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Thermodynamic analysis and calculation of solubility of Memantine hydrochloride in ethanol plus (acetonitrile, water, ethyl acetate) binary solvent mixtures
Journal of Molecular Liquids 229 (2017) 58–66
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Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq
Thermodynamic analysis and calculation of solubility of Memantine hydrochloride in ethanol plus (acetonitrile, water, ethyl acetate) binary solvent mixtures Fangfang Shen a, Dingqiang Lu a,b,⁎, Xiuquan Ling b, Xinxian Wang b, Tongqi Liu a, Tianhua Huang a, Kefei He a a b
School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, PR China Jiangsu Provincial Institute of Material Medica, Nanjing 210009, PR China
a r t i c l e
i n f o
Article history: Received 15 November 2016 Received in revised form 7 December 2016 Accepted 13 December 2016 Available online 18 December 2016 Keywords: Memantine hydrochloride Solubility Binary solvent mixtures Thermodynamic properties
a b s t r a c t In this work, we focus on measuring solubility and analyzing solution thermodynamics of Memantine hydrochloride in different binary solvent mixtures (ethanol + acetonitrile); (ethanol + water); and (ethanol + ethyl acetate) at the temperature range of 278.15–333.15 K under atmospheric pressure. The solubility data was correlated by the modified Apelblat model, the general cosolvency model and the Jouyban-Acree + van't Hoff model. The result show that modified Apelblat equation is best because of the lowest MD data and ethyl acetate could be used as effective anti-solvent in the crystallization process of Memantine hydrochloride In addition, the thermodynamic properties of the solution process, including the Gibbs free energy, enthalpy, and entropy were calculated by the van't Hoff analysis. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Memantine hydrochloride is chemically known as 1-amino-3,5dimethyladamantane hydrochloride (CAS: 41100-52-1, MW = 215.77, Fig. 1) developed by German Merz company which is the first FDA approved member of a new class of Alzheimer drugs with a moderate affinity towards N-methyl-D-aspartate (NMDA)-receptor antagonist, it produces symptomatic improvements in learning under conditions of tonic NMDA receptor activation in Alzheimer's disease [1,2]. Memantine hydrochloride is commercially available in the market because it is likely to show neuroprotective effect at a concentration used in the treatment of Alzheimer's disease and to slow down disease progression. Crystallization has been the most important separation and purification process in industrial mass production because the majority of active pharmaceutical ingredients (APIs) are produced in solid form [3]. Memantine hydrochloride is synthesized by Memantine and Hydrochloric acid, precipitation in water. In this crystallization process, we should require add an anti-solvent to the solution to achieve a certain degree of saturation, result in solute precipitation. The significance of solubility data of Memantine hydrochloride is not only to select the best crystallization binary solvent mixtures but to decide the maximum yield of industrial production. Therefore, it is necessary to explore the ⁎ Corresponding author at: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, PR China. E-mail address: [email protected] (D. Lu).
http://dx.doi.org/10.1016/j.molliq.2016.12.051 0167-7322/© 2016 Elsevier B.V. All rights reserved.
solubility of Memantine hydrochloride in different binary solvent mixtures because we find no report for it. The solubility of Memantine hydrochloride in different binary solvent mixtures (ethanol + acetonitrile), (ethanol + water), and (ethanol + ethyl acetate) was measured in the temperature range of 278.15–333.15 K under atmospheric pressure. All solvents were selected by us as binary solvent mixtures since they are inexpensive, and easily removed from the solution. In the temperature between 278.15 K and 333.15 K with the atmospheric pressure, the solubility of Memantine hydrochloride was measured when it in different binary solvent mixtures, ethanol + water, ethanol + acetonitrile and ethanol + ethyl acetate. The solubility data of Memantine hydrochloride was correlated by the modified Apelblat equation, the general cosolvency mode, the Jouyban-Acree + van't Hoff model. The thermodynamic properties of the solid-liquid equilibrium process were also calculated, with the Gibbs free energy, enthalpy, and entropy included, since it's the basis of the crystallization process and process optimization [4].
2. Experimental 2.1. Materials Memantine hydrochloride, a white crystalline powder was obtained from Aladdin Reagent Co., Ltd. It's purity was measured by gas chromatography and the mass fraction purity ≥ 0.990.
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
where m1, m2 represent the mass of Memantine hydrochloride, ethanol, and M1, M2 represent the molar mass of the Memantine hydrochloride, ethanol, respectively; m3 and M3 share a one-to-one mapping. The m3 represents the mass of acetonitrile, water, ethyl acetate in different binary solvent mixtures, respectively; M3 represents the molar mass of acetonitrile, water, ethyl acetate in different binary solvent mixtures, respectively.
NH2HCl
CH 3 CH3
3. Results and discussion 3.1. Solubility data
Fig. 1. Chemical structure of Memantine hydrochloride.
All solvents for dissolving have higher mass fraction purities that N0.980 and supplied by Shanghai Shenbo Chemical Co, Ltd. Table 1 listed more details of these solvents and their CAS registry numbers as well. Analytical balance (model PA225D) was provided by Sartorius Scientific Instrument (Beijing) Co., Ltd. with an uncertainty of ±0.1 mg. Smart thermostatic bath (model: DC-2006) was provided by Ningbo Scientz Biotechnology Co., Ltd. with an uncertainty of ±0.1 K. 2.2. Apparatus and procedures The solubility of Memantine hydrochloride was measured in binary solvent mixtures by the analytical stirred-flask method and we used the gravimetric method to measure the compositions of the saturated solutions. Saturated solutions of Memantine hydrochloride, which were produced by 8 ml solvent mixtures and some excess target were added into a 10 ml glass test tube with a stopper (avoid evaporation of solvent during experimental steps). The test tube was kept in a jacket glass vessel and the test temperature was maintained by circulating water through the outer jacket from a super thermostatic water-circulator bath (type HWC-52, Shanghai Cany Precision Instrument Co., Ltd. Error of plus or minus 0.05 K). Magnetically stirrers were used to mix the solid and binary solvent mixtures adequately. In order to reach solid-liquid equilibrium, the process was allowed to stir for 12 h and the solution was allowed to settle for 12 h. At last, a certain volume solution supernatant was transferred into a beaker with a cover and weighted immediately by using an analytical balance (model: CPA225D, was provided from Sartorius Scientific Instruments CO., Ltd.) with a resolution of ±0.1 mg. This breaker must be weighed before. All beakers were put into a dryer and weighted weekly until reaching constant weight. Each experiment was repeated three times, and the mean value was used to calculate the mole fraction solubility. The mole fraction solubility of Memantine hydrochloride (x) in ethanol plus (acetonitrile, water, ethyl acetate) binary solvent mixtures is calculated by Eq. (1) The mole fraction of ethanol (xA) in the binary solvent mixtures in the absence of the solute is defined using Eq. (2). x¼
59
m1 =M 1 m1 =M1 þ m2 =M 2 þ m3 =M 3
ð1Þ
Under the temperature from 278.15 to 333.15 K, the solubility data of Memantine hydrochloride (x) in the binary solvent mixtures with ethanol plus (acetonitrile, water, ethyl acetate) was obtained and presented in Tables 2–4. These data was listed in Figs. 2–4 that apply for prediction of the solubility under the different condition. From Tables 2–4 and Figs. 2–4, it is obvious that the solubility of Memantine hydrochloride (x) was influenced by temperature and solvent composition in ethanol plus (acetonitrile, water, ethyl acetate) binary solvent mixtures. It is observed that the solubility of Memantine hydrochloride (x) in ethanol plus (acetonitrile, water, ethyl acetate) binary solvent mixtures will increases with the rising the temperature, in addition, if keep the temperature constant, it also increases with increasing ethanol content. Because ethanol is a benign solvent for dissolving Memantine hydrochloride (x). 3.2. Modified Apelblat equation On the basis of the solid–liquid phase equilibrium theory, the changing trends of solubility against temperature in the solvent with same ratio are described by modified Apelblat equation. This model is firstly used by Apelblat, which can give a relatively accurate correlation with three parameters [5–6]: ln x ¼ A þ
B þ C ln ðT=KÞ T=K
ð3Þ
where x represents the mole fraction solubility of Memantine hydrochloride, T is the experimental temperature in K, and A, B and C are the regression curve parameters in the equation which are listed in Table 5. 3.3. General cosolvency model The changing trends of solubility against different ratio of ethanol in ethanol plus (water, acetonitrile, ethyl acetate) binary solvent mixtures under isothermal condition are described by the combined nearly ideal binary solvent/Redich–Kister (general cosolvency) model [7], which is one of the theoretical models for calculating the solute solubility in binary solvents and represented in Eq. (4): N
m2 =M 3 xA ¼ m2 =M2 þ m3 =M3
ð2Þ
Table 1 Provenance and purity of the materials used. Compound
Source
Mass fraction CAS RN purity
Memantine hydrochloride Ethanol Acetonitrile Water Ethyl acetate
Aladdin Reagent Co. Ltd. Shenbo Chemicals Shenbo Chemicals Our laboratory Shenbo Chemicals
≥0.990 ≥0.995 ≥0.992 ≥0.990 ≥0.990
41100-52-1 64-17-5 75-05-8 7732-18-5 141-78-6
ln x ¼ xA ln X A þ xB ln X B þ xA xB ∑ Si ðxA −xB Þi i¼0
ð4Þ
where x is the mole fraction solubility of Memantine hydrochloride. xA and xB represent the initial mole fraction composition of the binary solvent. XA and XB respectively represent the saturated mole solubility of Memantine hydrochloride in pure ethanol and pure acetonitrile, water, ethyl acetate respectively. Si is the model constant and N can be equal to 0–3. When N = 2 and substitution of (1 − xA) for xB, Eq. (4) can be written as ln x−ð1−xA Þ lnX h B −xA ln X A
¼ ð1−xA ÞxA S0 þ S1 ð2xA −1Þ þ S2 ð2xA −1Þ2
i
ð5Þ
60
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
Table 2 Mole fraction solubility (x) of Memantine hydrochloride (x) in (ethanol + acetonitrile) binary solvent mixtures at the temperature range from (278.15 to 333.15) K under atmospheric pressure.a 100 |x − xcal |/x (Eq. (3))
100 |x −xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
T = 278.15 K 0.093 0.721 0.227 0.604 0.378 0.500 0.512 0.362 0.678 0.220 0.892 0.101
0.077 0.039 0.103 0.638 0.022 4.761
0.073 0.463 1.362 2.249 2.303 1.346
4.369 1.871 6.244 0.423 8.545 16.198
T = 283.15 K 0.093 0.834 0.227 0.702 0.378 0.586 0.512 0.427 0.678 0.270 0.892 0.123
0.474 0.433 0.760 0.664 0.027 2.986
0.086 0.534 1.539 2.480 2.380 1.435
1.942 0.701 6.267 0.710 4.704 15.191
T = 288.15 K 0.093 0.965 0.227 0.825 0.378 0.682 0.512 0.501 0.678 0.320 0.892 0.149
0.509 0.638 0.384 0.151 0.032 1.568
0.061 0.361 1.062 1.696 1.546 0.878
1.420 1.709 4.498 0.266 3.969 9.620
T = 293.15 K 0.093 1.115 0.227 0.945 0.378 0.791 0.512 0.584 0.678 0.370 0.892 0.178
0.450 0.513 0.198 0.663 0.037 0.472
0.069 0.418 1.203 1.916 1.774 0.932
0.688 0.268 4.082 0.931 5.270 7.513
T = 298.15 K 0.093 0.129 0.227 0.110 0.378 0.091 0.512 0.068 0.678 0.044 0.892 0.021
0.298 0.362 0.360 0.399 0.044 0.331
0.056 0.337 0.979 1.519 1.350 0.727
0.731 0.570 3.320 0.017 3.068 7.757
T = 303.15 K 0.093 1.482 0.227 1.259 0.378 1.048 0.512 0.783 0.678 0.510 0.892 0.252
0.085 0.319 0.126 0.236 0.051 0.865
0.072 0.437 1.260 1.954 1.723 0.877
1.565 1.469 3.216 0.792 3.000 5.512
T = 308.15 K 0.093 0.171 0.227 0.145 0.378 0.120 0.512 0.090 0.678 0.059 0.892 0.030
0.393 0.154 0.109 0.182 0.059 1.152
0.055 0.336 0.985 1.512 1.303 0.632
1.209 1.419 2.613 0.507 2.661 2.000
T = 313.15 K 0.093 0.195 0.227 0.167 0.378 0.136 0.512 0.103 0.678 0.069 0.892 0.035
0.285 0.341 0.310 0.225 0.069 1.208
0.042 0.252 0.748 1.127 0.925 0.451
1.729 0.847 1.621 0.592 0.749 0.859
T = 318.15 K 0.093 2.241 0.227 1.891 0.378 1.546 0.512 1.173 0.678 0.790 0.892 0.407
0.084 0.153 0.245 0.058 0.079 1.050
0.056 0.343 1.016 1.535 1.250 0.582
1.075 1.602 1.611 0.998 0.559 1.116
T = 323.15 K 0.093 2.566 0.227 2.154
0.144 0.086
0.051 0.317
0.134 1.425
xA
10x
Table 2 (continued) xA
10x
100 |x − xcal |/x (Eq. (3))
100 |x− xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
0.378 0.512 0.678 0.892
1.745 1.331 0.910 0.473
0.252 0.132 0.091 0.688
0.951 1.420 1.121 0.521
1.066 0.924 0.648 1.328
T = 328.15 K 0.093 2.935 0.227 2.445 0.378 1.963 0.512 1.504 0.678 1.030 0.892 0.547
0.117 0.113 0.169 0.082 0.103 0.134
0.029 0.183 0.560 0.831 0.647 0.287
0.555 0.695 0.096 1.250 0.497 3.988
T = 333.15 K 0.093 3.352 0.227 2.775 0.378 2.201 0.512 1.694 0.678 1.180 0.892 0.629
0.052 0.097 0.012 0.033 0.117 0.605
0.027 0.171 0.532 0.779 0.585 2.094
1.892 0.017 0.287 1.311 1.915 4.879
a xA denotes the mole fraction of acetonitrile in the binary solvent mixtures; x denotes the mole fraction solubility of Memantine hydrochloride; xcal denotes the calculated solubility.
ln x ¼ lnX B þ ð lnX A − ln X B þ S0 −S1 þ S2 ÞxA þ ð−S0 þ 3S1 −5S2 Þx2A þ ð−2S1 þ 8S2 Þx3A þ ð−4S2 Þx4A
ð6Þ
Eq. (6) can be further simplified as: ln x ¼ A1 þ B1 xA þ C 1 x2A þ Dx3A þ Ex4A
ð7Þ
Eq. (7) called general cosolvency model A1 ¼ ln X B B1 ¼ ln X A − ln X B þ S0 −S1 þ S2 C 1 ¼ −S0 þ 3S1 −5S2 D ¼ −2S1 þ 8S2 E ¼ −4S2 where A1, B1, C1, D and E are model parameters calculated by this model [8]. They are listed in Tables 6–8. However, the general cosolvency model can be used only to describe the solubility data and to predict solubility data for different concentrations of a mixed solvent at a fixed temperature. To describe the effect of both solvent compositions and temperature on the solubility of Memantine hydrochloride, we adopt another equation [9]. 3.4. Jouyban-Acree model + van't Hoff model This was a relatively more versatile model to describe the solubility of a solute with the variation of both temperature and initial composition of binary solvent mixtures [10]: N
ln x;T ¼ xA ln X A;T þ xB ln X B;T þ xA xB ∑ i¼0
J i ðxA −xB Þi T
ð8Þ
where Ji was the parameter and T was the absolute temperature. Other symbols mean the same as Eq. (4). Solubility at different temperatures could be calculated using the van't Hoff equation. Experimental data required are the solute
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66 Table 3 Mole fraction solubility (x) of Memantine hydrochloride in (ethanol + water) binary solvent mixtures at the temperature range from (278.15 to 333.15) K under atmospheric pressure.a 100 |x − xcal |/x (Eq. (3))
100 |x −xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
T = 278.15 K 0.102 0.681 0.267 0.571 0.426 0.418 0.582 0.315 0.703 0.189 0.897 0.097
0.936 0.224 0.007 0.817 0.804 0.835
0.091 0.705 2.751 6.190 7.884 3.967
1.131 3.695 1.260 7.016 4.821 15.052
T = 283.15 K 0.102 0.792 0.267 0.658 0.426 0.489 0.582 0.364 0.703 0.217 0.897 0.111
0.250 0.046 0.004 0.206 0.624 0.327
0.082 0.652 2.495 5.742 7.465 3.782
0.071 2.128 1.000 6.264 6.406 13.063
T = 288.15 K 0.102 0.927 0.267 0.756 0.426 0.568 0.582 0.417 0.703 0.248 0.897 0.126
0.236 0.159 0.001 0.005 0.696 0.728
0.071 0.585 2.201 5.180 6.895 3.498
0.075 0.773 0.919 5.180 7.944 10.714
T = 293.15 K 0.102 1.079 0.267 0.866 0.426 0.657 0.582 0.475 0.703 0.283 0.897 0.145
0.242 0.401 0.001 0.461 0.713 0.155
0.059 0.509 1.903 4.589 6.184 3.054
0.097 0.374 0.749 4.021 9.117 10.069
T = 298.15 K 0.102 1.251 0.267 0.997 0.426 0.756 0.582 0.541 0.703 0.325 0.897 0.166
0.133 0.113 0.003 0.644 0.108 0.141
0.052 0.452 1.693 4.159 5.538 2.742
0.002 0.527 0.617 3.309 9.077 9.398
T = 303.15 K 0.102 1.442 0.267 1.143 0.426 0.866 0.582 0.618 0.703 0.371 0.897 0.189
0.124 0.449 0.004 0.245 0.519 0.124
0.049 0.440 1.663 4.094 5.472 2.718
0.004 0.631 0.479 3.317 9.218 8.624
T = 308.15 K 0.102 1.654 0.267 1.294 0.426 0.988 0.582 0.704 0.703 0.422 0.897 0.213
0.147 0.237 0.005 0.146 0.761 0.689
0.046 0.420 1.569 3.878 5.261 2.651
0.037 1.553 0.308 3.466 9.265 7.324
T = 313.15 K 0.102 1.902 0.267 1.474 0.426 1.123 0.582 0.797 0.703 0.478 0.897 0.242
0.521 0.079 0.005 0.177 0.766 0.468
0.043 0.405 1.523 3.789 5.126 2.562
0.620 1.425 0.095 3.425 9.310 7.149
T = 318.15 K 0.102 2.151 0.267 1.674 0.426 1.271 0.582 0.901 0.703 0.541 0.897 0.277
0.060 0.004 0.004 0.315 0.869 0.707
0.044 0.407 1.542 3.840 5.176 2.533
0.034 1.189 0.086 3.618 9.002 8.051
T = 323.15 K 0.102 2.438 0.267 1.901
0.023 0.276
0.045 0.417
0.065 0.573
xA
10x
61
Table 3 (continued) xA
10x
100 |x − xcal |/x (Eq. (3))
100 |x− xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
0.426 0.582 0.703 0.897
1.432 1.013 0.606 0.312
0.003 0.147 0.114 0.480
1.599 4.008 5.429 2.632
0.192 3.643 9.439 7.821
T = 328.15 K 0.102 2.752 0.267 2.137 0.426 1.608 0.582 1.134 0.703 0.679 0.897 0.349
0.016 0.252 0.002 0.222 0.450 0.239
0.043 0.404 1.555 3.915 5.302 2.574
0.067 0.608 0.322 3.589 9.440 7.307
T = 333.15 K 0.102 3.095 0.267 2.418 0.426 1.799 0.582 1.274 0.703 0.767 0.897 0.393
0.015 0.069 0.000 0.009 0.036 0.100
0.046 0.422 1.645 4.097 5.450 2.672
0.064 0.362 0.429 4.207 8.188 7.735
a xA denotes the mole fraction of water in the binary solvent mixtures; x denotes the mole fraction solubility of Memantine hydrochloride; xcal denotes the calculated solubility.
solubilities at the lowest and highest temperatures (lnX) to compute the model constants. The equation is [11] ln X ¼ a þ
b T
ð9Þ
where a and b are the model constants calculated. Combination of the Jouyban-Acree and van't Hoff model can predict the drug solubility in mixed solvents at different temperatures after training process using two solubility data points [12]. The combined version could be represented as N b1 b2 J ðx −xB Þi þ xB a2 þ þ xA x B ∑ i A ln x ¼ xA a1 þ T T T i¼0
ð10Þ
When N = 2, derived Eq. (11) as [13]: b1 b2 þ xB a2 þ ln x ¼ xA a1 þ T T i x xB h J 0 þ J 1 ðxA −xB Þ þ J 2 ðxA −xB Þ2 þ A T
ð11Þ
a1, b1, a2, b2, and J0, J1, J2 are model constants calculated by regressing, which are listed in Tables 9–11. I trained the model using the experimental data in this work for three solvent systems as: For ethanol (solvent A) + acetonitrile (solvent B): 2837:56 2651:34 ln x ¼ xA 5:29− þ xB 6:95− T T i x xB h 503:63 þ 1147:67ðxA −xB Þ−1040:34ðxA −xB Þ2 þ A T
ð12Þ
For ethanol (solvent A) + water (solvent B): 2584:10 2621:50 ln x ¼ xA 3:87− þ xB 6:84− T T i x xB h 756:89−174:63ðxA −xB Þ þ 456:29ðxA −xB Þ2 þ A T
ð13Þ
For ethanol (solvent A) + ethyl acetate (solvent B): 3955:11 2674:97 ln x ¼ xA 8:50− þ xB 7:11− T T i xA xB h 319:75−2732:84ðxA −xB Þ þ 2735:25ðxA −xB Þ2 þ T
ð14Þ
62
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
Table 4 Mole fraction solubility (x) of Memantine hydrochloride in (ethanol + ethyl acetate) binary solvent mixtures at the temperature range from (278.15 to 333.15) K under atmospheric pressure.a 100 |x− xcal |/x (Eq. (3))
100 |x −xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
T = 278.15 K 0.097 0.609 0.207 0.504 0.321 0.327 0.524 0.215 0.764 0.109 0.903 0.052
0.068 0.355 0.714 0.737 0.309 0.662
0.286 1.618 4.312 6.186 9.541 17.766
0.355 9.544 4.893 4.930 12.294 2.990
T = 283.15 K 0.097 0.726 0.207 0.594 0.321 0.399 0.524 0.258 0.764 0.134 0.903 0.064
0.256 0.733 0.069 0.360 0.084 0.795
0.204 1.215 3.133 4.612 7.102 12.134
0.511 7.626 4.286 2.549 10.522 6.385
T = 288.15 K 0.097 0.856 0.207 0.705 0.321 0.481 0.524 0.311 0.764 0.163 0.903 0.079
0.025 0.010 0.006 0.580 0.270 0.384
0.219 1.221 2.952 4.116 6.135 9.786
1.158 6.950 4.220 1.265 8.466 8.663
T = 293.15 K 0.097 1.007 0.207 0.835 0.321 0.578 0.524 0.372 0.764 0.198 0.903 0.097
0.060 0.875 0.369 0.863 0.461 0.259
0.197 1.089 2.578 3.602 5.354 8.079
1.440 6.623 3.824 0.128 6.919 10.722
xA
10x
T = 298.15 K 0.097 0.1178 0.207 0.0971 0.321 0.0688 0.524 0.0441 0.764 0.0241 0.903 0.0118
0.207 0.295 0.363 0.375 0.154 0.827
0.136 0.776 1.802 2.562 3.753 5.469
1.740 5.129 3.794 1.792 6.224 12.966
T = 303.15 K 0.097 1.378 0.207 1.124 0.321 0.813 0.524 0.523 0.764 0.291 0.903 0.145
0.072 0.401 0.181 0.045 0.364 0.145
0.100 0.578 1.292 1.776 2.535 3.457
0.885 0.943 1.488 0.172 4.089 3.289
T = 308.15 K 0.097 1.598 0.207 1.31 0.321 0.953 0.524 0.62 0.764 0.352 0.903 0.176
0.109 0.082 0.283 0.203 0.117 0.466
0.100 0.573 1.270 1.710 2.343 3.149
0.995 0.693 1.941 0.758 4.176 1.992
T = 313.15 K 0.097 1.851 0.207 1.525 0.321 1.117 0.524 0.735 0.764 0.429 0.903 0.214
0.013 0.437 0.257 0.326 1.145 0.384
0.099 0.547 1.173 1.497 1.935 2.578
0.735 0.826 1.880 0.778 2.844 1.503
T = 318.15 K 0.097 2.141 0.207 1.751 0.321 1.304 0.524 0.872 0.764 0.508 0.903 0.26
0.315 0.113 0.154 0.247 0.198 0.159
0.086 0.491 1.028 1.296 1.699 2.145
0.169 0.056 1.725 0.184 3.878 1.557
T = 323.15 K 0.097 2.449 0.207 2.014
0.113 0.195
0.090 0.506
0.284 0.090
Table 4 (continued) xA
10x
100 |x − xcal |/x (Eq. (3))
100 |x − xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
0.321 0.524 0.764 0.903
1.518 1.034 0.609 0.315
0.120 0.094 0.062 0.003
1.034 1.248 1.600 1.974
1.370 0.863 3.087 1.924
T = 328.15 K 0.097 2.804 0.207 2.314 0.321 1.756 0.524 1.227 0.764 0.727 0.903 0.381
0.101 0.102 0.197 0.258 0.101 0.212
0.116 0.644 1.293 1.483 1.871 2.252
0.110 0.086 1.196 2.445 2.173 2.677
T = 333.15 K 0.097 3.204 0.207 2.655 0.321 2.015 0.524 1.445 0.764 0.867 0.903 0.459
0.038 0.125 0.117 0.023 0.003 0.233
0.154 0.851 1.692 1.862 2.272 2.702
0.693 0.535 1.404 3.723 0.863 3.595
a xA denotes the mole fraction of ethyl acetate in the binary solvent mixtures; x denotes the mole fraction solubility of Memantine hydrochloride; xcal denotes the calculated solubility.
3.5. Mean deviation The mean deviation (MD) is adopted to describe the deviation between experimental data and calculated data.
MD ¼ 100
∑
x−xcal x N
ð15Þ
where N stands for the number of experimental points, x and xcal respectively stand for experimental data and calculated data. The quantitative values of MD are listed in Tables 5 to 11, along with the parameters. As we can see from Tables 2–4 and Figs. 2–4, the solubility of Memantine hydrochloride in ethanol plus (acetonitrile, water, ethyl acetate) binary solvent mixtures is a functional relationship of temperature and solvent composition. The solubility of Memantine hydrochloride increases with the rising of temperature, while it increases with increasing ethanol content at constant temperature. What's more, the solubility of Memantine hydrochloride in (ethanol + ethyl acetate)
Fig. 2. Mole fraction solubility (x) of Memantine hydrochloride versus temperature (T) in the binary (ethanol + acetonitrile) mixed solvent.
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
63
Table 5 Parameters of the Modified Apelblat equation for Memantine hydrochloride in the binary solution mixtures.a Mixtures
xI
A
B/100
C
MD
Ethanol + acetonitrile
0.093 0.227 0.378 0.512 0.678 0.892
−69.34 −32.82 7.70 5.56 −69.34 −51.57
8.48 −7.92 −25.76 −25.75 8.48 −3.93
11.31 5.84 −0.26 0.07 11.31 8.61
0.11 0.27 0.25 0.29 0.73 1.32
Ethanol + water
0.102 0.267 0.426 0.582 0.703 0.897
6.23 −43.70 5.54 −55.01 −52.83 −44.72
−25.53 −1.92 −24.52 3.78 2.45 −1.75
0.05 7.38 0.02 8.92 8.53 7.23
MD = 0.50 0.23 0.19 0.003 0.28 0.54 0.42
Ethanol + ethyl acetate
0.097 0.207 0.321 0.524 0.764 0.903
−15.38 −34.47 1.72 −103.17 −77.63 −96.43
−17.72 −9.14 −27.90 18.15 3.86 10.64
3.37 6.18 0.87 16.49 12.74 15.52
MD = 0.28 0.11 0.31 0.24 0.34 0.27 0.37
Fig. 3. Mole fraction solubility (x) of Memantine hydrochloride versus temperature (T) in the binary (ethanol + water) mixed solvent.
MD = 0.27
binary solvent mixtures have a large change with increasing ethanol content and temperature.it has a better solubility than other two binary solvent mixtures at higher temperature. By these properties, ethyl acetate could be used as effective anti-solvent in the crystallization process. Tables 5 and 11 show that the MD values of modified Apelblat equation, general cosolvency model, Eq. (11), were 0.50, 0.86 and 2.57, respectively, in (ethanol + acetonitrile) binary solvent mixtures. The MD values of modified Apelblat equation, general cosolvency model, and Eq. (11) were 0.28, 2.62 and 3.99, respectively, in (ethanol + water) binary solvent mixtures. The MD values of modified Apelblat equation, general cosolvency model, and Eq. (11) were 0.27, 2.57 and 5.06, respectively, in (ethanol + ethyl acetate) binary solvent mixtures. The result indicated that the calculated solubility was in good agreement with the experimental values, and the modified Apelblat equation was the best, while general cosolvency model and Eq. (11) caused high mean deviation (MD). In fact, using Jouyban-Acree + van't Hoff model, the solubility prediction in ethanol mixtures of acetonitrile, water and ethyl acetate at various temperatures and solvent composition is possible. Thus, to describe and predict the solubility of different temperature may completed by simply modify the Apelblat equation. Nevertheless, it is better to
a
When I = A, xA denotes the mole fraction of acetonitrile in the (ethanol + acetonitrile) binary solvent mixtures; when I = B, xB denotes the mole fraction of water in the (ethanol + water) binary solvent mixtures; when I = C, xC denotes the mole fraction of ethyl acetate in the (ethanol + ethyl acetate) binary solvent mixtures.
use modified Apelblat equation and assisted with JouybanAcree + van't Hoff model when both temperature and solvent composition are considered.
Table 6 Parameters of the general cosolvency model for Memantine hydrochloride in the (ethanol + acetonitrile) binary solution mixtures. T/K
A1
B1
C1
D
E
MD
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
−2.41 −2.30 −2.20 −2.05 −1.90 −1.76 −1.61 −1.53 −1.36 −1.22 −1.10 −0.98
−3.13 −2.73 −1.64 −2.09 −1.90 −2.05 −2.08 −1.25 −1.75 −1.68 −1.37 −1.17
9.93 8.36 3.55 5.84 4.53 5.26 5.16 1.37 3.25 2.38 0.82 −0.61
−19.23 −16.29 −8.75 −12.75 −9.87 −11.17 −10.89 −4.53 −7.31 −5.36 −2.83 −0.06
10.05 8.27 4.52 6.80 4.97 5.77 5.66 2.24 3.69 2.49 1.26 −0.33
1.30 1.41 0.93 1.05 0.83 1.05 0.80 0.59 0.80 0.73 0.42 0.35 MD = 0.86
Table 7 Parameters of the general cosolvency model for Memantine hydrochloride in the (ethanol + water) binary solution mixtures.
Fig. 4. Mole fraction solubility (x) of Memantine hydrochloride versus temperature (T) in the binary (ethanol + ethyl acetate) mixed solvent.
T/K
A1
B1
C1
D
E
MD
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
−2.63 −2.43 −2.21 −2.01 −1.85 −1.70 −1.52 −1.37 −1.26 −1.15 −1.02 −0.94
−0.33 −1.12 −1.97 −2.75 −2.88 −2.99 −3.54 −3.73 −3.56 −3.33 −3.40 −2.82
−2.36 0.91 4.16 7.22 7.63 7.98 9.93 10.50 9.91 9.01 9.21 6.80
1.05 −4.01 −8.85 −13.59 −14.24 −14.71 −17.39 −18.19 −17.48 −16.26 −16.53 −12.83
−0.94 1.62 4.03 6.50 6.86 7.08 8.31 8.72 8.46 7.91 8.05 6.18
3.60 3.37 3.07 2.72 2.44 2.41 2.30 2.24 2.26 2.36 2.30 2.39 MD = 2.62
64
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
Table 8 Parameters of the general cosolvency model for Memantine hydrochloride in the (ethanol + ethyl acetate) binary solution mixtures. T/K 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
B1
A1 −2.97 −2.73 −2.55 −2.39 −2.20 −1.99 −1.85 −1.71 −1.52 −1.38 −1.23 −1.09
4.53 3.44 3.10 3.01 2.45 1.63 1.69 1.78 1.00 0.83 0.60 0.56
C1 −33.05 −27.79 −25.63 −24.68 −21.98 −18.29 −18.38 −18.59 −15.10 −14.01 −12.86 −12.65
D
E −32.82 −27.79 −25.41 −24.12 −21.69 −18.53 −18.66 −18.94 −16.10 −15.24 −14.50 −14.62
57.31 48.32 44.28 42.26 37.81 31.90 32.11 32.58 27.11 25.41 23.79 23.79
Table 10 Parameters of Eq. (11) for Memantine hydrochloride in the (ethanol + water) binary solution mixtures.
MD
T/K
MD
Parameters
6.62 4.73 4.07 3.48 2.42 1.62 1.52 1.30 1.12 1.08 1.28 1.59
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
5.50 4.82 4.27 4.07 3.82 3.71 3.66 3.67 3.66 3.62 3.56 3.50
a1 b1 a2 b2 J0 J1 J2
MD = 3.99
MD = 2.57
where the intercept is obtained in plots of lnx versus (1/T − 1/Tmean). The standard molar entropy of solution (ΔsolS0m) is determined by:
3.6. Thermodynamic properties for the solution The van's Hoff analysis is an important research method in the thermodynamic filed. Firstly, another quantity called the standard molar dissolution enthalpy (ΔsolH0m) should be defined [14,15] Δsol H 0m ¼ −R
∂ ln x ∂ð1=T Þ
ð16Þ
where R represents universal gas constant (8.314 J·mol−1 K−1) and T represents the corresponding absolute temperature. Over a limited temperature interval, the standard molar enthalpy of solution would be valid for the mean temperature. So Eq. (15) can also be written as:
Δsol H 0m
∂ ln x ¼ −R ∂ð1=T−1=T mean Þ
ð17Þ
where Tmean represents the mean temperature of the temperature range, and its value is 305.65 K. The lnx versus (1/T − 1/Tmean) curves of Memantine hydrochloride in the binary solvent mixtures are shown in Figs. 5–7. Because of the lack of activity coefficients, in this work Gibbs free energy of solution can just be determined as an apparent value. Thus, the equation of mole Gibbs free energy is [16]: Δsol G0m ¼ −RT mean intercept
3.87 −2584.10 6.84 −2621.50 756.89 −174.63 456.29
Δsol S0m ¼
Δsol H 0m −Δsol G0m T mean
ð19Þ
The results of the standard Gibbs free energy, enthalpy, and entropy are shown in Table 12, together with ξH and ξS.The ξH and ξS Table 11 Parameters of Eq. (11) for Memantine hydrochloride in the (ethanol + ethyl acetate) binary solution mixtures. T/K
MD
Parameters
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
5.83 5.31 5.12 4.94 5.27 5.10 5.38 5.53 4.89 4.58 4.31 4.49
a1 b1 a2 b2 J0 J1 J2
8.50 −3955.11 7.11 −2674.97 319.75 −2732.84 2735.25
MD = 5.06
ð18Þ
Table 9 Parameters of Eq. (11) for Memantine hydrochloride in the (ethanol + acetonitrile) binary solution mixtures. T/K
MD
Parameters
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
6.27 4.92 3.58 3.13 2.58 2.59 1.73 1.07 1.16 0.92 1.18 1.72
a1 b1 a2 b2 J0 J1 J2
MD = 2.57
5.29 −2837.56 6.95 −2651.34 503.63 1147.67 −1040.34
Fig. 5. van't Hoff plot of the mole fraction solubility (lnx) of Memantine hydrochloride in the binary (ethanol + acetonitrile) mixed solvent against 1/T with a straight line to correlate the date.
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
65
represent the comparison of the relative contribution to the standard Gibbs free energy by enthalpy and entropy in the solution process, respectively [17]. Δsol H 0m 100% %ξH ¼ Δsol H 0m þ T mean Δsol S0m
ð20Þ
0 T mean Δsol Sm 100% %ξS ¼ 0 Δsol H0m þ T mean Δsol Sm
Fig. 6. van't Hoff plot of the mole fraction solubility (lnx) of Memantine hydrochloride in the binary (ethanol + water) mixed solvent against 1/T with a straight line to correlate the date.
ð21Þ
The results of Table 12 show that the enthalpy and the standard Gibbs free energy of Memantine hydrochloride are positive in the studied binary solvent mixtures, indicating the dissolving process of Memantine hydrochloride in all binary solvent mixtures is endothermic. Moreover, the main contributor to the standard molar Gibbs free energy of solution is the enthalpy during the dissolution, because values of %ξH are ≥55.80%. 4. Conclusion
Fig. 7. van't Hoff plot of the mole fraction solubility (lnx) of Memantine hydrochloride in the binary (ethanol + ethyl acetate) mixed solvent against 1/T with a straight line to correlate the date.
The solubility of Memantine hydrochloride in binary solvent mixtures consisting of (ethanol + water); (ethanol + water); and (ethanol + ethyl acetate) at temperature from (278.15 to 333.15) K was measured by the gravimetric method. We can get the following conclusions that the solubility of Memantine hydrochloride increases with the rising of temperature, while it increases with increasing ethanol content at a constant temperature. What's more, the solubility of Memantine hydrochloride in (ethanol + ethyl acetate) binary solvent mixtures have a large change with increasing ethanol content and temperature, it has a better solubility than other two binary solvent mixtures at higher temperature. By these properties, ethyl acetate could be used as effective anti-solvent in the crystallization process. The solubility data, as a whole, could be correlated with modified Apelblat equation best because of the lowest MD data. It can well account for the description of the dissolution of Memantine hydrochloride. Although the general cosolvency model and Jouyban-Acree + van't Hoff model may cause high deviation at low temperatures, we still advise that describing and predicting the solution process of Memantine hydrochloride use modified Apelblat equation assisted with general cosolvency model and Jouyban-Acree + van't Hoff model.
Table 12 Thermodynamic functions relative to solution process of Memantine hydrochloride in the binary solvent at mean temperature. Mixtures
x1
ΔsolHm/kJ·mol−1
ΔsolSm/J·mol−1·K−1
ΔsolGm/kJ·mol−1
ξH
ξS
Ethanol + acetonitrile
0.093 0.227 0.378 0.512 0.678 0.892 0.102 0.267 0.426 0.582 0.703 0.897 0.089 0.206 0.363 0.496 0.655 0.874
21.55 21.35 20.66 21.60 23.29 25.59 21.32 20.24 20.45 19.59 19.67 19.70 23.24 23.25 25.42 26.61 29.06 30.52
55.35 53.31 49.42 50.07 52.12 53.81 54.22 48.80 47.11 41.55 37.56 32.09 60.23 58.62 62.97 63.46 66.65 65.65
4.63 5.06 5.56 6.30 7.36 9.14 4.74 5.33 6.05 6.89 8.19 9.90 4.83 5.33 6.17 7.22 8.69 10.45
56.02% 56.72% 57.77% 58.53% 59.39% 60.87% 56.26% 57.58% 58.68% 60.67% 63.15% 66.77% 55.80% 56.47% 56.91% 57.84% 58.79% 60.33%
43.98% 43.28% 42.23% 41.47% 40.61% 39.13% 43.74% 42.42% 41.32% 39.33% 36.85% 33.23% 44.20% 43.53% 43.09% 42.16% 41.21% 39.67%
Ethanol + water
Ethanol + ethyl acetate
66
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
Through the van't Hoff analysis, the thermodynamic properties for the solution process including Gibbs free energy, enthalpy, and entropy were yielded. The solution process of Memantine hydrochloride in binary solvent mixtures is endothermic proved by the thermodynamic parameters values and what contributor to the standard molar Gibbs energy of solution was the enthalpy during the dissolution. Generally, for optimizing the purification process of Memantine hydrochloride in industry not only the experimental results but the parameters could be used. Acknowledgements This research work was financially supported by the National Natural Science Foundation of China (no. 21476113). We thank the editors and the anonymous reviewers. References [1] S.P. Sulochana, K. Sharma, R. Mullangi, et al., Review of the validated HPLC and LCMS/MS methods for determination of drugs used in clinical practice for Alzheimer's disease, Biomed. Chromatogr. 28 (2014) 1431–1490. [2] M.R. Farlow, NMDA receptor antagonists: a new therapeutic approach for Alzheimer's disease, Geriatrics 59 (2001) 22–27. [3] H.H. Tung, E.L. Paul, M. Midler, J.A. McCauley, Crystallization of organic compounds: an industrial perspective, Powder Technol. 150 (2005) 133–143. [4] Q. Zhang, Y. Yang, C.C. Cao, L.M. Cheng, Y. Shi, W.G. Yang, Y.H. Hu, Thermodynamic models for determination of the solubility of dibenzothiophene in (methanol + acetonitrile) binary solvent mixtures, J. Chem. Thermodyn. 80 (2015) 7–12. [5] A. Apelblat, E. Manzurla, Solubilities of o-acetylsalicylic, 4-aminosalicylic, 3,5dinitrosalicylic, and p-toluic acid, and magnesium-DL-aspartate in water from T = (278 to 348) K, J. Chem. Thermodyn. 31 (1999) 85–91.
[6] Y. Cheng, Y. Shao, W. Yan, Solubilities of betulinic acid in thirteen organic solvents at different temperature, J. Chem. Eng. Data 56 (2011) 4587–4591. [7] W.E. Acree Jr., Mathematical representation of thermodynamic properties. Part II. Derivation of the combined nearly ideal binary solvent (NIBS)/Redlich-Kister mathematical representation from a two-body and three-body interactional mixing model, Thermochim. Acta 198 (1992) 71–79. [8] M. Barzegar-Jalali, A. Jouyban-Gharamaleki, A general model from theoretical cosolvency models, Int. J. Pharm. 152 (1997) 247–250. [9] Y. Yang, Y.H. Hu, Q. Zhang, L.M. Cheng, C.C. Cao, W.G. Yang, F. Shen, Experimental measurement and thermodynamic models for solid–liquid equilibrium of hyodeoxycholic acid in different organic solvents, J. Mol. Liq. 202 (2015) 17–22. [10] A. Jouyban-Gharamaleki, W.E. Acree Jr., Comparison of models for describing multiple peaks in solubility profiles, Int. J. Pharm. 167 (1998) 177–182. [11] D.J.W. Grant, M. Mehdizadeh, A.H.L. Chow, J.E. Fairbrother, Non-linear van't Hoff solubility-temperature plots and their pharmaceutical interpretation, Int. J. Pharm. 18 (1984) 25–38. [12] F. Sardari, A. Jouyban, Solubility of nifedipine in ethanol + water and propylene glycol + water mixtures at 293.2 to 313.2 K, Ind. Eng. Chem. Res. 52 (2013) 14353–14358. [13] A. Jouyban, F. Martinez, W.E. Acree, Correct derivation of a combined version of the Jouyban–Acree and van't Hoff model and some comments on ‘Determination and correlation of the solubility of myricetin in ethanol and water mixtures from 288.15 to 323.15 K’, Phys. Chem. Liq. 55 (2017) 131–140. [14] D.W. Wei, H. Li, Y. Nan, J. Zhu, Effect of temperature on the solubility of 3aminopyridine in binary ethanol + toluene solvent mixtures, Fluid Phase Equilib. 316 (2012) 132–134. [15] B. Schroder, L. Santos, I. Marrucho, J. Coutinho, Prediction of aqueous solubilities of solid carboxylic acids with COSMO-RS, Fluid Phase Equilib. 289 (2010) 140–147. [16] D.R. Delgado, G.A. Rodríguez, A.R. Holguín, F. Martínez, A. Jouyban, Solubility of sulfapyridine in propylene glycol + water mixtures and correlation with the Jouyban–Acree model, Fluid Phase Equilib. 341 (2013) 86–95. [17] A.R. Holguin, D.R. Delgado, F. Martínez, Y. Marcus, Solution thermodynamics and preferential solvation of meloxicam in propylene glycol + water mixtures, J. Solut. Chem. 40 (2011) 1987–1999.
Contents lists available at ScienceDirect
Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq
Thermodynamic analysis and calculation of solubility of Memantine hydrochloride in ethanol plus (acetonitrile, water, ethyl acetate) binary solvent mixtures Fangfang Shen a, Dingqiang Lu a,b,⁎, Xiuquan Ling b, Xinxian Wang b, Tongqi Liu a, Tianhua Huang a, Kefei He a a b
School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, PR China Jiangsu Provincial Institute of Material Medica, Nanjing 210009, PR China
a r t i c l e
i n f o
Article history: Received 15 November 2016 Received in revised form 7 December 2016 Accepted 13 December 2016 Available online 18 December 2016 Keywords: Memantine hydrochloride Solubility Binary solvent mixtures Thermodynamic properties
a b s t r a c t In this work, we focus on measuring solubility and analyzing solution thermodynamics of Memantine hydrochloride in different binary solvent mixtures (ethanol + acetonitrile); (ethanol + water); and (ethanol + ethyl acetate) at the temperature range of 278.15–333.15 K under atmospheric pressure. The solubility data was correlated by the modified Apelblat model, the general cosolvency model and the Jouyban-Acree + van't Hoff model. The result show that modified Apelblat equation is best because of the lowest MD data and ethyl acetate could be used as effective anti-solvent in the crystallization process of Memantine hydrochloride In addition, the thermodynamic properties of the solution process, including the Gibbs free energy, enthalpy, and entropy were calculated by the van't Hoff analysis. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Memantine hydrochloride is chemically known as 1-amino-3,5dimethyladamantane hydrochloride (CAS: 41100-52-1, MW = 215.77, Fig. 1) developed by German Merz company which is the first FDA approved member of a new class of Alzheimer drugs with a moderate affinity towards N-methyl-D-aspartate (NMDA)-receptor antagonist, it produces symptomatic improvements in learning under conditions of tonic NMDA receptor activation in Alzheimer's disease [1,2]. Memantine hydrochloride is commercially available in the market because it is likely to show neuroprotective effect at a concentration used in the treatment of Alzheimer's disease and to slow down disease progression. Crystallization has been the most important separation and purification process in industrial mass production because the majority of active pharmaceutical ingredients (APIs) are produced in solid form [3]. Memantine hydrochloride is synthesized by Memantine and Hydrochloric acid, precipitation in water. In this crystallization process, we should require add an anti-solvent to the solution to achieve a certain degree of saturation, result in solute precipitation. The significance of solubility data of Memantine hydrochloride is not only to select the best crystallization binary solvent mixtures but to decide the maximum yield of industrial production. Therefore, it is necessary to explore the ⁎ Corresponding author at: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, PR China. E-mail address: [email protected] (D. Lu).
http://dx.doi.org/10.1016/j.molliq.2016.12.051 0167-7322/© 2016 Elsevier B.V. All rights reserved.
solubility of Memantine hydrochloride in different binary solvent mixtures because we find no report for it. The solubility of Memantine hydrochloride in different binary solvent mixtures (ethanol + acetonitrile), (ethanol + water), and (ethanol + ethyl acetate) was measured in the temperature range of 278.15–333.15 K under atmospheric pressure. All solvents were selected by us as binary solvent mixtures since they are inexpensive, and easily removed from the solution. In the temperature between 278.15 K and 333.15 K with the atmospheric pressure, the solubility of Memantine hydrochloride was measured when it in different binary solvent mixtures, ethanol + water, ethanol + acetonitrile and ethanol + ethyl acetate. The solubility data of Memantine hydrochloride was correlated by the modified Apelblat equation, the general cosolvency mode, the Jouyban-Acree + van't Hoff model. The thermodynamic properties of the solid-liquid equilibrium process were also calculated, with the Gibbs free energy, enthalpy, and entropy included, since it's the basis of the crystallization process and process optimization [4].
2. Experimental 2.1. Materials Memantine hydrochloride, a white crystalline powder was obtained from Aladdin Reagent Co., Ltd. It's purity was measured by gas chromatography and the mass fraction purity ≥ 0.990.
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
where m1, m2 represent the mass of Memantine hydrochloride, ethanol, and M1, M2 represent the molar mass of the Memantine hydrochloride, ethanol, respectively; m3 and M3 share a one-to-one mapping. The m3 represents the mass of acetonitrile, water, ethyl acetate in different binary solvent mixtures, respectively; M3 represents the molar mass of acetonitrile, water, ethyl acetate in different binary solvent mixtures, respectively.
NH2HCl
CH 3 CH3
3. Results and discussion 3.1. Solubility data
Fig. 1. Chemical structure of Memantine hydrochloride.
All solvents for dissolving have higher mass fraction purities that N0.980 and supplied by Shanghai Shenbo Chemical Co, Ltd. Table 1 listed more details of these solvents and their CAS registry numbers as well. Analytical balance (model PA225D) was provided by Sartorius Scientific Instrument (Beijing) Co., Ltd. with an uncertainty of ±0.1 mg. Smart thermostatic bath (model: DC-2006) was provided by Ningbo Scientz Biotechnology Co., Ltd. with an uncertainty of ±0.1 K. 2.2. Apparatus and procedures The solubility of Memantine hydrochloride was measured in binary solvent mixtures by the analytical stirred-flask method and we used the gravimetric method to measure the compositions of the saturated solutions. Saturated solutions of Memantine hydrochloride, which were produced by 8 ml solvent mixtures and some excess target were added into a 10 ml glass test tube with a stopper (avoid evaporation of solvent during experimental steps). The test tube was kept in a jacket glass vessel and the test temperature was maintained by circulating water through the outer jacket from a super thermostatic water-circulator bath (type HWC-52, Shanghai Cany Precision Instrument Co., Ltd. Error of plus or minus 0.05 K). Magnetically stirrers were used to mix the solid and binary solvent mixtures adequately. In order to reach solid-liquid equilibrium, the process was allowed to stir for 12 h and the solution was allowed to settle for 12 h. At last, a certain volume solution supernatant was transferred into a beaker with a cover and weighted immediately by using an analytical balance (model: CPA225D, was provided from Sartorius Scientific Instruments CO., Ltd.) with a resolution of ±0.1 mg. This breaker must be weighed before. All beakers were put into a dryer and weighted weekly until reaching constant weight. Each experiment was repeated three times, and the mean value was used to calculate the mole fraction solubility. The mole fraction solubility of Memantine hydrochloride (x) in ethanol plus (acetonitrile, water, ethyl acetate) binary solvent mixtures is calculated by Eq. (1) The mole fraction of ethanol (xA) in the binary solvent mixtures in the absence of the solute is defined using Eq. (2). x¼
59
m1 =M 1 m1 =M1 þ m2 =M 2 þ m3 =M 3
ð1Þ
Under the temperature from 278.15 to 333.15 K, the solubility data of Memantine hydrochloride (x) in the binary solvent mixtures with ethanol plus (acetonitrile, water, ethyl acetate) was obtained and presented in Tables 2–4. These data was listed in Figs. 2–4 that apply for prediction of the solubility under the different condition. From Tables 2–4 and Figs. 2–4, it is obvious that the solubility of Memantine hydrochloride (x) was influenced by temperature and solvent composition in ethanol plus (acetonitrile, water, ethyl acetate) binary solvent mixtures. It is observed that the solubility of Memantine hydrochloride (x) in ethanol plus (acetonitrile, water, ethyl acetate) binary solvent mixtures will increases with the rising the temperature, in addition, if keep the temperature constant, it also increases with increasing ethanol content. Because ethanol is a benign solvent for dissolving Memantine hydrochloride (x). 3.2. Modified Apelblat equation On the basis of the solid–liquid phase equilibrium theory, the changing trends of solubility against temperature in the solvent with same ratio are described by modified Apelblat equation. This model is firstly used by Apelblat, which can give a relatively accurate correlation with three parameters [5–6]: ln x ¼ A þ
B þ C ln ðT=KÞ T=K
ð3Þ
where x represents the mole fraction solubility of Memantine hydrochloride, T is the experimental temperature in K, and A, B and C are the regression curve parameters in the equation which are listed in Table 5. 3.3. General cosolvency model The changing trends of solubility against different ratio of ethanol in ethanol plus (water, acetonitrile, ethyl acetate) binary solvent mixtures under isothermal condition are described by the combined nearly ideal binary solvent/Redich–Kister (general cosolvency) model [7], which is one of the theoretical models for calculating the solute solubility in binary solvents and represented in Eq. (4): N
m2 =M 3 xA ¼ m2 =M2 þ m3 =M3
ð2Þ
Table 1 Provenance and purity of the materials used. Compound
Source
Mass fraction CAS RN purity
Memantine hydrochloride Ethanol Acetonitrile Water Ethyl acetate
Aladdin Reagent Co. Ltd. Shenbo Chemicals Shenbo Chemicals Our laboratory Shenbo Chemicals
≥0.990 ≥0.995 ≥0.992 ≥0.990 ≥0.990
41100-52-1 64-17-5 75-05-8 7732-18-5 141-78-6
ln x ¼ xA ln X A þ xB ln X B þ xA xB ∑ Si ðxA −xB Þi i¼0
ð4Þ
where x is the mole fraction solubility of Memantine hydrochloride. xA and xB represent the initial mole fraction composition of the binary solvent. XA and XB respectively represent the saturated mole solubility of Memantine hydrochloride in pure ethanol and pure acetonitrile, water, ethyl acetate respectively. Si is the model constant and N can be equal to 0–3. When N = 2 and substitution of (1 − xA) for xB, Eq. (4) can be written as ln x−ð1−xA Þ lnX h B −xA ln X A
¼ ð1−xA ÞxA S0 þ S1 ð2xA −1Þ þ S2 ð2xA −1Þ2
i
ð5Þ
60
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
Table 2 Mole fraction solubility (x) of Memantine hydrochloride (x) in (ethanol + acetonitrile) binary solvent mixtures at the temperature range from (278.15 to 333.15) K under atmospheric pressure.a 100 |x − xcal |/x (Eq. (3))
100 |x −xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
T = 278.15 K 0.093 0.721 0.227 0.604 0.378 0.500 0.512 0.362 0.678 0.220 0.892 0.101
0.077 0.039 0.103 0.638 0.022 4.761
0.073 0.463 1.362 2.249 2.303 1.346
4.369 1.871 6.244 0.423 8.545 16.198
T = 283.15 K 0.093 0.834 0.227 0.702 0.378 0.586 0.512 0.427 0.678 0.270 0.892 0.123
0.474 0.433 0.760 0.664 0.027 2.986
0.086 0.534 1.539 2.480 2.380 1.435
1.942 0.701 6.267 0.710 4.704 15.191
T = 288.15 K 0.093 0.965 0.227 0.825 0.378 0.682 0.512 0.501 0.678 0.320 0.892 0.149
0.509 0.638 0.384 0.151 0.032 1.568
0.061 0.361 1.062 1.696 1.546 0.878
1.420 1.709 4.498 0.266 3.969 9.620
T = 293.15 K 0.093 1.115 0.227 0.945 0.378 0.791 0.512 0.584 0.678 0.370 0.892 0.178
0.450 0.513 0.198 0.663 0.037 0.472
0.069 0.418 1.203 1.916 1.774 0.932
0.688 0.268 4.082 0.931 5.270 7.513
T = 298.15 K 0.093 0.129 0.227 0.110 0.378 0.091 0.512 0.068 0.678 0.044 0.892 0.021
0.298 0.362 0.360 0.399 0.044 0.331
0.056 0.337 0.979 1.519 1.350 0.727
0.731 0.570 3.320 0.017 3.068 7.757
T = 303.15 K 0.093 1.482 0.227 1.259 0.378 1.048 0.512 0.783 0.678 0.510 0.892 0.252
0.085 0.319 0.126 0.236 0.051 0.865
0.072 0.437 1.260 1.954 1.723 0.877
1.565 1.469 3.216 0.792 3.000 5.512
T = 308.15 K 0.093 0.171 0.227 0.145 0.378 0.120 0.512 0.090 0.678 0.059 0.892 0.030
0.393 0.154 0.109 0.182 0.059 1.152
0.055 0.336 0.985 1.512 1.303 0.632
1.209 1.419 2.613 0.507 2.661 2.000
T = 313.15 K 0.093 0.195 0.227 0.167 0.378 0.136 0.512 0.103 0.678 0.069 0.892 0.035
0.285 0.341 0.310 0.225 0.069 1.208
0.042 0.252 0.748 1.127 0.925 0.451
1.729 0.847 1.621 0.592 0.749 0.859
T = 318.15 K 0.093 2.241 0.227 1.891 0.378 1.546 0.512 1.173 0.678 0.790 0.892 0.407
0.084 0.153 0.245 0.058 0.079 1.050
0.056 0.343 1.016 1.535 1.250 0.582
1.075 1.602 1.611 0.998 0.559 1.116
T = 323.15 K 0.093 2.566 0.227 2.154
0.144 0.086
0.051 0.317
0.134 1.425
xA
10x
Table 2 (continued) xA
10x
100 |x − xcal |/x (Eq. (3))
100 |x− xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
0.378 0.512 0.678 0.892
1.745 1.331 0.910 0.473
0.252 0.132 0.091 0.688
0.951 1.420 1.121 0.521
1.066 0.924 0.648 1.328
T = 328.15 K 0.093 2.935 0.227 2.445 0.378 1.963 0.512 1.504 0.678 1.030 0.892 0.547
0.117 0.113 0.169 0.082 0.103 0.134
0.029 0.183 0.560 0.831 0.647 0.287
0.555 0.695 0.096 1.250 0.497 3.988
T = 333.15 K 0.093 3.352 0.227 2.775 0.378 2.201 0.512 1.694 0.678 1.180 0.892 0.629
0.052 0.097 0.012 0.033 0.117 0.605
0.027 0.171 0.532 0.779 0.585 2.094
1.892 0.017 0.287 1.311 1.915 4.879
a xA denotes the mole fraction of acetonitrile in the binary solvent mixtures; x denotes the mole fraction solubility of Memantine hydrochloride; xcal denotes the calculated solubility.
ln x ¼ lnX B þ ð lnX A − ln X B þ S0 −S1 þ S2 ÞxA þ ð−S0 þ 3S1 −5S2 Þx2A þ ð−2S1 þ 8S2 Þx3A þ ð−4S2 Þx4A
ð6Þ
Eq. (6) can be further simplified as: ln x ¼ A1 þ B1 xA þ C 1 x2A þ Dx3A þ Ex4A
ð7Þ
Eq. (7) called general cosolvency model A1 ¼ ln X B B1 ¼ ln X A − ln X B þ S0 −S1 þ S2 C 1 ¼ −S0 þ 3S1 −5S2 D ¼ −2S1 þ 8S2 E ¼ −4S2 where A1, B1, C1, D and E are model parameters calculated by this model [8]. They are listed in Tables 6–8. However, the general cosolvency model can be used only to describe the solubility data and to predict solubility data for different concentrations of a mixed solvent at a fixed temperature. To describe the effect of both solvent compositions and temperature on the solubility of Memantine hydrochloride, we adopt another equation [9]. 3.4. Jouyban-Acree model + van't Hoff model This was a relatively more versatile model to describe the solubility of a solute with the variation of both temperature and initial composition of binary solvent mixtures [10]: N
ln x;T ¼ xA ln X A;T þ xB ln X B;T þ xA xB ∑ i¼0
J i ðxA −xB Þi T
ð8Þ
where Ji was the parameter and T was the absolute temperature. Other symbols mean the same as Eq. (4). Solubility at different temperatures could be calculated using the van't Hoff equation. Experimental data required are the solute
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66 Table 3 Mole fraction solubility (x) of Memantine hydrochloride in (ethanol + water) binary solvent mixtures at the temperature range from (278.15 to 333.15) K under atmospheric pressure.a 100 |x − xcal |/x (Eq. (3))
100 |x −xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
T = 278.15 K 0.102 0.681 0.267 0.571 0.426 0.418 0.582 0.315 0.703 0.189 0.897 0.097
0.936 0.224 0.007 0.817 0.804 0.835
0.091 0.705 2.751 6.190 7.884 3.967
1.131 3.695 1.260 7.016 4.821 15.052
T = 283.15 K 0.102 0.792 0.267 0.658 0.426 0.489 0.582 0.364 0.703 0.217 0.897 0.111
0.250 0.046 0.004 0.206 0.624 0.327
0.082 0.652 2.495 5.742 7.465 3.782
0.071 2.128 1.000 6.264 6.406 13.063
T = 288.15 K 0.102 0.927 0.267 0.756 0.426 0.568 0.582 0.417 0.703 0.248 0.897 0.126
0.236 0.159 0.001 0.005 0.696 0.728
0.071 0.585 2.201 5.180 6.895 3.498
0.075 0.773 0.919 5.180 7.944 10.714
T = 293.15 K 0.102 1.079 0.267 0.866 0.426 0.657 0.582 0.475 0.703 0.283 0.897 0.145
0.242 0.401 0.001 0.461 0.713 0.155
0.059 0.509 1.903 4.589 6.184 3.054
0.097 0.374 0.749 4.021 9.117 10.069
T = 298.15 K 0.102 1.251 0.267 0.997 0.426 0.756 0.582 0.541 0.703 0.325 0.897 0.166
0.133 0.113 0.003 0.644 0.108 0.141
0.052 0.452 1.693 4.159 5.538 2.742
0.002 0.527 0.617 3.309 9.077 9.398
T = 303.15 K 0.102 1.442 0.267 1.143 0.426 0.866 0.582 0.618 0.703 0.371 0.897 0.189
0.124 0.449 0.004 0.245 0.519 0.124
0.049 0.440 1.663 4.094 5.472 2.718
0.004 0.631 0.479 3.317 9.218 8.624
T = 308.15 K 0.102 1.654 0.267 1.294 0.426 0.988 0.582 0.704 0.703 0.422 0.897 0.213
0.147 0.237 0.005 0.146 0.761 0.689
0.046 0.420 1.569 3.878 5.261 2.651
0.037 1.553 0.308 3.466 9.265 7.324
T = 313.15 K 0.102 1.902 0.267 1.474 0.426 1.123 0.582 0.797 0.703 0.478 0.897 0.242
0.521 0.079 0.005 0.177 0.766 0.468
0.043 0.405 1.523 3.789 5.126 2.562
0.620 1.425 0.095 3.425 9.310 7.149
T = 318.15 K 0.102 2.151 0.267 1.674 0.426 1.271 0.582 0.901 0.703 0.541 0.897 0.277
0.060 0.004 0.004 0.315 0.869 0.707
0.044 0.407 1.542 3.840 5.176 2.533
0.034 1.189 0.086 3.618 9.002 8.051
T = 323.15 K 0.102 2.438 0.267 1.901
0.023 0.276
0.045 0.417
0.065 0.573
xA
10x
61
Table 3 (continued) xA
10x
100 |x − xcal |/x (Eq. (3))
100 |x− xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
0.426 0.582 0.703 0.897
1.432 1.013 0.606 0.312
0.003 0.147 0.114 0.480
1.599 4.008 5.429 2.632
0.192 3.643 9.439 7.821
T = 328.15 K 0.102 2.752 0.267 2.137 0.426 1.608 0.582 1.134 0.703 0.679 0.897 0.349
0.016 0.252 0.002 0.222 0.450 0.239
0.043 0.404 1.555 3.915 5.302 2.574
0.067 0.608 0.322 3.589 9.440 7.307
T = 333.15 K 0.102 3.095 0.267 2.418 0.426 1.799 0.582 1.274 0.703 0.767 0.897 0.393
0.015 0.069 0.000 0.009 0.036 0.100
0.046 0.422 1.645 4.097 5.450 2.672
0.064 0.362 0.429 4.207 8.188 7.735
a xA denotes the mole fraction of water in the binary solvent mixtures; x denotes the mole fraction solubility of Memantine hydrochloride; xcal denotes the calculated solubility.
solubilities at the lowest and highest temperatures (lnX) to compute the model constants. The equation is [11] ln X ¼ a þ
b T
ð9Þ
where a and b are the model constants calculated. Combination of the Jouyban-Acree and van't Hoff model can predict the drug solubility in mixed solvents at different temperatures after training process using two solubility data points [12]. The combined version could be represented as N b1 b2 J ðx −xB Þi þ xB a2 þ þ xA x B ∑ i A ln x ¼ xA a1 þ T T T i¼0
ð10Þ
When N = 2, derived Eq. (11) as [13]: b1 b2 þ xB a2 þ ln x ¼ xA a1 þ T T i x xB h J 0 þ J 1 ðxA −xB Þ þ J 2 ðxA −xB Þ2 þ A T
ð11Þ
a1, b1, a2, b2, and J0, J1, J2 are model constants calculated by regressing, which are listed in Tables 9–11. I trained the model using the experimental data in this work for three solvent systems as: For ethanol (solvent A) + acetonitrile (solvent B): 2837:56 2651:34 ln x ¼ xA 5:29− þ xB 6:95− T T i x xB h 503:63 þ 1147:67ðxA −xB Þ−1040:34ðxA −xB Þ2 þ A T
ð12Þ
For ethanol (solvent A) + water (solvent B): 2584:10 2621:50 ln x ¼ xA 3:87− þ xB 6:84− T T i x xB h 756:89−174:63ðxA −xB Þ þ 456:29ðxA −xB Þ2 þ A T
ð13Þ
For ethanol (solvent A) + ethyl acetate (solvent B): 3955:11 2674:97 ln x ¼ xA 8:50− þ xB 7:11− T T i xA xB h 319:75−2732:84ðxA −xB Þ þ 2735:25ðxA −xB Þ2 þ T
ð14Þ
62
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
Table 4 Mole fraction solubility (x) of Memantine hydrochloride in (ethanol + ethyl acetate) binary solvent mixtures at the temperature range from (278.15 to 333.15) K under atmospheric pressure.a 100 |x− xcal |/x (Eq. (3))
100 |x −xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
T = 278.15 K 0.097 0.609 0.207 0.504 0.321 0.327 0.524 0.215 0.764 0.109 0.903 0.052
0.068 0.355 0.714 0.737 0.309 0.662
0.286 1.618 4.312 6.186 9.541 17.766
0.355 9.544 4.893 4.930 12.294 2.990
T = 283.15 K 0.097 0.726 0.207 0.594 0.321 0.399 0.524 0.258 0.764 0.134 0.903 0.064
0.256 0.733 0.069 0.360 0.084 0.795
0.204 1.215 3.133 4.612 7.102 12.134
0.511 7.626 4.286 2.549 10.522 6.385
T = 288.15 K 0.097 0.856 0.207 0.705 0.321 0.481 0.524 0.311 0.764 0.163 0.903 0.079
0.025 0.010 0.006 0.580 0.270 0.384
0.219 1.221 2.952 4.116 6.135 9.786
1.158 6.950 4.220 1.265 8.466 8.663
T = 293.15 K 0.097 1.007 0.207 0.835 0.321 0.578 0.524 0.372 0.764 0.198 0.903 0.097
0.060 0.875 0.369 0.863 0.461 0.259
0.197 1.089 2.578 3.602 5.354 8.079
1.440 6.623 3.824 0.128 6.919 10.722
xA
10x
T = 298.15 K 0.097 0.1178 0.207 0.0971 0.321 0.0688 0.524 0.0441 0.764 0.0241 0.903 0.0118
0.207 0.295 0.363 0.375 0.154 0.827
0.136 0.776 1.802 2.562 3.753 5.469
1.740 5.129 3.794 1.792 6.224 12.966
T = 303.15 K 0.097 1.378 0.207 1.124 0.321 0.813 0.524 0.523 0.764 0.291 0.903 0.145
0.072 0.401 0.181 0.045 0.364 0.145
0.100 0.578 1.292 1.776 2.535 3.457
0.885 0.943 1.488 0.172 4.089 3.289
T = 308.15 K 0.097 1.598 0.207 1.31 0.321 0.953 0.524 0.62 0.764 0.352 0.903 0.176
0.109 0.082 0.283 0.203 0.117 0.466
0.100 0.573 1.270 1.710 2.343 3.149
0.995 0.693 1.941 0.758 4.176 1.992
T = 313.15 K 0.097 1.851 0.207 1.525 0.321 1.117 0.524 0.735 0.764 0.429 0.903 0.214
0.013 0.437 0.257 0.326 1.145 0.384
0.099 0.547 1.173 1.497 1.935 2.578
0.735 0.826 1.880 0.778 2.844 1.503
T = 318.15 K 0.097 2.141 0.207 1.751 0.321 1.304 0.524 0.872 0.764 0.508 0.903 0.26
0.315 0.113 0.154 0.247 0.198 0.159
0.086 0.491 1.028 1.296 1.699 2.145
0.169 0.056 1.725 0.184 3.878 1.557
T = 323.15 K 0.097 2.449 0.207 2.014
0.113 0.195
0.090 0.506
0.284 0.090
Table 4 (continued) xA
10x
100 |x − xcal |/x (Eq. (3))
100 |x − xcal |/x (Eq. (7))
100 |x − xcal |/x (Eq. (11))
0.321 0.524 0.764 0.903
1.518 1.034 0.609 0.315
0.120 0.094 0.062 0.003
1.034 1.248 1.600 1.974
1.370 0.863 3.087 1.924
T = 328.15 K 0.097 2.804 0.207 2.314 0.321 1.756 0.524 1.227 0.764 0.727 0.903 0.381
0.101 0.102 0.197 0.258 0.101 0.212
0.116 0.644 1.293 1.483 1.871 2.252
0.110 0.086 1.196 2.445 2.173 2.677
T = 333.15 K 0.097 3.204 0.207 2.655 0.321 2.015 0.524 1.445 0.764 0.867 0.903 0.459
0.038 0.125 0.117 0.023 0.003 0.233
0.154 0.851 1.692 1.862 2.272 2.702
0.693 0.535 1.404 3.723 0.863 3.595
a xA denotes the mole fraction of ethyl acetate in the binary solvent mixtures; x denotes the mole fraction solubility of Memantine hydrochloride; xcal denotes the calculated solubility.
3.5. Mean deviation The mean deviation (MD) is adopted to describe the deviation between experimental data and calculated data.
MD ¼ 100
∑
x−xcal x N
ð15Þ
where N stands for the number of experimental points, x and xcal respectively stand for experimental data and calculated data. The quantitative values of MD are listed in Tables 5 to 11, along with the parameters. As we can see from Tables 2–4 and Figs. 2–4, the solubility of Memantine hydrochloride in ethanol plus (acetonitrile, water, ethyl acetate) binary solvent mixtures is a functional relationship of temperature and solvent composition. The solubility of Memantine hydrochloride increases with the rising of temperature, while it increases with increasing ethanol content at constant temperature. What's more, the solubility of Memantine hydrochloride in (ethanol + ethyl acetate)
Fig. 2. Mole fraction solubility (x) of Memantine hydrochloride versus temperature (T) in the binary (ethanol + acetonitrile) mixed solvent.
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
63
Table 5 Parameters of the Modified Apelblat equation for Memantine hydrochloride in the binary solution mixtures.a Mixtures
xI
A
B/100
C
MD
Ethanol + acetonitrile
0.093 0.227 0.378 0.512 0.678 0.892
−69.34 −32.82 7.70 5.56 −69.34 −51.57
8.48 −7.92 −25.76 −25.75 8.48 −3.93
11.31 5.84 −0.26 0.07 11.31 8.61
0.11 0.27 0.25 0.29 0.73 1.32
Ethanol + water
0.102 0.267 0.426 0.582 0.703 0.897
6.23 −43.70 5.54 −55.01 −52.83 −44.72
−25.53 −1.92 −24.52 3.78 2.45 −1.75
0.05 7.38 0.02 8.92 8.53 7.23
MD = 0.50 0.23 0.19 0.003 0.28 0.54 0.42
Ethanol + ethyl acetate
0.097 0.207 0.321 0.524 0.764 0.903
−15.38 −34.47 1.72 −103.17 −77.63 −96.43
−17.72 −9.14 −27.90 18.15 3.86 10.64
3.37 6.18 0.87 16.49 12.74 15.52
MD = 0.28 0.11 0.31 0.24 0.34 0.27 0.37
Fig. 3. Mole fraction solubility (x) of Memantine hydrochloride versus temperature (T) in the binary (ethanol + water) mixed solvent.
MD = 0.27
binary solvent mixtures have a large change with increasing ethanol content and temperature.it has a better solubility than other two binary solvent mixtures at higher temperature. By these properties, ethyl acetate could be used as effective anti-solvent in the crystallization process. Tables 5 and 11 show that the MD values of modified Apelblat equation, general cosolvency model, Eq. (11), were 0.50, 0.86 and 2.57, respectively, in (ethanol + acetonitrile) binary solvent mixtures. The MD values of modified Apelblat equation, general cosolvency model, and Eq. (11) were 0.28, 2.62 and 3.99, respectively, in (ethanol + water) binary solvent mixtures. The MD values of modified Apelblat equation, general cosolvency model, and Eq. (11) were 0.27, 2.57 and 5.06, respectively, in (ethanol + ethyl acetate) binary solvent mixtures. The result indicated that the calculated solubility was in good agreement with the experimental values, and the modified Apelblat equation was the best, while general cosolvency model and Eq. (11) caused high mean deviation (MD). In fact, using Jouyban-Acree + van't Hoff model, the solubility prediction in ethanol mixtures of acetonitrile, water and ethyl acetate at various temperatures and solvent composition is possible. Thus, to describe and predict the solubility of different temperature may completed by simply modify the Apelblat equation. Nevertheless, it is better to
a
When I = A, xA denotes the mole fraction of acetonitrile in the (ethanol + acetonitrile) binary solvent mixtures; when I = B, xB denotes the mole fraction of water in the (ethanol + water) binary solvent mixtures; when I = C, xC denotes the mole fraction of ethyl acetate in the (ethanol + ethyl acetate) binary solvent mixtures.
use modified Apelblat equation and assisted with JouybanAcree + van't Hoff model when both temperature and solvent composition are considered.
Table 6 Parameters of the general cosolvency model for Memantine hydrochloride in the (ethanol + acetonitrile) binary solution mixtures. T/K
A1
B1
C1
D
E
MD
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
−2.41 −2.30 −2.20 −2.05 −1.90 −1.76 −1.61 −1.53 −1.36 −1.22 −1.10 −0.98
−3.13 −2.73 −1.64 −2.09 −1.90 −2.05 −2.08 −1.25 −1.75 −1.68 −1.37 −1.17
9.93 8.36 3.55 5.84 4.53 5.26 5.16 1.37 3.25 2.38 0.82 −0.61
−19.23 −16.29 −8.75 −12.75 −9.87 −11.17 −10.89 −4.53 −7.31 −5.36 −2.83 −0.06
10.05 8.27 4.52 6.80 4.97 5.77 5.66 2.24 3.69 2.49 1.26 −0.33
1.30 1.41 0.93 1.05 0.83 1.05 0.80 0.59 0.80 0.73 0.42 0.35 MD = 0.86
Table 7 Parameters of the general cosolvency model for Memantine hydrochloride in the (ethanol + water) binary solution mixtures.
Fig. 4. Mole fraction solubility (x) of Memantine hydrochloride versus temperature (T) in the binary (ethanol + ethyl acetate) mixed solvent.
T/K
A1
B1
C1
D
E
MD
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
−2.63 −2.43 −2.21 −2.01 −1.85 −1.70 −1.52 −1.37 −1.26 −1.15 −1.02 −0.94
−0.33 −1.12 −1.97 −2.75 −2.88 −2.99 −3.54 −3.73 −3.56 −3.33 −3.40 −2.82
−2.36 0.91 4.16 7.22 7.63 7.98 9.93 10.50 9.91 9.01 9.21 6.80
1.05 −4.01 −8.85 −13.59 −14.24 −14.71 −17.39 −18.19 −17.48 −16.26 −16.53 −12.83
−0.94 1.62 4.03 6.50 6.86 7.08 8.31 8.72 8.46 7.91 8.05 6.18
3.60 3.37 3.07 2.72 2.44 2.41 2.30 2.24 2.26 2.36 2.30 2.39 MD = 2.62
64
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
Table 8 Parameters of the general cosolvency model for Memantine hydrochloride in the (ethanol + ethyl acetate) binary solution mixtures. T/K 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
B1
A1 −2.97 −2.73 −2.55 −2.39 −2.20 −1.99 −1.85 −1.71 −1.52 −1.38 −1.23 −1.09
4.53 3.44 3.10 3.01 2.45 1.63 1.69 1.78 1.00 0.83 0.60 0.56
C1 −33.05 −27.79 −25.63 −24.68 −21.98 −18.29 −18.38 −18.59 −15.10 −14.01 −12.86 −12.65
D
E −32.82 −27.79 −25.41 −24.12 −21.69 −18.53 −18.66 −18.94 −16.10 −15.24 −14.50 −14.62
57.31 48.32 44.28 42.26 37.81 31.90 32.11 32.58 27.11 25.41 23.79 23.79
Table 10 Parameters of Eq. (11) for Memantine hydrochloride in the (ethanol + water) binary solution mixtures.
MD
T/K
MD
Parameters
6.62 4.73 4.07 3.48 2.42 1.62 1.52 1.30 1.12 1.08 1.28 1.59
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
5.50 4.82 4.27 4.07 3.82 3.71 3.66 3.67 3.66 3.62 3.56 3.50
a1 b1 a2 b2 J0 J1 J2
MD = 3.99
MD = 2.57
where the intercept is obtained in plots of lnx versus (1/T − 1/Tmean). The standard molar entropy of solution (ΔsolS0m) is determined by:
3.6. Thermodynamic properties for the solution The van's Hoff analysis is an important research method in the thermodynamic filed. Firstly, another quantity called the standard molar dissolution enthalpy (ΔsolH0m) should be defined [14,15] Δsol H 0m ¼ −R
∂ ln x ∂ð1=T Þ
ð16Þ
where R represents universal gas constant (8.314 J·mol−1 K−1) and T represents the corresponding absolute temperature. Over a limited temperature interval, the standard molar enthalpy of solution would be valid for the mean temperature. So Eq. (15) can also be written as:
Δsol H 0m
∂ ln x ¼ −R ∂ð1=T−1=T mean Þ
ð17Þ
where Tmean represents the mean temperature of the temperature range, and its value is 305.65 K. The lnx versus (1/T − 1/Tmean) curves of Memantine hydrochloride in the binary solvent mixtures are shown in Figs. 5–7. Because of the lack of activity coefficients, in this work Gibbs free energy of solution can just be determined as an apparent value. Thus, the equation of mole Gibbs free energy is [16]: Δsol G0m ¼ −RT mean intercept
3.87 −2584.10 6.84 −2621.50 756.89 −174.63 456.29
Δsol S0m ¼
Δsol H 0m −Δsol G0m T mean
ð19Þ
The results of the standard Gibbs free energy, enthalpy, and entropy are shown in Table 12, together with ξH and ξS.The ξH and ξS Table 11 Parameters of Eq. (11) for Memantine hydrochloride in the (ethanol + ethyl acetate) binary solution mixtures. T/K
MD
Parameters
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
5.83 5.31 5.12 4.94 5.27 5.10 5.38 5.53 4.89 4.58 4.31 4.49
a1 b1 a2 b2 J0 J1 J2
8.50 −3955.11 7.11 −2674.97 319.75 −2732.84 2735.25
MD = 5.06
ð18Þ
Table 9 Parameters of Eq. (11) for Memantine hydrochloride in the (ethanol + acetonitrile) binary solution mixtures. T/K
MD
Parameters
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15
6.27 4.92 3.58 3.13 2.58 2.59 1.73 1.07 1.16 0.92 1.18 1.72
a1 b1 a2 b2 J0 J1 J2
MD = 2.57
5.29 −2837.56 6.95 −2651.34 503.63 1147.67 −1040.34
Fig. 5. van't Hoff plot of the mole fraction solubility (lnx) of Memantine hydrochloride in the binary (ethanol + acetonitrile) mixed solvent against 1/T with a straight line to correlate the date.
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
65
represent the comparison of the relative contribution to the standard Gibbs free energy by enthalpy and entropy in the solution process, respectively [17]. Δsol H 0m 100% %ξH ¼ Δsol H 0m þ T mean Δsol S0m
ð20Þ
0 T mean Δsol Sm 100% %ξS ¼ 0 Δsol H0m þ T mean Δsol Sm
Fig. 6. van't Hoff plot of the mole fraction solubility (lnx) of Memantine hydrochloride in the binary (ethanol + water) mixed solvent against 1/T with a straight line to correlate the date.
ð21Þ
The results of Table 12 show that the enthalpy and the standard Gibbs free energy of Memantine hydrochloride are positive in the studied binary solvent mixtures, indicating the dissolving process of Memantine hydrochloride in all binary solvent mixtures is endothermic. Moreover, the main contributor to the standard molar Gibbs free energy of solution is the enthalpy during the dissolution, because values of %ξH are ≥55.80%. 4. Conclusion
Fig. 7. van't Hoff plot of the mole fraction solubility (lnx) of Memantine hydrochloride in the binary (ethanol + ethyl acetate) mixed solvent against 1/T with a straight line to correlate the date.
The solubility of Memantine hydrochloride in binary solvent mixtures consisting of (ethanol + water); (ethanol + water); and (ethanol + ethyl acetate) at temperature from (278.15 to 333.15) K was measured by the gravimetric method. We can get the following conclusions that the solubility of Memantine hydrochloride increases with the rising of temperature, while it increases with increasing ethanol content at a constant temperature. What's more, the solubility of Memantine hydrochloride in (ethanol + ethyl acetate) binary solvent mixtures have a large change with increasing ethanol content and temperature, it has a better solubility than other two binary solvent mixtures at higher temperature. By these properties, ethyl acetate could be used as effective anti-solvent in the crystallization process. The solubility data, as a whole, could be correlated with modified Apelblat equation best because of the lowest MD data. It can well account for the description of the dissolution of Memantine hydrochloride. Although the general cosolvency model and Jouyban-Acree + van't Hoff model may cause high deviation at low temperatures, we still advise that describing and predicting the solution process of Memantine hydrochloride use modified Apelblat equation assisted with general cosolvency model and Jouyban-Acree + van't Hoff model.
Table 12 Thermodynamic functions relative to solution process of Memantine hydrochloride in the binary solvent at mean temperature. Mixtures
x1
ΔsolHm/kJ·mol−1
ΔsolSm/J·mol−1·K−1
ΔsolGm/kJ·mol−1
ξH
ξS
Ethanol + acetonitrile
0.093 0.227 0.378 0.512 0.678 0.892 0.102 0.267 0.426 0.582 0.703 0.897 0.089 0.206 0.363 0.496 0.655 0.874
21.55 21.35 20.66 21.60 23.29 25.59 21.32 20.24 20.45 19.59 19.67 19.70 23.24 23.25 25.42 26.61 29.06 30.52
55.35 53.31 49.42 50.07 52.12 53.81 54.22 48.80 47.11 41.55 37.56 32.09 60.23 58.62 62.97 63.46 66.65 65.65
4.63 5.06 5.56 6.30 7.36 9.14 4.74 5.33 6.05 6.89 8.19 9.90 4.83 5.33 6.17 7.22 8.69 10.45
56.02% 56.72% 57.77% 58.53% 59.39% 60.87% 56.26% 57.58% 58.68% 60.67% 63.15% 66.77% 55.80% 56.47% 56.91% 57.84% 58.79% 60.33%
43.98% 43.28% 42.23% 41.47% 40.61% 39.13% 43.74% 42.42% 41.32% 39.33% 36.85% 33.23% 44.20% 43.53% 43.09% 42.16% 41.21% 39.67%
Ethanol + water
Ethanol + ethyl acetate
66
F. Shen et al. / Journal of Molecular Liquids 229 (2017) 58–66
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