Propylthiouracil Solubility in Aqueous Solutions of Ethylene Glycol, N

Article Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Propylthiouracil Solubility in Aqueous Solutions of Ethylene Glycol, N,N‑Dimethylformamide, N‑Methyl-2-pyrrolidone, and Dimethylsulfoxide: Measurement and Thermodynamic Modeling Hao Yin, Hongkun Zhao,* and Youhua Zhao*

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College of Chemistry & Chemical Engineering, YangZhou University, YangZhou, Jiangsu 225002, People’s Republic of China ABSTRACT: Solubility values of propylthiouracil dissolved in four neat solvents of N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), and ethylene glycol (EG) and aqueous cosolvent solutions of DMF, NMP, EG, and DMSO from 293.15 to 333.15 K were determined. The determination process was carried out using the saturation shake-flask method at 101.1 kPa. At the identical temperature and cosolvent composition of DMF, NMP, EG, or DMSO, the solubility of propylthiouracil in mole fraction was maximum in DMSO (DMF) (1) + water (2) systems, and minimum in EG (1) + water (2) systems. Through the van’t Hoff−Jouyban−Acree, Jouyban−Acree, and Apelblat− Jouyban−Acree models, the solubility of propylthiouracil was correlated very well, acquiring root-mean-square deviation values that are smaller than 9.75 × 10−4 and relative average deviation values that are smaller than 3.01%.

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INTRODUCTION Investigation of the solubilities of drugs and their improvement has become an extensive issue in the pharmaceutical area at present. Drug solubility in cosolvent solutions is an important physicochemical property1−4 because it is commonly used in designing liquid dosage forms, purifying raw materials, and understanding mechanisms, in relation to the chemical and physical stability of the dissolution process of drugs.3,5,6 In addition, solubility is regarded as a significiant factor in designing the crystallization process, in which the knowledge concerning solubility is required in regulating the particle size, supersaturation, yield, and polymorphic form. Moreover, cosolvency is an effective and optional solubilization way because aqueous cosolvent solution is very important for chemical and pharmaceutical industries. It can be used as a recrystallization solvent or reaction medium.1,6 Poor aqueous solubility of drugs may give rise to formulation difficulty or low bioavailability in clinical drug development.1,7 Propylthiouracil (CAS Reg. No. 51-52-5; its chemical structure is given in Figure 1) is a useful drug employed in treating hyperthyroidism caused by toxic multinodular goiter and Graves’ disease.8−10 Nevertheless, propylthiouracil presents low aqueous solubility,11−18 which is a main disadvantage in dosage design and greatly reduces its bioavailability. Lots of

solubilization ways have been put forward to increase the drug solubility in water.1−3,5 The most powerful and effective technique for improving the drug solubility is mixing water with a miscible and safe cosolvent.1−3,5 Nevertheless, in spite of the usefulness of propylthiouracil, a little information on drug solubility has been studied. A comprehensive literature observation demonstrates that only the solubilities of propylthiouracil dissolved in water11−13,17,18 and in ethanol (n-propanol, methanol, and isopropanol) + water mixtures19 have been reported in the literature. However, propylthiouracil solubility is observed up to only approximately 102-fold rise on going from neat water to the four alcohols. Investigation of the chemical structure of the propylthiouracil molecule demonstrates that it presents high dipole moments. Because of its two >HH groups (Figure 1),20 it may offer strong interactions of nonspecific dipole−dipole with aprotic solvents such as N-methyl-2pyrrolidone (NMP), N,N-dimethylformamide (DMF), and dimethylsulfoxide (DMSO) to increase the drug solubility. This case encourages our research group to perform a deep investigation on the solubility of propylthiouracil in aqueous solutions of these aprotic solvents. NMP is a common cosolvent used in the pharmaceutical industry.21 It has very strong solubilizing ability and is a significant solvent in crystallization, purification, and extraction of many drugs.22 DMF is an aprotic agent with water.23 DMF− water solution is a strong nonideal solution.24 Drug solubility in DMSO is a significant parameter during the early stage of drug discovery.25 Ethylene glycol (EG) is an acceptable and safe agent in the pharmaceutical field.26,27 Thus, the main objective of this Received: March 1, 2019 Accepted: May 3, 2019

Figure 1. Chemical structure of propylthiouracil. © XXXX American Chemical Society

A

DOI: 10.1021/acs.jced.9b00201 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Table 1. Detailed Information of the Materials Used in the Work chemicals

CAS NO

molar mass g·mol−1

propylthiouracil

51-52-5

170.23

DMF

68-12-2

73.09

NMP EG DMSO water

872-50-4 107-21-1 67-68-5 7732-18-5

99.13 72.07 78.13 18.01

source

initial Mass fraction purity

purification method

0.986

recrystallization

0.996

HPLCa

0.995

none

0.995

GCb

0.994 0.994 0.995

none none none distillation

0.994 0.994 0.995 conductivity < 2 μS·cm−1

GC GC GC conductivity meter

Sigma Chemical Co., Ltd, China Sinopharm Chemical Reagent Co., Ltd., China

Our lab

ÅÄÅ ÑÉÑ B1 Å Ñ + C1 ln(T /K )ÑÑÑ ln xw , T = w1ÅÅÅA1 + ÅÅÇ ÑÑÖ T /K ÄÅ ÉÑ ÅÅ ÑÑ B2 + w2ÅÅÅA 2 + + C2 ln(T /K)ÑÑÑ ÅÇÅ ÑÑÖ T /K 2 ww + 1 2 ∑ Ji (w1 − w2)i T /K i = 0

a

High-performance liquid chromatography. bGas chromatography.

paper is to determine propylthiouracil solubility in solvent solutions of (NMP + water), (DMF + water), (DMSO + water), and (EG + water) at several temperatures. This research extends the available propylthiouracil solubility3,11−19 and also permits some thermodynamic study of the dissolution procedure.

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THEORETICAL CONSIDERATION Jouyban has reviewed the cosolvency models for solid solubility in a cosolvent mixture.28 Here, the Jouyban−Acree,21,28,29 van’t Hoff−Jouyban−Acree,21,29 and Apelblat−Jouyban−Acree models21,29 are used in describing propylthiouracil solubility in aqueous cosolvent solutions of EG, NMP, DMF, and DMSO. This Jouyban−Acree model (eq 1) presents a precise description of the dependence of solubility upon both solvent composition and temperature for binary mixtures.21,28,29

F=

∑ (ln xwe ,T − ln xwc ,T )2 i=1

w1w2 ∑ J (w1 − w2)i T /K i = 0 i

N

RMSD =

here, xw,T refers to the mole fraction solubility of the solute in mixed solvents at T/K; w1 and w2 refer to the mass fractions of solvents 1 (namely EG, DMF, NMP, and DMSO) and 2 (namely water) in the absence of propylthiouracil, respectively; x1,T and x2,T stand for the solubility of propylthiouracil in mole fraction in pure solvents. The model parameters are denoted Ji. The van’t Hoff equation is described by B T /K

RAD =

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

N

ij |xwc , T − xwe , T | yz zz ∑ jjjj zz e x w,T k {

(7)

(8)

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EXPERIMENTAL SECTION Materials. The raw material propylthiouracil was purchased from Sigma Chemical Co., Ltd, China, which had a purity of 0.986 in mass fraction. The crude propylthiouracil was recrystallized in neat methanol three times. The mass fraction of the purified propylthiouracil was 0.996, obtained through high-performance liquid chromatography (HPLC) with Agilent 1260. The solvents such as EG, DMSO, NMP, and DMF were obtained from Sinopharm Chemical Reagent Co., Ltd., China. The mass fraction purity of these solvents was no smaller than 0.994, which was confirmed using gas chromatography with Smart GC-2018. The conductivity of water was less than 2 μS· cm−1, which was prepared by distillation in our laboratory. Table 1 present more detailed information of the compounds. Solubility Determination. The solvent mixtures were prepared by using a BSA224S analytical balance. Each mixed or neat solvent employed in solubility determination was around 15 mL, the relative standard uncertainty of which was less than 0.0002. The mass fraction of EG, DMF, NMP, and DMSO in the mixed solvents was within the range from 0 to 1. The local ambient pressure was about 101.1 kPa in experiment.

(2)

(3)

where A1, B1, A2, B2, and Ji are the parameters of the van’t Hoff− Jouyban−Acree model. The Apelblat equation is expressed by21,28−30 ln xT = A +

1 N

∑i = 1 (xwc , T − xwe , T )2

In eqs 7 and 8, N signifies the number of experimental data points. xew,T is the mole fraction obtained in the present paper c and xw,T is the back-calculated solubility values with the corresponding solubility model.

Combining eqs 2 and 1, the van’t Hoff−Jouyban−Acree equation is attained as eq 3.21,29 i i B1 yz B2 yz zz + w2jjjA 2 + zz ln xw , T = w1jjjjA1 + z j T /K { T /K z{ k k 2 ww + 1 2 ∑ Ji (w1 − w2)i T /K i = 0

(6)

In addition, the root-mean-square deviation (RMSD) and the relative average deviation (RAD) are, respectively, expressed by eqs 7 and 8.

(1)

ln xT = A +

(5)

The objective function in the regression procedure is

2

ln xw , T = w1 ln x1, T + w2 ln x 2, T +

analytical method

final mass fraction purity

(4)

here, A, B, and C stand for the Apelblat equation parameters; xT refers to the propylthiouracil solubility in neat solvents at absolute temperature T. By combining eqs 4 and 1, the Apelblat−Jouyban−Acree model is derived and described as21,28,29 B



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RESULTS AND DISCUSSION X-ray Powder Diffraction. The XRD scans of raw propylthiouracil together with the solid equilibrating with its liquid phase are given in Figure 2. As can be seen, all of the XRD

Propylthiouracil solubility in mixed solvents of (EG + water), (DMF + water), (NMP + water), and (DMSO + water) was determined through a saturation shake-flask technique.31,32 This method was validated via measuring the solubility of benzoic acid in toluene.32 Propylthiouracil solubility in equilibrium liquor was determined using HPLC. The solubility of propylthiouracil was measured at temperatures from T = 293.15 to 333.15 K every 5 K. An excess amount of solute propylthiouracil was added to solvent mixtures in triplicates. The propylthiouracil solutions were transferred to a thermostatic shaker, which was provided by Tianjin Ounuo Instrument Co. Ltd., China. The temperature of the solution was regulated through water coming from a QYHX-1030 smart thermostatic bath, which was purchased from Shanghai Joyn Electronic Co., Ltd., China and had a standard uncertainty of 0.02 K. In an attempt to get the equilibrium time, about 0.5 mL of liquid phase was taken out by using a 2 mL syringe every 1 h and tested by HPLC. If the composition of the solution did not vary, the system was believed to arrive at equilibrium. The results indicated that 19 h was sufficient for solution systems studied to arrive at equilibrium. The solution was then kept static to guarantee that all undissolved solid phase was precipitated from the mixture. The clear liquid phase was taken out through a 2 mL precooled or preheated syringe and transferred speedily into a 25 mL preweighed volumetric flask. The extracted sample was then diluted with methanol if necessary and tested through HPLC. The solubility of propylthiouracil in mole fraction (xw,T) in the solvent mixtures is calculated by eq 9. The original compositions of solvent mixtures (w) are obtained by eqs 10 and 11. xw , T =

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

w1 = w = w2 =

m2 m 2 + m3

m3 m 2 + m3

Article

Figure 2. XRD patterns of propylthiouracil: (a) equilibrated with neat DMF; (b) equilibrated with neat NMP; (c) equilibrated with neat DMSO; (d) equilibrated with neat EG; (e) equilibrated with neat water; (f) equilibrated with the neat DMF + water mixture; (g) equilibrated with the NMP + water mixture; (h) equilibrated with the DMSO + water mixture; (i) equilibrated with the EG + water mixture.

scans of solid equilibrated with corresponding liquor show similar characteristic peaks with raw propylthiouracil. As a result, no solvate formation or polymorph transformation occurs during the experiment. Solubility Data. The mole fraction solubility (x) of propylthiouracil determined in pure EG, DMF, NMP, and DMSO and aqueous mixtures of EG, DMF, NMP, and DMSO at the temperatures from 293.15 to 333.15 K is tabulated in Tables 2−5 and plotted in Figure 3. It should be noted that propylthiouracil solubility in neat water is not determined in this work but cited in ref 19. As shown in Tables 2−5, the solubility of propylthiouracil increases with rising temperature for neat solvents EG, DMF, NMP, or DMSO. For the two neat solvents DMSO and DMF, the solubility value intersects at about 323 K. It is smaller in DMF than in DMSO below 323 K, whereas above 323 K, this situation is vice versa. At a certain temperature, the solubility of propylthiouracil in mole fraction is the highest in pure solvents DMSO and DMF. Propylthiouracil is observed to demonstrate up to about 103-fold rise in mole fraction solubility on going from pure water to the three aprotic solvents. The propylthiouracil solubility in pure EG is higher than that in methanol, ethanol, n-propanol, and isopropanol19 and lower than that in DMF, NMP, and DMSO. The propylthiouracil molecule has large dipole moments. Accordingly, it provides strong interactions of dipole−dipole with the solvents of DMF, NMP, and DMSO attributable to its >HH groups.34 The formed H-bonds between the free electron pairs of the oxygen atom of NMP, DMF, and DMSO and >HH groups of propylthiouracil may enhance the propylthiouracil solubility. So the propylthiouracil solubility in DMSO, NMP, and DMF is greater than that in neat alcohols. Solubility Modeling. On the basis of the acquired mole fraction solubility, the model parameters can be attained by

(9)

(10)

(11)

here, m1 refers to the mass of propylthiouracil; m2 refers to the mass of EG, DMSO, NMP, and DMF; and m3 refers to the mass of water. Their corresponding molar masses are referred to as M1, M2, and M3, respectively. The relative standard uncertainty is assessed to be less than 0.045 for the mole fraction solubility. Analysis Method. The propylthiouracil composition in equilibrium liquor was analyzed through an Agilent 1260 HPLC. A reverse phase column was used at about 303 K, the type of which is LP-C18 (250 mm × 4.6 mm). The wavelength of the UV detector was 275 nm.33 The mobile phase was neat methanol, the flow speed of which was 1.0 mL·min−1. Every test was repeated three times. The average data of triple determinations were used to calculate the final solubility. Solid Characterization. To discover the presence of polymorph transformation or solvate formation of propylthiouracil in the experimental process, the solid in equilibration with the liquid phase was collected and confirmed by X-ray powder diffraction (XRD) analysis. The examination of solid samples was made using an HaoYuan DX-2700B instrument (HaoYuan, China) through Cu Kα radiation (1.54184 nm). The scan rate was 6° min−1. The tube current and tube voltage were set to, respectively, 30 mA and 40 kV. The obtained data were gathered from 5 to 70° (2θ) under ambient pressure of 101.1 kPa. C



Article

Table 2. Experimental Propylthiouracil Solubility in Mole Fraction (xeT,W × 102) in the DMF (w) + Water (1 − w) Mixture from T/ K = (293.15 to 333.15) under Atmospheric Pressure p = 101.1 kPaa w b

T/K

0

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0.009862 0.01263 0.01564 0.01903 0.02326 0.02862 0.03459 0.04128 0.05023

0.02351 0.02866 0.03502 0.04298 0.05227 0.06396 0.07799 0.09553 0.1151

0.04845 0.05965 0.07564 0.09303 0.1135 0.1356 0.1628 0.1947 0.2334

0.1076 0.1311 0.1607 0.1953 0.2417 0.2922 0.3486 0.4168 0.4962

0.1937 0.2354 0.2891 0.3525 0.4286 0.5215 0.6224 0.7385 0.8722

0.3869 0.4715 0.5747 0.6993 0.8416 1.018 1.211 1.438 1.716

0.8795 1.056 1.263 1.496 1.783 2.153 2.614 3.152 3.737

1.899 2.282 2.758 3.359 4.016 4.781 5.662 6.685 7.808

4.178 4.979 6.017 7.218 8.586 10.28 12.24 14.41 17.01

7.807 9.383 11.44 13.75 16.41 19.52 22.97 26.91 31.41

12.36 15.03 17.96 21.44 25.54 30.42 35.96 42.22 49.36

a

Standard uncertainties (u) are 0.02 K for temperature, 0.4 kPa for pressure, and 0.0002 for solvent mixtures; the relative standard uncertainty (ur) is 0.045 for mole fraction solubility. w stands for the mass fraction of DMF in the DMF (w) + water (1 − w) mixture. bCited in ref 19.

Table 3. Experimental Propylthiouracil Solubility in Mole Fraction (xeT,W × 102) in the NMP (w) + Water (1 − w) Mixture from T/ K = (293.15−333.15) under Atmospheric Pressure p = 101.1 kPaa w b

T/K

0

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0.009862 0.01263 0.01564 0.01903 0.02326 0.02862 0.03459 0.04128 0.05023

0.02318 0.02721 0.03343 0.04203 0.05207 0.06339 0.07578 0.09091 0.1093

0.05208 0.06194 0.07546 0.09278 0.1140 0.1397 0.1687 0.2032 0.2424

0.1035 0.1212 0.1489 0.1819 0.2235 0.2703 0.3227 0.3829 0.4519

0.2176 0.2503 0.2961 0.3539 0.4282 0.5062 0.6033 0.7162 0.8481

0.3825 0.4673 0.5617 0.6594 0.7826 0.9304 1.093 1.274 1.495

0.7553 0.9071 1.091 1.275 1.512 1.770 2.076 2.406 2.826

1.551 1.853 2.183 2.559 2.989 3.491 4.079 4.712 5.481

3.123 3.663 4.315 5.025 5.859 6.863 7.937 9.191 10.52

5.427 6.322 7.418 8.652 10.05 11.72 13.56 15.62 17.99

8.394 9.713 11.41 13.22 15.32 17.63 20.38 23.31 26.77

a Standard uncertainties (u) are 0.02 K for temperature, 0.4 kPa for pressure, and 0.0002 for solvent mixtures; the relative standard uncertainty (ur) is 0.045 for mole fraction solubility. w stands for the mass fraction of NMP in the NMP (w) + water (1 − w) mixture. bCited in ref 19.

e Table 4. Experimental Propylthiouracil Solubility in Mole Fraction (xT,W × 102) in the EG (w) + Water (1 − w) Mixture from T/K a = (293.15 to 333.15) under Atmospheric Pressure p = 101.1 kPa

w T/K

0b

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0.009862 0.01263 0.01564 0.01903 0.02326 0.02862 0.03459 0.04128 0.05023

0.01298 0.01539 0.01871 0.02339 0.02903 0.03546 0.04259 0.05073 0.06057

0.01794 0.02117 0.02563 0.03153 0.03848 0.04676 0.05656 0.06770 0.08129

0.02709 0.03261 0.04002 0.04837 0.05872 0.07048 0.08441 0.1002 0.1211

0.04286 0.04984 0.06003 0.07331 0.09019 0.1081 0.1290 0.1525 0.1822

0.06351 0.07437 0.08959 0.1076 0.1298 0.1555 0.1859 0.2232 0.2676

0.1055 0.1207 0.1411 0.1681 0.2025 0.2440 0.2961 0.3584 0.4302

0.1792 0.2058 0.2365 0.2823 0.3367 0.4041 0.4905 0.5989 0.7283

0.2982 0.3375 0.3871 0.4605 0.5569 0.6808 0.8191 0.9755 1.165

0.4637 0.5326 0.6219 0.7376 0.8784 1.056 1.264 1.507 1.782

0.7264 0.8431 0.9960 1.179 1.377 1.606 1.868 2.185 2.548

a Standard uncertainties (u) are 0.02 K for temperature, 0.4 kPa for pressure, and 0.0002 for solvent mixtures; the relative standard uncertainty (ur) is 0.045 for mole fraction solubility. w stands for the mass fraction of EG in the EG (w) + water (1 − w) mixture. bCited in ref 19.

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using Mathcad software. The attained values of model parameters along with the values of RMSD and RAD are given in Table 6. The evaluated solubility values based on the regressed model parameters by the Jouyban−Acree equation are shown graphically in Figure 3. It shows that the achieved values of RMSD and RAD for the four mixed solvents are quite minor. The maximum values are, respectively, 9.59 × 10−4 and 3.01 × 10−2. Compared with the other equations, the obtained RMSD and RAD values by using the Jouyban−Acree model are relatively minor. On the whole, the three equations can be used to correlate the solubility of propylthiouracil in the aqueous solutions of EG, DMF, NMP, and DMSO.

CONCLUSIONS

Propylthiouracil solubility in mixed solvents of DMF + water, NMP + water, EG + water, and DMSO + water was acquired through the saturation shake-flask method at temperatures from 293.15 to 333.15 K under 101.1 kPa. The mole fraction solubility of propylthiouracil was the largest in DMF (DMSO) + water solutions at the same mass fraction of EG, DMF, NMP, or DMSO and temperature. The acquired mole fraction solubility was described mathematically through the Jouyban−Acree, van’t Hoff−Jouyban−Acree, and Apelblat−Jouyban−Acree D



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Table 5. Experimental Propylthiouracil Solubility in Mole Fraction (xeT,W × 102) in the DMSO (w) + Water (1 − w) Mixture from T/K = (293.15 to 333.15) under Atmospheric Pressure p = 101.1 kPaa w b

T/K

0

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0.009862 0.01263 0.01564 0.01903 0.02326 0.02862 0.03459 0.04128 0.05023

0.01806 0.02181 0.02627 0.03248 0.04007 0.04878 0.05925 0.07126 0.08539

0.03333 0.04027 0.04961 0.06061 0.07329 0.08871 0.1073 0.1283 0.1533

0.06208 0.07529 0.09113 0.1091 0.1320 0.1579 0.1903 0.2271 0.2698

0.1202 0.1461 0.1770 0.2121 0.2532 0.3038 0.3603 0.4219 0.4991

0.2432 0.2988 0.3580 0.4231 0.5034 0.5961 0.7012 0.8181 0.9603

0.5681 0.6829 0.8149 0.9547 1.126 1.323 1.533 1.774 2.075

1.509 1.771 2.098 2.427 2.833 3.289 3.791 4.348 4.959

4.077 4.617 5.314 6.186 7.102 8.183 9.369 10.77 12.24

9.045 10.42 12.05 13.76 15.72 17.82 20.16 22.77 25.65

16.70 19.08 21.88 24.87 28.33 31.91 35.94 40.34 45.19

a

Standard uncertainties (u) are 0.02 K for temperature, 0.4 kPa for pressure, and 0.0002 for solvent mixtures; the relative standard uncertainty (ur) is 0.045 for mole fraction solubility. w stands for the mass fraction of DMSO in the DMSO (w) + water (1 − w) mixture. bCited in ref 19.

Figure 3. Mole fraction solubility (x) of propylthiouracil in (a) EG (w) + water (1 − w), (b) DMF (w) + water (1 − w), (c) NMP (w) + water (1 − w), and (d) DMSO (w) + water (1 − w) mixed solutions with various mass fractions at different temperatures: w, mass fraction of EG (DMF, NMP, or DMSO) in aqueous cosolvent mixtures free of solute. Δ, w = 0; ☆, w = 0.1000; ◊, w = 0.2000; ○, w = 0.3000; □, w = 0.4000; ★, w = 0.5000; ▰, w = 0.6000; ■, w = 0.7000; ●, w = 0.8000; ⧫, w = 0.9000; ▼, w = 1. , calculated curves by the Jouyban−Acree model.

E



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Table 6. Regressed Parameter Values of Solubility Models Jouyban−Acree parameter J0 J1 J2

RAD × 102 RMSD × 104

van’t Hoff−Jouyban−Acree value 152.84 180.57 881.51

parameter DMF + Water A1 B1 A2 B2 J0 J1 J2

2.17 9.59 J0 J1 J2

RAD × 102 RMSD × 104

365.06 63.170 583.17

RAD × 102 RMSD × 104

−358.43 337.41 15.810

NMP + Water A1 B1 A2 B2 J0 J1 J2

RAD × 102 RMSD × 104

−577.09 480.66 909.02

9.4990 −3400.2 4.2468 −3947.6 153.79 181.32 883.35

A1 B1 C1 A2 B2 C2 J0 J1 J2

−16.221 −2194.2 3.8051 −34.621 −2121.6 5.7483 152.34 182.42 879.73 2.22 9.75

A1 B1 C1 A2 B2 C2 J0 J1 J2

−41.616 −578.14 7.2363 −34.621 −2121.6 5.7483 364.60 64.550 582.01 2.27 7.89

A1 B1 C1 A2 B2 C2 J0 J1 J2

−88.629 1286.5 13.962 −34.621 −2121.6 5.7483 −359.18 338.21 13.627 2.69 1.86

A1 B1 C1 A2 B2 C2 J0 J1 J2

−2.9864 −1994.4 1.4080 −34.621 −2121.6 5.7483 −577.62 481.19 904.35 2.26 9.47

2.28 8.09 EG + Water A1 B1 A2 B2 J0 J1 J2

5.7239 −3132.5 4.2468 −3947.6 −356.19 339.97 21.460

3.01 1.96 DMSO + Water A1 B1 A2 B2 J0 J1 J2

6.5246 −2438.7 4.2468 −3947.6 −576.32 479.82 907.60

2.20 9.59

2.25 9.38

Notes

models, acquiring RAD values that are smaller than 3.01% for correlative investigations.

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value

7.2799 −2866.0 4.2468 −3947.6 366.29 63.930 586.15

2.69 1.86 J0 J1 J2

parameter

2.23 9.33

2.22 7.78 J0 J1 J2

Apelblat−Jouyban−Acree

value

The authors declare no competing financial interest.

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AUTHOR INFORMATION

REFERENCES

(1) Yalkowsky, S. H. Solubility and Solubilization in Aqueous Media; American Chemical Society and Oxford University Press: New York, 1999; pp 180−235. (2) Sanghvi, R.; Narazaki, R.; Machatha, S. G.; Yalkowsky, S. H. Solubility Improvement of Drugs using N-Methyl Pyrolidone. AAPS PharmSciTech 2008, 9, 366−376.

Corresponding Authors

*E-mail: [email protected]. Tel: +86 514 87975244 (H.Z.). *E-mail: [email protected]. (Y.Z.) ORCID

Hongkun Zhao: 0000-0001-5972-8352 F



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Propylthiouracil Solubility in Aqueous Solutions of Ethylene Glycol, N

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