The dissolution behaviour and apparent thermodynamic analysis of doxifluridine in twelve pure solvents at various temperatures

J. Chem. Thermodynamics 144 (2020) 106073

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The dissolution behaviour and apparent thermodynamic analysis of doxifluridine in twelve pure solvents at various temperatures Jiao Sha a, Teng Ma a, Rui Zhao a,b, Pengshuai Zhang a, Renren Sun a, Gaoliang Jiang a, Yameng Wan a, Haixia He a, Xinding Yao c,d, Yu Li a, Tao Li a,⇑, Baozeng Ren a,⇑ a

School of Chemical Engineering, Zhengzhou University, Zhengzhou 450001, PR China Henan Chemical Technician College, Kaifeng 475000, Henan, PR China Environment Engineering Department, Yellow River Conservancy Technical Institute, Kaifeng 475004, PR China d Henan Engineering Technology Research Center of Green Coating Materials, Kaifeng 475004, PR China b c

a r t i c l e

i n f o

Article history: Received 15 December 2019 Received in revised form 3 February 2020 Accepted 3 February 2020 Available online 13 February 2020 Keywords: Doxifluridine Solubility Correlation Apparent thermodynamic properties

a b s t r a c t In this work, the solubility of doxifluridine in methanol, ethanol, n-propanol, n-butanol, isobutanol, nPentanol, n-hexanol, n-octanol, (±)-2-ethyl-1-hexanol, acetone, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) were experimentally determined by a laser dynamic method within the temperature range from 278.15 K to 333.15 K at 101.3 kPa. The measured results demonstrated that the experimental solubility of doxifluridine in all selected pure solvents increased with the rise of temperature. It was also found that the order of the mole fraction solubility of doxifluridine in the twelve mono-solvents was: DMSO > DMF > methanol > acetone > ethanol > n-propanol > n-butanol > n-pentanol > n-hexanol
iso butanol > n-octanol > (±)-2-ethyl-1-hexanol. In order to facilitate the industrial application and other studies, the experimental data of solubility were fitted well using the kh equation, the van’t Hoff equation, the modified Apelblat equation, the NRTL model and the UNIQUAC model. Moreover, the apparent thermodynamic properties of doxifluridine in all mono-solvents were investigated by the famous modified Van’t Hoff equation from the solubility data. Ó 2020 Elsevier Ltd.

1. Introduction Doxifluridine (CAS Registry No. 3094-09-5) is a white solid powder chemical, which has a molar mass of 246.192 gmol1. The molecular formula of doxifluridine is C9H11FN2O5, and the molecular structure is presented in Fig. 1. Doxifluridine is a very important antitumor drug, which has been mainly used for the treatment of breast and gastrointestinal malignancies and other solid tumors [1–3]. The purity and crystal form have a vital impact on the efficacy of drugs [4]. And the purity and crystal form of doxifluridine depends on the crystallization process. So, it is essential to extend the practical database on doxifluridine solubility data and choose a suitable solvent for the crystallization process [5,6]. However, in existing researching files, the solubility data of doxifluridine in the pure solvents (methanol, ethanol, n-propanol, n-butanol, isobutanol, n-Pentanol, n-hexanol, n-octanol, (±)-2ethyl-1-hexanol, acetone, dimethyl formamide (DMF), dimethyl sulfoxide(DMSO)) have not been reported. Therefore, the solubility of doxifluridine in above-mentioned twelve organic solvents at dif⇑ Corresponding authors. E-mail addresses: [email protected] (T. Li), [email protected] (B. Ren). https://doi.org/10.1016/j.jct.2020.106073 0021-9614/Ó 2020 Elsevier Ltd.

ferent temperatures under 101.3 kPa from 278.15 K to 333.15 K was measured by using a laser dynamic method in this work [7]. The kh equation, van’t Hoff equation, modified Apelblat equation, NRTL model and UNIQUAC model were chosen to correlate solubility of doxifluridine in different pure solvents. Furthermore, the apparent dissolution enthalpy, entropy and Gibbs energy change of doxifluridine dissolution in the studied solvents were calculated through the measured solubility data and the parametric van’t Hoff equation.

2. Experimental method and apparatus 2.1. Materials Doxifluridine (molar mass: 246.192 gmol1) used in the experiments was purchased from Aladdin Biochemical Corporation (Shanghai, China). Its mass faction purity was 0.990 which was determined by HPLC (high-performance liquid phase chromatograph,); the analysis was carried out in a Diamonsil C18 column (250 mm  4.6 mm, 5 lm) using acetonitrile–water (v: v = 1:1) as the mobile phase at a flow rate of 0.8 mLmin1 at

2

J. Sha et al. / J. Chem. Thermodynamics 144 (2020) 106073 Table 2 The contribution Van der Waals volume (R) and surface (Q) of element and chemical bonds of doxifluridine.a

Fig. 1. Chemical structure of doxifluridine.

25 °C, the injection volume was 20 lL and the eluent was monitored at 269 nm for quantification of doxifluridine, and doxifluridine was stored in a desiccator. The sources of the materials (methanol, ethanol, n-propanol, etc.) used in the experiments were listed in Table 1. 2.2. Thermogravimetric differential scanning calorimetry (TG-DSC) Values of fusion enthalpy (DfusH) and melting temperature (Tm) of doxifluridine could be obtained by TG-DSC instrument TA-2000, which was purchased from Water world Technology Co., Ltd., China. The TG-DSC equipment was calibrated by using standard substance of zinc (0.9999 in mass fraction) to verify the accuracy of the measurement. Then approximately 8.5 mg doxifluridine was added to the closed alumina crucible and determined at T = (300 to 600) K, heating rate of 10 Kmin1, nitrogen atmosphere (100 mLmin1). Values of DfusH and Tm can be calculated by using corresponding TA Universal Analysis software. 2.3. PXRD (Powder X-ray diffraction) In order to determine the existence of crystalline transformation or solvate formation of doxifluridine in the process of dissolution process, PXRD instrument was applied to analyze crystal forms of recovered equilibrated doxifluridine from the twelve pure solvents, which was provided by Bruker D8 Advance Bruker Corporation, Germany. Samples were collected in the 2h range from 5° to 70° at conditions: scanning rate of 0.167°s1, temperature of 298.15 K, electric current of 40 mA and the tube voltage of 45 kV. 2.4. Apparatus and experimental method It is well known that the synthetic method is one of the most classical methods for determining the solubility of a solid in

a

Element or chemical bonds

number

R/(cm3∙mol1)

Q/(109cm2∙mol1)

C H F O N CAC (ring) CAC C-N (ring) C-N NAH CAH C@O CAO (ring) CAF CAO C@C (ring) OAH Total

9 11 1 5 2 4 1 4 1 1 8 2 2 1 2 1 2 –

12.39 4.36 8.01 8.51 9.39 4.77 4.3 3.7 3.76 2.95 3.17 4.87 4.69 4.44 4.82 5.55 2.59 114.63

2.19 1.09 1.63 1.70 1.82 1.21 1.16 1.18 1.07 0.66 0.92 1.15 1.07 0.96 1.13 1.31 0.83 15.03

Taken from Ref. [25].

solvents [8]. In this work, as one of the synthetic methods, the laser monitoring observation technique was chosen to determine the solubility of doxifluridine in twelve mono-solvents at 101.3 kPa, which has been described in detail in our previous literatures [9–11]. The process is simply described here: First, an excess amount of solid solute (doxifluridine) was put into a double-jacketed glass vessel (120 mL) which contained a certain amount of pure solvent. The mass of doxifluridine and the mono-solvents were accurately measured by using an electronic analytical balance (type ME204E, Shanghai Mettler Toledo Instruments co. LTD, Shanghai, China) having an uncertainty of ± 0.0001 g. Second, the temperature of the solution system was controlled by using a constant temperature water bath (DCW-0506, Shanghai Bilon Instrument Co., Ltd., Shanghai, China) with precision of 0.01 K, which was calibrated by a calibrated precision mercury in-glass thermometer (uncertainty of ± 0.05 K). Then the magnetic stirrer (type GL-3250A, Beijing Zhongyi HSBC Technology Co., Ltd., Beijing, China) was activated which accelerated the dissolution speed of doxifluridine for approximately 12 h. At the beginning, the heating rate was changed to about 3 Kh1 until the desired temperature was reached. There was substantial solute dissolved and the electrical signal of the laser recorder changed during this period. And then, when there was

Table 1 Purity and source of solute and solvents.

a b c

Chemical name

CASRN

Mass fraction purity

Source

doxifluridinea Methanol Ethanol n-Propanol n-butanol Isobutanol n-Pentanol n-Hexanol n-octanol (±)-2-ethyl-1-hexanol Acetone DMF DMSO Acetonitrile NaCl Water

3094-09-5 67-56-1 64-17-5 71-23-8 71-36-3 78-83-1 71-41-0 111-27-3 111-87-5 104-76-7 67-64-1 68-12-2 67-68-5 75-05-8 7647-14-5 7732-18-5

0.99b 0.999c 0.995c 0.99c 0.995c 0.995c 0.99c 0.98c 0.99c 0.99c 0.997c 0.995c 0.995c 0.999c 0.995c conductivity  0.1lS/cm

Aladdin biochemical co., LTD Tianjin fengchuan chemical reagent technology co., LTD Tianjin fengchuan chemical reagent technology co., LTD Sinopharm chemical reagent co., LTD Tianjin fengchuan chemical reagent technology co., LTD Aladdin biochemical co., LTD Aladdin biochemical co., LTD Aladdin biochemical co., LTD Aladdin biochemical co., LTD Aladdin biochemical co., LTD Tianjin kermel chemical reagent co., LTD Aladdin biochemical co., LTD Tianjin kemio chemical reagent co., LTD Aladdin biochemical co., LTD Aladdin biochemical co., LTD Our laboratory (double distilled)

Doxifluridine stands for 50 -deoxy-5-fluorouridine. Determined by HPLC (High-performance liquid chromatography). The purities of selected solvents were provided by the supplier.

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J. Sha et al. / J. Chem. Thermodynamics 144 (2020) 106073

Table 3 Values of experimental mole-fraction solubility (x1) and calculated solubility data (xcal 1 ) of doxifluridine in twelve pure solvents at different temperature T and pressure p = 101.3 kPa.a,b T/K

103 x1

103xcal 1

100RD

Apelblat

kh

Van’t Hoff

NRTL

uniquac

Apelblat

kh

Van’t Hoff

NRTL

uniquac

Methanol 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 100ARD

2.960 3.342 4.141 4.663 5.610 6.532 7.574 8.491 10.10 11.32 13.35

2.918 3.445 4.053 4.750 5.548 6.459 7.495 8.672 10.01 11.51 13.21

2.872 3.424 4.042 4.753 5.564 6.481 7.523 8.692 10.02 11.51 13.18

2.878 4.290 4.059 4.779 5.596 6.517 7.553 8.713 10.01 11.44 13.03

2.915 3.443 4.052 4.752 5.552 6.464 7.502 8.678 10.01 11.50 13.19

2.958 3.461 4.043 4.717 5.496 6.395 7.432 8.628 10.01 11.60 13.44

1.41 3.16 2.11 1.92 1.11 1.09 0.99 2.15 0.94 1.68 1.08 1.60

3.04 2.40 2.42 1.93 0.89 0.77 0.66 2.36 0.79 1.68 1.27 1.65

2.75 2.66 1.94 2.56 0.26 0.20 0.22 2.62 0.94 1.07 2.41 1.60

1.52 3.10 2.12 1.96 1.04 1.00 0.90 2.22 0.92 1.63 1.23 1.60

0.06 3.62 2.34 1.23 2.03 2.06 1.82 1.62 0.92 2.47 0.70 1.72

Ethanol 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 100ARD

0.7067 0.8741 1.069 1.222 1.536 1.865 2.246 2.732 3.301 3.991 4.795

0.7132 0.8634 1.045 1.266 1.533 1.856 2.248 2.721 3.293 3.983 4.815

0.6451 0.8111 1.012 1.251 1.543 1.891 2.294 2.772 3.331 3.984 4.751

0.6807 0.8494 1.052 1.293 1.578 1.914 2.307 2.764 3.293 3.902 4.599

0.6907 0.8537 1.050 1.285 1.564 1.896 2.289 2.751 3.293 3.926 4.663

0.7205 0.8661 1.043 1.259 1.521 1.840 2.232 2.707 3.293 4.015 4.911

0.93 1.23 2.22 3.60 0.18 0.47 0.10 0.40 0.23 0.20 0.41 0.91

8.73 7.22 5.53 2.29 0.26 1.32 1.97 1.40 0.91 0.27 0.94 2.82

3.64 2.87 1.79 5.56 2.87 2.40 2.86 1.03 0.31 2.27 4.07 2.70

2.26 2.33 1.81 5.11 1.85 1.67 1.93 0.71 0.21 1.61 2.75 2.02

1.95 0.91 2.42 3.00 0.98 1.34 0.69 0.90 0.21 0.62 2.42 1.40

n-Propanol 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 100ARD

0.3570 0.4425 0.5910 0.7420 0.9202 1.172 1.449 1.733 2.122 2.618 3.311

0.3550 0.4556 0.5804 0.7344 0.9232 1.153 1.432 1.768 2.171 2.652 3.223

0.3414 0.4424 0.5682 0.7239 0.9149 1.152 1.434 1.771 2.180 2.662 3.247

0.3516 0.4541 0.5812 0.7376 0.9287 1.161 1.439 1.774 2.171 2.641 3.193

0.3564 0.4562 0.5801 0.7331 0.9209 1.151 1.429 1.766 2.171 2.656 3.235

0.3691 0.4608 0.5752 0.7179 0.8960 1.118 1.396 1.743 2.179 2.728 3.426

0.55 2.96 1.79 1.02 0.32 1.61 1.24 2.02 2.4 1.3 2.62 1.62

4.48 0.11 3.89 2.43 0.56 1.88 1.37 2.14 2.83 1.61 2.12 2.14

1.4 2.6 1.69 0.54 0.96 1.02 0.68 2.14 2.36 0.85 3.63 1.62

0.28 3.05 1.86 1.21 0.09 1.88 1.37 2.14 2.36 1.61 2.42 1.66

3.39 4.14 2.67 3.25 2.63 4.59 3.73 0.58 2.78 4.23 3.48 3.22

n-butanol 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 100ARD

0.2781 0.3662 0.4749 0.5871 0.7413 0.9431 1.150 1.452 1.793 2.291 2.753

0.2829 0.3631 0.4635 0.5886 0.7438 0.9355 1.171 1.460 1.812 2.239 2.757

0.2661 0.3484 0.4518 0.5813 0.7412 0.9377 1.184 1.472 1.824 2.251 2.752

0.2767 0.3603 0.4649 0.5945 0.7542 0.9491 1.186 1.471 1.812 2.218 2.698

0.2805 0.3620 0.4640 0.5909 0.7479 0.9409 1.177 1.461 1.812 2.230 2.732

0.2877 0.3649 0.4619 0.5833 0.7349 0.9238 1.159 1.451 1.813 2.263 2.821

1.83 2.57 0.71 0.81 0.07 1.60 0.83 0.21 0.73 2.03 1.36 1.15

4.32 4.92 4.84 1.02 0.00 0.53 2.61 1.38 1.68 1.75 0.00 2.09

0.36 1.64 2.11 1.36 1.75 0.64 3.48 1.38 1.12 3.06 1.82 1.70

0.89 1.10 2.32 0.67 0.93 0.22 2.34 0.76 1.21 2.60 0.64 1.24

3.49 0.29 2.76 0.63 0.83 2.04 0.76 0.04 1.28 1.19 2.60 1.45

Isobutanol 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 100ARD

0.1585 0.2092 0.2989 0.3698 0.5199 0.6433 0.829 1.102 1.333 1.791 2.284

0.1593 0.2144 0.2861 0.3790 0.4982 0.6504 0.8434 1.087 1.391 1.771 2.241

0.1481 0.2029 0.2749 0.3688 0.4899 0.6448 0.8414 1.092 1.403 1.784 2.261

1.570 2.133 2.867 3.815 5.028 6.567 8.503 1.091 1.394 1.763 2.211

1.587 2.142 2.865 3.799 4.999 6.526 8.457 1.088 1.391 1.766 2.229

0.1612 0.2153 0.2858 0.3771 0.4947 0.6453 0.8375 1.082 1.391 1.781 2.273

0.18 2.56 4.31 2.42 4.18 1.16 1.73 1.22 4.60 1.08 1.72 2.29

6.92 2.87 8.03 0.27 5.77 0.31 1.45 0.91 5.26 0.56 0.88 3.02

1.26 1.91 4.01 2.97 3.27 2.18 2.53 0.91 4.51 1.68 3.07 2.57

0.17 2.48 4.19 2.69 3.87 1.49 2.01 1.07 4.58 1.32 2.22 2.37

1.38 3.02 4.41 1.92 4.87 0.36 1.03 1.67 4.57 0.50 0.32 2.19

0.2365 0.3251 0.4182

0.2412 0.3181 0.4149

0.2473 0.3231 0.4180

2.432 3.190 4.145

0.2461 0.3201 0.4134

0.2497 0.3213 0.4117

2.19 2.14 0.74

4.66 0.62 0.00

2.97 1.85 0.96

4.28 1.51 1.10

5.78 1.15 1.50

n-Pentanol 278.15 283.15 288.15

(continued on next page)

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J. Sha et al. / J. Chem. Thermodynamics 144 (2020) 106073

Table 3 (continued) T/K

103 x1

103xcal 1

100RD

Apelblat

kh

Van’t Hoff

NRTL

uniquac

Apelblat

kh

Van’t Hoff

NRTL

uniquac

0.5372 0.6828 0.8642 1.083 1.364 1.673 2.075 2.513

0.5357 0.6851 0.8680 1.090 1.358 1.678 2.058 2.505

0.5361 0.683 0.8646 1.079 1.354 1.692 2.064 2.523

5.337 6.815 8.632 1.085 1.354 1.678 2.065 2.526

0.5303 0.6758 0.8559 1.077 1.348 1.678 2.078 2.559

0.5256 0.6682 0.8462 1.068 1.342 1.682 2.100 2.616

0.23 0.30 0.46 0.93 0.17 0.46 0.60 0.18 0.76

0.19 0.15 0.12 0.09 0.74 1.20 0.48 0.40 0.96

0.56 0.29 0.12 0.93 0.74 0.60 0.48 0.80 0.93

1.25 1.05 0.94 0.24 0.85 0.50 0.38 1.96 1.28

2.13 2.17 2.06 1.15 1.31 0.69 1.46 4.21 2.15

n-Hexanol 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 100ARD

0.2347 0.2899 0.3758 0.4850 0.6233 0.7682 0.9675 1.290 1.462 1.813 2.244

0.2286 0.2966 0.3816 0.4874 0.6179 0.7780 0.9731 1.209 1.494 1.835 2.242

2.297 2.985 3.844 4.909 6.219 7.821 9.766 1.212 1.494 1.833 2.231

2.286 2.966 3.816 4.874 6.179 7.780 9.731 1.209 1.494 1.835 2.242

2.303 2.974 3.814 4.859 6.153 7.746 9.694 1.207 1.494 1.841 2.256

0.2354 0.2993 0.3796 0.4802 0.6059 0.7624 0.9569 1.198 1.496 1.865 2.322

2.72 2.26 1.50 0.49 0.82 1.30 0.63 6.25 2.34 1.40 0.10 1.80

2.13 2.76 2.13 1.24 0.16 1.82 1.03 6.20 2.05 1.10 0.45 1.92

2.55 2.41 1.60 0.41 0.80 1.30 0.62 6.20 2.05 1.66 0.00 1.78

1.99 2.54 1.43 0.19 1.23 0.85 0.25 6.46 2.34 1.69 0.73 1.79

0.15 3.20 0.95 0.99 2.75 0.72 1.04 7.13 2.49 3.04 3.57 2.37

n-octanol 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 100ARD

0.2113 0.2642 0.3243 0.4032 0.4685 0.6073 0.6851 0.8763 1.033 1.265 1.512

0.2132 0.2627 0.3226 0.3950 0.4821 0.5868 0.7123 0.8622 1.043 1.253 1.505

0.2006 0.2526 0.3157 0.3916 0.4826 0.5909 0.7191 0.8704 1.052 1.263 1.504

0.2074 0.2602 0.3238 0.3999 0.4905 0.5976 0.7233 0.8703 1.041 1.238 1.465

0.2106 0.2615 0.3230 0.3969 0.4856 0.5913 0.7169 0.8656 1.045 1.247 1.488

0.2178 0.2642 0.3209 0.3903 0.4749 0.5782 0.7039 0.8568 1.043 1.268 1.543

1.06 0.49 0.43 1.99 3.02 3.32 3.98 1.58 1.05 0.53 0.31 1.62

4.74 4.17 2.47 2.73 3.21 2.64 4.96 0.68 1.94 0.00 0.66 2.56

1.90 1.52 0.00 0.74 4.91 1.48 5.55 0.68 0.97 1.59 2.65 2.00

0.18 0.95 0.32 1.50 3.75 2.59 4.66 1.19 1.06 1.04 1.45 1.70

3.23 0.06 0.96 3.16 1.48 4.75 2.75 2.20 1.22 0.66 2.15 2.06

(±)-2-ethyl-1-hexanol 278.15 0.01433 283.15 0.02227 288.15 0.03134 293.15 0.04660 298.15 0.06852 303.15 0.09628 308.15 0.1393 313.15 0.1825 318.15 0.2524 323.15 0.3731 328.15 0.4960 100ARD

0.01454 0.02170 0.03199 0.04662 0.06721 0.09590 0.1355 0.1896 0.2629 0.3615 0.4930

0.01331 0.02024 0.03034 0.04486 0.06546 0.09433 0.1344 0.1892 0.2637 0.3637 0.4969

0.01436 0.02160 0.03204 0.04689 0.06775 0.09670 0.1364 0.1904 0.2630 0.3595 0.4869

0.01465 0.02193 0.03239 0.04719 0.06790 0.09654 0.1357 0.1887 0.2598 0.3541 0.4782

0.01476 0.02207 0.03253 0.04731 0.06796 0.09648 0.1354 0.1880 0.2585 0.3519 0.4747

1.49 2.56 2.07 0.05 1.91 0.39 2.74 3.89 4.18 3.10 0.61 2.09

7.19 9.30 3.32 3.65 4.41 2.06 3.80 3.56 4.60 2.44 0.20 4.05

0.22 2.99 2.24 0.62 1.13 0.43 2.05 4.33 4.18 3.64 1.83 2.15

2.22 1.51 3.34 1.26 0.91 0.27 2.58 3.41 2.92 5.09 3.58 2.46

3.03 0.91 3.78 1.53 0.81 0.20 2.79 3.04 2.41 5.68 4.29 2.59

Acetone 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 100ARD

2.814 3.207 3.593 3.950 4.365 4.854 5.411 5.980 6.633 7.292 7.961

2.840 3.179 3.551 3.958 4.401 4.884 5.409 5.979 6.598 7.267 7.991

2.850 3.192 3.564 3.965 4.403 4.882 5.401 5.973 6.595 7.277 8.013

2.810 3.168 3.556 3.977 4.431 4.919 5.442 6.002 6.598 7.233 7.907

2.836 3.179 3.553 3.960 4.404 4.887 5.412 5.981 6.597 7.264 7.986

2.880 3.194 3.543 3.930 4.361 4.838 5.366 5.952 6.601 7.320 8.116

0.92 0.85 1.16 0.19 0.83 0.62 0.04 0.00 0.53 0.34 0.37 0.53

1.28 0.52 0.92 0.25 0.80 0.54 0.21 0.16 0.65 0.30 0.62 0.57

0.15 1.14 0.92 0.75 1.49 1.36 0.53 0.34 0.50 0.85 0.64 0.79

0.79 0.88 1.13 0.25 0.90 0.69 0.00 0.01 0.55 0.38 0.31 0.53

2.34 0.40 1.40 0.50 0.10 0.33 0.83 0.46 0.49 0.38 1.95 0.84

175.2 182.0 185.6 192.0 197.8 206.4 212.6 218.6 226.4

175.6 180.8 186.4 192.2 198.5 205.1 212.0 219.3 227.0

175.1 180.7 186.4 192.5 198.8 205.3 212.2 219.4 227.2

173.3 180.2 186.7 193.4 200.1 206.9 213.6 220.3 227.3

175.2 180.6 186.4 192.5 198.9 205.5 212.3 219.5 227.1

176.7 182.0 187.6 193.3 199.2 205.3 211.7 218.3 225.2

0.24 0.64 0.40 0.15 0.33 0.66 0.26 0.33 0.30

0.11 0.54 0.21 0.02 0.59 0.69 0.27 0.18 0.29

1.25 1.08 0.75 0.54 1.10 0.28 0.67 0.64 0.29

0.08 0.74 0.45 0.29 0.52 0.47 0.11 0.42 0.29

0.86 0.04 1.05 0.69 0.69 0.53 0.42 0.14 0.52

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 100ARD

DMF 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

5

J. Sha et al. / J. Chem. Thermodynamics 144 (2020) 106073 Table 3 (continued) 103 x1

T/K

323.15 328.15 100ARD DMSO 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15 100ARD

103xcal 1

100RD

Apelblat

kh

Van’t Hoff

NRTL

uniquac

Apelblat

kh

Van’t Hoff

NRTL

uniquac

235.2 244.0

235.1 243.6

235.0 243.3

233.7 240.4

234.8 249.6

232.3 239.8

0.02 0.15 0.32

0.09 0.28 0.30

0.49 1.63 0.79

0.14 2.30 0.53

1.20 1.71 0.71

229.0 235.7 241.8 247.1 254.8 261.8 270.2 276.9 285.2

229.3 235.2 241.4 247.9 254.8 261.9 269.4 277.2 285.3

229.4 235.3 241.4 247.9 254.7 261.8 269.3 277.2 285.5

229.3 235.2 241.4 247.9 254.8 261.9 269.4 277.2 285.3

229.2 235.2 241.4 248.0 254.8 261.9 269.4 277.4 285.4

226.6 233.5 240.6 247.9 255.5 263.3 271.4 279.9 288.6

0.13 0.23 0.14 0.34 0.01 0.06 0.28 0.08 0.04 0.15

0.19 0.20 0.14 0.31 0.05 0.00 0.33 0.09 0.13 0.16

0.13 0.23 0.14 0.34 0.01 0.06 0.28 0.08 0.04 0.15

0.10 0.23 0.13 0.35 0.00 0.05 0.29 0.17 0.08 0.16

1.03 0.95 0.49 0.32 0.27 0.58 0.47 1.05 1.21 0.71

a cal xexp 1 is the experimental value for solubility. x1 is the calculated solubility by the Apelblat model, kh model, Van’t Hoff model, NRTL model and UNIQUAC model. RD is the relative deviation between the experimental value and the corresponding fitting equation. b The standard uncertainty of temperature u(T) = 0.05 K, u (P) = 0.3 kPa. The relative standard uncertainty of the solubility is ur(x) = 0.05.

negligible solute undissolved in the selected mono-solvent, the solvent was dropped slowly (about 2 ~ 3 drops per minute) into the solution system by using a syringe till doxifluridine was just completely dissolved. The solid–liquid phase reached equilibrium and the electrical signal of the laser recorder reached its maximum stable value. Finally, we recorded the mass of doxifluridine, the mass of the selected solvent and the experimental temperature. For each temperature point, the experimental process was repeated at least three times and the average value was used as the final result. The saturated mole fraction solubility (x1) of doxifluridine in selected pure solvents can be calculated by using the following equations:

x1 ¼

m1 =M 1 m1 =M1 þ m2 =M2

ð1Þ

where m1, m2 represent the mass of doxifluridine and solvents, respectively; M1, M2 stand for the molar mass of doxifluridine and selected solvents, respectively.

using Eq. (1); the Tm was derived the TG-DSC curve (Fig. 2), Tm = 464.61 K; where k and h can be obtained from fitting the experimental solubility data using the Eq. (2), and the values of k and h are listed in Table 4. 3.2. Van’t Hoff model The van’t Hoff equation is based on the principle of thermodynamics, which is the most commonly used equation to describe and correlation the solid–liquid equilibrium data [16,17], the van’t Hoff model is shown as Eq. (3).

lnx ¼

a þb T

ð3Þ

The T is the absolute temperature (K), x represents the experimental value of mole fraction of doxifluridine in different monosolvents at T, and  can be calculated using Eq. (1); where a and b are the empirical constants. The values of a and b were obtained from fitting the experimental solubility data using Eq. (3), and they are listed in Table 4.

2.5. Experimental reliability proof 3.3. Modified Apelblat model To ensure the accuracy and precision rate of the experimental results, the solubility curve of sodium chloride in water was tested and compared to the values in the Ref. [12]. The experimental values and the literature data are listed in Table S1, and the solubility points are shown in Fig. S1. It was found that the data are in good agreement.

The modified Apelblat model is a widely used semi-empirical model, which was derived from Clausius-Clapeyron equation. The

100

3. Thermodynamic modelling

The kh equation [13] was first proposed on the basis of the generalized relational equation in 1980 and widely used by many researchers for solid and liquid equilibrium experimental data correlation [14,15], which was described as Eq. (2):

ð2Þ

here k is the factor representing the non-ideal degree of saturated solution, for ideal solution k = 1, h is the constant of the equation, Tm represents the melting point of the solute. The T is the absolute temperature (K); x represents the mole fraction solubility of doxifluridine at T, which can be calculated

Weight (%)

90

3.1. kh model


   1x 1 1 ln 1 þ k ¼ kh  x T=K T m =K

0

110

-1

80

TG

DSC

70 60 50

-2

Tm= 464.64 K

fusH = 45299.328J·mol

-1

-3

40 30 360

420

T/K

480

Fig. 2. TG-DSC curve of doxifluridine.

540

-4

6

J. Sha et al. / J. Chem. Thermodynamics 144 (2020) 106073

Table 4 The regression parameters and the root-mean-square deviation (RMSD) of the kh model and Van’t Hoff model for doxifluridine in twelve pure solvents (p = 101.3 kPa).a Solvents

Methanol Ethanol n-Propanol n-butanol isobutanol n-Pentanol n-Hexanol n-octanol (±)-2-ethyl-1-hexanol acetone DMF DMSO a

Kh

Van’t Hoff

K

h

R

0.13137 0.11334 0.12102 0.11728 0.18834 0.1077 0.08648 0.0364 1.2070 0.02534 0.06194 0.42

20263.6029 31637.4918 33634.5648 35948.7217 26307.0391 39162.6784 47551.6959 99120.3718 6808.9331 62638.2656 3859.9122 0.11

0.999 0.999 0.998 0.999 0.999 0.999 0.999 0.999 0.999 0.999 0.999 0.999

2

4

10 RMSD

a

b

R2

104RMSD

1.17 0.42 0.35 0.21 0.26 0.17 0.27 0.15 0.05 0.30 7.33 4.82

2756.28334 3487.63612 4027.29480 4156.85486 4826.97178 4272.59552 4168.23043 3568.67464 6432.27569 1888.80883 604.20616 533.78101

4.05884 5.24632 6.52593 6.75225 8.59442 7.03914 6.59532 4.34934 11.97421 0.91591 0.41569 0.34166

0.998 0.998 0.999 0.998 0.999 0.999 0.999 0.999 0.999 0.998 0.998 0.998

1.39 0.75 0.42 0.30 0.31 0.09 0.28 0.20 0.06 0.43 18.64 4.58

The standard uncertainty is u(p) = 0.3 kPa.

model can be used to simulate the relationship between the mole fraction of doxifluridine in mono-solvents and temperature [18,19]. It can be expressed as follows:

B lnx ¼ A þ þ ClnðT Þ T

3.4. NRTL equation Renon and Prausnitz proposed the NRTL model derived from Scott’s two-liquid model and the theory of local composition in 1968 [20,21]. This model can offer an activity coefficient expression of excess Gibbs energy for a solution of m components. The expression of gE of NRTL equation can be described as:

  gE s21 G21 s12 G12 þ ¼ x1 x2 RT x1 þ x2 G21 x2 þ x1 G12

ð5Þ

With

s12 ¼

g 12  g 22 Dg 12 ¼ RT RT

" lnc1 ¼

x22

lnc2 ¼

x21

ð4Þ

where T is the absolute temperature (K), x represents the mole fraction solubility of doxifluridine in mono-solvents at T, and x was calculated with the Eq. (1); where A, B and C are the empirical constants. The values of A, B and C were obtained from correlating the experimental solubility values with the Eq. (4) and they are listed in Table 5.

G12 ¼ expða12  s12 Þ

The expressions of activity coefficient can be expressed as:

G12 ¼ expða12  s21 Þ

s21 ¼

ð6Þ

g 21  g 11 Dg 21 ¼ RT RT

ð7Þ

s21 "

s12



G21 x1 þ x2  G21



G12 x2 þ x1  G12

2 þ 2 þ

s12  G12

# ð8Þ

ðx2 þ x1  G12 Þ

s21  G21

# ð9Þ

ðx1 þ x2  G21 Þ2

where R represents the universal gas constant and T stands for absolute temperature in Kelvin; Dg12 and Dg21 stand for the interaction energy parameters (Jmol1) between two different components; s12 and s21 are the equation dimensionless interaction parameters; the variable range of a12, which relates with nonrandomness in the mixture, is always from 0.2 to 0.47. However, a12 can be arbitrarily specified, when there is of absence supporting of experiment data. The Dg12, Dg21 and a12 are listed in Table 6. 3.5. UNIQUAC equation The UNIQUAC model, which was first proposed by Abrams in 1975, is a theoretical equation based on the lattice model and the concept of local composition [22]. This model is also a second-generation activity coefficient equation consisting of an entropy term (combinatorial part) and an enthalpy term (residual part). The expression of gE for UNIQUAC model can be expressed as [23]:

Table 5 The regression parameters and the root-mean-square deviation (RMSD) of the modified Apelblat equation for doxifluridine in twelve pure solvents (p = 101.3 kPa).a Solvent

Methanol Ethanol n-Propanol n-butanol isobutanol n-Pentanol n-Hexanol n-octanol (±)-2-ethyl-1-hexanol Acetone DMF DMSO a

modified Apelblat equation A

B

C

R2

104RMSD

40.5797 146.2644 24.7644 141.1719 38.74 34.1831 15.1931 85.2401 1.61589 33.9263 43.0676 3.4786

748.6165 3326.7238 2619.9766 2561.6254 2698.0558 5493.4271 3188.2697 460.7059 7272.8203 321.7422 1356.8765 3.116

6.6512 22.5755 4.6623 22.0046 7.0529 4.0445 3.2465 13.3490 2.8669 5.1915 6.4763 0.15

0.999 0.999 0.999 0.999 0.999 0.999 0.999 0.999 0.999 0.999 0.999 0.999

1.14 0.17 0.35 0.19 0.25 0.06 0.28 0.13 0.05 0.27 7.29 4.58

The standard uncertainty is u(p) = 0.3 kPa.

7

J. Sha et al. / J. Chem. Thermodynamics 144 (2020) 106073 Table 6 The regression parameters and the root-mean-square deviation (RMSD) of the NRTL model and UNIQUAC model for doxifluridine in twelve pure solvents (p = 101.3 kPa).a,b Solvents

NRTL

Methanol Ethanol n-Propanol n-butanol isobutanol n-Pentanol n-Hexanol n-octanol (±)-2-ethyl-1-hexanol acetone DMF DMSO a b

UNIQUAC equation

4g12

4g21

a12

10 RMSD

r

q

a12

a21

104RMSD

50436.56 44460.17 663.09 37558.94 26245.12 34552.70 37080.92 50318.53 4.16 79157.50 55882.60 57801.91

22820.39 19368.71 1353.56 16846.16 13344.82 16084.39 16263.73 16701.63 7557.73 20516.42 34956.63 36401.84

0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.05 0.05

1.15 0.53 0.35 0.22 0.27 0.17 0.29 0.15 0.08 0.28 8.46 4.62

1.43 2.11 2.78 3.45 3.45 4.13 4.80 6.15 6.15 2.59 3.115 2.78

1.43 1.97 2.51 3.05 3.05 3.59 4.13 5.21 5.21 2.33 2.768 2.46

2264.62 2503.35 2546.51 2488.55 2043.95 2231.67 2405.63 2726.47 10.71679 2117.61 14425.1 60672.9

2055.19 3849.54 4754.04 4598.42 3644.87 3733.89 4398.57 5392.75 1227.79 17.57455 7231.38 31,122

1.32 0.41 0.58 0.25 0.22 0.35 0.42 0.17 0.09 0.58 18.70 20.40

4

r is the volume parameter, q is the surface of interaction. The standard uncertainty is u(p) = 0.3 kPa.

gE g E ðcombinatorialÞ g E ðresidualÞ þ ¼ RT RT RT

ð10Þ

with m m g E ðcombinatorialÞ X / zX hi ¼ xi ln i þ xi qi ln RT 2 x / i i i¼1 i¼1

g ðresidualÞ ¼ RT E

m X

qi xi ln

i¼1

m X

ð11Þ

! hj sji



Du12 RT



 a  12 ¼ exp  T

   a  Du21 21 ¼ exp  ¼ exp  RT T

s21

ð13Þ

  /2 z h2 r2 þ q2 ln þ /1 l2  l1  q2 lnðh2 þ h1 r 12 Þ x2 2 /2 r1   s12 s21  þ h1 q2 h2 þ h1 s12 h1 þ h2 s21

ð14Þ

ð15Þ

lnc2 ¼ ln

ð16Þ

with

xi r i /1 ¼ segment or v olume fraction of species i ¼ P j xj q j

ð17Þ

xi q h1 ¼ area fraction of species ¼ P i j xj qj

ð18Þ

li ¼

z ðr i  qi Þ  ðri  1Þ 2

RR i V VW

ð20Þ

q¼

RQ i AVW

ð21Þ

Ri and Qi denote the contribution of Van der Waals volume and surface of elements and chemical bonds; VVW (standard segment volume) and AVW (standard segment surface) are the constant with values of 15.17 cm3mol1 and 2.5  109 cm2mol1. The r, q, a12 and a21 are also listed in Table 6. 4. Results and discussion

The activity coefficient for any compound could be given by:

  / z h1 r1 lnc1 ¼ ln 1 þ q1 ln þ /2 l1  l2  q1 lnðh1 þ h2 r 21 Þ x1 2 /1 r2   s21 s21 þ h2 q1  h1 þ h2 s21 h2 þ h1 s12

r¼ ð12Þ

j¼1

Characteristic energies Du12 and Du21, which stand for the average interaction energy of species 1- species 2, represent the adjustable parameter s12 and s21 for a binary mixture. Values of s12 and s21 could be calculated by Eqs. (15) and (16):

s12 ¼ exp 

Lattice coordination number z is frequently set to 10; the volume parameter (r) as well as surface area parameter (q) for investigated solvents can be gained from Dortmund Data Bank [23] and previous published literature [24]; r and q of solute (doxifluridine) are evaluated adopting group-contribution technique (Shown in Table 2) reported in literature as [25].

ð19Þ

4.1. Solid state characterization TG-DSC analysis of doxifluridine was carried out by TA 2000 instrument, and the thermal analysis curve is shown in Fig. 2. It can be seen from Fig. 2 that the TG-DSC curve has an endothermic peak beginning at 464.64 K during the heating process between 300 K and 600 K. Therefore, the values of Tm and DfusH of doxifluridine acquired by TA Universal Analysis software are 464.64 K (standard uncertainties of 0.5 K, literature data: (192–193) °C [26], (189–190) °C [26], (186–188) °C [26], and 190 °C [27]) and 45.30 kJmol1 (relative standard uncertainties of 0.05). The Tm of doxifluridine is close to that of the literature and the relative deviations are all less than 0.03. These slight deviations of melting point between literature data and our experimental values may be due to the differences of measurement method, sample source and the experiment environment. PXRD results of raw doxifluridine and recovered equilibrated doxifluridine from twelve solvents are shown in Fig. 3, and the 2theta range is from 5° to 70°. It can be seen from Fig. 3 that prominent peaks of all samples after experiments appear at the same location. This confirms that there are no solvates or other polymorphic or crystal transformation occurring throughout the dissolution process.

r i ¼ v olume parameter for species i

4.2. Solubility values

qi ¼ surface area parameter for species i

The measured mole fraction solubility of doxifluridine (x1) in twelve mono-solvents at different temperature are listed in Table 3

8

J. Sha et al. / J. Chem. Thermodynamics 144 (2020) 106073

0.28

0.28 DMF DMSO

0.26

10

20

30

2θ

40

50

60

70

Fig. 3. PXRD patterns of raw doxifluridine and recovered equilibrated doxifluridine from twelve solvents.

and graphically shown in Figs. 4 and 5. As can be observed from Figs. 4 and 5, the mole fraction solubility of doxifluridine in twelve mono-solvents decreases according to the following order: dimethyl sulfoxide (DMSO) > dimethyl formamide (DMF) > methanol > acetone > ethanol > n-propanol > n-butanol > n-pentanol > n-hexanol
isobutanol > n-octanol > (±)-2-ethyl-1hexanol. We can conclude that the solubility of doxifluridine in twelve pure solvents increases with rising temperature. At the same temperature, the mole fraction solubility of doxifluridine in DMSO and DMF is much greater than in low-carbon alcohol and acetone. Moreover, the solubility of doxifluridine in low-carbon alcohol decreases with increasing number of carbon atom. Besides, the solubility of doxifluridine in linear low-carbon alcohols is greater than in starch low-carbon alcohols, such as nbutanol > iso-butanol; n-octanol > (±)-2-ethyl-1-hexanol. Isobutanol and (±)-2-ethyl-1-hexanol possess greater steric hindrance because of the branched chains, which makes it harder to form hydrogen bonds with the solute compared to n-butanol and noctanol [28–30]. Therefore, the solubility of doxifluridine in iso-b utanol/(±)-2-ethyl-1-hexanol is low. According to the Refs. [31,32], the polarity of the twelve selected solvents decreases in

0.014 0.012 0.010

x1

0.014

methanol ethanol n-propanol n-butanol isobutanol n-pentanol n-hexanol n-octanol (±)-2-ethyl-1-hexanol Acetone

0.008

0.012 0.010 0.008

0.006

0.006

0.004

0.004

0.002

0.002

0.000

0.000 280

290

300

T/K

310

320

330

Fig. 4. Solubility of doxifluridine in ten solvents; x1 is experimental solubility of doxifluridine while the solid lines stands for the calculated solubility value by modified Apelblat model at different temperatures.

0.24

0.24

x1

intensity

DMSO DMF Acetone (±)-2-ethyl-1-hexanol n-Octanol n-Hexanol n-Pentanol isobutanol n-butanol n-Propanol Ethanol Methanol Raw

0.26

0.22

0.22

0.20

0.20

0.18

0.18

0.16

280

290

300

T/K

310

320

330

0.16 340

Fig. 5. Solubility of doxifluridine in DMF and DMSO; x1 is experimental solubility of Doxifluridine while the solid lines stands for the calculated solubility value by modified Apelblat model at different temperatures.

the following order: methanol > ethanol > n-propanol > n-butano l > n-pentanol > n-hexanol > isobutanol > n-octanol > (±)-2-ethy l-1-hexanol > DMSO > DMF > acetone. For the selected alcohol solvents, the solubility order of doxifluridine is related to the polarity. However, the solubility of doxifluridine in DMSO and DMF with a lower polarity is greater than that in methanol with a higher polarity, and the doxifluridine solubility in acetone with a lower polarity was greater than that in ethanol with a higher polarity, which means that polarity of the solvents is not the only factor that determines solubility of doxifluridine. The dissolution of doxifluridine in different solvents is a complex process. Various other factors that influence solubility of doxifluridine include physicochemical properties of solute and solvents and interaction of the solute–solvent molecules, such as van der Waals force, electrostatic force, hydrogen bonding, dipole–dipole interaction, size of molecules, the structure and functional group of molecules and stereoscopic effect [33–35]. The specific mechanism of the dissolution process of doxifluridine needs more further study. 4.3. Data correlation Solubility of doxifluridine was correlated by the kh equation, van’t Hoff equation, modified Apelblat equation, NRTL model and UNIQUAC model with the aim of expanding the application range of the solubility data for the industrial crystallization and purification. The relative deviation (RD), average relative deviation (ARD) and root-mean square deviation (RMSD) between experimental solubility (x1) and corresponding calculated solubility (x1cal) were applied to evaluate the applicability of the five models [4,8].

RD ¼

x1 xcal 1 x1

ARD ¼

ð22Þ

 Pn x1 xcal 1  i¼1  x1 

RMSD ¼

n

2 Pn cal i¼1 x1  x1 n

ð23Þ

ð24Þ

The n represents the number of experimental temperature points. The results of x1cal, RD and ARD are listed in Table 3. The results of regression parameters and RMSD are listed in Tables 4–6. From Table 3, the corresponding average values of ARD with five thermodynamic models are 1.85% (kh), 1.57% (van’t Hoff), 1.24% (modified

9

J. Sha et al. / J. Chem. Thermodynamics 144 (2020) 106073

-4 -5 -6 -7

lnx1

Apelblat), 1.45% (NRTL) and 1.78% (UNIQUAC), respectively. This demonstrates that all the models investigated in this work have good accordance with the results of experimental solubility data. From Tables 4–6, the total RMSD of kh model, the van’t Hoff, Apelblat model, NRTL model and UNIQUAC model are 1.292  104, 2.288  104, 1.230  104, 1.381  104, 3.624  104, respectively. All the R2 (R-square) of the kh model, the van’t Hoff model and Apelblat model are no less than 0.998. The results indicate that the five models are all able to fit the dissolution process well and the modified Apelblat model provides more accurate mathematical description than the others.

-9

4.4. Thermodynamic parameter

-10

The thermodynamic parameters are the important parameters for the research of the solid–liquid equilibrium systems. We can get important information from the thermodynamic parameters. The apparent standard dissolution enthalpy (DsolH0), entropy (DsolS0) and Gibbs energy (DsolG0) change of doxifluridine in the studied solvents were calculated by the modified van’t Hoff equation from the measured solubility data [36–38]. First of all, we introduce the parameter Thm (the mean harmonic temperature) and can be obtained with Eq. (25).

n T hm ¼ Pn

-8

-11 -0.0003 -0.0002 -0.0001 0.0000

-1.2

In Eq. (25), n equals the number of temperature points and Tj the experimental temperature. In the case of constant pressure, the relationship between the temperature and the solubility of doxifluridine in solution and the DsolH0 can be obtained from the well-known modified van’t Hoff equation as follows:

-1.3

-1.4

-1.5



ð26Þ -1.6

The x1 is the saturated mole fraction solubility of doxifluridine in the twelve studied solvents and can be calculated with Eq (1); where T is the absolute temperature (K); where R is the universal gas constant having a value of 8.314 JK1mol1; where DsolH0 is the apparent standard mole dissolution enthalpy change of doxifluridine dissolved in the twelve studied solvents, the DsolH0 can be obtained from the slope of the fitted line curves lnx1 versus (1/T-1/Thm). The DsolG0 (apparent standard dissolution Gibbs energy change) can be acquired with Eq. (27).

Dsol G0 ¼ R  T hm  Intercept

ð27Þ

The R is the universal gas constant having a value of 8.314 JK1mol1; Intercept can be calculated from the intercept of the fitted line curves lnx1 versus (1/T-1/Thm). The fitted curves are shown in Figs. 6 and 7. The DsolS0 (apparent standard dissolution entropy change) can be acquired from Eq. (28):

Dsol S0 ¼

Dsol H0  Dsol G0 T hm

ð28Þ

The DsolH0 and DsolG0 can be calculated from Eq. (26) and Eq. (27). In order to evaluate the influence and contribution of DsolH0 and DsolS0 to DsolG0 in the dissolving process, here fH and fTS are introduced and they are defined as follows [39,40]:

1H

   0 Dsol H     ¼   0 0 Dsol H  þ T hm Dsol S 

0.0003

lnx1

 @lnx1 Dsol H0 ¼ @ ð1=T  1=T hm Þ p R

0.0002

Fig. 6. Plot of lnx1 against 1/T-1/Thm for doxifluridine in ten pure solvents.

ð25Þ

1 j¼1 T j

0.0001

1/T-1/Thm

ð29Þ

-1.7

-1.8

-0.0003 -0.0002 -0.0001 0.0000

0.0001

0.0002

0.0003

1/T-1/Thm Fig. 7. Plot of lnx1 against 1/T-1/Thm for doxifluridine in DMF and DMSO.

1TS

   0 T hm Dsol S     ¼   0 0 Dsol H  þ T hm Dsol S 

ð30Þ

The fH (relative contribution of enthalpy) can be calculated from Eq. (29) and fTS (relative contribution of entropy) can be acquired from Eq. (30). The apparent thermodynamics properties of doxifluridine solution including 4sol G°, 4sol H°, 4sol S°, fTS and fH were listed in Table 7. From Table 7, all the values of the 4solG° for doxifluridine dissolution in twelve mono-solvents are recorded as positive values in the range of (3.55–23.38) kJmol1. The values of 4solG° for doxifluridine dissolution is in reverse order of the solubility, which was recorded highest in (±)-2-ethyl-1-hexanol (23.38 kJmol1) followed by n-octanol (18.74 kJmol1), isobutanol (18.53 kJmol1), n-hexanol (18.08 kJmol1), n-pentanol (17.83 kJmol1), nbutanol (17.59 kJmol1), n-propanol (17.08 kJmol1), ethanol (15.81 kJmol1), acetone (13.40 kJmol1), methanol

10

J. Sha et al. / J. Chem. Thermodynamics 144 (2020) 106073

Table 7 Values of intercept, slope, R-square (R2), apparent thermodynamic properties of solutions (4solG°, 4solH° and 4solS°), relative contribution of entropy (fTS) and relative contribution of enthalpy (fH) for doxifluridine in selected solvents (p = 101.3 kPa).a,b

a b

Solvents

intercept

slope

R2

4solG°/kJmol1

4solH°/kJmol1

4solS°/JK1mol1

fH

fTS

Methanol Ethanol n-Propanol n-butanol isobutanol n-Pentanol n-Hexanol n-octanol (±)-2-ethyl-1-hexanol acetone DMF DMSO

5.05816 6.28978 6.79521 6.99744 7.37182 7.09339 7.19200 7.45482 9.30192 5.33173 1.58285 1.36580

2756.28334 3487.63612 4027.29480 4156.85486 4826.97178 4272.59552 4168.23043 3568.67464 6432.27569 1888.80883 604.20616 533.78101

0.9992 0.9975 0.9992 0.9993 0.9988 0.9997 0.9988 0.9983 0.9994 0.9992 0.9983 0.9963

12.71 15.81 17.08 17.59 18.53 17.83 18.08 18.74 23.38 13.40 3.98 3.55

22.92 28.99 33.48 34.56 40.13 35.52 34.65 29.67 53.48 15.70 5.02 4.44

33.77 43.59 54.25 56.13 71.44 58.51 54.81 36.15 99.56 7.61 3.45 2.84

0.69 0.69 0.67 0.67 0.65 0.67 0.68 0.73 0.64 0.87 0.83 0.83

0.31 0.31 0.33 0.33 0.35 0.33 0.32 0.27 0.36 0.13 0.17 0.17

The relative standard uncertainties u are u(4solG°) = 0.05; u(4solH°) = 0.05; u(4solS°) = 0.05 (0.95 level of confidence). The standard uncertainty is u(p) = 0.3 kPa.

(12.71 kJmol1), DMF (3.98 kJmol1) and DMSO (3.55 kJmol1). The mean value of 4solG° for doxifluridine dissolution was obtained as 15.06 kJmol1 with the relative standard uncertainties of 0.05. The minimum values of 4solG° for doxifluridine dissolution are recorded in DMSO. This was possible due to the maximum solubility of doxifluridine in DMSO [41]. The results of 4solG° measurements for doxifluridine dissolution are in good agreement with measured solubility data. All the values of the apparent standard enthalpy change (4solH °) for doxifluridine dissolution in studied solvents are also recorded as positive values in the range of (4.44–53.48) kJ mol1. The values of 4solH° for doxifluridine dissolution is recorded highest in (±)-2ethyl-1-hexanol (53.48 kJmol1) followed by isobutanol (40.13 kJmol1), n-pentanol (35.52 kJmol1), n-hexanol (34.65 kJmol1), n-butanol (34.56 kJmol1), n-propanol (33.48 kJmol1), n-octanol (29.67 kJmol1), ethanol (28.99 kJmol1), methanol (22.92 kJmol1), acetone (15.70 kJmol1), DMF (5.02 kJmol1) and DMSO (4.44 kJmol1). The mean value of 4solH° for doxifluridine dissolution was obtained as 28.21 kJ  mol1 with the relative standard uncertainties of 0.05. In general, the values of 4solH° for doxifluridine dissolution were lower for pure solvents with higher solubility such as DMSO, DMF, acetone and methanol. On the contrary, the values of 4solH° for doxifluridine dissolution were higher for pure solvents with lower solubility such as n-propanol, n-butanol, npentanol, n-Hexanol, isobutanol, n-octanol,(±)-2-ethyl-1-hexanol. The positive values of 4solG° and 4solH° in all selected pure solvents under experimental conditions in this work indicates that the doxifluridine dissolution is an endothermic process [42–44], which may be due to the strong interaction between doxifluridine and solvent molecules (twelve pure solvents) than those between doxifluridine-doxifluridine and solvent–solvent molecules [45]. And this can be explained why the solubility of doxifluridine in all twelve pure solvents increases with increasing temperature. All the values of the apparent standard entropy change (4solS°) for doxifluridine dissolution in selected solvents are also recorded as positive from 2.84 JK1mol1 to 27.98 JK1mol1. The mean values of 4solS° for doxifluridine dissolution was calculated as 43.51 JK1mol1 with the relative standard uncertainties of 0.05. The positive values of 4solS° in all selected pure solvents suggests that the doxifluridine dissolution is an entropy-driven process [40–43]. Moreover, it is observed that for all the selected pure solvents investigated in this work, all the values of the relative contribution of enthalpy (fH) are higher than 0.64. This indicates that the main contributor to the apparent standard Gibbs energy (4solG°) of solution process of doxifluridine in selected solvents is the enthalpy [8,46,47].

5. Conclusion In this work, the solubility of doxifluridine in methanol, ethanol, n-propanol, n-butanol, isobutanol, n-Pentanol, n-Hexanol, noctanol, (±)-2-ethyl-1-hexanol, acetone, DMF and DMSO was measured by the synthetic method within the temperature range from 278.15 K to 333.15 K under atmospheric pressure. The results demonstrate that solubility of doxifluridine increases with increasing temperature in twelve selected pure solvents. The mole faction solubility of doxifluridine in twelve mono-solvents decreases as the order of: DMSO > DMF > methanol > acetone > ethanol > n-p ropanol > n-butanol > n-pentanol > n-hexanol
isobutanol > n-o ctanol > (±)-2-ethyl-1-hexanol. In addition, five thermodynamic models (kh model, van’t Hoff model, modified Apelblat model, NRTL model and UNIQUAC model) were employed to fit measured doxifluridine solubility data. The results show that all the five models give good correlation with experimental solubility values, and the modified Apelblat model is better than other four models. Furthermore, apparent thermodynamic properties of doxifluridine solutions in the studied solvents were investigated by the van’t Hoff equation. The process of doxifluridine solutions is endothermic and entropy-driven, and the 4G° is mostly contributed by enthalpy because all the fH values are greater than 0.64. The solubility and apparent standard dissolution properties of doxifluridine in this work could provide basic support for optimizing the purification and crystallization process of doxifluridine in industry.

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments The report was funded by the Henan Science and Technology Plan Project (No. 182102210002) and the Henan Provincial Higher Education Key Research Project (No. 19A530004).

Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jct.2020.106073.

J. Sha et al. / J. Chem. Thermodynamics 144 (2020) 106073

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JCT 2019-958