Solubility of l-Phosphinothricin and Its Hydrochloride in Water+

Article Cite This: J. Chem. Eng. Data 2019, 64, 2955−2962

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Solubility of L‑Phosphinothricin and Its Hydrochloride in Water + (Methanol and Ethanol) Binary Solvent Mixtures from 278.15 to 318.15 K Yayun Liu, Lijun Meng, Xinjian Yin, Haisheng Zhou, Jianping Wu, Gang Xu, and Lirong Yang* Institute of Bioengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China

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S Supporting Information *

ABSTRACT: The solubility of L-phosphinothricin (L-PPT) and its hydrochloride in water + (methanol and ethanol) binary solvent mixtures was experimentally measured from 278.15 to 318.15 K by a static analytic method under atmospheric pressure. The experimental data showed that the solubility increased with the increasing temperature and decreased with the increase of alcohol concentration in binary solvent mixtures. The experimental data were correlated by the modified Apelblat equation and combined nearly ideal binary solvent/Redlich−Kister model. The results indicated that the modified Apelblat equation showed better agreement with the experimental data. The parameters characterizing preferential solvation of L-PPT in water + methanol binary solvents had been calculated. The results showed that the preferential solvation of L-PPT was related to the solvent composition and temperature.

1. INTRODUCTION Phosphinothricin (PPT) is a widely used broad-spectrum, nonselective herbicide.1,2 It has two optical isomers: D-PPT and L-PPT [(2S)-2-amino-4-(hydroxymethylphosphinyl) butanoic acid, CAS no. 35597-44-5, Figure 1]. L-PPT is a structural

the manufacturing process of L-PPT. L-Phosphinothricin hydrochloride (CAS no. 73777-49-8) is usually obtained as an alternative product. In the process of preparing L-PPT from L-PPT hydrochloride, L-phosphinothricin monohydrate (LPPT·H2O) may be obtained depending on the operational condition.8 Crystallization is a typically used separation method in the industrial production of amino acids.9−11 Water removal and the addition of an antisolvent are commonly used in the crystallization process.12 Several potential antisolvents, such as methanol, ethanol, and acetone, were screened in our pretests for the efficient crystallization of L-PPT and its hydrochloride. Methanol and ethanol were considered to be suitable antisolvents for their good miscibility with the enzymatic reaction solution6,7 and high efficiency. The operational level of the antisolvent crystallization process has a great effect on product quality;13 therefore, a reliable knowledge of the solubility of L-PPT and its hydrochloride in two binary solvents (water + methanol and water + ethanol) is necessary for the

Figure 1. Chemical structure of L-PPT.

analogue of L-glutamic acid and can inhibit glutamine synthetase. The herbicidal activity of L-PPT is twice that of racemic mixtures because D-PPT is inactive;3 however, as far as we know, the commercially available formulated products are still racemic mixtures of PPT. Therefore, it is of great importance to develop a new technology for the large-scale industrial production of L-PPT.4−7 The separation and purification of L-PPT from aqueous solution containing organic and inorganic salts is one of the key technologies in © 2019 American Chemical Society

Received: January 3, 2019 Accepted: May 29, 2019 Published: June 11, 2019 2955

DOI: 10.1021/acs.jced.9b00004 J. Chem. Eng. Data 2019, 64, 2955−2962

Journal of Chemical & Engineering Data

Article

temperature. An electronic analytical balance (ME204E, Mettler Toledo, Switzerland) with an uncertainty of ±0.1 mg was used for the mass measurements. The solutions were prepared by adding an excess amount of the solute into the mixed solvents in the equilibrium cell and constantly stirring for 16 h to establish equilibrium of the solute−solvent mixtures at a given temperature. The undissolved solid was then allowed to settle at least 8 h without stirring before sampling. A sample of the upper saturated solution was quickly withdrawn using a preheated syringe through a 0.22 μm membrane filter and transferred into a previously weighed sample vial. The sample vial was tightly closed using a rubber plug to prevent evaporation of the solvents during the weighing procedure. The mass of the sample vial with the saturated solution was measured. The plug was removed, and the vial was placed in a vacuum oven until the solvent had completely evaporated, and the mass of the solid residue was then determined. Each experiment was repeated three times to obtain an average value. The mole fraction solubility (x1) of L-PPT and its hydrochloride was calculated by eq 1, and the initial mole fraction (x2) of the organic solvent in each binary solvent mixture was calculated by eq 2

design of a good crystallization process. To our knowledge, the solubility of L-PPT and its hydrochloride in water + (methanol and ethanol) binary solvent mixtures has not been reported. In this study, the solubility data of L-PPT and its hydrochloride in water + (methanol and ethanol) mixed solvents were measured from 278.15 to 318.15 K under atmospheric pressure. The experimental data were correlated by the modified Apelblat equation and the combined nearly ideal binary solvent/Redlich−Kister (CNIBS/R−K) model. The correlation models were evaluated according to the relative average deviations (RADs). In addition, the local mole fractions of methanol around L-PPT were calculated, and the preferential solvation of L-PPT in water + methanol binary solvents was discussed. The measured solubility data and corresponding models can be used as essential data for the industrial production of L-PPT and its hydrochloride.

2. EXPERIMENTAL SECTION 2.1. Materials. L-PPT, L-PPT·H2O, and L-PPT hydrochloride were obtained by recrystallization after separation from the enzymatic reaction solution6,7 in our lab and dried in a vacuum oven (DZF-6050, Shanghai Jing Hong Laboratory Instrument Co., Ltd., China) at 323.15 K for 12 h and stored in a desiccator. Their purities were greater than 98.5%, as determined by high-performance liquid chromatography (HPLC; Agilent 1100, USA). Methanol, ethanol, and DLphenylalanine used for the experiments were of reagent grade and purchased from Sinopharm Chemical Reagent Co., Ltd., (China). The organic solvents were used without further purification. Double-distilled water was used in all experiments. The sources and purities of the materials are listed in Table 1.

mass fraction purity

analysis method

Sinopharm Chemical Reagent Co., Ltd., China Sinopharm Chemical Reagent Co., Ltd., China our laboratory our laboratory

≥99.5%a

GCb

≥99.7%a

GC

≥98.5% ≥98.5%

HPLCc HPLC

L-PPT

our laboratory

≥98.5%

HPLC

hydrochloride water

our laboratory

doubledistilled water ≥99.0%a

none

Methanol Ethanol L-PPT L-PPT

sources

monohydrate

DL-phenylalanine

Sinopharm Chemical Reagent Co., Ltd., China

m1/M1 m1/M1 + m2 /M 2 + m3 /M3

(1)

x2 =

m2 /M 2 m2 /M 2 + m3 /M3

(2)

where m1, m2, and m3 represent the mass of L-PPT or its hydrochloride, organic solvent, and water, respectively; M1, M2, and M3 are the molar mass of L-PPT or its hydrochloride, organic solvent, and water, respectively. In order to verify the validity of the experimental method, the solubility of DL-phenylalanine in water was measured and compared with the literature values.17 The determined solubility data and the relative deviation were listed in Table S1 in the Supporting Information. The results indicate that the experimental solubility data are in good agreement with the values published in the literature. Thus, the reliability of the experimental method was validated. 2.3. Characterization of L-PPT, L-PPT·H2O, and L-PPT Hydrochloride. The crystal structures of the L-PPT, L-PPT· H2O, and L-PPT hydrochloride were determined by powder Xray diffraction (PXRD) carried out on a PANalytical X’Pert diffractometer using Cu Kα radiation. The data were collected from 10° to 60° (2θ range) with a scan step size of 0.02° in the continuous scan type. Thermogravimetric analysis (TGA) of L-PPT, L-PPT·H2O, and L-PPT hydrochloride was carried on a thermogravimetric analyzer (Q50, TA Corporation USA) within the temperature range from 298.15 to 669.15 K. The melting properties of the solutes were also measured by differential scanning calorimeter (DSC 1/400, Mettler-Toledo, Switzerland). The temperature range was from 303.15 to 513.15 K. Both TGA and DSC measurements were under a nitrogen atmosphere, and the heating rate was 10 K·min−1.

Table 1. Sources and Purities of Materials Used in This Work chemical name

x1 =

a

Stated by the supplier. bGas chromatography. cHigh-performance liquid chromatography.

2.2. Apparatus and Procedure. The solubility of L-PPT and its hydrochloride in water + (methanol and ethanol) binary solvent mixtures were measured by a static analytic method.14−16 A magnetically stirred, jacketed equilibrium cell with a volume of 100 mL was used for solubility determination. The cell was sealed with Parafilm to prevent the solvents from evaporating. The temperature was controlled by a superthermostatic water bath (DC-0506, Shanghai HengPing Instrument and Meter Factory, China), which is capable of maintaining the temperature within ±0.05 K. A calibrated glass thermometer with ±0.1 K accuracy was used to measure the

3. RESULTS AND DISCUSSION 3.1. Powder X-ray Diffraction. The PXRD patterns of LPPT, L-PPT·H2O, and L-PPT hydrochloride were shown in Figures S1 and S2. Figure S1 indicates that L-PPT can be 2956



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Table 2. Experimental Mole Fraction Solubility of L-PPT in Water (1 − x2) + Methanol (x2) Binary Solvent Mixtures from 278.15 to 318.15 K at Atmospheric Pressure (p = 0.1 MPa)a 102RD T (K) x2 = 0 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.2726 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.6922 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 1 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

2

10 x1

eq 3

102RD T (K)

eq 6

2.670 2.990 3.255 3.718 4.179 4.870 5.593 6.410 7.330

0.11 1.07 −1.59 −0.17 −1.07 1.03 1.09 0.40 −1.02

1.32 1.16 1.17 1.34 1.14 1.04 0.93 0.89 0.76

0.871 0.972 1.055 1.228 1.364 1.595 1.832 2.138 2.461

0.13 0.94 −2.01 1.15 −1.21 0.81 0.32 0.75 −0.80

2.70 2.36 3.01 3.20 2.93 2.18 2.29 3.24 3.62

0.063 0.072 0.080 0.087 0.098 0.107 0.127 0.142 0.163

−1.90 1.78 2.00 −0.49 −0.02 −3.23 1.54 −0.11 0.46

−5.57 −4.91 −3.61 −4.70 −3.57 −4.19 −3.11 −0.83 1.01

0.017 0.018 0.019 0.021 0.022 0.024 0.026 0.027 0.029

0.94 −0.39 −1.99 1.09 −1.14 0.73 1.95 −0.98 −0.49

−1.07 −0.95 −0.77 −0.95 −0.75 −0.82 −0.64 −0.31 −0.02

x2 = 0.1232 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.4575 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.8350 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

2

10 x1

eq 3

eq 6

1.732 1.953 2.101 2.428 2.731 3.187 3.673 4.250 4.893

−0.11 1.64 −2.25 0.18 −0.92 0.92 0.82 0.48 −0.95

−3.78 −3.30 −3.50 −3.97 −3.42 −2.95 −2.76 −2.91 −2.71

0.277 0.311 0.335 0.383 0.425 0.502 0.576 0.642 0.723

0.39 1.42 −2.26 −0.48 −2.22 1.87 2.62 0.14 −1.70

1.52 1.37 0.32 0.79 0.35 1.09 0.44 −1.30 −2.54

0.034 0.038 0.041 0.045 0.049 0.052 0.060 0.063 0.069

−0.78 1.25 −0.14 0.27 −0.02 −2.82 2.87 −0.73 −0.06

4.46 3.95 3.12 3.92 3.09 3.41 2.65 1.13 −0.22

a

Standard uncertainty u is u(T) = 0.05 K; relative standard uncertainties ur are ur(p) = 0.05, ur(x2) = 0.01, and ur(x1) = 0.15.

K. However, Figures S3b and S5b showed that the heat flow did not change before 485.15 and 430.15 K, respectively. Thus, the samples decomposed before they melted, that is, both LPPT and its hydrochloride have no certain melting point. 3.3. Solubility Data. The experimental solubility data of LPPT and its hydrochloride in water + (methanol and ethanol) binary solvent mixtures are presented in Tables 2−5 and plotted in Figures 2 and 3. In all the studied solvents, the solubility increases with increasing temperature at a given solvent composition and decreases with the increase of the proportion of organic solvent. Figures 2 and 3 also show that the mole fraction solubility of the solutes is larger in water + methanol mixtures than in water + ethanol mixtures at the same water composition and a certain temperature. When x2 is equal to 0 or 1, the experimental data are the solubility of the solutes in pure water or pure organic solvent, respectively.

solvated by water to form L-PPT·H2O depending on the solvent composition and temperature. Figure S2 shows that the solid L-PPT hydrochloride in equilibration with solvents has the same characteristic peaks as the raw material. Thus, no transformation of the crystal form of L-PPT hydrochloride occurred during the experiments. 3.2. Thermodynamic Properties. The experimental TGA and DSC measurements of L-PPT, L-PPT·H2O, and L-PPT hydrochloride were shown in Figures S3−S5, respectively. It can be seen from Figure S4b that two endothermic peaks appear at about 391 and 492 K. The first peak corresponds to the dehydration of L-PPT·H2O, and the second peak represents the melting process. From Figure S3a, it can be seen that the weight of the sample of L-PPT began to decrease at about 485.15 K. Similarly, Figure S5a shows that the sample of L-PPT hydrochloride started to decompose at about 430.15 2957



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Table 3. Experimental Mole Fraction Solubility of L-PPT in Water (1 − x2) + Ethanol (x2) Binary Solvent Mixtures from 278.15 to 318.15 K at Atmospheric Pressure (p = 0.1 MPa)a 102RD T (K) x2 = 0.1099 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.2833 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.4296 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

2

10 x1

eq 3

102RD T (K)

eq 6

1.178 1.389 1.577 1.887 2.113 2.301 2.539 2.822 3.173

−0.36 0.29 −1.65 2.76 1.64 −1.30 −2.00 −1.06 1.83

−1.95 −1.20 −0.64 −0.48 −1.16 −1.69 −0.24 0.79 0.08

0.309 0.385 0.457 0.522 0.629 0.711 0.832 0.992 1.149

−2.33 2.09 2.14 −1.17 1.30 −2.21 −1.83 0.81 0.91

−5.37 −2.86 −1.52 −2.74 −0.45 −2.04 0.38 2.37 2.99

0.112 0.138 0.159 0.177 0.199 0.216 0.246 0.275 0.310

−3.42 2.66 2.89 0.56 −0.04 −3.47 −1.29 −0.35 2.02

−0.14 0.10 0.06 −0.70 1.17 1.07 0.48 0.19 1.34

x2 = 0.2000 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.3500 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.5366 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

2

10 x1

eq 3

eq 6

0.626 0.735 0.846 1.004 1.182 1.357 1.468 1.642 1.901

0.82 −0.25 −2.28 −0.19 2.00 2.57 −1.94 −2.33 1.49

4.48 2.66 1.45 1.55 1.90 3.17 0.27 −1.97 −1.05

0.209 0.253 0.292 0.336 0.372 0.423 0.486 0.560 0.626

−2.18 1.83 1.61 1.60 −1.78 −2.03 −0.78 1.15 0.46

2.49 1.09 0.58 2.17 −1.51 −0.65 −0.84 −1.33 −3.33

0.038 0.045 0.056 0.066 0.075 0.084 0.097 0.108 0.117

0.66 −2.35 1.48 1.58 −0.32 −2.18 0.49 0.84 −0.27

−0.07 −0.07 −0.04 0.07 −0.22 −0.23 −0.07 0.02 −0.18

a


From Tables 2−5, one can find that the solubility in pure solvent follows the order as follows: water > methanol > ethanol, which is consistent with decreasing polarity of the solvents. When the initial mole fraction of ethanol in mixed solvent is greater than 0.5366, the solubility of L-PPT is too small to accurately determine using the experimental method. The experimental results are in agreement with the fact that the solubility of amino acids in pure alcohol is low and even insoluble.18−20 It is worth noting that the solubilities of L-PPT and its hydrochloride are large in water. As shown in Figure 1, L-PPT can act as both hydrogen acceptor and donor, which allows the solutes to form a hydrogen bond with the studied solvents. Furthermore, if the interactions of solute−solvent and solvent−solvent are similar, then the dissolution is easier. Considering that there is strong self-association among water molecules through the hydrogen bond, the main interaction between the solutes and water may be also hydrogen bonds. Thus, both the hydrogen bond and van der Waals interaction (represented by polarity) affect the solubility in the experimental system. Moreover, the organic solvent present in the binary solvent system can weaken intermolecular interactions between the solute and water molecules. Actually, the solubility is determined by the mutual competition of the complex interactions between solute−solvent and solvent− solvent.

Additionally, there is a great difference in the variation trend of the solubility in different solvent compositions. Specifically, in water + methanol mixtures, the solubility difference of LPPT in (0 < x2 < 0.4575) is far greater than that in (0.4575 < x2 < 1). However, for L-PPT hydrochloride, the solubility difference in (0 < x2 < 0.4575) is less than (0.4575 < x2 < 1). Similarly, obvious distinction in the variation trend of solubility exists between (0 < x2 < 0.2833) and (0.2833 < x2 < 0.5366) for L-PPT, and between (0 < x2 < 0.3697) and (0.3697 < x2 < 1) for L-PPT hydrochloride, in the water + ethanol binary solvent system. Therefore, the studied organic solvents, methanol, and ethanol, can be used as effective antisolvents in crystallization processes of L-PPT and its hydrochloride from aqueous solution. Considering the dosage of antisolvent, it is better to directly obtain L-PPT through the antisolvent crystallization process. 3.4. Modified Apelblat Equation. The modified Apelblat equation is a commonly used model in solubility correlation based on nonideal solution. The mole fraction solubility as a function of temperature at the same solvent composition can be correlated by the modified Apelblat equation,21−23 expressed as follows ln x1 = A + 2958

B + C ln(T /K) T /K

(3)



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Table 4. Experimental Mole Fraction Solubility of L-PPT Hydrochloride in Water (1 − x2) + Methanol (x2) Binary Solvent Mixtures from 278.15 to 318.15 K at Atmospheric Pressure (p = 0.1 MPa)a 102RD T (K) x2 = 0 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.2726 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.6922 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 1 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

2

10 x1

eq 3

102RD T (K)

eq 6

5.756 5.889 6.163 6.584 6.762 7.109 7.308 7.708 8.174

0.61 −1.10 −0.67 1.69 0.03 0.58 −1.20 −0.48 0.69

0.77 0.68 0.63 0.69 −0.07 0.00 −0.28 −0.19 0.22

4.590 4.734 5.028 5.270 5.390 5.639 5.764 5.988 6.362

0.07 −1.11 0.76 1.39 −0.30 0.35 −1.24 −1.12 1.33

1.20 1.34 1.79 1.23 −1.90 −0.87 −2.32 −2.02 −0.52

2.269 2.401 2.669 2.801 2.961 3.298 3.575 3.840 4.043

0.49 −1.22 1.96 −0.61 −2.53 0.81 1.39 1.06 −1.29

−4.02 −2.92 −1.57 −3.29 −3.17 −1.71 −2.22 −2.31 −2.81

0.996 1.089 1.135 1.186 1.268 1.337 1.404 1.470 1.598

−1.46 1.87 0.43 −0.76 0.36 0.10 −0.56 −1.49 1.35

−0.73 −0.56 −0.35 −0.62 −0.43 −0.24 −0.25 −0.28 −0.44

x2 = 0.1232 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.4575 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.8350 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

2

10 x1

eq 3

eq 6

5.036 5.154 5.401 5.720 6.075 6.316 6.578 6.776 7.050

1.44 −1.28 −1.44 −0.36 1.15 0.71 0.59 −0.48 −0.42

−2.09 −1.91 −1.90 −1.91 0.63 0.22 1.21 0.97 −0.36

3.714 3.840 4.098 4.384 4.772 4.939 5.273 5.569 5.778

1.57 −1.55 −1.31 −0.64 1.91 −0.38 0.57 0.59 −1.03

1.52 0.86 −0.09 1.11 2.68 1.38 2.39 2.30 1.79

1.693 1.773 1.912 2.065 2.143 2.361 2.584 2.768 2.992

0.40 −0.88 0.33 1.27 −2.17 0.07 1.29 0.08 −0.51

3.15 2.38 1.46 2.62 2.09 1.16 1.33 1.45 2.03

a


conditions can be described by the CNIBS/R−K model,24,25 shown as follows

where x1 is the mole fraction solubility of the solute; A, B, and C are the model parameters regressed from the experimental data; and T is the absolute temperature in K. The values of the model parameters are listed in Tables S2 and S4. The relative deviations between the experimental data and the calculated solubility values are given according to the following equation RD =

x1exp − x1cal x1exp

N

ln x1 = x 2 ln x1,2 + x3 ln x1,3 + x 2x3∑ Si(x 2 − x3)i i=0

(5)

where x1, x1,2, and x1,3 represent the saturated mole fraction solubility of the solute in binary solvents, organic solvent, and water, respectively; x2 and x3 represent the initial mole fraction compositions of organic solvent and water in mixed solvents, respectively; Si (i = 0, 1, 2, ...) represent the model parameters. x3 can be replaced by (1 − x2) in a binary solvent (N = 2). Thus, eq 5 can be turned into eq 6

(4)

cal where xexp 1 and x1 represent the experimental and calculated solubility values, respectively. 3.5. CNIBS/R−K Model. The relationship between the solubility data and solvent compositions under isothermal

ln x1 = B0 + B1x 2 + B2 x 2 2 + B3x 2 3 + B4 x 2 4 2959

(6)



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Table 5. Experimental Mole Fraction Solubility of L-PPT Hydrochloride in Water (1 − x2) + Ethanol (x2) Binary Solvent Mixtures from 278.15 to 318.15 K at Atmospheric Pressure (p = 0.1 MPa)a 102RD T (K) x2 = 0.0891 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.3697 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.7787 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

2

10 x1

eq 3

102RD T (K)

eq 6

4.754 4.880 5.062 5.276 5.585 5.777 6.114 6.383 6.692

0.56 −0.37 −0.54 −0.48 0.89 −0.28 0.65 0.02 −0.37

−5.74 −5.95 −5.56 −5.65 −3.87 −3.88 −1.96 −2.06 −2.96

3.054 3.187 3.427 3.765 4.144 4.370 4.761 5.077 5.379

1.90 −1.62 −2.06 −0.22 1.87 −0.20 1.06 0.28 −1.06

1.30 1.00 2.76 2.99 3.25 1.88 3.03 3.03 1.03

0.716 0.781 0.871 0.951 1.041 1.125 1.281 1.392 1.552

−0.22 −0.56 1.12 0.51 −0.02 −1.99 1.16 −0.49 0.32

2.36 2.26 3.10 3.25 2.91 2.16 2.24 2.27 1.43

x2 = 0.2068 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 0.6100 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 x2 = 1 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

2

10 x1

eq 3

eq 6

4.322 4.487 4.577 4.817 5.048 5.291 5.438 5.702 6.177

−0.15 0.52 −0.97 0.30 0.79 0.98 −1.10 −1.45 1.21

3.46 3.78 2.45 2.37 0.92 1.77 −0.37 −0.28 1.60

1.455 1.567 1.696 1.899 2.123 2.371 2.657 2.901 3.290

1.08 −0.37 −1.83 −0.34 0.56 0.97 1.36 −1.18 −0.23

−3.58 −3.37 −5.01 −5.28 −4.83 −3.42 −3.81 −3.85 −2.22

0.133 0.143 0.148 0.154 0.169 0.175 0.187 0.192 0.206

−0.31 1.40 −0.64 −2.13 1.77 −0.09 1.21 −1.43 0.38

−0.42 −0.40 −0.55 −0.57 −0.49 −0.36 −0.38 −0.37 −0.26

a


Figure 2. Solubility of L-PPT in water + methanol (a) and water + ethanol (b) binary solvent mixtures. N

where B0, B1, B2, B3, and B4 refer to the model parameters regressed from the experimental data and are tabulated in Tables S3 and S5. 3.6. Relative Average Deviation. The accuracy of the correlation models is estimated by the RAD, described as follows

RAD =

x exp − x cal 1 ∑ i exp i N i=1 xi

(7)

xexp i

where N is the number of experimental points and and xcal i represent the experimental and calculated solubility values, respectively. The values of RAD for the correlation models are also presented in Tables S2−S5. It can be seen that both 2960



Article

Figure 3. Solubility of L-PPT hydrochloride in water + methanol (a) and water + ethanol (b) binary solvent mixtures.

equations fit the experimental data well. The maximum values of RAD of the modified Apelblat equation and the CNIBS/R− K model are 1.86 and 3.22% respectively, which indicates that the former can correlate the experimental data better than the latter. The different values of RAD for the two models may be due to the difference between the number of experimental points used to fit the equations and the number of equation parameters. In addition, it must be noted that the CNIBS/R− K model for predicting solubility of L-PPT in the binary (water + ethanol) solvent system as a function of solvent compositions was fitted within the experimental temperature and the solvent composition range. Therefore, any extrapolation of these curve-fit equations should be performed with care. The experimental data and the corresponding models are important for the separation and purification of L-PPT and its hydrochloride. 3.7. Preferential Solvation of L-PPT. Table 2 indicates that the natural logarithm of mole fraction solubility of L-PPT in water + methanol binary solvent mixtures is nonlinearly dependent on solvent compositions. The deviation from linearity can be described using a dimensionless parameter calculated by the following equation26,27 δ=

Hence, the parameter δ represents the deficit or excess of the cosolvent around the solute. The positive and negative values of δ for L-PPT in water + methanol mixtures indicate that there is an excess or a deficit of methanol in the local area around LPPT. More specifically, L-PPT is preferentially solvated by water with solvent composition x2 ≤ 0.4575 and by methanol with x2 ≥ 0.6922 except for the temperature of 318.15 K. The extent of preferential solvation can be described by parameter Kps defined by eq 12.26,30 K ps =

↔ solvent 2 (local) + solvent 3

where “local” represents solvent i in the local zone. The calculated values of Kps are listed in Table S7. It can be found that the values of Kps for L-PPT in water + methanol mixtures increase with the increasing methanol content and decrease with the increase of temperature, which may be related to the complex interactions between L-PPT and the binary solvents.

The calculated values of δ for L-PPT in water + methanol mixed solvents are tabulated in Table S6. All of the δ values are negative at the solvent composition x2 ≤ 0.4575. When x2 ≥ 0.6922, δ values are positive except for 318.15 K at x2 = 0.6922. Marcus28 has elucidated that the nonlinear variation of log x1 with solvent composition is due to preferential solvation of the solute which occurs when there is a difference between the local mole fraction of solvent i (xLi ) around the solute and the mean value (xi). xLi can be described by eq 9.26,29

According to the relation: obtained.

xL2

+

4. CONCLUSIONS The solubility of L-PPT and its hydrochloride in water + (methanol and ethanol) binary solvent mixtures was measured from (278.15 to 318.15) K by a static analytic method under atmospheric pressure. The solubility increases with increasing temperature and decreases with the increase of the mole fraction of organic solvents in the mixed solvents. The experimental data were correlated by the modified Apelblat equation and CNIBS/R−K model. The results indicate that the modified Apelblat equation and the CNIBS/R−K model show good agreement with the experimental data, and the largest values of RAD are 1.86 and 3.22%, respectively. The parameters characterizing preferential solvation of L-PPT in water + methanol mixtures were calculated. L-PPT is preferentially solvated by water with composition x2 ≤ 0.4575 and by methanol with composition x2 ≥ 0.6922 except for the temperature of 318.15 K at x2 = 0.6922. The experimental data and the corresponding models can be used

(9)

xL3

= 1, eq 10 can be

x 2L = (log x1 − log x1,3)/(log x1,2 − log x1,3)

(10)

From eqs 8 and 10, we have δ = x 2L − x 2

(12)

Solvent 2 + solvent 3 (local)

(8)

log x1 = x 2L log x1,2 + x3L log x1,3

x 2·x3L

Kps is related to the following solvent exchange process:

log x1 − (x 2 log x1,2 + x3 log x1,3) log x1,2 − log x1,3

x 2L·x3

(11) 2961



Article

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as essential data in the design of the crystallization process of LPPT and its hydrochloride.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.9b00004.

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PXRD patterns; TGA and DSC scans; solubility of DLphenylalanine determined in this work and reported in the previous publication; parameters of the equations; and values of δ and Kps (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: (+86)-571-8795-2363. Fax: (+86)-571-8795-2363. ORCID

Gang Xu: 0000-0001-8516-8731 Lirong Yang: 0000-0002-6378-8451 Funding

This work was financially supported by the National Natural Science Foundation of China (nos. 21476199, 21676240). Notes

The authors declare no competing financial interest.

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Solubility of l-Phosphinothricin and Its Hydrochloride in Water+

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