Equilibrium solubility determination, modelling and thermodynamic aspects of 6-chloroguanine in aqueous co-solvent mixtures of N,N-dimethylformamide, isopropanol, 1,4-dioxane and dimethyl sulfoxide

J. Chem. Thermodynamics 134 (2019) 52–60

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Equilibrium solubility determination, modelling and thermodynamic aspects of 6-chloroguanine in aqueous co-solvent mixtures of N,N-dimethylformamide, isopropanol, 1,4-dioxane and dimethyl sulfoxide Min Zheng a, Renjie Xu b, Hongkun Zhao a,⇑ a b

College of Chemistry & Chemical Engineering, YangZhou University, YangZhou, Jiangsu 225002, People’s Republic of China Guangling College, Yangzhou University, YangZhou, Jiangsu 225009, People’s Republic of China

a r t i c l e

i n f o

Article history: Received 10 February 2019 Received in revised form 3 March 2019 Accepted 4 March 2019 Available online 5 March 2019 Keywords: 6-Chloroguanine Solubility Jouyban-Acree Inverse Kirkwood–Buff integrals Preferential solvation Transfer property

a b s t r a c t The equilibrium solubility of 6-chloroguanine in four co-solvent mixtures of dimethyl sulfoxide (DMSO) (1) + water (2), N,N-dimethylformamide (DMF) + water (2), isopropanol (1) + water (2) and 1,4-dioxane (1) + water (2) over the temperature range from (278.15 to 333.15) K were reported. At the same temperature and composition of DMSO, DMF, isopropanol or 1,4-dioxane, the mole fraction solubility of 6-chloroguanine was highest in DMSO (1) + water (2) mixtures, and lowest in 1,4-dioxane (1) + water (2) mixtures. By using the Jouyban-Acree, van’t Hoff-Jouyban-Acree and Apelblat-Jouyban-Acree models, 6-chloroguanine solubility was well correlated obtaining RAD lower than 5.83% and RMSD lower than 4.82
104. Quantitative values for the local mole fraction of DMSO (DMF, isopropanol or 1,4-dioxane) and water around the 6-chloroguanine were computed by using the Inverse Kirkwood–Buff integrals method applied to the determined solubility data. For the DMF (1) + water (2) mixture with composition 0.20 < x1 < 0.69, DMSO (1) + water (2) mixture with composition 0.20 < x1 < 1 and 1,4-dioxane (1) + water (2) mixture with composition 0.18 < x1 < 0.35, 6-chloroguanine is preferentially solvated by the co-solvent. For the isopropanol (1) + water (2) mixture with composition 0.25 < x1 < 0.70, 6-chloroguanine is preferentially solvated neither by isopropanol nor by water. However, in the other regions for the four co-solvent mixtures, 6-chloroguanine is preferentially solvated by water. The dissolution process of 6-chloroguanine in solvent solutions was endothermic. Furthermore, transfer Gibbs energy (DtrG°), enthalpy (DtrH°), and entropy (DtrS°) were calculated, demonstrating that the solubilization capacity was more favorable with the increase in the co-solvent concentration. Ó 2019 Elsevier Ltd.

1. Introduction Recently, investigation of the solubility of drugs and pharmaceutical intermediates and its improvement has become an increasing research subject in pharmaceutical areas. Solubility of drugs and pharmaceutical intermediates in co-solvents mixtures is one of the most important physicochemical properties, which plays a significant role in various biological and physical processes [1–4]. The solubility in co-solvent solutions as a function of composition and temperature is evaluated importantly for raw material purification and understanding the mechanisms relating to the physical and chemical stability of a solid dissolutions [3,5,6]. It provides important data and is generally considered as an essential ⇑ Corresponding author. E-mail address: [email protected] (H. Zhao). https://doi.org/10.1016/j.jct.2019.03.004 0021-9614/Ó 2019 Elsevier Ltd.

factor in the design of crystallization process, where knowledge of the solubility is needed in controlling the supersaturation, particle size, desired polymorphicform and yield. Co-solvency is an optional and effective solubilization technique which is considered to alternate the solubility, as aqueous co-solvent solutions is necessary for pharmaceutical and chemical industries since the mixtures could be used as synthesis reaction medium of some compounds [1,6]. Poor aqueous solubility is likely to cause formulation difficulty or low bioavailability during clinical development [1,5,7]. In addition, solid solubility in co-solvent mixtures allows carrying out a thermodynamic analysis to insight deeply into the molecular mechanisms regarding the drug dissolution process and to estimate the preferential solvation of a solute by solvent components in mixtures [8–11]. The compound 6-chloroguanine (CAS Reg. No. 10310-21-1, structure shown in Fig. 1) is an useful intermediate for preparing

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M. Zheng et al. / J. Chem. Thermodynamics 134 (2019) 52–60

Fig. 1. The chemical structure of 6-chloroguanine.

nucleoside analogue antiviral agents, such as famciclovir and penciclovir [12–14]. The intermediate is 9-substituded with an appropriate side chain precursor, followed by conversion of the 6-chloro moiety to a hydroxyl (a guanine) or hydrogen (a 2-aminopurine) [15]. 6-Chloroguanine is the most ubiquitous nitrogen-containing heterocycle in nature. However, the 6-chloroguanine solubility is very low in water [12,16]. Cosolvency, pH adjustment, surfactant addition and complexation are the most used pharmaceutical approaches for solubilizing drug candidates with low aqueous solubility [1,5]. Among them, the most effective and powerful tool for improving the solubility of poorly water soluble drugs is mixing a miscible and safe co-solvent with water [1–3,5]. However, despite the usefulness of this intermediate, the information about physicochemical properties such as solubility in different solvents and solvent mixtures are very scarce. A thorough literature search shows that only the 6-chloroguanine solubility in some neat solvent at temperature range from 278.15 K to 333.15 K is available in literature [17]. However, the physicochemical property of 6chloroguanine in solvent mixtures has not yet been systematically investigated. According to the literatures’ results, 6-chloroguanine is found to exhibit up to near 102-103-fold increase in mole fraction solubility in going from water to the solvents DMSO and DMF. The large increase in solubility strongly suggests the presence of preferential solvation of 6-chloroguanine in the co-solvent mixtures [10,11]. This prompt us to conduct in-depth research about the 6-chloroguanine solubility in aqueous co-solvent mixtures of DMSO and DMF and analysis the solute-solvent and solventsolvent interactions of 6-chloroguanine at different temperatures in the co-solvent mixtures. For co-solvency approach, solvent selection is a essential process. Practicable solvents should be commercially available, noncorrosive, nontoxic (environmentally safe) and thermally stable. The commonly used co-solvents in the pharmaceutical fields are ethanol, isopropanol, dimethyl sulfoxide (DMSO), N,Ndimethylformamide (DMF), ethylene glycol (EG) and so forth [1,3,5,6]. Isopropanol is a colourless and flammable compound with a strong odor. It is miscible with ethanol, water, ether and chloroform, and dissolves a wide range of non-polar compounds. Compared to alternative solvents, isopropanol is relatively nontoxic. It is used solely or in mixtures with other solvents for different purposes including in penetration-enhancing pharmaceutical compositions for topical transepidermal and percutaneous applications [18,19]. DMSO is an important polar aprotic solvent with immense biological importance and very low toxic [20]. It dissolves both nonpolar and polar compounds and is miscible in a wide range of organic solvents and water. It is chosen to obtain further broader insight about chemistry aqueous solutions for amino acid solvation. DMSO possesses two hydrophobic methyl groups with +I effect, and these hydrogen atoms of two CH3- groups are of acidic character. Because of its aprotic and miscible with water, DMF is used as a co-solvent to investigate the interrelation between drug solubility and medium polarity [21]. The DMFwater solution has very strong non-ideal, so it can act in the

solute solvation process through preferential solvation and hydrophobic interactions [22]. It is noteworthy that 1,4-dioxane are not employed in developing liquid medicine due to its high toxicity. Nevertheless 1,4-dioxane is completely miscible with water [23]. It is broadly employed as a model co-solvent. Even more, the Jouyban–Acree model has been used to correlate the solubility for lots of drugs in 1,4-dioxane (1) + water (2) mixed solvents [24]. Considering these points-of-view, the main objective of this work is to report the equilibrium solubility of 6-chloroguanine in aqueous co-solvent mixtures of DMF and DMSO as well as isopropanol and 1,4-dioxane at temperatures ranging from 278.15 K to 328.15 K under atmospheric conditions as well as evaluate the respective thermodynamic quantities of the solutions. 2. Theoretical consideration Several models have been proposed to correlate the solubility of a solid in solvent mixtures [25]. In this paper, the JouybanAcree model [25,26], a combination of the JouybanAcree model with van’t Hoff equation [25,26] and a combination of the Jouyban  Acree model with modified Apelblat equation [25,26] are used to describe the 6-chloroguanine solubility in aqueous co-solvent mixtures of DMF, DMSO, isopropanol and 1,4-dioxane. 2.1. Jouyban-Acree model The Jouyban-Acree model is expressed as Eq. (1). This model may provide accurate mathematical description for the dependence of solute solubility upon both temperature and solvent composition for solvent mixtures [25,26].

ln xw;T ¼ w1 ln x1;T þ w2 ln x2;T þ

2 w1 w2 X J ðw1  w2 Þi T=K i ¼ 0 i

ð1Þ

here xw,T denotes the mole fraction solubility of solute in solvent mixtures at temperature T/K; w1 and w2 are the mass fraction of co-solvents 1 (DMF, DMSO, isopropanol or 1,4-dioxane) and 2 (water) in the absence of the 6-chloroguanine, respectively; x1,T and x2,T are the 6-chloroguanine solubility in mole fraction in neat solvents; and Ji are the Jouyban-Acree model parameters. 2.2. Van’t Hoff-Jouyban-Acree model The van’t Hoff equation is an ideal model described as

ln xT ¼ A þ

B T=K

ð2Þ

Combining Eqs. (1) and (2), the van’t Hoff-Jouyban-Acree model can be obtained as Eq. (3) [25,26].

ln xw;T

!i   2 B1 B2 w1 w2 X ¼ w1 A1 þ J ðw1  w2 þ w2 A2 þ Þþ T=K T=K T=K i¼0 i ð3Þ

A1, B1, A2, B2 and Ji are model parameters. 2.3. Modified Apelblat-Jouyban-Acree model The modified Apelblat equation is a semi-empirical model described as [27,28]

ln xT ¼ A þ

B þ ClnðT=KÞ T=K

ð4Þ

where A, B, and C are equation parameters; and also xT is the mole fraction solubility of 6-chloroguanine in studied solvent mixtures at temperature T in Kelvin.

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M. Zheng et al. / J. Chem. Thermodynamics 134 (2019) 52–60

By substituting Eq. (4) into Eq. (1), the modified ApelblatJouyban-Acree model can be obtained as Eq. (5) [25,26].

B1 B2 þ C 1 ln ðT=KÞ þ w2 ½ðA2 þ þ C 2 lnðT=KÞ T=K T=K 2 w1 w2 X J ðw1  w2 Þi ð5Þ þ T=K i¼0 i

ln xw;T ¼ w1 ½A1 þ

During the regression process, the objective function is described as

F¼

2 X ln xew;T  ln xcw;T

ð6Þ

In addition, the relative average deviation (RAD) and rootmean-square deviation (RMSD) are employed to evaluate the different models, which are expressed as Eqs. (7) and (8).

1 0 c e  1 X @xw;T  xw;T A RAD ¼ xew;T N

ð7Þ

sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi PN 2 c e i¼1 ðxw;T  xw;T Þ RMSD ¼ N

ð8Þ

here N stands for the number of experimental data points. xew;T denotes the mole fraction solubility determined in this work; and xcw;T , the mole fraction solubility calculated with solubility model.

from 0.1 to 0.9. During the experiment, the local atmospheric pressure was about 101.2 kPa. The solubility of 6-chloroguanine in the binary solvent mixtures of (DMF + water), (DMSO + water), (isopropanol + water) and (1,4dioxane + water) was determined by a saturation shake-flask technique [17,29], and the HPLC (Agilent-1260) was employed to determine the 6-chloroguanine solubility in equilibrium liquor [17]. The 6-chloroguanine solubility was determined at temperatures ‘‘T = 278.15 K to 333.15 K” at intervals of 5 K and pressure ‘‘p = 101.2 kPa”. The excess 6-chloroguanine was added into a certain amount of each co-solvent mixture in triplicates. Each 6chloroguanine solution was mixed completely and then transferred to a thermostatic shaker obtained from Tianjin Ounuo Instrument Co. Ltd., China. The solution was shaken through the shaker at a speed of 100 rpm. So as to obtain equilibration time, 0.5 mL liquor was withdrawn with a 2 mL syringe at intervals of 1 h and then analysed using the HPLC. Analytical results indicated that 19 h was enough for all solutions to reach equilibrium. Then each mixture was removed from the shaker and allowed to settle 6-chloroguanine particles for 3 h. The upper liquid was withdrawn carefully, diluted and analysed by the HPLC. The equilibrium mole fraction solubility of 6-chloroguanine (xw;T ) in the four binary solvent mixtures are obtained with Eq. (9), and the initial compositions of the mixed solvents (w) are calculated with Eqs. (10) and (11).

xw;T ¼ 3. Experimental

m1 =M1 m1 =M1 þ m2 =M2 þ m3 =M3

w1 ¼ w ¼

3.1. Materials 6-Chloroguanine was provided by Sigma Chemical Co., Ltd, China with a mass fraction of 0.982. It was crystallized in methanol for three times. The final mass fraction of 6-chloroguanine used in experiment was 0.996, which was analysed by using a high-performance liquid chromatography (HPLC, Agilent 1260). The organic solvents namely DMSO, DMF, isopropanol and 1.4-dioxane were provided by Sinopharm Chemical Reagent Co., Ltd., China, which purities were all no<0.994 in mass fraction determined by gas chromatography (Smart (GC-2018)). The twice-distilled water (conductivity < 2 mS cm1) was prepared in our lab. The detailed descriptions of the above substances were collected and presented in Table 1. 3.2. Solubility measurement During the experiment, we use the analytical balance (BSA224S) to prepare the aqueous co-solvent mixtures. Each mixture used in solubility determination was about 15 mL, and the relative standard uncertainty of which was estimated to be 0.0002. The mass fractions of organic solvent in the binary mixtures varied

w2 ¼

m2 m2 þ m3

ð9Þ

ð10Þ

m3 m2 þ m3

ð11Þ

where m1 is the mass of 6-chloroguanine; m2 is the mass of DMF, DMSO, isopropanol and 1,4-dioxane, and m3 is the mass of water. M1, M2 and M3 are the corresponding molar mass. The relative standard uncertainty for mole fraction solubility is evaluated to be 0.044. 3.3. Analysis method The concentration of 6-chloroguanine was analysed by the Agilent-1260 HPLC. The chromatographic column was a reverse phase column with a type of LP-C18 (250 mm
4.6 mm), which temperature was kept at 303 K. The wavelength of the UV detector was set to 260 nm [17]. The mobile phase was neat methanol at a flow rate of 1.0 mLmin1. Each analysis was made three times, and the average value of three determinations was regarded as the final solubility value of the analysis.

Table 1 Detailed information on the materials used in the work.

a b

Chemicals

Molar mass/ gmol1

Source

Initial mass fraction purity

Final mass fraction purity

Purification method

Analytical method

6-chloroguanine isopropanol DMF 1,4-dioxane DMSO water

169.57 60.10 73.09 88.11 78.13 18.02

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

0.982 0.995 0.995 0.995 0.994

0.996 0.995 0.995 0.995 0.994 Conductivity < 2 mScm1

Recrystallization none none none none Distillation

HPLCa GCb GC GC GC Conductivity meter

Our lab

High-performance liquid phase chromatography. Gas chromatography.

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those in the other three mixtures at the same temperature and co-solvent composition.

3.4. X-ray powder diffraction With the object of checking the existence of the polymorph transformation or solvate formation of 6-chloroguanine during the solubility determination, the equilibrium solid is collected and identified by X-ray powder diffraction (XRD). The experiment was carried out on a HaoYuan DX-2700B (HaoYuan, China) instrument. The samples were determined by Cu Ka radiation (k = 1.54184 nm), and the tube voltage and current were, respectively, set at 40 kV and 30 mA. The data were collected at room temperature from 10° to 80° (2-Theta) at a scan speed of 6 degmin1 under atmospheric pressure. 4. Results and discussion 4.1. X-ray powder diffraction analysis The patterns of the raw material 6-chloroguanine together with the solids equilibrated in liquid are shown in Fig. S1 of Supporting material. It can be seen that all the XRD patterns of solid phase of 6-chloroguanine in equilibrium with its solution have the same characteristic peaks with the raw material. Therefore, no polymorph transformation or solvate formation is observed during the whole experiment. 4.2. Solubility data The determined mole fraction solubility of 6-chloroguanine in binary mixtures of (DMSO + water), (DMF + water), (isopropanol + water) and (1,4-dioxane + water) is presented in Tables 2–5, respectively. In addition, the relationship between the mole fraction solubility and temperature and solvent composition are shown graphically in Fig. 2. it demonstrates that, for the studied co-solvent mixtures, the 6-chloroguanine solubility is a function of temperature and solvent composition. For the binary (DMSO + water) mixtures, the solubility of 6-chloroguanine increases with increasing temperature and mass fraction of DMSO. The maximum solubility of 6-chloroguanine is observed in pure DMSO. However, for the binary systems of DMF + water, isopropanol + water and 1,4-dioxane + water, the 6-chloroguanine solubility reaches a maximum in the mixture with x1 = 0.90 for DMF (1) + water (2) mixtures, and x1 = 0.80 for isopropanol (1) + water (2) and 1,4dioxane (1) + water (2) mixtures. Tables 2–5 also show that the solubility of 6-chloroguanine in (DMSO + water) is greater than

4.3. Solubility modelling On the basis of the experimental solubility data, the parameters in Eqs. (1)–(5) were acquired by using Mathcad software. The obtained equation parameters together with the RAD and RMSD values are presented in Table S1 of the Supporting material. The solubility of 6-chloroguanine in the four binary mixtures is evaluated on the basis of the regressed parameters’ values. The calculated ones by using the JouybanAcree model are plotted in Fig. 2. As can be seen from Table S1, the obtained values of relative average deviations (RAD) root-mean-square deviation (RMSD) for the four co-solvent mixtures are a little large. The largest ones are 5.83
102 and 4.82
104, respectively. Comparison with the other models, the values of RAD and RMSD obtained with the Jouyban-Acree model is relatively small. On the whole, the three models may all be employed to describe the 6-chloroguanine solubility in the binary mixtures of DMF + water, DMSO + water, isopropanol + water and 1,4-dioxane + water at all initial composition ranges, and the Jouyban-Acree model gives relative better correlation results among the selected models. 4.4. Transfer properties In order to understand the solubilization conditions in all of the aqueous solutions of DMF, DMSO, isopropanol and 1,4-dioxane, the enthalpy of the solution (DsolH°) is calculated from the slopes of the van’t Hoff plots as follows:

ln xw;T ¼ 

Dsol Ho þC RT

ð12Þ

here, xw,T denotes the experimental mole fraction solubility of 6chloroguanine, and C is a constant and independent upon temperature. At a constant co-solvent concentration, the linear regression of lnxw,T versus 1/T gives a slope equal to DsolH°/R. Considering the process of transferring 6-chloroguanine (1) from pure water (3) to the aqueous co-solvent solutions (1 + 2), the transfer Gibbs energy (DtrG°), enthalpy (DtrH°), and entropy (DtrS°) are computed with Eqs. (13)–(15), respectively [30,31].

  x3;2 Dtr Go3:2!1þ2 ¼ RT ln x3;1þ2

ð13Þ

Table 2 Mole fraction solubility (xeT;W  104 ) of 6-chloroguanine in mixed solvent of DMF (w) + water (1-w) with various mass fractions within the temperature range from T/K = (278.15 to 333.15) under p = 101.2 kPa.a T/K

xeT;W  104 W

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0b

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1b

0.03283 0.04657 0.06526 0.09040 0.1239 0.1680 0.2256 0.3001 0.3956 0.5171 0.6704 0.8625

0.5801 0.7759 1.028 1.349 1.756 2.266 2.901 3.686 4.651 6.279 8.332 11.10

2.219 2.875 3.696 4.714 5.969 7.505 9.374 10.71 13.40 15.62 18.54 22.21

3.747 4.772 6.035 7.582 9.464 11.40 13.52 16.41 20.64 25.01 28.12 32.31

4.754 6.230 7.951 10.20 11.91 15.17 17.85 21.24 26.43 31.62 35.70 41.11

6.959 8.628 10.62 13.11 16.07 19.42 23.51 28.35 34.04 40.62 48.41 55.42

10.77 13.18 15.98 19.37 23.27 27.94 33.42 39.97 47.45 56.21 66.34 78.12

20.95 25.06 29.94 35.51 42.12 49.87 58.86 69.17 81.14 94.91 110.2 130.3

36.27 42.15 48.54 56.95 65.04 75.61 86.11 101.4 119.7 141.1 164.3 186.5

52.55 60.84 70.47 81.48 94.01 110.2 125.4 143.9 166.8 190.2 220.4 250.2

22.59 26.62 31.27 36.61 42.74 49.74 57.73 66.83 77.15 88.84 100.1 120.7

a Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.044. Solvent mixtures were prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of DMF in mixed solvents of DMF(w) + water (1-w). b Taken from Ref. [17].

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Table 3 Mole fraction solubility (xeT;W  104 ) of 6-chloroguanine in mixed solvent of DMSO (w) + water (1-w) with various mass fractions within the temperature range from T/K = (298.15 to 333.15) under p = 101.2 kPa.a T/K

xeT;W  104 W

298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0b

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1b

0.1239 0.1680 0.2256 0.3001 0.3956 0.5171 0.6704 0.8625

0.2288 0.3135 0.3901 0.5067 0.6408 0.8147 1.044 1.255

0.3387 0.4399 0.5653 0.7323 0.9137 1.137 1.477 1.838

0.5963 0.7581 0.9638 1.229 1.566 1.934 2.306 2.847

1.072 1.335 1.715 2.056 2.545 3.151 3.757 4.469

1.747 2.288 2.772 3.341 4.158 4.972 6.122 7.518

2.916 3.718 4.553 5.517 6.650 8.232 9.432 11.49

6.057 7.301 8.730 10.36 12.75 15.08 17.37 20.45

13.10 15.53 17.94 22.21 25.31 29.70 34.58 38.99

32.05 38.28 45.94 52.87 61.93 73.26 83.49 96.24

108.1 126.9 150.1 171.8 203.5 240.0 284.2 331.3

a Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.044. Solvent mixtures were prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of DMSO in mixed solvents of DMSO (w) + water (1-w). b Taken from Ref. [17].

Table 4 Mole fraction solubility (xeT;W  104 ) of 6-chloroguanine in mixed solvents of isopropanol (w) + water (1-w) with various mass fractions within the temperature range from T/K = (278.15 to 333.15) under p = 101.2 kPa.a T/K

xeT;W  104 W

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0b

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1b

0.03283 0.04657 0.06526 0.09040 0.1239 0.1680 0.2256 0.3001 0.3956 0.5171 0.6704 0.8625

0.1071 0.1472 0.2003 0.2697 0.3596 0.4748 0.6215 0.8065 1.038 1.326 1.681 2.116

0.2392 0.3212 0.4273 0.5629 0.7348 0.9509 1.220 1.554 1.907 2.347 2.779 3.336

0.4019 0.5501 0.7209 0.9410 1.175 1.516 1.835 2.284 2.698 3.277 3.983 4.652

0.5277 0.7433 0.9635 1.269 1.619 2.114 2.514 3.012 3.668 4.392 5.322 6.261

0.7164 0.9635 1.206 1.579 2.082 2.680 3.206 3.745 4.576 5.515 6.634 7.775

1.008 1.251 1.561 2.069 2.599 3.291 3.978 4.616 5.641 6.827 7.968 9.316

1.318 1.611 1.970 2.523 3.238 3.972 4.837 5.596 6.737 8.099 9.464 11.10

1.738 2.136 2.680 3.306 4.008 4.751 5.727 6.808 8.142 9.632 11.30 13.00

1.173 1.472 1.803 2.214 2.692 3.258 3.865 4.622 5.528 6.533 7.646 8.983

0.5988 0.7430 0.9383 1.137 1.367 1.650 1.950 2.304 2.660 3.141 3.629 4.313

a Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.044. Solvent mixtures were prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of isopropanol in mixed solvents of isopropanol (w) + water (1-w). b Taken from Ref. [17].

Table 5 Mole fraction solubility (xeT;W  104 ) of 6-chloroguanine in mixed solvents of 1,4-dioxane (w) + water (1-w) with various mass fractions within the temperature range from T/K = (288.15 to 333.15) under p = 101.2 kPaa. T/K

xeT;W  104 W

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0b

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1b

0.06526 0.09040 0.1239 0.1680 0.2256 0.3001 0.3956 0.5171 0.6704 0.8625

0.2142 0.2883 0.3841 0.5072 0.6638 0.8615 1.109 1.418 1.798 2.266

0.4421 0.5828 0.7616 0.987 1.269 1.619 2.051 2.581 3.226 4.007

0.7234 1.072 1.375 1.751 2.109 2.777 3.464 4.294 5.291 6.484

1.283 1.767 2.229 2.793 3.478 4.186 5.297 6.482 7.891 9.248

2.004 2.510 3.124 3.865 4.959 5.817 7.411 8.902 10.70 12.41

3.191 3.931 4.817 5.871 7.121 8.596 10.31 12.53 14.32 16.71

4.525 5.496 6.642 7.992 9.574 11.43 13.62 16.01 18.61 21.51

6.078 7.250 8.822 10.24 12.42 14.32 17.14 20.12 23.41 26.42

2.941 3.537 4.237 5.058 6.015 7.129 8.422 9.916 11.64 13.61

0.7484 0.9156 1.124 1.349 1.621 1.949 2.359 2.768 3.253 3.960

a Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.044. Solvent mixtures were prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of 1,4-dioxane in mixed solvents of 1,4-dioxane (w) + water (1-w). b Taken from Ref. [17].

Dtr Ho3;2!1 þ 2 ¼ Dsol Ho3;1 þ 2  Dsol Ho3;2

Dtr So3;2!1þ2 ¼

Dtr Ho3;2!1 þ 2  Dtr Go3;2!1þ2 T

ð14Þ

ð15Þ

here, x3,1+2 and x3,2 represent the solubilities of 6-chloroguanine in aqueous co-solvent solutions and neat water, respectively; and DsolH° is the corresponding molar enthalpy. The thermodynamic parameters shown in Table S2 of Supporting material provide further information regarding the increased

57

M. Zheng et al. / J. Chem. Thermodynamics 134 (2019) 52–60

250

300

200

(a)

200

4

4

10 x

150

10 x

( b)

250

100

150 100

50

50

0 330 320 310

300

T/K

0.4 290

280

0.2 270

0.0

0 330

1.0 0.8 0.6

T/K

0.2

300 290

1.0 0.8 0.6

w

0.0

(d)

(c) 20

10 x

10 4

8

4

10 x

0.4

310

w

25

12

320

6

15 10

4 5

2 0 330 320

310

T/K 300 290

0.4 0.2 280

0.6

1.0 0.8

0 330

0.6

320

0.4

310

w

T/K

0.0

0.2

300 290

0.8

1.0

w

0.0

Fig. 2. Mole fraction solubility (x) of 6-chloroguanine in (a) DMF (w) + water (1-w), (b) DMSO (w) + water (1-w), (c) isopropanol (w) + water (1-w) and (d) 1,4-dioxane (w) + water (1-w) mixed solutions with various mass fractions at different temperatures: w, mass fraction; j, w = 0 [17]; d, w = 0.1000; ▲, w = 0.2000; ◆, w = 0.3000; ., w = 0.4000; w, w = 0.5000; 4, w = 0.6000; s, w = 0.7000; q, w = 0.8000; J, w = 0.9000; h, w = 1 [17]. —, calculated curves by the JouybanAcree model.

solubility of 6-chloroguanine in the aqueous co-solvent solutions. The DsolH° values calculated from slopes of the van’t Hoff plots are always positive, but the increase in the co-solvent concentration led to the decrease in the corresponding DsolH° of 6-chloroguanine. These results indicate that the endothermic effect resulting from the breaking of the self-association bonds is compensated by the exothermic effect resulting from the hydrogen bonds between allopurinol and water [30]. The DtrG° and DtrH° values are negative, indicating that the transfer of allopurinol from only water to an aqueous co-solvent solution is spontaneous and energetically favorable. Furthermore, the DtrG° and DtrH° values decrease with the increase in the co-solvent concentration, demonstrating that the solubilization capacity becomes more favorable with the increase in the co-solvent concentration. 4.5. Preferential solvation of 6-chloroguanine The Inverse Kirkwood–Buff integrals (IKBI) provide a valuable method for calculating the preferential solvation of a nonelectrolyte drug in binary aqueous solvent mixtures. It expresses the local solvent composition near the solute in comparison with the global solution composition [8,9]. The inverse Kirkwood-Buff integral equation is described as:

Z Gi;3 ¼ 0

r cor

ðg i;3  1Þ4pr 2 dr

ð16Þ

where, gi,3 is the pair correlation function for molecules of solvent i in the co-solvent (1) + water (2) solutions around 6-chloroguanine (3); r is the distance between the centers of molecules of 6chloroguanine (3) and those of co-solvent (1) or water (2); and rcor is a correlation distance. Consequently, for all distances r > rcor up to infinite, the integral value is essentially zero. The preferential solvation parameter of 6-chloroguanine (compound 3) by the co-solvent (compound 1) in co-solvent (1) + water (2) mixtures is expressed as [8–11,26,32]:

dx1;3 ¼ xL1;3  x1 ¼ dx2;3

ð17Þ

where xL1;3 is the local mole fraction composition of co-solvent (1) in the environment around 6-chloroguanine (3) and x1 is the bulk mole fraction composition of co-solvent (1) in the initial mixtures. If dx1,3 is greater than zero, 6-chloroguanine is preferentially solvated by solvent (1); on the contrary, if dx1,3 is less than zero, 6chloroguanine is preferentially solvated by water (2). However, when |dx1,3| < 0.01, the preferential solvation procedure can be negligible, but if xL1;3  1, then complete solvation of 6-chloroguanine is performed by the DMF, DMSO, isopropanol or 1,4-dioxane (1). Values of dx1,3 is attained from the IKBI for the individual solvent components evaluated according to the several following thermodynamic quantities [8–11,26,32]:

dx1;3 ¼

x1 x2 ðG1;3  G2;3 Þ x1 G1;3 þ x2 G2;3 þ V cor

ð18Þ

M. Zheng et al. / J. Chem. Thermodynamics 134 (2019) 52–60

with

  3 þ x2 V 2 D G1;3 ¼ RT jT  V Q

ð19Þ

  3 þ x1 V 1 D G2;3 ¼ RT jT  V Q

ð20Þ

 3  1=3  2 V cor ¼ 2522:5 r3 þ 0:1363 xL1;3 V 1 þ xL2;3 V  0:085

ð21Þ

In Eqs. (18)–(21), jT denotes the isothermal compressibility of 1 the co-solvent (1) + water (2) mixtures (expressed in GPa1); V  and V2 denote the partial molar volumes of the solvents in the 3 is the parmixed solvents (expressed in cm3mol1); similarly, V tial molar volume of 6-chloroguanine in these mixtures (expressed in cm3mol1). The function D expressed by Eq. (22) is the derivative of the standard molar Gibbs energies of transfer of 6chloroguanine from neat water (2) to co-solvent (1) + water (2) mixtures with respect to the solvent composition (expressed in kJmol1, as is RT). The function Q defined by Eq. (23) involves the second derivative of the excess molar Gibbs energy of mixing of the two solvents (GExc 1 þ 2 ) with respect to the water proportion in the solvent mixtures (also expressed in kJmol1). Vcor is the correlation volume and r3 is the molecular radius of 6-chloroguanine calculated with Eq. (24) with NAv as the Avogadro’s number.

D¼

@ Dtr Goð3;2!1þ2Þ

!

@x1

ð22Þ T;P

" # @ 2 GExc 1þ2 Q ¼ RT þ x1 x2 @x22

ð23Þ

T;p

sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 21  3 3
10 V3 r3 ¼ 4pNAV

ð24Þ

Due to the dependence of jT on composition, this term is not known for all the systems investigated. On the other hand, because of the slight contribution of RTjT to the IKBIs, the jT can be evaluated approximately as an additive property by using the solution compositions and the reported values for pure solvents by [10,11,26,32]:

jT ¼ x1 joT;1 þ x2 joT;2

ð25Þ

here xi is the mole fraction of component i in co-solvent mixture and joT;i is the isothermal compressibility of the pure component i. So the RTjT values are obtainable with the reported joT;i values for DMF (0.653 GPa1), DMSO (0.524 GPa1), isopropanol (1.332 GPa1), 1,4-dioxane (0.738 GPa1) and water (0.457 GPa1) at 298.15 K [33], taken as independent of temperature [8]. The calculated Dtr Go3;2!1þ2 values tabulated in Table S2 of Supplementary material are correlated with Eq. (26) for the DMSO (1) + water (2), isopropanol (1) + water (2) + and 1,4-dioxane (1) + water (2) mixtures; and Eq. (27) for the DMF (1) + water (2) system. Fig. S2 of Supporting material presents the values of Gibbs energy of transfer at 298.15 K. The obtained coefficients in Eqs. (26) and (27) are tabulated in Table S3 of Supplementary material.

Dtr Go3;2!1þ2 ¼ a þ bx1 þ cx21 þ dx31 þ ex41 x1

x1

Dtr Go3;2!1þ2 ¼ a þ bx11:5 þ ce d þ ee f

ð26Þ ð27Þ

Thus, D values are calculated from the first derivative of Eqs. (26) and (27) solved according to the co-solvent mixture composi-

tion varying by 0.05 in mole fraction of DMF (1), DMSO (1), isopropanol (1) or 1,4-dioxane (1). The obtained D values are reported in Tables S4–S7 of Supplementary material. Because no partial molar volumes of 6-chloroguanine (3) in the studied solutions can be found in previous works, here they are believed as similar to that of pure 6-chloroguanine [8–11,26,32]. A value of Vs = 77.4 cm3mol1 is taken from Ref. [17] which is estimated by using the Fedors’ method [34]. As a result, solute radius value (r3) is computed with Eq. (24) as 0.313 nm. In addition, the values of RTjT and the partial molar volumes of two neat solvents in the DMSO (1) + water (2), DMF (1) + water (2), isopropanol (1) + water (2) and 1,4-dioxane (1) + water (2) mixtures as well as the Q values at the studied temperatures have been reported [10,11,26]. Therefore, the values of G1,3 and G2,3 in the four binary co-solvent mixtures can be obtained and shown in Tables S4–S7 of Supplementary material. Because definitive correlation volume depends on the local mole fractions around the solute, it needs iteration. This iteration procedure is made by substituting dx1,3 and Vcor into the Eqs. (18), (19) and (22) to recalculate xL1;3 until a non-variant Vcor value is obtained. The achieved values of Vcor and dx1,3 are also presented in Tables S4–S7 of Supplementary material for DMF (1) + water (2), DMSO (1) + water (2), isopropanol (1) + water (2) and 1,4-dioxane (1) + water (2) co-solvent mixtures, respectively. In addition, the dependence of dx1,3 values upon solvent composition in mole fraction is shown graphically in Fig. 3. It shows that the values of dx1,3 vary non-linearly with the co-solvent (1) proportion in all the aqueous mixtures. According to Fig. 3, addition of water (1) makes negative the dx1,3 values of 6-chloroguanine (3) from neat DMF (DMSO, isopropanol or 1,4-dioxane) (1) up to x1 = 0.20 mol fractions of DMF and DMSO, x1 = 0.25 mol fraction of isopropanol and x1 = 0.18 mol fraction of 1,4-dioxane. In these regions, the local mole fractions of DMF (DMSO, isopropanol or 1,4-dioxane)) (1) are smaller than those of the mixtures and therefore the dx1,3 values are negative, which indicates that 6-chloroguanine is preferentially solvated by water. Similar behavior can also found in the DMF (1) + water (2) mixtures with composition 0.69 < x1 < 1, isopropanol (1) + water (2) mixtures with composition 0.70 < x1 < 1 and 1,4dioxane (1) + water (2) mixtures with composition 0.35 < x1 < 1. Probably the structuring of water molecules around the 6chloroguanine contributes to lowering of the net dx1,3 to negative values in the DMF (DMSO, isopropanol or 1,4-dioxane) mixtures. Maximum negative values are obtained with the composition x1 = 0.05 with dx1,3 =  3.967
102 for the DMF (1) + water (2), x1 = 0.10 with dx1,3 =  2.999
102 for the DMSO (1) + water

3 0 -3

x1,3

58

-6 -9 -12 -15 -18 0.0

0.2

0.4

x1

0.6

0.8

1.0

Fig. 3. dx1,3 values of 6-chloroguanine (3) in (a) DMF (1) + water (2), (b) DMSO (1) + water (2), (c) isopropanol (1) + water (2) and (d) 1,4-dioxane (1) + water (2) mixtures at 298.15 K. j, DMF (1) + water (2); d, DMSO (1) + water (2); ▲, isopropanol (1) + water (2); ., 1,4-dioxane (1) + water (2).

M. Zheng et al. / J. Chem. Thermodynamics 134 (2019) 52–60

(2), x1 = 0.10 with dx1,3 =  3.410
102 for isopropanol (1) + water (2) and x1 = 0.60 with dx1,3 =  16.76
102 for the 1,4dioxane (1) + water (2) mixtures. In the DMF (1) + water (2) mixtures with composition 0.20 < x1 < 0.69, DMSO (1) + water (2) mixtures with composition 0.20 < x1 < 1.00, 1,4-dioxane (1) + water (2) mixtures with composition 0.18 < x1 < 0.35, the local mole fractions of DMF, DMSO and 1,4-dioxane are higher than those of the mixtures and therefore the dx1,3 values are positive indicating preferential solvation of 6-chloroguanine by the DMF (DMSO or 1,4-dioxane). The co-solvents action to increase the solute solubility may be related to the breaking of the ordered structure of water around the polar moiety of 6-chloroguanine which increases the solvation having maximum values near to x1 = 0.40 with dx1,3 = 1.718
102 for the DMF (1) + water (2), x1 = 0.60 with dx1,3 = 2.302
102 for the DMSO (1) + water (2) and x1 = 0.25 with dx1,3 = 1.441
102 for the 1,4-dioxane (1) + water (2) mixtures. It can also be found from Fig. 3 that for the isopropanol (1) + water (2) mixtures with composition 0.25 < x1 < 0.70, the absolute values of dx1,3 are all lower than 1.0
102. In this region, the 6-chloroguanine is preferentially solvated neither by isopropanol nor by water. This result is a consequence of the effect of uncertainties propagation instead of the preferential solvation [35]. On the basis of a structural and functional group analysis, 6chloroguanine can act as a Lewis acid in solution due to the ability of the acidic hydrogen atom in its >NH and –NH2 groups (Fig. 1) to establish hydrogen bonds with proton-acceptor functional groups of the co-solvents (oxygen atoms in AOA, @O and AOH groups and nitrogen atom in > N- group). In addition, 6-chloroguanine can also act as a Lewis base because of the free electron pairs in nitrogen atoms of AN@ (Fig. 1), which interact with acidic hydrogen atoms of water. Based on the preferential solvation results, it is conjecturable that in the region of 0.20 < x1 < 0.69 for DMF, 0.20 < x1 < 1 for DMSO and 0.18 < x1 < 0.35 for 1,4-dioxane, 6chloroguanine is acting as a Lewis acid with DMSO, isopropanol or 1,4-dioxane molecules, because these co-solvents are more basic than water, as described by the Kamlet–Taft hydrogen bond acceptor parameters, i.e. b = 0.76 for DMSO, b = 0.84 for isopropanol, b = 0.84 for 1,4-dioxane and 0.47 for water [33,36]. On the other hand, in the other regions for the three co-solvent mixtures and in water-rich and co-solvent-rich regions for isopropanol (1) + water (2) mixtures, where 6-chloroguanine is preferentially solvated by water, 6-chloroguanine could be acting mainly as a Lewis base in front to water because the water is more acidic than DMF, DMSO, isopropanol or 1,4-dioxane as described by the Kamlet–Taft hydrogen bond donor parameters, i.e. a = 1.17 for water, 0.00 for DMF and DMSO, 0.792 for isopropanol and 0.76 for 1,4-dioxane, respectively [33,37].

5. Conclusion The equilibrium solubility of 6-chloroguanine in co-solvent mixtures of DMF (1) + water (2), DMSO (1) + water (2), isopropanol (1) + water (2) + and 1,4-dioxane (1) + water (2) were determined experimentally by using the saturation shake-flask technique within the temperature range from 278.15 K to 333.15 K under atmospheric pressure (101.2 kPa). At the same temperature and mass fraction of DMF (DMSO, isopropanol or 1,4-dioxane), the mole fraction solubility of 6-chloroguanine was greater in (DMSO + water) than that in the other three mixtures. The transfer properties including Gibbs energy, enthalpy, and entropy were calculated according to the solubility data. The values of preferential solvation parameters (dx1,3) for DMSO, isopropanol or 1,4-dioxane were positive in the DMF mixture with composition 0.20 < x1 < 0.69, 1,4-dioxane mixture with composition

59

0.18 < x1 < 0.35 and DMSO mixture with composition 0.20 < x1 < 1, which indicated that 6-chloroguanine was preferentially solvated by co-solvent. The higher solvation by co-solvent could be elucidated based on the higher basic behavior of the cosolvent which interacted with the Lewis acidic groups of 6chloroguanine. Nevertheless in the isopropanol + water mixtures with in intermediate compositions, 6-chloroguanine was preferentially solvated neither by isopropanol nor by water. In addition, the drug’ solubilities were mathematically expressed through the Jouyban-Acree model, van’t Hoff-Jouyban-Acree model and Apelblat-Jouyban-Acree model obtaining average relative deviations lower than 5.83% for correlative studies. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jct.2019.03.004. References [1] S.H. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society and Oxford University Press, New York, 1999, pp. 180–235. [2] R. Sanghvi, R. Narazaki, S.G. Machatha, S.H. Yalkowsky, Solubility improvement of drugs using N-methyl pyrolidone, Aaps Pharmscitech 9 (2008) 366–376. [3] A. Jouyban, Handbook of Solubility Data for Pharmaceuticals, CRC Press, BocaRaton, FL, 2010. [4] F. Martínez, A. Jouyban, W.E. Acree Jr, Pharmaceuticals solubility is still nowadays widely studied everywhere, Pharmaceut. Sci. 23 (2017) 1–2. [5] J.T. Rubino, Co-solvents and cosolvency, in: J. Swarbrick, J.C. Boylan (Eds.), Encyclopedia of Pharmaceutical Technology, Marcel Dekker, New York, NY, 1988. [6] P. Kolárˇ, J.W. Shen, A. Tsuboi, T. Ishikawa, Solvent selection for pharmaceuticals, Fluid Phase Equilibr. 194–197 (2002) 771–782. [7] M.E. Aulton, Pharmaceutics., The Science of Dosage Forms Design, second ed., Churchill Livingstone, London, 2002. [8] Y. Marcus, Solvent Mixtures: Properties and Selective Solvation, Marcel Dekker Inc., New York, NY, 2002. [9] Y. Marcus, Preferential solvation in mixed solvents, in: P.E. Smith, E. Matteoli, J.P. O’Connell (Eds.), Fluctuation Theory of Solutions: Applications in Chemistry, Chemical Engineering, and Biophysics, CRC, Press, Taylor & Francis Group, BocaRaton, FL, 2013. [10] F. Martínez, A. Jouyban, W.E. Acree, Jr, Preferential solvation of etoricoxib in some aqueous binary co-solvent mixtures at 298.15 K, Phys. Chem. Liq. 55 (2016) 291–303. [11] A. Jouyban, W.E. Acree Jr, F. Martínez, Modelling the solubility and preferential solvation of gallic acid in co-solvent + water mixtures, J. Mol. Liq. 224 (2016) 502–506. [12] X. Jin, L. Ji, W.X. Chen, W. Qian, D.D. Shen, An improved synthetic process of famciclovir and penciclovir, Chin. J. Pharm. 47 (2016) 1352–1356 (Chinese). [13] L.Y. Dai, Q.L. Shi, J. Zhang, X.Z. Wang, Y.Q. Chen, Accelerated effect on Mitsunobu reaction via bis-N-tert-butoxycarbonylation protection of 2amino-6-chloropurine and its application in a novel synthesis of penciclovir, J. Zhejiang Univ. 14A (2013) 760–766 (Chinese). [14] M.R. Harnden, R.L. Jarvest, Process for the preparation of 2-amimo-6-chloropurine, WO Patent 940,789,214, April 14, 1994. [15] V. Balachandran, K. Parimala, Tautomeric purine forms of 2-amino-6chloropurine (N9H10 and N7H10): Structures, vibrational assignments, NBO analysis, hyperpolarizability, HOMO–LUMO study using B3 based density functional calculations, Spectrochim. Acta 96A (2012) 340–351. [16] S. Fletcher, V.M. Shahani, A.J. Lough, P.T. Gunning, Concise access to N9-mono-, N2-mono- and N2, N9-di-substituted guanines via efficient Mitsunobu reactions, Tetrahedron 66 (2010) 4621–4632. [17] W.T. Li, Y.Q. Zhu, X.C. Wang, M. Zheng, X.B. Li, H.K. Zhao, Solubility modelling and solvent effect of 2-amino-6-chloropurine in twelve neat solvents, J. Chem. Eng. Data 64 (2019) 771–777. [18] G.D. Maia, M. Giulietti, Solubility of acetylsalicylic acid in ethanol, acetone, propylene glycol, and 2-propanol, J. Chem. Eng. Data 53 (2008) 256–258. [19] M. Mohammadzade, M. Barzegar-Jalali, A. Jouyban, Solubility of naproxen in 2propanol + water mixtures at various temperatures, J. Mol. Liq. 206 (2015) 110–113. [20] P.B. Undre, P.W. Khirade, V.S. Rajenimbalkar, S.N. Helambe, S.C. Mehrotra, Dielectric relaxation in ethylene glycoldimethyl sulfoxide mixtures as a function of composition and temperature, J. Korean Chem. Soc. 56 (2012) 416– 423. [21] P.B. Rathi, V.K. Mourya, Solubility prediction of satranidazole in aqueous N, Ndimethylformamide mixtures using extended Hildebrand solubility approach, Indian J. Pharm. Sci. 74 (2012) 254–258. [22] R.J. Sindreu, M.L. Moya, B.F. Sanchez, A.G. Gonzalez, Solvent effects on the dissociation of aliphatic carboxylic acids in water-N, N-dimethylformamide

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JCT 2019-140