T/K
100x
273.15
0.2739
100xcal Modified Apelblat equation Ethanol 0.2677
278.15
0.3463
0.3453
0.3491
283.15
0.4322
0.4388
0.4367
288.15
0.5454
0.5498
0.542
293.15
0.6800
0.6797
0.6678
298.15
0.8363
0.8298
0.8171
303.15
0.9965
1.0012
0.9931
308.15
1.200
1.1944
1.1995
313.15
1.407
1.410
1.440
0.76
1.15
e
100 RAD n-Propanol
λh equation 0.2768
273.15
0.7236
0.7274
0.746
278.15
0.859
0.8624
0.8672
283.15
1.017
1.011
1.0033
288.15
1.180
1.173
1.1553
293.15
1.348
1.3477
1.3245
298.15
1.528
1.5342
1.5125
303.15
1.730
1.7313
1.7204
308.15
1.936
1.9378
1.9500
313.15
2.155
2.1521
2.2028
0.31
1.53
100 RAD Isopropanol 273.15
0.1130
0.1146
0.1170
278.15
0.1400
0.1396
0.1402
283.15
0.1689
0.1681
0.1669
288.15
0.2019
0.2003
0.1976
293.15
0.2354
0.2362
0.2326
298.15
0.2759
0.2760
0.2726
303.15
0.3200
0.3196
0.3179
308.15
0.3650
0.3670
0.3691
313.15
0.4193
0.4181
0.4268
0.48
1.44
100 RAD Acetonitrile 273.15
0.2229
0.2259
0.2337
278.15
0.2887
0.2882
0.2902
283.15
0.3631
0.3617
0.3577
288.15
0.4484
0.4472
0.4377
293.15
0.5451
0.5449
0.532
298.15
0.6569
0.6552
0.6424
303.15
0.7785
0.7779
0.7712
308.15
0.9059
0.9125
0.9204
313.15
1.0620
1.0580
1.0926
0.40
2.15
100 RAD Ethyl acetate
273.15
0.0885
0.088
0.0865
278.15
0.0988
0.0989
0.0985
283.15
0.1111
0.1112
0.1117
288.15
0.1247
0.1251
0.1263
293.15
0.1405
0.1408
0.1423
298.15
0.1580
0.1584
0.1599
303.15
0.1795
0.1783
0.1791
308.15
0.2008
0.2007
0.2000
313.15
0.2255
0.2259
0.2229
0.27
0.96
100 RAD a
Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45kPa; Relative standard uncertainty ur is ur (x) = 0.046.
Table 3 Experimental (xe) and calculated (xcal) mole fraction solubility of promethazine hydrochloride in two mixtures of ethanol (w) + ethyl acetate (1-w) and isopropanol (w) + ethyl acetate (1-w) at the temperature range from T = (273.15 To 313.15) K under 101.3kPa.a w w=0.200
T/K
102xexp
w=0.400 102xJ-A
102xexp
102xJ-A
w=0.800
w=0.600 102xexp
102xJ-A
102xexp
102xJ-A
ethanol (w) + ethyl acetate (1-w) 273.15
0.3486
0.5052
0.6531
0.7065
0.5424
0.5796
0.4339
0.4263
278.15
0.4355
0.5629
0.7695
0.8054
0.6454
0.6824
0.5321
0.5195
283.15
0.5488
0.6296
0.9129
0.9179
0.7854
0.8001
0.6347
0.6276
288.15
0.6682
0.7053
1.067
1.051
0.9239
0.9442
0.7702
0.7651
293.15
0.8200
0.7913
1.245
1.201
1.100
1.109
0.9269
0.9247
298.15
0.9933
0.8847
1.437
1.365
1.284
1.291
1.107
1.105
303.15
1.180
0.9917
1.635
1.542
1.487
1.482
1.303
1.292
308.15
1.379
1.101
1.842
1.735
1.722
1.703
1.519
1.518
313.15
1.603
1.221
2.109
1.937
1.956
1.930
1.754
1.748
isopropanol (w) + ethyl acetate (1-w) 273.15
0.3713
0.4149
0.9949
1.005
0.9536
1.088
0.5261
0.5106
278.15
0.4117
0.4606
1.124
1.122
1.063
1.239
0.6075
0.6025
283.15
0.4637
0.5118
1.278
1.246
1.205
1.395
0.7120
0.6976
a
288.15
0.5243
0.5673
1.442
1.379
1.373
1.563
0.8374
0.8023
293.15
0.5896
0.6282
1.669
1.517
1.561
1.731
0.9533
0.9060
298.15
0.6790
0.6958
1.908
1.673
1.759
1.923
1.087
1.028
303.15
0.7846
0.7761
2.160
1.850
2.037
2.134
1.233
1.160
308.15
0.8845
0.8527
2.430
2.015
2.322
2.333
1.380
1.288
313.15
1.004
0.9417
2.702
2.210
2.634
2.569
1.544
1.441
Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45kPa; Relative standard uncertainty ur is ur (x) = 0.052. 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 alcohols in system of alcohol(w) + ethyl acetate (1-w).
Table 4 Hildebrand solubility parameters (δH) and solvatochromic parameters , and * for the selected solvents.a 2
α
Solvent
a
β
δH/1000
π*
(J/cm3)
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
ethyl acetate
0
0.45
0.55
0.331
acetonitrile
0.19
0.4
0.75
0.5806
from ref.13.
Table 5 Parameters of the modified Apelblat equation and h equation for promethazine hydrochloride in different solvents.
h equation
Modified Apelblat equation Solvent A
B
104RMS D
C
h
104 RMSD
Ethanol
134.482
-9126.348
-19.072
0.48
0.976
3612.397
1.36
n-Propanol
110.466
-6996.197
-16.003
0.42
0.309
7281.626
2.29
Isopropanol
95.606
-6803.296
-13.809
0.12
0.105
25709.366
0.39
Ethyl acetate
-96.923
2239.55
14.561
0.05
0.019
98826.054
0.15
Acetonitrile
165.492
-10280.108
-23.877
0.28
0.549
5979.812
1.43
Table 6 Values of parameters of Jouyban-Acree model along with RAD and RMSD values. J0
J1
J2
102RAD
103RMSD
ethanol + ethyl acetate
1576.958
-1206.609
800.054
4.45
8.46
isopropanol + ethyl acetate
2679.672
86.257
-202.989
4.98
12.41
20
Table 7 Standard dissolution enthalpy of promethazine hydrochloride in pure and mixture solvents at mean harmonic temperature (292.58 K). o Gsol
o H sol
o S sol
kJ·mol-1
kJ·mol-1
J·mol-1·K-1
Ethanol
12.241
29.388
58.605
n-Propanol
10.552
19.316
29.956
Isopropanol
14.790
23.079
28.329
Acetonitrile
12.790
27.542
50.422
Ethyl acetate
15.970
16.746
2.652
ethanol (w) + ethyl acetate (1-w),w=0.2
11.779
27.295
53.031
ethanol (w) + ethyl acetate (1-w), w=0.4
10.738
20.831
34.497
ethanol (w) + ethyl acetate (1-w), w=0.6
11.044
22.988
40.823
ethanol (w) + ethyl acetate (1-w), w=0.8
11.448
25.015
46.367
isopropanol(w) + ethyl acetate (1-w),w=0.2
12.437
17.950
18.841
isopropanol (w) + ethyl acetate (1-w), w=0.4 9.977
18.113
27.807
isopropanol (w) + ethyl acetate (1-w), w=0.6 10.108
18.246
27.818
isopropanol (w) + ethyl acetate (1-w), w=0.8 11.380
19.308
27.098
solvents
21
1. Research the solubility profiles of promethazine hydrochloride in pure and mixed solvents; 2. Discuss the effect of solvent properties on the dissolution process; 3. The interaction between promethazine hydrochloride molecule and solvent molecules was analyzed. 4. Some thermodynamic properties of dissolution process are evaluated.
22
Abstract Graphic
23