Solubility and dissolution thermodynamic properties of Mequindox in binary solvent mixtures

Journal Pre-proof Solubility and dissolution thermodynamic Mequindox in binary solvent mixtures

properties

of

Shiqi Chen, Quanjin Liu, Haibo Dou, Li Zhang, Linlin Pei, Rouyue Huang, Gang Shu, Zhixiang Yuan, Juchun Lin, Wei Zhang, Guangneng Peng, Zhijun Zhong, Lizi Yin, Ling Zhao, Hualin Fu PII:

S0167-7322(19)35640-5

DOI:

https://doi.org/10.1016/j.molliq.2020.112619

Reference:

MOLLIQ 112619

To appear in:

Journal of Molecular Liquids

Received date:

11 October 2019

Revised date:

3 January 2020

Accepted date:

30 January 2020

Please cite this article as: S. Chen, Q. Liu, H. Dou, et al., Solubility and dissolution thermodynamic properties of Mequindox in binary solvent mixtures, Journal of Molecular Liquids(2018), https://doi.org/10.1016/j.molliq.2020.112619

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© 2018 Published by Elsevier.

Journal Pre-proof

Solubility and dissolution thermodynamic properties of Mequindox binary solvent mixtures Shiqi Chen1,+, Quanjin Liu1,+, Haibo Dou1,+, Li Zhang1, Linlin Pei1, Rouyue Huang1, Gang Shu1, Zhixiang Yuan1, Juchun Lin1, Wei Zhang1, Guangneng Peng1, Zhijun Zhong1, Lizi Yin1, Ling Zhao1, Hualin Fu1*

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1 Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural

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University, Chengdu, Sichuan 611130, People’s Republic of China

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Abstract:The solubility of Mequindox(MEQ) in two kinds of binary mixtures(acetone+isopropanol; N-propanol+N-butanol) with different ratio was determined by shake flask method through UV/Vis spectrophotometer over the temperature from 293.15 to 323.15K at atmospheric pressure(p=0.1 MPa). The results showed that the solubility of mequindox in binary solvent mixtures was increased with temperature raised in the investigated temperature range. In the binary-solvent of acetone and isopropanol, the data was increased as the mole fraction of acetone increased. However, the solubility of MEQ was not significantly changed in the mixed solvents of N-propanol and N-butanol with different ratio. Furthermore, thermodynamic models including the modified Apelblat equation, λh equation, GSM equation and the Jouyban-Acree model were used to correlate the experimental data. In addition, thermodynamic properties, enthalpy (△H0sol), entropy (△S0sol) and Gibbs free energy (△G0sol), were calculated and analyzed in the dissolution process. This study provides a certain theoretical basis for the isolation purification and pharmaceutical formulation design of MEQ. Keywords：Mequindox;Solubility;Modeling;Dissolution thermodynamic

+

These authors contributed equally to this work. Corresponding author E-mail addresses: [email protected] *

Journal Pre-proof

1. Introduction Solubility data is not only the basic parameter of drug crystallization and purification, but also an important factor affecting drug absorption. Once a new drug was synthesized, most studies was focused on pharmacodynamics and pharmacology, physicochemical properties including solubility were delayed and even ignored. Based on the solubility to design the pharmaceutical formulation of drugs is the most elemental works for Pharmaceutics. IUPAC

name:

3-methyl-2-acetylquinoxaline-1,4-dioxide

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Mequindox[Fig.1;

(MEQ);molecular formula: C11H10N2O3;molar mass: 218.21g•mol-1], as a yellow

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needle or crystal. is dissolved in acetone, chloroform and benzene, but slightly in

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water, methanol, ether and petroleum ether[1]. Mequindox has been widely used for animal breeding in China as antibacterial and growth-promoting agent[2]. However,

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its application was limited due to its poor water solubility and fast metabolism[3].

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Solubility, as an important parameter in the formulation optimization of MEQ oral solution and injection, provides essential information for the selection of solvent

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system and the optimization of dosage form to increasing bio-availability[4]. There are not systematical experimental or theoretical researches about solubility of MEQ

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until now. Thus, it was necessary to investigated MEQ dissolution behaviour in different solvents and temperatures, and screened the best model to accurately reflected the process[5]. Furthermore, solvent mixing is a simple, feasible and effective method for solubilization in Pharmaceutics[6]. Therefore, accurate and reliable predicting the solubility of MEQ in different mixed solvents is helpful for designing and optimizing its pharmaceutical dosage forms to enhance absorption and bioavailability[7]. In this article, the solubility of Mequindox(MEQ) in two kinds of binary mixtures(acetone+isopropanol;

N-propanol+N-butanol)with different

ratio was

determined by shake flask method over the temperature from 293.15 to 323.15 K under atmospheric pressure (p=0.1 MPa)[8]. The temperature range is commonly used for the water baths in pharmacy industry. The data was correlated by the

Journal Pre-proof modified Apelblat equation, λh equation, GSM equation and the Jouyban-Acree model[9]. Furthermore, the thermodynamic properties in dissolution, such as the change of enthalpy (△H0sol), entropy (△S0sol) and Gibbs free energy(△G0sol), were calculated[10].

2. Experimental 2.1. Materials Mequindox

(IUPAC

name:3-methyl-2-acetylquinoxaline-1,4-dioxide)

was

of

purchased from Huana Chemicals Co., Ltd (China) with mass fraction ≥0.995, confirmed by the High Performance Liquid Chromatography (HPLC). Detailed

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information about solvents including the sources and purity were listed in Table 1.

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2.2.The selection of solvents

Selecting appropriate solvents, including types and proportions, can increase the

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solubility for optimization of dosage form and recrystallization. It was deduced that

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the relatively low polarity solvents could provide the better solution conditions from the chemical structure of MEQ[11]. It has not been reported the solubility data in the

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binary solvents that used in this article. It is very meaningful to screen the ratio of mixed solvent systems for purification and preparation.

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2.3. Solubility measurement

Dissolution is the balance between multi- and single molecular form of solute. The supersaturation was inevitable and unignored in the process. The dynamic method, one of common used means, could obtained the solubility by laser detector. It is simple and intuitive to observed the transformation of solute, but difficulty to defined the key point of solid-liquid equilibrium, especially in smooth container. Solubility is the mass of the solute when get saturation in a certain amount of solvent at a definite temperature and pressure. The balance method, a traditional and typical ways, is not focus on the whole process of transformation but the equilibrium point. Therefore this approach completely conformed the demands for solubility measurement.

Journal Pre-proof In this paper, the solubility of MEQ was determined by gravimetric analysis in a binary solvent mixture[12]. The process can be simplified description:excess MEQ was added to mixture solvent with a certain amount, and the 150mL Erlenmeyer flask with a glass stopper to prevent solvent evaporation[13]. These Erlenmeyer flasks were placed in a thermostatic mechanical shaker (HZS-H Water Bath Oscillator, China) at the desired temperature. According to preliminary experiments, the mixture needs to be shaken for 5 hours with 160 rpm to achieve solid-liquid equilibrium. Then, the suspension was kept staticfor at least 3 hours to precipitate undissolved material.

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After that, the supernatant (1mL) was withdrawn by a preheated syringe and filtered

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through a microporous membrane (PTFE 0.22 μm) into a pre-weighed and preheated volumetric flask (50 mL). The bottle containing the filtrate was quickly covered and

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weighed. Finally, the samples were diluted appropriately with ethanol and tested by

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using UV/Vis spectrophotometry at a maximum absorption wavelength of λmax= 381

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nm. In order to obtain an accurate solubility, all experiments were repeated three times at each temperature to minimize experimental error and obtain the desired

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average. The saturated mole fraction (x) of MEQ in different mixed solvents could be obtained by the following Eq.(1)[14]. 𝑚1 ⁄𝑀1 ⁄ 𝑀 1 1 +∑(𝑚𝑖 ⁄𝑀𝑖 )

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x=𝑚

—— (1)

Where m1 and mi represent the mass of the solute and solvents, respectively. m1 was obtained by standard curve. M1 and Mi represent the molar mass of the solute and the solvents, respectively.

3. Solid-liquid phase equilibrium models In order to find an appropriate model to describe the solubility behavior for MEQ in different binary solvent mixtures and extend the use of the obtained solubility data. In the present work, four thermodynamic models, the modified Apelblat equation, λh equation, GSM equation and the Jouyban-Acree model were employed to correlate the MEQ solubility in different solvents[15]. 3.1. the modified Apelblat equation

Journal Pre-proof The modified Apelblat equation is a semi-empirical model that has been widely used to correlate the solubility of solutes in binary mixed solvents[16].The equation is shown as Eq. (2). 𝑎

lnx = 𝑇(𝐾) + 𝑏 + 𝑐𝑙𝑛(𝑇(𝐾)) —— (2) Where x represents the saturated mole fraction of MEQ; T is the absolute temperature; a,b and c are empirical parameters. 3.2. λh equation

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The λh equation was first introduced by Buchowski with two parameters, λ and h,

The equation is defined as Eq. (3). 𝜆(1−𝑥) 𝑥

1

1 ] 𝑚 (𝐾)

] = 𝜆ℎ [𝑇(𝐾) − 𝑇

—— (3)

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ln [1 +

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which have a good effect on the solubility of solutes in binary mixed solvents[17].

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Where x is the mole fraction solubility of MEQ in two binary solvent mixtures；λ and h are two adjustable parameters in λh equation；Tm is the melting temperature of

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MEQ in Kelvin. 3.3. GSM equation

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The general single model (GSM),a power series equation, was derived from CNIBS/R-K model and EFE model[18]. It is commonly used to demonstrate the

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connection between solubility and composition in binary solvent at same temperature especially in an enormous literature of pharmaceutics[19, 20]. The equation can be described as follows Eq. (4).

2

3

4

lnx = a + b𝑥𝑗0 + c(𝑥𝑗0 ) + d(𝑥𝑗0 ) + e(𝑥𝑗0 ) —— (4)

Where x0j is the initial mole fraction of solvent in the absence of solutes (acetone in acetone+isopropanol; N-propanol in N-propanol+ N-butanol). a, b, c, d and e are the parameters of the model. 3.4. Jouyban-Acree model The Jouyban-Acree model also considers the effect of temperature on the solubility of solutes in the binary solvent mixture. The equation is shown as Eq. (5)[21].

Journal Pre-proof 𝑖

lnx 𝑇 = 𝑥𝑗0 𝑙𝑛(𝑥𝑗 ) 𝑇 + 𝑥𝑖0 𝑙𝑛(𝑥𝑖 ) 𝑇 + 𝑥𝑗0 𝑥𝑖0 ∑𝑛𝑖=0 𝐽𝑖 (𝑥𝑗0 − 𝑥𝑖0 ) ⁄𝑇(𝐾) —— (5) where xT is the mole fraction solubility of MEQ at experimental temperature in solvent mixture, (xj)T and (xi)T are the mole fraction solubility of solute in pure solvent (j or i) of mixture composition at T, x0j and x0i is the initial mole fraction of solvent in the absence of solutes (eg: the initial mole fraction of acetone and isopropanol in acetone+isopropanol, respectively) and Ji is the model constant. In order to simplify the Jouyban-Acree model, the (Xj)T and (Xi)T can be replaced

of

through combined Van't Hoff Eq. (6). When n=2, a new equation (7) which called Van’t-JA model can be obtained. 𝑎

+𝑏𝑗 ⁄𝑇(𝐾)) +

𝑥𝑖0 (𝑎𝑖

+𝑏𝑖 ⁄𝑇(𝐾)) +

2

𝑥𝑗0 𝑥𝑖0 [𝐽0 +𝐽1 (𝑥𝑗0 −𝑥𝑖0 )+𝐽(𝑥𝑗0 −𝑥𝑖0 ) ]

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lnx =

𝑥𝑗0 (𝑎𝑗

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lnx = 𝑇(𝐾) + 𝑏 —— (6)

𝑇(𝐾)

——(7)

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Introducing constant parameters (V0 to V6) to Eq. (7), it can be further simplified

𝑉1

𝑉2 𝑥𝑗0

+

2

3

4

[𝑉3 𝑥𝑗0 +𝑉4 (𝑥𝑗0 ) +𝑉5 (𝑥𝑗0 ) +𝑉6 (𝑥𝑗0 ) ] 𝑇(𝐾)

—— (8)

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lnx = 𝑉0 + 𝑇(𝐾) +

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as Eq. (8).

3.5. Evaluation of thermodynamic models

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In order to evaluate the applicability of the tested models, the average relative deviation (ARD) and the root mean square deviations (RMSD) were calculated. The equation is shown as Eq. (9) (10)[22]. 1

ARD = 𝑁 ∑𝑁 𝑖=1 |

𝑥 𝑒𝑥𝑝 −𝑥 𝑐𝑎𝑙 𝑥 𝑒𝑥𝑝

𝑒𝑥𝑝 −𝑥 𝑐𝑎𝑙 ) ∑𝑁 𝑖=1(𝑥

RMSD = √

𝑁

|—— (9)

2

—— (10)

Where N refers the number of experimental data points, xexp and xcal denote the experimental data and model predicted data, respectively.

4. Results and discussion 4.1 Solubility of MEQ The decomposition product of solute also is a noteworthy factor which could affect the accurate measurement. On the one hand, it has not been detected by HPLC

Journal Pre-proof in the supernatant through preliminary experiment, on the other hand the decomposition only occurs at the melt point as previous reported, so it can be ignored in the process. Then, the condition for solubility equilibrium was obtained, which include kept shaking for 5 hours with 160 rpm and standing for 3 hours. The mole fraction solubility data of MEQ in binary solvent mixtures of acetone+isopropanol, N-propanol+N-butanol from 293.15 K to 323.15 K are listed in Table 2–3 and graphically plotted in Figs. 2-3. The solubility of MEQ depends on both temperature and solvent composition. It can be seen that the solubility of MEQ

of

increased along with temperature in both investigated binary solvent mixtures. In the

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mixture of acetone and isopropanol, the data was increased as the mole fraction of acetone increases.However, the solubility of MEQ is not significantly different in the

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mixed solvents of N-propanol and N-butanol. As is known to all, dissolution include

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digestion and spread from multimolecular form, as well as the interaction with solvent. The polarity is the essential interaction between solvent and solute, and the

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experimental data almost matched the “like dissolves like” rule. Therefore, it can be

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conclude that the polarity is the main driven force for MEQ dissolution, and the polarity span between the composition in binary solvent could be responsible for

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different behaviour in dissolution process. Moreover, the dielectric constant is positive correlated with polarity of the solvent and raised with temperature in general.The change patterns of solubility data was conforming preferably with the trend of dielectric constant under a series of temperature in a same solvent, which can explain the relationship between solubility, temperature and polarity. It was necessary to investigate the solubility of MEQ in N-propanol and N-butanol, and reduce poisoning accidents during the recrystallization and pharmaceutical processes. The polarity of N-propanol and N-butanol is similar[23], but Gerald L. Kennedy reported the acute toxicity of N-propanol was higher than N-butanol in the rat following either oral or inhalation exposure[24]. The same result has been found by Walter S. Eisenmenger through compared the elongation of soy-bean roots in different alcoholic solutions[25]. These results can be used to guide the prescription design and optimization of crystallization.

Journal Pre-proof To extend the applicability of experimental solubility data, the solubility of MEQ is related to several thermodynamic models in this study[26]. As Tables 2-3 shown, the 103ARD and 103RMSD values of the modified Apelblat equation, λh equation, GSM equation and the Van’t-JA model were calculated respectively. This result showed that the GSM equation was the best that compared with the others models by using the ARD and RMSD values as appraisal standard. Based systematical observation, prediction the change of parameters by mathematical models is the commonly used method in both humane and natural subjects. There is common

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ground between this models but each have a slightly different slant to it. The modified

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Apelblat equation and λh equation is focus on the effect of temperature change on solubility at a constant solvent composition. The solubility variation from temperature

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and solvent composition is comprehensively described by Van’t-JA model. However,

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The GSM model pays more attention to the effect by the ratio ingredient in mixture

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solvent at the same temperature. The calculated data by GSM exhibited more accurate prediction also revealed the fact that polarity is the principal influence factor for MEQ

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dissolution.

4.2 Apparent thermodynamics functions of dissolution

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Apparent thermodynamic analysis is widely used to evaluation the dissolution behavior of solute[27]. The molar dissolution thermodynamic properties of MEQ were calculated and analyzed based on the experimental solubility data. Because of the lack of activity coefficients, the standard molar enthalpy ( H d ) and standard molar entropy ( Sd ) could be calculated by the well-known van’t Hoff equation[28]. The equation is shown as Eq. (11-13). [

∂lnx

]=−

0 ∆𝐻𝑠𝑜𝑙

1 1 ) 𝑇 𝑇ℎ𝑚

𝜕( −

𝑅

—— (11)

0 ∆G𝑠𝑜𝑙 = −𝑅𝑇ℎ𝑚 ∙ 𝑖𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡 —— (12) 0 ∆S𝑠𝑜𝑙 =

∆H0𝑠𝑜𝑙 −∆G0𝑠𝑜𝑙 𝑇ℎ𝑚

—— (13)

Journal Pre-proof Where x is the mole fraction of solute in saturated solution, R represents the gas constant (8.314 J·mol-1·K-1). Where Thm represents the mean harmonic temperature of the temperature range. The equation is shown as Eq. (14)[29]. Tℎ𝑚 =

𝑛 1 ∑𝑛 𝑖=1T 𝑖

—— (14)

Where n is the number of experimental temperatures points. In this work, the value of Thm is 307.825 K. In addition, the following equation(15) is used to compare the relative

ξH = |∆H0

|∆H0𝑠𝑜𝑙 |

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contributions of enthalpy (ΔH0sol) and entropy (ΔS0sol) in the dissolving process[30]. |T∙∆S0𝑠𝑜𝑙 |

0 𝑠𝑜𝑙 |+|T∙∆S𝑠𝑜𝑙 |

—— (15)

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0 𝑠𝑜𝑙 |+|T∙∆S𝑠𝑜𝑙

; ξS = |∆H0 |

All the thermodynamic data(ΔH0sol ,ΔG0sol, ΔS0sol, ξH and ξS) results of MEQ are

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shown in Table.4-5 and illustrated in Fig. 4-5. According to the results in the Table.4-5,

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In acetone+isopropanol solvent, ΔG0sol decreased when acetone was increased, consistent with the solubility. This suggests lower ΔG0sol corresponding to the stronger

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interactions between MEQ and solvents leads to the higher solubility. It could also partly explained the solubility have remained essentially flat in N-propanol+

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N-butanol with the composition changed. Furthermore, all the values of ΔH0sol are positive, and all %ξH are ≥ 56.2%. So ΔH0sol was the main contributor to the standard

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molar Gibbs energy of solution during the dissolution. It was also explained the solubility increased with temperature increasing, and also enough to demonstrated that the process of MEQ in both binary mixed solvents is endothermic and spontaneous. Of course, the calculation above was simply considered the thermodynamic changes in idea condition, and it need to further studies on the actual changes.

5. Conclusions In this work, the solubility of MEQ in two binary mixtures (acetone+ isopropanol;

N-propanol+N-butanol)

with

different

ratio

was

determined

experimentally by using a static analytical method within the temperature range (293.15 to 323.15) K under atmospheric pressure (p=0.1 MPa). The results showed

Journal Pre-proof that the solubility data of MEQ in the studied binary solvent mixtures increased with the rising of temperature in the investigated temperature range.In the mixture of acetone and isopropanol, the solubility data of MEQ increases as the mole fraction of acetone increases. However, the solubility of MEQ is not significantly different between the mixed solvents of N-propanol and N-butanol. Furthermore, four thermodynamic models including the modified Apelblat equation, λh equation, GSM equation and the Jouyban-Acree model were used to correlate the experimental solubility data. The result showed that the GSM equation was the best that compared

of

with the others models by using the ARD and RMSD values as appraisal standard. In

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addition, the molar dissolution thermodynamic properties of MEQ including enthalpy,

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entropy and Gibbs free energy were calculated and analyzed based on the experimental solubility data. According to the results，indicating that the dissolution

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process of MEQ in both binary mixed solvents studied is endothermic and

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spontaneous. All the experimental data and thermodynamic studies will offer an

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Guo H-j, Dang X, Yang F, Cao D-l, Li Y-x, Hu W-h, et al. Solubility and thermodynamic properties of a kind of explosives in four binary solvents. Journal of Molecular Liquids. 2017;247:313-27 https://doi.org/10.1016/j.molliq.2017.09.097. Li J, Hao H, Guo N, Wang N, Hao Y, Luan Y, et al. Solubility and thermodynamic properties of

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https://doi.org/10.1016/j.molliq.2017.08.054. 23.

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maltol in different pure solvents. Journal of Molecular Liquids. 2017;243:313-23 Roy MC, Roy MN. Conductometric investigation of ion–solvent interactions of an ionic liquid

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{[emim] CH3SO3} in pure n-alkanols. Journal of Molecular Liquids. 2014;195:87-91. Kennedy GL, Jay Graepel G. Acute toxicity in the rat following either oral or inhalation Eisenmenger WS. Toxicity of Some Aliphatic Alcohols. Plant Physiology.5(1):131-56 https://doi.org/10.1104/pp.5.1.131.

Chen G, Chen J, Cheng C, Cong Y, Du C, Zhao H. Solubility determination and thermodynamic

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26.

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exposure. Toxicology Letters.56(3):317-26 https://doi.org/10.1016/0378-4274(91)90160-8. 25.

modelling of 2-amino-5-methylthiazole in eleven organic solvents from T = (278.15 to 313.15) K and mixing properties of solutions. Journal of Molecular Liquids. 2017;232:226-35 27.

na

https://doi.org/10.1016/j.molliq.2017.02.084. Mercado KC, Rodríguez GA, Delgado DR, Martínez F, Romdhani A. Solution thermodynamics

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of methocarbamol in some ethanol+ water mixtures. Química Nova. 2012;35(10):1967-72. Yang Y, Cao Y, Hu Y, Zhang Q, Yang W, Shen F. Thermodynamic analysis and correlation of solid–liquid equilibrium of hyodeoxycholic acid in ethanol+(acetone, ethyl acetate) binary solvent

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Kumar N, Mandal A. Thermodynamic and physicochemical properties evaluation for formation and characterization of oil-in-water nanoemulsion. Journal of Molecular Liquids. 2018;266:147-59 https://doi.org/10.1016/j.molliq.2018.06.069.

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Lou Y, Wang Y, Li Y, He M, Su N, Xu R, et al. Thermodynamic equilibrium and cosolvency of florfenicol in binary solvent system. Journal of Molecular Liquids. 2018;251:83-91 https://doi.org/10.1016/j.molliq.2017.12.046.

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Cui Y, Xu S, Wu S, Du S, Cao Y, Chen Y, et al. Temperature and solvent dependent thermodynamic behavior of tetrabromobisphenol A. Journal of Molecular Liquids. 2017;241:150-62 https://doi.org/10.1016/j.molliq.2017.05.118.

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Author statement: Shiqi Chen：Methodology, Data Curation, Writing-Original draft preparation. Quanjin Liu: Conceptualization, Investigation, Formal analysis. Haibo Dou: Visualization, Validation. Li Zhang: Visualization. Linlin Pei: Validation. Rouyue Huang: Visualization. Gang Shu: Supervision. Zhixiang Yuan: Software. Juchun Lin: Supervision. Wei Zhang: Software. Guangneng Peng: Writing-Reviewing & Editing. Zhijun Zhong: Writing-Review & Editing. Lizi Yin: Writing-Review & Editing. Ling Zhao: Writing-Review & Editing. Hualin Fu: Project administration, Funding acquisition,Writing-Reviewing & Edit ing.

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Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

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Fig. 1. Molecular structure of MEQ.

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Fig. 2. Mole fraction solubility lnx of MEQ at various temperatures T(K) and different mole fraction compositions of acetone x 0j in acetone+ isopropanol bi nary mixtures.

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Fig. 3. Mole fraction solubility lnx of MEQ at various temperatures T(K) and different mole fraction compositions of acetone x 0j in N-propanol and N-butan ol binary mixtures.

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Fig. 4. The Van't Hoff plots for MEQ between lnx and 1/T-1/Thm for MEQ in the mixed solvents of acetone and isopropanol.

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Fig. 5. The Van't Hoff plots for MEQ between lnx and 1/T-1/Thm for MEQ in the mixed solvents of n-propyl alcohol+ n-butyl alcohol.

Journal Pre-proof Tables. 1 The provenance and mass fraction purity of MEQ and solvents. Compound

Source

mequindox acetone isopropanol n-propyl alcohol n-butyl alcohol

Huana Chron Chron Chron Chron

Chemicals Chemicals Chemicals Chemicals Chemicals

Co.,Ltd Co.,Ltd Co.,Ltd Co.,Ltd Co.,Ltd

Mass fraction purity

CAS no.

≥0.995 ≥0.997 ≥0.997 ≥0.997 ≥0.997

13297-17-1 67-64-1 67-63-0 71-23-8 71-36-3

(China) (China) (China) (China) (China)

-p

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2.74 4.72 6.65 8.41 9.39 10.85 12.26 14.75 20.43

lP

re

2.81 4.77 6.72 8.52 9.56 11.07 12.57 15.15 20.91

na

3.16 4.79 6.56 8.20 9.59 10.86 12.40 15.00 20.41

3.42 4.59 5.98 7.51 9.18 11.02 13.12 15.77 19.52

3.16 4.79 6.56 8.20 9.59 10.86 12.40 15.00 20.41

3.96 6.31 8.78 10.29 12.19 14.29 16.37 19.86 26.09

3.83 6.10 8.47 10.69 12.2 14.23 16.32 19.66 26.41

3.79 6.08 8.44 10.65 12.13 14.12 16.16 19.46 26.19

4.48 6.00 7.79 9.78 11.93 14.3 17.03 20.44 25.27

4.02 6.30 8.56 10.54 12.27 14.07 16.38 19.94 26.06

5.24 7.99 10.95 13.57 15.51 18.27 21.15 25.66

5.18 7.77 10.63 13.37 15.52 18.21 21.10 25.40

5.17 7.78 10.64 13.38 15.54 18.23 21.12 25.42

5.81 7.77 10.06 12.61 15.37 18.41 21.90 26.27

5.21 8.07 10.91 13.45 15.73 18.13 21.17 25.67

Jo ur

T=293.15K 0.1031 0.2054 0.3071 0.4081 0.5084 0.6080 0.7070 0.8053 0.9030 T=298.15K 0.1031 0.2054 0.3071 0.4081 0.5084 0.6080 0.7070 0.8053 0.9030 T=303.15K 0.1031 0.2054 0.3071 0.4081 0.5084 0.6080 0.7070 0.8053

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Tables. 2 Mole fraction solubility of MEQ in different ratio acetone+isopropanol solvent over the temperature range from 293.15 K–323.15 K(p = 101.3 kpa).a,b,c 103xApel 103xλh 103xexp 103xVan’t-JA 103xGSM x0j

Journal Pre-proof 33.24

33.28

32.43

33.08

6.87 10.08 13.61 17.37 19.65 23.26 27.22 32.89 41.79

6.97 9.84 13.29 16.66 19.66 23.21 27.18 32.69 41.69

7.00 9.87 13.34 16.72 19.75 23.34 27.35 32.91 41.95

7.48 9.97 12.89 16.13 19.64 23.51 27.95 33.49 41.29

6.77 10.23 13.72 16.95 19.98 23.21 27.20 32.88 41.80

8.99 11.41 15.36 20.08 24.81 29.51 34.88 41.78 52.59

9.33 12.41 16.55 20.68 24.81 29.47 34.86 41.89 52.09

9.39 12.45 16.61 20.75 24.94 29.64 35.10 42.21 52.46

16.73 19.70 25.61 31.14 39.10 46.94 56.64 68.53 79.58

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9.55 12.69 16.38 20.47 24.90 29.78 35.38 42.37 52.16

8.86 11.63 15.40 19.90 24.72 29.68 34.95 41.65 52.63

12.44 15.60 20.54 25.58 31.20 37.28 44.53 53.48 64.87

12.47 15.61 20.57 25.62 31.27 37.38 44.68 53.68 65.09

12.10 16.04 20.66 25.78 31.33 37.45 44.46 53.20 65.41

12.19 16.07 20.73 25.94 31.49 37.44 44.17 52.82 65.91

16.49 19.52 25.42 31.54 39.10 46.98 56.67 68.02 80.51

16.44 19.47 25.35 31.47 38.97 46.81 56.42 67.67 80.16

15.21 20.13 25.87 32.24 39.14 46.75 55.47 66.33 81.46

16.43 20.36 25.27 31.29 38.55 47.20 57.11 68.06 79.70

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12.29 15.82 20.81 26.27 31.20 37.28 44.53 52.63 65.94

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33.08

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0.9030 T=308.15K 0.1031 0.2054 0.3071 0.4081 0.5084 0.6080 0.7070 0.8053 0.9030 T=313.15K 0.1031 0.2054 0.3071 0.4081 0.5084 0.6080 0.7070 0.8053 0.9030 T=318.15K 0.1031 0.2054 0.3071 0.4081 0.5084 0.6080 0.7070 0.8053 0.9030 T=323.15K 0.1031 0.2054 0.3071 0.4081 0.5084 0.6080 0.7070 0.8053 0.9030

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0.02 0.38

0.02 0.04 0.01 0.38 0.71 0.21 Apel λh Van’t-JA-JA GSM is the experimentally solubility;x , x , x and x denote the calc 3

a: xexp ulated mole fraction solubility by the modified Apelblat equation, λh equation, NRTL Model, the Jouyban-Acree model and GSM equation respectively. b: The relative standard deviation of the solubility measurement u(x) =0.001，u (T)=0.05K, u(P)=2KPa. c: ARD and RMSD are the average relative deviation and the root-mean-square deviations, respectively.

ro

2.58 2.80 2.86 2.80 2.69 2.57 2.49 2.48 2.56

2.70 2.75 2.72 2.66 2.61 2.57 2.55 2.53 2.49

3.21 3.41 3.47 3.44 3.28 3.20 3.11 3.13 3.18

3.20 3.41 3.47 3.43 3.28 3.19 3.11 3.12 3.18

3.32 3.39 3.36 3.30 3.24 3.20 3.18 3.17 3.12

3.20 3.43 3.48 3.41 3.30 3.19 3.12 3.11 3.18

3.94 4.15 4.20 4.16 4.01 3.94 3.86 3.89

3.95 4.15 4.20 4.17 4.02 3.94 3.87 3.89

4.06 4.15 4.13 4.06 4.00 3.96 3.95 3.94

3.94 4.17 4.21 4.14 4.03 3.94 3.88 3.88

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2.58 2.79 2.85 2.82 2.67 2.57 2.48 2.49 2.56

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3.94 4.16 4.21 4.14 4.03 3.94 3.88 3.88

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3.20 3.42 3.48 3.41 3.30 3.19 3.12 3.11 3.18

2.60 2.80 2.86 2.83 2.68 2.58 2.51 2.51 2.57

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2.58 2.80 2.86 2.80 2.68 2.58 2.49 2.48 2.56

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T=293.15K 0.1205 0.2357 0.3458 0.4512 0.5522 0.6491 0.7421 0.8315 0.9174 T=298.15K 0.1205 0.2357 0.3458 0.4512 0.5522 0.6491 0.7421 0.8315 0.9174 T=303.15K 0.1205 0.2357 0.3458 0.4512 0.5522 0.6491 0.7421 0.8315

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Tables. 3 Mole fraction solubility of MEQ in different ratio N-propanol+N-butanol solven t over the temperature range from 293.15 K–323.15 K(p = 101.3 kpa).a,b,c 103xApel 103xλh 103xexp 103xVan’t-JA-JA 103xGSM x0j

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3.92

3.89

3.93

4.84 5.03 5.06 5.00 4.91 4.83 4.80 4.80 4.83

4.84 5.02 5.06 5.03 4.88 4.83 4.77 4.81 4.81

4.84 5.03 5.06 5.03 4.89 4.84 4.79 4.82 4.82

4.93 5.05 5.03 4.96 4.9 4.86 4.86 4.86 4.82

4.84 5.04 5.06 5.00 4.91 4.83 4.80 4.80 4.83

5.94 6.02 6.05 6.21 5.83 5.92 5.81 6.04 5.86

5.91 6.07 6.08 6.05 5.92 5.91 5.88 5.93 5.89

5.91 6.07 6.08 6.05 5.93 5.91 5.89 5.94 5.90

8.71 8.77 8.71 8.64 8.65 8.73 8.85 8.90 8.73

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5.95 6.11 6.10 6.03 5.97 5.94 5.94 5.96 5.92

5.91 6.08 6.09 6.02 5.95 5.91 5.90 5.92 5.90

7.19 7.30 7.29 7.26 7.16 7.20 7.22 7.29 7.18

7.19 7.30 7.28 7.26 7.16 7.20 7.23 7.29 7.18

7.13 7.34 7.35 7.28 7.22 7.20 7.22 7.26 7.22

7.18 7.31 7.29 7.22 7.18 7.20 7.25 7.27 7.19

8.72 8.76 8.70 8.68 8.63 8.74 8.85 8.93 8.73

8.71 8.76 8.70 8.68 8.63 8.73 8.83 8.92 8.72

8.51 8.77 8.80 8.74 8.68 8.68 8.73 8.78 8.76

8.71 8.77 8.71 8.64 8.65 8.73 8.85 8.89 8.73

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7.18 7.31 7.29 7.23 7.18 7.20 7.25 7.27 7.19

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3.93

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0.9174 T=308.15K 0.1205 0.2357 0.3458 0.4512 0.5522 0.6491 0.7421 0.8315 0.9174 T=313.15K 0.1205 0.2357 0.3458 0.4512 0.5522 0.6491 0.7421 0.8315 0.9174 T=318.15K 0.1205 0.2357 0.3458 0.4512 0.5522 0.6491 0.7421 0.8315 0.9174 T=323.15K 0.1205 0.2357 0.3458 0.4512 0.5522 0.6491 0.7421 0.8315 0.9174

Journal Pre-proof ARD 10 RMSD

0.01 0.03

0.01 0.01 0.01 0.03 0.04 0.08 Apel λh Van’t-JA-JA GSM is the experimentally solubility; x , x , x and x denote the ca 3

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a: xexp lculated mole fraction solubility by the modified Apelblat equation, λh equation, NRTL Model, the Jouyban-Acree model and GSM equation respectively. b: The relative standard deviation of the solubility measurement u(x) =0.0001，u (T)=0.05K, u(P)=2KPa. c: ARD and RMSD are the average relative deviation and the root-mean-square deviations, respectively.

na

ξH ξS

12.74

11.84

43.84

36.20

11.07

10.51

10.08

9.65

9.25

8.77

8.16

34.61

35.31

36.94

38.21

39.72

39.36

36.03

101.05

79.16

76.46

80.56

87.27

92.76

99.00

99.36

90.53

0.9948 0.585 0.415

0.9935 0.598 0.402

0.9933 0.595 0.405

0.9969 0.587 0.413

0.9997 0.579 0.421

0.9999 0.572 0.428

0.9999 0.566 0.434

0.9996 0.563 0.437

0.9998 0.564 0.436

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ΔG0sol/KJ *mol-1 ΔH0sol/KJ *mol-1 ΔS0sol/J* mol-1*K-1 R2

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Table. 4 Thermodynamic parameters of MEQ dissolution in different ratio acetone+isopro panol solvent.a,b X0j paramet ers 0.121 0.236 0.346 0.451 0.552 0.649 0.742 0.831 0.917

a: X0j refers to the initial mole fraction of isopropanol in the binary solvent an d assumption of solute is not present. b: ΔH0sol, ΔS0sol , and ΔG0sol are the enthalpy, entropy, and Gibbs energy of the solute, respectively. ξH and ξS are the contribution of enthalpy and entropy to t he standard Gibbs energy, respectively.

Journal Pre-proof Table. 5 Thermodynamic parameters of MEQ dissolution in different ratio n-propyl alcoh ol+n-butyl alcohol solvent.a,b X0j paramet ers 0.121 0.236 0.346 0.451 0.552 0.649 0.742 0.831 0.917

ξH ξS

13.67

13.56

13.54

13.57

13.64

13.67

13.70

13.68

13.68

31.95

29.90

29.16

29.77

30.60

32.03

33.17

33.62

32.14

59.39

53.06

50.72

52.63

55.12

59.66

63.25

64.79

59.98

0.9999 0.636 0.364

0.9997 0.647 0.353

0.9998 0.651 0.349

0.9993 0.648 0.352

0.9995 0.643 0.357

0.9999 0.636 0.364

0.9997 0.630 0.370

0.9998 0.628 0.372

0.9999 0.635 0.365

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ΔG0sol/KJ *mol-1 ΔH0sol/KJ *mol-1 ΔS0sol/J* mol-1*K-1 R2

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a: X0j refers to the initial mole fraction of n-butyl alcohol in the binary solven t and assumption of solute is not present. b: ΔH0sol, ΔS0sol , and ΔG0sol are the enthalpy, entropy, and Gibbs energy of the solute, respectively. ξH and ξS are the contribution of enthalpy and entropy to t he standard Gibbs energy, respectively.

Apel A B C

λh λ h

0.1031 0.2054 -99.95 -74.54 -415.60 -590.82 16.81 12.54 0.61

0.3071 -82.97 20.13 13.71

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Table. 6 The models’parameters for the solubility data in different ratio binary-solvents. acetone+isopropanol 0.4081 -81.71 28.67 13.53

0.5084 -88.85 94.81 14.77

0.5084 0.7070 -87.06 -92.98 -79.08 35.86 14.58 15.57

0.8053 0.9030 -92.74 -84.58 45.25 95.83 15.56 14.15

0.31 0.34 0.41 0.67 0.91 1.31 1.61 1.37 13975.70 11992.12 9202.49 9815.12 6617.31 5083.82 3718.09 3034.00 3194.59

N-propanol+N-butanol Apel

x0j A B C

λh λ h

0.1031 0.2054 0.3071 0.4081 0.5084 0.5084 0.7070 -68.49 -66.33 -64.99 -64.05 -67.96 -62.09 -91.39 -371.52 -278.87 -262.16 -332.72 -281.93 -682.55 539.50 11.23 10.81 10.57 10.44 11.09 10.29 14.71

0.8053 0.9030 -73.21 -69.24 -310.05 -367.46 12.02 11.36

0.08 0.07 0.06 0.06 0.07 0.08 0.10 0.10 0.09 43907.27 48953.58 51625.94 50875.85 47492.34 43414.62 39750.80 39074.86 43097.17

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Table. 7 The models’parameters for the solubility data in different ratio binary-solvents. acetone+isopropanol van't-JA 10.26

V1

-4767.63

V2

1.32

V3

574.90

V4

-278.33

V5

-493.52

V6

493.00

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V0

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N-propanol+N-butanol van't-JA

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V0 V1

-4767.63 1.32

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V2

10.26

-278.33

V5

-493.52

V6

493.00

574.90

V4

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Table. 8 Parameters for the GSM model for the solubility in different ratio binary-solve nts.a GSM acetone+isopropanol T(K) a b c

d e

293.15 298.15 -6.28 -6.17 5.57 7.45 -4.47 -11.84 -2.46 8.64 4.24 -1.36

303.15 -5.89 7.21 -11.46 8.70 -1.64

308.15 -5.57 6.56 -9.86 7.37 -1.36

313.15 -4.94 1.62 5.83 -11.54 6.43

318.15 -4.69 2.69 0.94 -4.46 3.09

323.15 -4.32 2.03 0.28 -0.21 -0.17

318.15 -5.00 0.91 -3.40

323.15 -4.79 0.71 -3.17

N-propanol+N-butanol T(K) a b c

293.15 -6.13 2.17 -5.37

298.15 -5.89 1.89 -4.94

303.15 -5.66 1.66 -4.66

308.15 -5.42 1.25 -3.69

313.15 -5.21 1.09 -3.61

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4.84 -2.33

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4.13 4.29 4.63 3.97 d -0.69 -1.05 -1.48 -1.43 e a: Standard uncertainties u are u(T)=0.05

5.14 -2.70

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Highlight 1)The solubility of MEQ in selected binary solvents was systematic studied. 2)The dissolution thermodynamics of MEQ in binary solvents was studied. 3)Polarity is the main driven force for the dissolution of MEQ. 4)The dissolution of MEQ was endothermic and spontaneous.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5