Solubility and thermodynamics of tenoxicam in (PEG-400 + water) binary solvent systems at different temperatures

Journal of Molecular Liquids 213 (2016) 221–227

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Solubility and thermodynamics of tenoxicam in (PEG-400 + water) binary solvent systems at different temperatures Faiyaz Shakeel a,b,⁎, Nazrul Haq a,b, Fars K. Alanazi b, Ibrahim A. Alsarra a,b a b

Center of Excellence in Biotechnology Research, College of Science, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia Kayyali Chair for Pharmaceutical Industry, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia

a r t i c l e

i n f o

Article history: Received 17 September 2015 Accepted 27 October 2015 Available online xxxx Keywords: Correlation Cosolvent mixture Tenoxicam PEG-400 Solubility Thermodynamics

a b s t r a c t In this study, the solubility and thermodynamics of an anti-inflammatory drug tenoxicam (TNX) in various [polyethylene glycol-400 (PEG-400) + water] binary solvent systems was measured at temperatures T = (298.15 to 323.15) K and pressure p = 0.1 MPa. The solubilities of TNX were measured by an isothermal method and correlated with calculated ones. The mole fraction solubility of TNX was recorded highest in neat PEG-400 (3.50 × 10−2 at T = 323.15 K) and lowest in neat water (4.13 × 10−6 at T = 298.15 K) over the entire temperature range investigated. Thermodynamic studies on solubility of TNX indicated an endothermic, spontaneous and entropy driven dissolution behavior of TNX in all binary solvent systems investigated. The solubility experimental data of this research work could be useful in preformulation studies and formulation development of TNX. © 2015 Elsevier B.V. All rights reserved.

1. Introduction Tenoxicam (TNX, Fig. 1, molar mass: 337.37 g·mol−1, molecular formula: C13H11N3O4S2, IUPAC name: 4-hydroxy-2-methyl-N-2-pyridinyl2H-thieno (2, 3-e)-1, 2-thiazine-3-carboxamide-1, 1 dioxide) is a newly launched non-steroidal anti-inflammatory drug (NSAID) [1,2]. It belongs to oxicam class of NSAIDs and recommended in the treatment of various type of pains [3–5]. Its daily dose is relatively lower than other drugs in same class [2,3]. The solubility data of TNX in aqueous cosolvent mixtures at different temperatures are still scare. Its solubility in water is very low due to which it has been considered as practically insoluble drug [2]. In order to enhance solubilization of TNX in various pharmaceutical systems, some approaches such as cosolvency approach, rapidly disintegrating tablets, and solid dispersions have been developed in literature [3,6–10]. The solubility data of drugs in aqueous cosolvents mixtures or binary solvent mixtures are important in pharmaceutical and chemical industries [11–13]. Polyethylene glycol-400 (PEG-400) is reported to be miscible with water over the entire range of compositions and it had great power for solubilization of poorly aqueous soluble drugs [14]. Due to this fact, it has been investigated extensively in the development of liquid dosage forms [14,15]. Several studies proved the potential of PEG-400 in enhancing the solubility of various poorly water soluble drugs such as meloxicam, acetaminophen, indomethacin, tadalafil, isatin and silymarin [15–20]. These studies ⁎ Corresponding author at: Center of Excellence in Biotechnology Research, College of Science, King Saud University, Riyadh, Saudi Arabia. E-mail address: [email protected] (F. Shakeel).

http://dx.doi.org/10.1016/j.molliq.2015.10.057 0167-7322/© 2015 Elsevier B.V. All rights reserved.

demonstrate the importance of PEG-400 in formulation development of such drugs [15,20]. The solubilities and thermodynamics analysis of crystalline TNX in water and PEG-400 at different temperatures have been published very recently [2]. Thermodynamics of solubility of TNX in various (PEG-400 + water) binary solvent mixtures has not been reported in literature so far. Hence, in this study, the mole fraction solubilities of crystalline TNX in various (PEG-400 + water) binary solvent mixtures were measured at T = (298.15 to 323.15) K and p = 0.1 MPa by an isothermal method. From solubility data of TNX, various thermodynamic parameters were also determined in order to evaluate its dissolution behavior in various (PEG-400 + water) binary solvent mixtures. 2. Experimental 2.1. Materials TNX and PEG-400 [IUPAC name: polyoxyethylene glycol)] were procured from Sigma Aldrich (St. Louis, MO). The water used in this study was highly pure deionized water and obtained from Milli-Q water purification unit (Berlin, Germany). The other details about materials are listed in Table 1. 2.2. Determination of TNX solubility The solubility of crystalline TNX against mass fraction of PEG-400 (m = 0.0 to 1.0) in (PEG-400 + water) binary mixtures was determined at T = (298.15 to 323.15) K and pressure p = 0.1 MPa by an isothermal

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F. Shakeel et al. / Journal of Molecular Liquids 213 (2016) 221–227 Table 2 Experimental solubilities (xe) of TNX in various (PEG-400 + water) binary solvent mixtures at temperatures T = (298.15 to 323.15) K and pressure p = 0.1 MPaa. m

xe T = 298.15 K

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

−6

4.13 × 10 9.03 × 10−6 1.98 × 10−5 4.29 × 10−5 9.33 × 10−5 2.08 × 10−4 4.42 × 10−4 9.59 × 10−4 2.10 × 10−3 4.54 × 10−3 9.80 × 10−3

T = 303.15 K −6

5.10 × 10 1.15 × 10−5 2.51 × 10−5 5.46 × 10−5 1.21 × 10−4 2.64 × 10−4 5.74 × 10−4 1.28 × 10−3 2.84 × 10−3 6.16 × 10−3 1.34 × 10−2

T = 308.15 K −6

6.62 × 10 1.50 × 10−5 3.24 × 10−5 7.12 × 10−5 1.61 × 10−4 3.46 × 10−4 7.61 × 10−4 1.61 × 10−3 3.72 × 10−3 8.18 × 10−3 1.78 × 10−2

T = 313.15 K −6

8.49 × 10 1.89 × 10−5 4.09 × 10−5 9.13 × 10−5 2.04 × 10−4 4.42 × 10−4 9.72 × 10−4 2.22 × 10−3 4.73 × 10−3 1.09 × 10−2 2.28 × 10−2

T = 323.15 K 1.40 × 10−5 2.99 × 10−5 6.55 × 10−5 1.50 × 10−4 3.25 × 10−4 7.04 × 10−4 1.56 × 10−3 3.37 × 10−3 7.37 × 10−3 1.64 × 10−2 3.50 × 10−2

a The standard uncertainties u are u(T) = 0.12 K, ur(m) = 0.1%, u(p) = 0.003 MPa and ur(xe) = 1.2%; the symbol m refers to the mass fraction of PEG-400.

Fig. 1. Chemical structure of tenoxicam (TNX).

method [21]. Approximately 700 mg of solid TNX was added in 3 g of each binary solvent mixture in air tight glass vials. The experiments were performed in triplicates. The glass vials containing concentrated suspension of TNX were transferred to biological shaker (Julabo, PA) at 100 rpm speed for 48 h [2,3]. In order to optimize saturation time, preliminary studies were performed at 24, 48, 72 and 96 h and solubility of TNX was measured. It was observed that negligible changes were observed in solubility of TNX after 48 h, hence 48 h saturation time was selected in this work. After 48 h, the samples were removed from the shaker and allowed to settle TNX solid particles for the period of 2 h [11,12]. Appropriate amount of supernatants were taken from each glass vial, centrifuged, diluted and subjected for analysis of TNX content spectrophotometrically at 360 nm [2,9]. Experimental solubilities of TNX in mole fraction (xe) were calculated using standard formula reported in literature [12,13]. 3. Results and discussion 3.1. Solubility data of TNX with respect to its literature values The xe values of TNX in various (PEG-400 + water) binary solvent mixtures at different temperatures and atmospheric pressure are presented in Table 2. The solubilities of TNX in these solvent systems at different temperature have not been reported in literature. However, the xe values of TNX in neat water and neat PEG-400 at T = (298.15 to 323.15) K and atmospheric pressure have been reported in literature [2]. The mole fraction solubility of TNX in neat water and neat PEG400 at T = 298.15 K has been reported as 4.11 × 10− 6 and 9.76 × 10−3, respectively [2]. In this study, the mole fraction solubility of TNX in neat water and neat PEG-400 at T = 298.15 K was recorded as 4.13 × 10−6 and 9.80 × 10−4, respectively. The graphical correlation between xe values and literature values of TNX in water and PEG-400 at T = (298.15 to 323.15) K is also presented in Fig. 2A–B. The results Table 1 The sample table for materials used in the experiment. Materials

Mass fraction purity

Purification method

Analysis method

Source

TNX PEG-400 Water

N0.990 0.999 1.000

None None None

HPLC GC Conductivity b 1 μS·cm−1

Sigma Aldrich Sigma Aldrich Milli-Q purification unit

High performance liquid chromatography (HPLC); gas chromatography (GC); tenoxicam (TNX); polyethylene glycol-400 (PEG-400).

presented in Fig. 2A–B showed good correlation between xe and literature values of TNX in both solvents over the entire temperature range. These results showed good agreement of xe values of TNX with its literature values. Generally, the xe values of TNX were found to be increasing with the rise in temperature and mass fraction of PEG-400 in all binary solvent mixtures investigated. The highest and lowest values of xe were recorded in neat PEG-400 (3.50 × 10−2 at T = 323.15 K) and neat water (4.13 × 10−6 at T = 298.15 K), respectively over the entire temperature range investigated. The highest xe values of TNX in neat PEG-400 were possible due to lower polarity of PEG-400 as compared to higher polarity of water [17,18]. The influence of mass fraction of solvent 1 i.e. PEG400 on xe values of TNX at T = (298.15 to 323.15) K was also evaluated and results are presented in Fig. 3. The xe values of TNX were found to be increasing linearly with increase in mass fraction of PEG-400 in (PEG400 + water) binary solvent mixtures over the entire temperature range. Based on the results obtained from this study, TNX is proposed as slightly soluble in neat PEG-400 and poorly soluble (practically insoluble) in neat water [2].

3.2. Correlation of xe values of TNX with calculated ones The xe values of TNX were correlated and compared with the solubilities calculated by Van't Hoff, the modified Apelblat and Yalkowsky– Roseman models [22–25]. Van't Hoff model solubility (xVan't) of TNX in various (PEG-400 + water) binary solvent mixtures can be calculated using Eq. (1) [22]:

0

ln xVan t ¼ a þ

b T

ð1Þ

In which, the coefficients a and b are the Van't Hoff model parameters which were calculated by plotting ln xe against 1/T. The xe values of TNX were correlated with xVan't values of TNX in terms of root mean square deviations (RMSD) and correlation coefficients. The RMSD values between xe and xVan't were calculated using standard formula of RMSD reported in our previous research [19,20]. The model fitting and graphical correlation between xe and xVan't in all binary solvent mixtures are shown in Fig. 4A. The results of this correlation in all binary solvent mixtures are presented in Table 3. The RMSD values in all investigated binary solvent mixtures were obtained as (0.60 to 3.06) %. However, the values of R2 were obtained as 0.9952 to 0.9998. The results of this correlation indicated good correlation of xe values with Van't Hoff model.

F. Shakeel et al. / Journal of Molecular Liquids 213 (2016) 221–227

223

Fig. 2. Comparison of experimental solubilities of TNX in (A) water and (B) PEG-400 with literature values at T = (298.15 to 323.15) K; symbol represents the experimental solubilities of TNX and solid line represents the literature values of TNX taken from reference [2].

The modified Apelblat solubility (xApl) of TNX in several binary solvent mixtures can be calculated using Eq. (2) [23,24]: lnxApl ¼ A þ

B þ C ln ðT Þ T

ð2Þ

In which, T is the absolute temperature (K) and the coefficients A, B and C are the model parameters of Eq. (2). These parameters were

calculated by nonlinear multivariate regression analysis [19]. For correlation of xe with xApl, RMSD values were calculated again by using its standard formula [19,20]. The model fitting and graphical correlation between xe and xApl in several binary solvent mixtures are shown in Fig. 4B. The results of this correlation in various binary solvent mixtures are presented in Table 4. The RMSD values in all binary solvent mixtures were obtained as (0.54 to 2.23) %. However, the R2 values in all binary solvent mixtures

Fig. 3. Influence of mass fraction of PEG-400 (m) on ln xe values of TNX at different temperatures.

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F. Shakeel et al. / Journal of Molecular Liquids 213 (2016) 221–227

Table 3 The parameters (a and b) of Eq. (1) for TNX in various (PEG-400 + water) binary solvent mixtures. m

a

b

R2

RMSD (%)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

3.49 3.91 4.63 6.21 6.89 7.36 8.63 9.44 9.99 11.38 11.79

−4747.80 −4632.00 −4613.00 −4855.90 −4822.80 −4726.30 −4876.20 −4886.20 −4811.50 −4995.10 −4885.00

0.9978 0.9998 0.9996 0.9994 0.9995 0.9996 0.9997 0.9967 0.9980 0.9952 0.9961

1.98 0.60 0.74 1.05 0.97 0.78 0.72 2.48 1.89 3.06 2.75

0

1 ∂ ln xe

Δ H @
A ¼ − sol R ∂ 1 =T −1 =T hm

0

ð4Þ

P

The Thm value was 308.91 K in this study. For the measurement of ΔsolH0 values for TNX dissolution, its ln xe values were plotted against   of 1 T  1 T (Fig. 5). These plots in all binary solvent mixtures were hm

The symbol m refers to the mass fraction of PEG-400.

were obtained as 0.9975 to 0.9998. The results of this correlation again indicated good correlation of xe values with the modified Apelblat model. The logarithmic Yalkowsky–Roseman model solubility of TNX (logxYal ) in various binary solvent mixtures was calculated using Eq. (3) [25]: logxYal ¼ m1 logx1 þ m2 logx2

energy (ΔsolG0) and standard entropy (ΔsolS0). The ΔsolH0 values of TNX in binary solvent mixtures were measured at mean harmonic temperature (Thm) by Van't Hoff analysis using Eq. (4) [26,27]:

ð3Þ

In which, x1 and x2 are the mole fraction solubilities of TNX in neat solvent 1 (PEG-400) and neat solvent 2 (water), respectively; and m1 and m2 are the mass fractions of PEG-400 and water in the absence of TNX, respectively. The results of Yalkowsky–Roseman model correlation are presented in Table 5. The RMSD values in all binary solvent mixtures were obtained as (0.97 to 2.36) %. These results again showed good correlation of xe values of TNX with Yalkowsky–Roseman model. 3.3. Thermodynamic parameters for TNX dissolution Thermodynamic analysis was carried out to investigate the dissolution behavior TNX in various (PEG-400 + water) binary solvent mixtures via calculation of standard enthalpy (ΔsolH0), standard Gibbs

found to be linear with R2 values in the range of 0.9951 to 0.9998. The ΔsolG0 values of TNX in binary solvent mixtures were also calculated at Thm by Krug et al. analysis using the standard formula [28]. Finally, the ΔsolS0 values of TNX in binary solvent mixtures were measured by using the combined approach of Van't Hoff and Krug et al. analysis using its standard formula [26–28]. The results of thermodynamic analysis for TNX dissolution in all binary solvent mixtures are presented in Table 6. Results presented in Table 6 indicated that the Δsol H0 values for TNX dissolution in all binary solvent mixtures were positive values in the range of (38.3 to 41.5) kJ·mol− 1 . The mean value of Δ sol H 0 for TNX dissolution was observed as 39.9 ± 1.0 kJ·mol − 1 with RSD of 2.4%. The Δsol H0 values among different binary solvent mixtures were not significantly different. This observation was probably due to the fact that the slopes of Van't Hoff plots were not variable significantly among different (PEG-400 + water) binary solvent mixtures. The ΔsolG0 values for TNX dissolution in all binary solvent mixtures were also observed as positive values in the range of (10.3 to 30.4) kJ·mol− 1. The highest and lowest values of ΔsolG0 were observed in neat water (30.4 kJ·mol − 1 ) and neat PEG-400 (10.3 kJ·mol − 1 ), respectively as shown in Table 6. The positive values of ΔsolH0 and ΔsolG0 for TNX dissolution in all binary solvent mixtures indicated an endothermic and spontaneous dissolution of TNX in these binary solvent mixtures. The ΔsolS0 values for TNX dissolution in all binary solvent mixtures were also recorded as positive values in the range of (29.1 to 98.1) J·mol − 1 . K − 1 , indicating

Fig. 4. Model fitting and correlation of experimental solubilities (ln xe) of TNX with (A) ideal model and (B) Apelblat model in various (PEG-400 + water) binary solvent mixtures at T = (298.15 to 323.15) K (solid lines represent ideal model or Apelblat model solubilities and symbol represents experimental solubilities).

F. Shakeel et al. / Journal of Molecular Liquids 213 (2016) 221–227

225

Fig. 5. Van't Hoff plots for TNX in various (PEG-400 + water) binary solvent mixtures at T = (298.15 to 323.15) K.

Fig. 6. ΔsolH0 vs. ΔsolG0 enthalpy-entropy compensation curve for solubility of TNX in various (PEG-400 + water) binary solvent mixtures at mean harmonic temperature of 308.91 K.

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Table 4 The parameters (A, B and C) of Eq. (2) for TNX in various (PEG-400 + water) binary solvent mixtures. m

A

B

C

R2

RMSD (%)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

−281.63 −14.45 −110.64 −157.63 92.75 −23.95 59.91 184.84 279.74 474.07 424.30

8394.82 −3788.51 698.29 2694.95 −8784.98 −3285.96 −7244.37 −12,976.70 −17,252.20 −26,331.80 −23,908.10

42.31 2.72 17.10 24.31 −12.73 4.64 −7.60 −26.02 −40.02 −68.65 −61.20

0.9994 0.9998 0.9998 0.9998 0.9997 0.9996 0.9998 0.9975 0.9996 0.9996 0.9997

0.95 0.63 0.62 0.54 0.78 0.76 0.63 2.23 0.67 1.39 0.65

solubilities of crystalline TNX were found to be increasing with increase in temperature and mass fraction of PEG-400 in binary solvent mixtures. The experimental solubility data of TNX were correlated well with Van't Hoff, the modified Apelblat and Yalkowsky–Roseman models based on RMSD and R2 values. The xe value of TNX was recorded highest in neat PEG-400 and lowest in neat water over the entire temperature investigated. Thermodynamic analysis indicated an endothermic, spontaneous and entropy driven dissolution of TNX in all binary solvent mixtures investigated. Based on the results obtained from this study, TNX is proposed as slightly soluble in neat PEG-400 and poorly soluble (practically insoluble) in neat water. Conflict of interest

The symbol m refers to the mass fraction of PEG-400.

The authors report no conflict of interest. Acknowledgments an entropy-driven dissolution of TNX in all binary solvent mixtures investigated. 3.4. Enthalpy-entropy compensation analysis of TNX solution This analysis was carried out to investigate the mechanisms of cosolvent action [11,26]. The weighted plots of ΔsolH° vs. ΔsolG° at Thm are helpful in evaluation of such an analysis [11]. The results of solvation behavior of TNX in various (PEG-400 + water) binary solvent mixtures are presented in Fig. 6. From Fig. 6, it was observed that TNX in all (PEG400 + water) binary solvent system shows nonlinear ΔsolH° vs. ΔsolG° curve with positive slope value of less than unity. Hence, the driving mechanism for solvation of TNX was proposed as an enthalpy-driven in all (PEG-400 + water) binary solvent mixtures. This observation was probably due to better solvation of TNX in PEG-400 molecules as reported in literature [11,16]. 4. Conclusion The solubilities of an anti-inflammatory drug TNX in various (PEG400 + water) binary solvent mixtures were measured at different temperatures and atmospheric pressure using an isothermal method. The

The project was financially supported by King Saud University, Vice Deanship of Research Chairs, Kayyali Chair for Pharmaceutical Industry (Grant no. FN-2015). References [1] W.E. Acree Jr., J. Phys. Chem. Ref. Data 43 (2014), E023102. [2] F. Shakeel, N. Haq, G.A. Shazly, F.K. Alanazi, I.A. Alsarra, J. Chem, Eng. Data 59 (2014) 2510–2514. [3] M.K. Yeh, L.C. Chang, H.J. Chiou, AAPS Pharm. Sci. Tech. 10 (2009) 166–171. [4] H.W. Hsu, Y.J. Cheng, L.K. Chen, Y.P. Wang, C.J. Lin, C.N. Lee, W.Z. Sun, Clin. J. Pain. 19 (2003) 55–58. [5] H.S. Gwak, I.K. Chun, Int. J. Pharm. 236 (2002) 57–64. [6] O.S. Park, I.K. Chun, Dongduk Pharm. Res. 5 (2001) 15–26. [7] J.R. Patel, R.A. Carlton, F. Yuniatine, T.E. Needham, L. Wu, F.G. Vogt, J. Pharm. Sci. 101 (2012) 641–663. [8] K.V.R.N.S. Ramesh, S. Usman, O. Sarheed, F. Shah, T. Parveen, B.V.K. Rao, M.V. Kumar, Indones. Am. J. Pharm. Res. 4 (2014) 4074–4084. [9] A. Saritha, N. Shastri, J. Pharm. Sci. Technol. 2 (2010) 308–311. [10] M.K. Darwish, M.M. Foad, Drug Dis. Ther. 3 (2009) 27–36. [11] F. Shakeel, M.M. Salem-Bekhit, M. Iqbal, N. Haq, J. Chem. Thermodyn. 89 (2015) 159–163. [12] F. Shakeel, N. Haq, N.A. Siddiqui, F.K. Alanazi, I.A. Alsarra, J. Chem. Thermodyn. 85 (2015) 57–60. [13] F. Shakeel, F.K. Alanazi, I.A. Alsarra, N. Haq, J. Mol. Liq. 191 (2014) 68–72.

Table 5 Logarithmic solubilities of TNX (Log xYal) calculated by Yalkowsky model in various (PEG-400 + water) binary solvent mixtures at T = (298.15 to 323.15) K. Log xYal

m

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

T = 298.15 K

T = 303.15 K

T = 308.15 K

T = 313.15 K

T = 323.15 K

−5.04 −4.70 −4.37 −4.03 −3.69 −3.35 −3.02 −2.68 −2.34

−4.95 −4.60 −4.26 −3.92 −3.58 −3.23 −2.89 −2.55 −2.21

−4.83 −4.49 −4.15 −3.80 −3.46 −3.12 −2.77 −2.43 −2.09

−4.72 −4.38 −4.04 −3.69 −3.35 −3.01 −2.67 −2.32 −1.98

−4.51 −4.17 −3.83 −3.49 −3.15 −2.81 −2.47 −2.13 −1.79

RMSD (%) 2.04 1.56 1.36 1.96 1.62 0.97 2.43 1.31 2.56

The symbol m refers to the mass fraction of PEG-400.

Table 6 Standard dissolution enthalpy (ΔsolH0), standard dissolution entropy (ΔsolS0), standard Gibbs energy (ΔsolG0) and R2 values for TNX dissolution in various (PEG-400 + water) binary solvent mixturesa. Parameters 0

−1

ΔsolH /kJ·mol ΔsolG0/kJ·mol−1 ΔsolS0/J·mol−1·K−1 R2 a

m = 0.0

m = 0.1

m = 0.2

m = 0.3

m = 0.4

m = 0.5

m = 0.6

m = 0.7

m = 0.8

m = 0.9

m = 1.0

39.4 30.4 29.1 0.9978

38.5 28.4 32.6 0.9998

38.3 26.4 38.4 0.9997

40.3 24.4 51.7 0.9994

40.1 22.3 57.4 0.9995

39.3 20.3 61.3 0.9996

40.5 18.3 71.8 0.9997

40.6 16.3 78.6 0.9967

40.0 14.3 83.1 0.9980

41.5 12.2 94.7 0.9951

40.6 10.3 98.1 0.9960

The average uncertainties are u(ΔsolH0) = 0.18 kJ·mol−1, u(ΔsolG0) = 0.15 kJ·mol−1 and u(ΔsolS0) = 0.21 J·mol−1 K−1; the symbol m refers to the mass fraction of PEG-400.

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