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. 2024 May 2;9(19):21333–21345. doi: 10.1021/acsomega.4c01550

Thermodynamic Analysis of Eplerenone in 13 Pure Solvents at Temperatures from 283.15 to 323.15 K

Jianfang Liu 1,*, Ting Liu 1, Rongrong Zhang 1, Sicheng Yang 1, Yaoyun Zhang 1, Chenglingzi Yi 1, Shuai Peng 1, Qing Yang 1
PMCID: PMC11097358  PMID: 38764651

Abstract

graphic file with name ao4c01550_0007.jpg

The solubility of eplerenone (EP) in 13 pure solvents (acetonitrile, N,N-dimethylformamide (DMF), acetone, 2-butanone, 4-methyl-2-pentanone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, ethanol, and 1-propanol) was determined by the gravimetric method at atmospheric pressure and various temperatures (from 283.15 to 323.15 K). The results showed that the solubility of EP in the selected solvents was positively correlated with the thermodynamic temperature, and the order of solubility of EP at 298.15 K was acetonitrile > DMF > 2-butanone > methyl acetate > 4-methyl-2-pentanone > methyl propionate > ethyl acetate > propyl acetate > ethyl formate > acetone > butyl acetate > ethanol >1-propanol. The modified Apelblat model, van’t Hoff model, λh model, and polynomial empirical model were used for fitting the solubility data, and then the λh model was found to have the highest fitting accuracy with a minimum ARD of 7.0 × 10–3 and a minimum RMSD of 6.1 × 10–6. The solvent effect between the solute and the solvent was analyzed using linear solvation energy relationship (LSER), and the enthalpy of solvation (ΔsolH°), entropy of solvation (ΔsolS°), and Gibbs free energy of solvation (ΔsolG°) of the dissolution process of EP were calculated by the van’t Hoff model, which indicated that the dissolution process of EP in the selected solvents was endothermic, nonspontaneous, and entropy-increasing. In this work, the solubility, dissolution characteristics, and thermodynamic parameters of EP were studied, which will provide data support for the production, crystallization, and purification of EP and will provide important guidance for the crystallization optimization of EP in industry.

1. Introduction

Eplerenone (EP) is a novel selective aldosterone receptor antagonist first developed by Pfizer, which was initially marketed in the US in 2002 for the treatment of hypertension and heart failure.1−3 EP, CAS No. 107724-20-9, the systematic name of 9α,11-epoxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21,17-carbolactonean, molecular formula: C24H30O6, molecular weight: 414.49 g·mol–1, is an odorless, white or off-white crystal powder, and its chemical structure and three-dimensional (3D) structure are depicted in Figure 1.4,5

Figure 1.

Figure 1

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Chemical structure and 3D structure of EP.4 (a) Chemical structure; (b) 3D structure.

As a novel selective aldosterone receptor antagonist, EP has stronger antagonistic effects on aldosterone than spironolactone. Additionally, it exhibits minimal affinity for androgen and progesterone receptors, leading to reduce adverse reactions. Due to its improved tolerance and fewer adverse reactions, EP can be considered an excellent alternative to spironolactone for the treatment of hypertension, heart failure, and myocardial infarction.6,7 Pardo-Martínez et al.8 evaluated the efficacy of spironolactone and EP in patients with heart failure and reduced ejection fraction (HFrEF) in a clinical trial in 2022, and the results of the study showed that EP reduced cardiovascular mortality and all-cause mortality in patients with HFrEF compared to spironolactone. In addition, EP can be combined with other drugs. El Mokadem’s team9 found that angiotensin-converting enzyme inhibitors (ramipril) combined with mineralocorticoid receptor antagonists (EP) were effective in patients with chronic kidney disease. And the combination of ramipril and EP improved antialbuminuric effects when compared to monotherapy. In recent years, researchers have found that EP may be used to treat chronic central serous chorioretinopathy,10 but the role of EP in this regard was controversial. Katrin Fasler’s research group11 reported that there was no evidence of efficacy of EP on subretinal fluid (SRF) regression in patients with acute and chronic central serous chorioretinopathy (CSCR) in clinical trials, and this study was still under exploration. Nowadays, studies on EP have mainly focused on clinical observation and treatment, chemical synthesis, and the pharmacological and biological activities of drugs.6,12 However, the solubility and thermodynamic properties of EP in organic solvents have not been reported. Solubility is the physicochemical property of drugs which is crucial for the bioavailability of drugs in the human body. Moreover, studying the solubility of drugs in different solvents can provide effective data support and reference for subsequent industrial production and crystallization process research. Therefore, it is necessary to study the solid–liquid equilibrium of EP. Currently, the methods for the determination of solubility primarily include gravimetry, spectroscopy, chromatography, and dynamic laser monitoring. Bhola et al.13 used gravimetric methods to determine the solubility of benzethonium chloride (BTC) in 9 pure solvents and two mixed solvents. Daniela’s group14 adopted UV–vis spectrophotometry to determine the solubility of isoniazid in nine (PEG 200 + water) cosolvent mixtures and calculated thermodynamic solution, mixing, and transfer functions, which showed that solution entropy was beneficial to the solution dissolution process. Cheng15 exploited high-performance liquid chromatography (HPLC) to determine the solubility of esculetin in 10 single solvents and concluded that it was highest in methanol and lowest in water. Vahid16 measured the solubility of ketoconazole in a mixed solvent of propylene glycol and ethanol by a laser monitoring technique in the temperature range of 293.2 to 313.2 K.

In this paper, the solubility of EP was investigated. Under atmospheric pressure and temperatures ranging from 283.15 to 323.15 K, the solubility of EP in 13 pure solvents (acetonitrile, N,N-dimethylformamide (DMF), acetone, 2-butanone, 4-methyl-2-pentanone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethanol, and 1-propanol) was determined by the gravimetric method. Four thermodynamic models (such as the modified Apelblat model, van’t Hoff model, λh model, and polynomial empirical model) were employed to fit the solubility data. The model that exhibited a better fitting degree was selected. Furthermore, the solvent effect between solutes was analyzed by linear solvation energy relationship, and according to the van’t Hoff model, the thermodynamic properties of the dissolution process of EP were obtained.

2. Experimental Section

2.1. Material

The raw material for the experiment, eplerenone (purity ≥98%), was purchased from Hubei Widely Reagent Co., Ltd. in China, and other analytical research-grade organic reagents are listed in Table 1 for details. The selected solvents were commonly used organic solvents, and the chosen temperature fell within the optimal range for industrial production. Studying the solubility of EP in various solvents under conditions of 283.15 to 323.15 K could provide valuable insights for practical production and crystallization. Some analysis methods used for materials, such as high-performance liquid chromatography (HPLC) and gas chromatography (GC), were provided by the supplier.

Table 1. Descriptions of the Materials Used in the Experiments.

materials CAS NO. molecular formula molar mass (g·mol-1) molar volume (cm3·mol–1)a mass fractionb analysis methodc source
eplerenone 107724-20-9 C24H30O6 414.49 318.84 ≥0.980 HPLC Hubei Widely Reagent Co., Ltd.
benzoic acidd 65-85-0 C7H6O2 122.12 92.52 ≥0.980 HPLC Tianjin Institute of Metrology Supervision and Testing Science
sodium chloride 7647-14-5 NaCl 58.44   ≥0.995 HPLC Sinopharm Chemical Reagent Co., Ltd.
ethanol 64-17-5 C2H6O 46.07 58.52 ≥0.997 GC Sinopharm Chemical Reagent Co., Ltd.
1-propanol 71-23-8 C3H8O 60.1 74.94 ≥0.995 GC Tianjin Damao Chemical Reagent Factory
ethyl formate 109-94-4 C3H6O2 74.08 80.83 ≥0.990 GC Tianjin Damao Chemical Reagent Factory
methyl acetate 79-20-9 C3H6O2 74.08 79.89 ≥0.980 GC Tianjin Damao Chemical Reagent Factory
ethyl acetate 141-78-6 C4H8O2 88.11 96.94 ≥0.995 GC Tianjin Fuyu Fine Chemical Co., Ltd.
propyl acetate 109-60-4 C5H10O2 102.13 115.48 ≥0.990 GC Shanghai Macklin Biochemical Co., Ltd.
butyl acetate 123-86-4 C6H12O2 116.16 132.55 ≥0.990 GC Tianjin Damao Chemical Reagent Factory
methyl propionate 554-12-1 C4H8O2 88.11 98.59 ≥0.990 GC Shanghai Macklin Biochemical Co., Ltd.
N,N-dimethylformamide (DMF) 68-12-2 C3H7NO 73.09 77.37 ≥0.995 GC Tianjin Fuyu Fine Chemical Co., Ltd.
acetonitrile 75-05-8 C2H3N 41.05 52.68 ≥0.995 GC Tianjin Kermel Chemical Reagent Co., Ltd.
acetone 67-64-1 C3H6O 58.08 73.93 ≥0.990 GC Tianjin Damao Chemical Reagent Factory
2-butanone 78-93-3 C4H8O 72.11 90.20 ≥0.990 GC Tianjin Damao Chemical Reagent Factory
4-methyl-2-pentanone 108-10-1 C6H12O 100.16 125.76 ≥0.990 GC Sinopharm Chemical Reagent Co., Ltd.
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a

Molar volumes of 13 pure solvents were taken from the literature ,17 and molar volumes of EP and benzoic acid were calculated by the formula (Molar volume = Molar mass/Density), whose densities were equal to 1.30 and 1.32 g·cm–3 respectively.18,19

b

Mass fractions of all materials were provided by the supplier.

c

Analysis methods of all materials were provided by the supplier, and no additional purification steps were performed.

d

Benzoic acid purchased was the melting point standard material GBW13233e.

2.2. Characterization Methods

2.2.1. Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA)

The melting temperature (Tm) of EP was determined by using a differential scanning calorimeter (DSC 204 HP, NETZSCH, Germany) under the following conditions: EP sample weight: 5–10 mg, nitrogen flow rate: 20 mL/min, heating rate: 10 K/min, and temperature range: 298.15 to 573.15 K.

A thermal gravimetric analyzer (METTLER TOLEDO) was used to determine whether the weightless decomposition of EP occurred prior to the melting peak, and the determination conditions were the same as DSC, but the temperature range was 303.15 to 873.15 K.

2.2.2. Powder X-ray Diffraction (PXRD)

PXRD could make sure whether the crystal structure of EP changes when dissolved in various solvents. The test samples were the solid–liquid mixtures that remained in the system after reaching solid–liquid phase equilibrium, which were dried in a vacuum drying oven at −0.09 MPa and 60 °C and were milled before testing. The X-ray diffractometer (model: SmartLab SE) of Rigaku Company in Japan was used in this experiment. The measurement conditions included a Cu target, tube voltage of 40 kV, tube current of 40 mA, test angle range of 5–80°, and scanning step length of 0.02°.

2.3. Solubility Determination

The solubility of EP in 13 pure solvents (acetonitrile, DMF, acetone, 2-butanone, 4-methyl-2-pentanone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethanol, and 1-propanol) was determined by the gravimetric method13,20 over the temperature range from 283.15 to 323.15 K under atmospheric pressure. All test temperatures were controlled by a cryogenic bath (DHC-1005-A, Hangzhou Qiwei Co., Ltd.) with an error of ±0.05 K. The cryogenic bath was turned on and the test temperature was set; 30 mL of the solvent and excessive EP were added into the glass jacket crystallizer after the temperature was constant. Pre-experiments indicate that the solution reaches a saturated state after stirring for 10 h at a constant temperature. Therefore, the solution was stirred for 10 h with a magnetic stirrer and then let to stand for 2 h at the experimental temperature. The supernatant liquid was taken with a disposable syringe and filtered through a 0.22 μm nylon filter into a beaker of known mass. To ensure accuracy and prevent data inaccuracies caused by solvent evaporation, the nylon filter and the beaker were preheated to the testing temperature before filtration. After that, the beaker with supernatant liquid was put into a vacuum drying oven to dry at 60 °C for 24 h and then weighed using an analytical balance with an accuracy of ±0.0001 g (model: FA214A, Shanghai Haosheng Scientific Instrument Co., Ltd.) until the quality of the product was unchanged. The above procedures were repeated three times, changing the temperatures or solvents to measure the next set of data. To check the stability of the device, the solubility of sodium chloride (NaCl) in water was measured first, and the experimental results are shown in Figure 2. The solubilities of NaCl in water measured by this device were consistent with the reported results.21

Figure 2.

Figure 2

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Experimental and literature values for the solubility of sodium chloride in water. w represents the mass fraction.

The measured solubility data were used to calculate the molar solubility (x1) of EP in different pure solvents, according to eq 1

2.3. 1

where m1 and m2 are the mass (g) of EP and the selected solvents, respectively; M1 and M2 are the molar mass (g·mol–1) of EP and the selected solvents, respectively.

3. Calculation Models

3.1. Thermodynamic Models

3.1.1. Modified Apelblat Model

The modified Apelblat model, derived from the Clausius–Clapeyron equation, is a semiempirical thermodynamic model commonly used to describe the relationships between the molar solubility of the solute and its temperature.22,23 The equation can be described as follows

3.1.1. 2

The solubility data is modeled using the following equation

3.1.1. 3

where x1 is the molar solubility of EP at temperature T/K and A1, B1, and C1 are model parameters. The values of A1 and B1 show the change in the activity coefficient, describing the effect of the nonideality of the solution on the solubility of the solute, and C1 shows the effect of temperature on the heat of melting as a heat capacity deviation.

3.1.2. van′t Hoff Model

The van’t Hoff model was first proposed by Jacobus Henricus van’t Hoff, which can be expressed as a two-parameter empirical model, reflecting the existence of a link between solubility and thermodynamic temperature.13,24 And the van’t Hoff model exhibits that the logarithm of the molar solubility of the solute is linearly related to the reciprocal of the thermodynamic temperature. It is shown by eq 4

3.1.2. 4

Solve eq 4 to get the following modeling equation

3.1.2. 5

where x1 is the molar solubility of EP at temperature T/K and A2 and B2 are model parameters. The values of A2 and B2 are model parameters related to the entropy and enthalpy of the solution.

3.1.3. λh Model

In 1980, Buchowski et al.25 derived and proposed the λh model based on the generalized solubility equation. The λh model is a two-parameter empirical model, which is simple and suitable for associating solubility data with thermodynamic temperature.20 The expression is as follows:

3.1.3. 6

The modeling equation is as follows:

3.1.3. 7

where x1 is the molar solubility of EP at temperature T/K, Tm is the melting point of EP, λ, and h are model parameters, the value of λ represents the nonideality of the solution system, and h represents the enthalpy of the solution.

3.1.4. Polynomial Empirical Model

The polynomial empirical model can be applied to correlate and fit the solubility data. Additionally, the molar solubility of solute is a function of temperature when the external influence conditions are fixed,26,27 which is expressed as

3.1.4. 8

where x1 is the molar solubility of EP at temperature T/K and A3, B3, C3, and D3 are model parameters.

3.2. Evaluation Criteria of Models

The average relative deviation (ARD) and root-mean-square deviation (RMSD) are regularly used to evaluate the accuracy of the fitting results of thermodynamic models and their corresponding formulas as follows:

3.2. 9
3.2. 10

where N represents the number of data points, x1 represents the experimentally observed value, and xcal represents the predicted value from the model.

3.3. KAT-LSER Model

The linear solvation energy relationship (LSER) is a quantitative structure–activity relationship (QSAR) model used to describe the solvent effect of solute–solvent interactions on the dissolution process.28 At present, the LSER model has been successfully applied to predict the solubility of substances, octanol/water partition coefficient, and various biological toxicity properties.29 The LSER model explains solvent effects by dividing solvent–solvent interactions into specific (such as hydrogen bond force) and nonspecific (including electrostatic force, dipole–dipole force, dipole–induced dipole force, and dispersion force) interactions.30 The Gibbs free energy (XYZ) during dissolution is the sum of solute–solvent interaction energy and cavity creation energy,31−33 as shown in eq 11

3.3. 11

where XYZ0 is the intercept of the equation, which is only related to the properties of the solvent.

In the 1980s, Kamlet et al.31 developed the KAT-LSER model by analyzing the solubility data in conjunction with the solvent properties, which explains the change of Gibbs free energy during the dissolution process from multiple perspectives. The KAT-LSER model is expressed as follows

3.3. 12

where x1 is the molar solubility of EP at temperature T/K, π*, α, and β are denoted as polarity/dipolarity of the solvent, summation of the hydrogen bond donor propensities of the solvent, and summation of the hydrogen bond acceptor propensities of the solvent, respectively. Vs is the molar volume of the solvent (cm3/mol), δH is the Hildebrand solubility parameter, and R is the molar constant of the gas (which takes the value of 8.314 J/(mol·K). The conversion of δH to Vs(δH)2/(100RT) is to make it dimensionless and within a certain range with the other three properties. In the equation, c0 is the intercept of the model when π* = α = β = δH = 0. c1 and c4 denote the sensitivities of the solute–solvent and the solvent–solvent via nonspecific electrostatic interactions, while c2 and c3 represent the interactions of the solute–solvent through the specific hydrogen-bonding interactions.

3.4. Thermodynamic Properties of the Solution

The solubility of a solute is closely related to the thermodynamic properties of solutions. To investigate the thermodynamic behavior of the dissolution process between EP and pure solvents, several thermodynamic parameters such as standard enthalpy of dissolution (ΔsolH°), standard entropy of dissolution (ΔsolS°), and standard Gibbs free energy of dissolution (ΔsolG°) can be analyzed.24,34,35 The standard enthalpy of dissolution (ΔsolH°) can be calculated according to the van’t Hoff model, as shown in eq 13

3.4. 13
3.4. 14

where x1 is the molar solubility of EP at temperature T/K and Tav is the average harmonic temperature of the experiment. From eq 13, ln x1 is linearly related to (1/T – 1/Tav), and the slope of the curve is (−ΔsolH°)/R with an intercept of b, as obtained by graphing with the software.

The equations of standard entropy of dissolution (ΔsolS°) and standard Gibbs free energy of dissolution (ΔsolG°) are expressed as eqs 15 and 16, respectively.

3.4. 15
3.4. 16

To compare the contribution of ΔsolH° and ΔsolS° to Gibbs free energy, the relative contribution of enthalpy (ξH/%) and entropy (ξTS/%)36,37 during the dissolution process can be calculated by eqs 17 and 18.

3.4. 17
3.4. 18

4. Results and Discussion

4.1. Characterizations of EP

4.1.1. DSC and TGA

The calibration material of DSC in this paper was benzoic acid, the standard material of melting point, which was measured three times according to the steps in Section 2.2.1. The average melting point and melting enthalpy (ΔfusH) of benzoic acid were 395.65 K and 16.49 kJ/mol, respectively, and the standard uncertainties of melting point and melting enthalpy of benzoic acid were 0.05 K and 0.28 kJ/mol, respectively. The melting point and melting enthalpy (ΔfusH) of benzoic acid in the literature38 were 395.40 K and 17.1 kJ/mol, respectively. The relative deviation was less than 4%, indicating that the device was reliable.

The DSC and TGA curves of EP are presented in Figure 3, and it could be found that there is no weightless decomposition of EP before the endothermic peak. And EP had an endothermic melting peak (Tp) at 512.00 K, and its standard uncertainty was 0.25 K. In addition, EP had another endothermic melting peak at 517.85 K. The test results were similar to the literature results.39 The average melting point (Tm) and average melting enthalpy (ΔfusH) of EP obtained by DSC analysis software were 506.60 K and 25.70 kJ/mol, respectively, and their standard uncertainties were 0.65 K and 0.03 kJ/mol, respectively. Due to the different experimental conditions, environment, and sample sources, there were some deviations between the test and the literature results.

Figure 3.

Figure 3

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DSC and TGA curves of EP.

4.1.2. PXRD

EP raw material and EP recovered from solvents were analyzed by PXRD, and since the characteristic peak positions of EP were mainly concentrated at 5 to 35°, only the spectra of 5 to 35° are shown in Figure 4. It was clear that the characteristic peak position of EP recovered from solvents was consistent with that of the raw material, indicating that the crystalline form of EP had not been transformed in the process of dissolution. But the peak strength changed, which may be due to factors such as the roughness of the crystal surface, the presence of defects on the crystal surface, and the degree of crystallinity.

Figure 4.

Figure 4

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PXRD patterns of raw material and EP recovered from solvents.

4.2. Solubility Results

The trends of solubility of EP in 13 pure solvents are plotted in Figure 5. The fitting curve in Figure 5 was obtained by fitting the polynomial empirical model. And the solubility and the fitted data are listed in Table 2. From Table 2, it could be found that the solubility of EP in 13 solvents increased with an increase in temperature. However, the influence of temperature on the solubility of each solvent was not uniform, so some same kinds of solvents had an increasing difference in solubility as the temperature increased. In addition, the solubility sequence of EP at 298.15 K was acetonitrile > DMF > 2-butanone > methyl acetate > 4-methyl-2-pentanone > methyl propionate > ethyl acetate > propyl acetate > ethyl formate > acetone > butyl acetate > ethanol > 1-propanol. Within the experimental range, EP had the maximum molar solubility in acetonitrile solution (2.67 × 10–2, 323.15 K) and the minimum molar solubility in 1-propanol solution (3.65 × 10–5, 283.15 K).

Figure 5.

Figure 5

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Molar solubility of EP in 13 pure solvents. (a) Ester solvents, (b) ketone solvents, (c) alcohol solvents, and (d) others.

Table 2. Experimental and Fitting Data of Molar Solubility of EP in 13 Pure Solvents at Temperatures from 283.15–323.15 K and Pressure 101.3 kPaa,b.

T/K 104xexp1 104xApelblat1 104xvan′tHoff1 104xλh1 104xpolynomial1
Ethyl Formate
283.15 10.3252 10.1607 9.4000 9.4328 10.3967
288.15 12.0202 12.1064 11.6335 11.6579 12.0973
293.15 14.8700 14.4605 14.2933 14.3069 14.3165
298.15 16.8370 17.3108 17.4403 17.4416 17.1436
303.15 20.2534 20.7638 21.1411 21.1302 20.6681
308.15 25.3326 24.9491 25.4675 25.4475 24.9795
313.15 29.9784 30.0244 30.4976 30.4755 30.1671
318.15 36.6205 36.1812 36.3147 36.3043 36.3205
323.15 43.3808 43.6519 43.0085 43.0325 43.5289
Methyl Acetate
283.15 24.6822 23.8355 24.8952 25.0074 24.7655
288.15 27.9883 28.7029 29.2930 29.3547 28.4687
293.15 34.4863 34.1599 34.2769 34.2854 33.5278
298.15 40.3703 40.2059 39.8980 39.8561 39.6875
303.15 46.0086 46.8298 46.2088 46.1271 46.6924
308.15 52.4982 54.0097 53.2633 53.1635 54.2872
313.15 62.8985 61.7130 61.1170 61.0348 62.2166
318.15 71.8265 69.8973 69.8262 69.8160 70.2251
323.15 77.1693 78.5112 79.4482 79.5882 78.0576
Ethyl Acetate
283.15 20.6757 20.4522 20.0454 20.2062 20.6293
288.15 22.7423 22.6862 22.5037 22.5833 22.6235
293.15 24.5364 25.1507 25.1641 25.1680 25.0074
298.15 27.9556 27.8673 28.0336 27.9743 27.7542
303.15 30.8534 30.8595 31.1194 31.0171 30.8373
308.15 34.8187 34.1525 34.4279 34.3130 34.2298
313.15 37.3006 37.7738 37.9656 37.8798 37.9049
318.15 41.8303 41.7530 41.7382 41.7372 41.8359
323.15 46.1055 46.1221 45.7513 45.9066 45.9961
Propyl Acetate
283.15 12.3694 12.0194 10.9726 11.0363 12.5370
288.15 13.8637 13.6339 13.0587 13.1014 13.5120
293.15 15.1359 15.5719 15.4494 15.4686 15.1939
298.15 17.3686 17.8986 18.1750 18.1703 17.5551
303.15 20.6262 20.6937 21.2672 21.2416 20.5676
308.15 24.0728 24.0547 24.7589 24.7201 24.2037
313.15 28.5204 28.1010 28.6843 28.6466 28.4357
318.15 33.3844 32.9790 33.0786 33.0652 33.2356
323.15 38.4751 38.8677 37.9783 38.0236 38.5758
Butyl Acetate
283.15 3.9511 4.0077 4.2634 4.2754 3.9261
288.15 5.1100 5.1390 5.3071 5.3151 5.1452
293.15 6.5641 6.4912 6.5571 6.5601 6.5375
298.15 7.9483 8.0839 8.0443 8.0417 8.1316
303.15 10.2477 9.9337 9.8025 9.7946 9.9564
308.15 12.0042 12.0539 11.8686 11.8570 12.0406
313.15 14.2454 14.4533 14.2826 14.2714 14.4130
318.15 17.1843 17.1363 17.0879 17.0844 17.1024
323.15 20.1350 20.1021 20.3311 20.3472 20.1374
Methyl Propionate
283.15 24.0936 24.0650 23.1973 23.3920 23.9443
288.15 26.1842 26.3305 25.9522 26.0493 26.3785
293.15 28.5936 28.8820 28.9234 28.9302 28.9780
298.15 32.6294 31.7537 32.1177 32.0494 31.8227
303.15 34.3830 34.9841 35.5417 35.4229 34.9924
308.15 39.0631 38.6169 39.2018 39.0681 38.5670
313.15 42.3920 42.7011 43.1036 43.0038 42.6261
318.15 47.1056 47.2918 47.2526 47.2509 47.2498
323.15 52.6321 52.4511 51.6538 51.8323 52.5178
Acetone
283.15 9.8301 9.1744 8.8552 8.8907 9.6448
288.15 10.5105 10.9881 10.7952 10.8196 10.8829
293.15 12.8691 13.1322 13.0716 13.0827 12.8059
298.15 15.5404 15.6615 15.7269 15.7236 15.3725
303.15 18.2994 18.6394 18.8064 18.7898 18.5413
308.15 22.9550 22.1385 22.3588 22.3333 22.2709
313.15 25.9253 26.2421 26.4357 26.4105 26.5202
318.15 31.2586 31.0457 31.0919 31.0829 31.2476
323.15 36.5097 36.6584 36.3851 36.4176 36.4120
2-Butanone
283.15 25.3266 25.1259 24.9352 24.9884 25.4650
288.15 30.7864 30.7883 30.6692 30.7060 30.7507
293.15 37.8333 37.4975 37.4564 37.4729 37.2898
298.15 45.0327 45.4046 45.4399 45.4341 45.1953
303.15 53.8321 54.6759 54.7747 54.7481 54.5800
308.15 65.8053 65.4943 65.6281 65.5871 65.5568
313.15 78.5798 78.0595 78.1795 78.1387 78.2385
318.15 92.7111 92.5894 92.6204 92.6059 92.7381
323.15 109.0753 109.3205 109.1547 109.2085 109.1684
4-Methyl-2-pentanone
283.15 25.7568 26.4928 25.6915 25.9085 25.5549
288.15 28.8281 28.9381 28.5993 28.7032 29.2948
293.15 32.3161 31.6656 31.7199 31.7210 32.4338
298.15 36.0587 34.7064 35.0591 34.9762 35.2925
303.15 38.2014 38.0949 38.6220 38.4843 38.1916
308.15 41.1332 41.8694 42.4137 42.2622 41.4515
313.15 44.5408 46.0724 46.4384 46.3286 45.3929
318.15 51.4835 50.7513 50.7004 50.7039 50.3364
323.15 56.2323 55.9586 55.2034 55.4106 56.6025
Ethanol
283.15 0.7097 0.7104 0.7423 0.7436 0.7263
288.15 0.9442 0.9534 0.9774 0.9784 0.9579
293.15 1.3627 1.2616 1.2748 1.2755 1.2581
298.15 1.5867 1.6476 1.6481 1.6482 1.6404
303.15 2.0927 2.1250 2.1127 2.1121 2.1184
308.15 2.6624 2.7084 2.6865 2.6853 2.7054
313.15 3.4184 3.4136 3.3900 3.3887 3.4150
318.15 4.3549 4.2569 4.2466 4.2459 4.2606
323.15 5.2062 5.2554 5.2826 5.2843 5.2559
1-Propanol
283.15 0.3654 0.3956 0.3471 0.3474 0.3683
288.15 0.5539 0.5278 0.4879 0.4882 0.5460
293.15 0.7011 0.7045 0.6780 0.6782 0.7265
298.15 0.9919 0.9405 0.9317 0.9319 0.9475
303.15 1.2321 1.2557 1.2670 1.2671 1.2469
308.15 1.6722 1.6763 1.7060 1.7058 1.6622
313.15 2.1431 2.2373 2.2752 2.2750 2.2313
318.15 3.0962 2.9847 3.0071 3.0069 2.9919
323.15 3.9465 3.9799 3.9403 3.9405 3.9817
Acetonitrile
283.15 138.9418 140.4332 136.4462 137.5795 138.2878
288.15 150.4217 151.0072 149.4428 149.9469 151.8765
293.15 165.3174 162.7465 163.1702 163.1263 164.5486
298.15 176.6819 175.7631 177.6341 177.1640 177.1092
303.15 190.8641 190.1814 192.8392 192.1106 190.3636
308.15 206.3069 206.1396 208.7885 208.0212 205.1169
313.15 220.5818 223.7908 225.4841 224.9564 222.1744
318.15 242.4299 243.3041 242.9266 242.9828 242.3413
323.15 266.6956 264.8664 261.1157 262.1735 266.4228
DMF
283.15 23.3492 24.6754 23.9144 23.9245 23.4771
288.15 31.3367 30.7435 30.2376 30.2465 31.0421
293.15 38.8070 38.1400 37.9279 37.9349 38.9126
298.15 47.7039 47.1213 47.2138 47.2183 47.7315
303.15 57.7826 57.9868 58.3502 58.3516 58.1419
308.15 71.4673 71.0851 71.6195 71.6177 70.7868
313.15 85.6799 86.8211 87.3329 87.3286 86.3092
318.15 105.7395 105.6638 105.8320 105.8270 105.3522
323.15 128.4462 128.1547 127.4894 127.4875 128.5589
Open in a new tab
a

xexp1, xApelblat1, xvan’tHoff1, xλh1, and xpolynomial1 represent the experimental value and fitted value, respectively.

b

Standard uncertainties u: u(T) = 0.05 K, u(P) = 0.3 kPa, and relative standard uncertainty ur: ur(x) = 0.05.

Moreover, Figure 5a revealed that the solubility of EP in ester (R1COOR2) solvents decreased with the increase of R2. The solubility of EP in methyl acetate increased significantly more than that of several other esters with the rising temperature. The order of solubility of EP in six ester solvents was methyl acetate > methyl propionate > ethyl acetate > propyl acetate > ethyl formate > butyl acetate. According to Figure 5b, the solubility sequence of EP in the three ketone solvents was 2-butanone > 4-methyl-2-pentanone > acetone; the solubility of EP in ketone (CH3COR1) solvents increased with the increase of R1 but decreased if R1 had branched chains. At lower temperatures, the solubility of 4-methyl-2-pentanone was close to 2-butanone. But with the increase of temperature, the solubility of 4-methyl-2-pentanone was much lower than 2-butanone. As shown in Figure 5c, with the growth of the carbon chain, the solubility of EP in alcoholic solvents became smaller. The order of solubility of EP in both alcoholic solvents was ethanol > 1-propanol. Lastly, as shown in Figure 5d, the solubility of EP in acetonitrile was higher than DMF.

The physical properties of the 13 organic solvents such as boiling point (bp), polarity/dipolarity (π*), dipole moment (μ), dielectric constant (ε), hydrogen bond donor capacity (α), hydrogen bond acceptor capacity (β), and Hildebrand solubility parameters (δH) are listed in Table 3. The order of boiling points was DMF > butyl acetate > 4-methyl-2-pentanone > propyl acetate > 1-propanol > acetonitrile > 2-butanone ≈ methyl propionate > ethanol > ethyl acetate > methyl acetate > acetone > ethyl formate; the polarizability of solvents obeyed the order as DMF > acetonitrile > acetone > 4-methyl-2-pentanone > ethyl formate > methyl acetate > ethyl acetate > ethanol > 1-propanol > propyl acetate > butyl acetate; the order of dipole moments was acetonitrile > DMF > acetone > 4-methyl-2-pentanone > 2-butanone > ethyl formate = butyl acetate > propyl acetate > ethyl acetate > methyl acetate > ethyl acetate > ethanol > 1-propanol; dielectric constant was ranked as DMF > acetonitrile > ethanol > 1-propanol > acetone > 2-butanone > 4-methyl-2-pentanone > ethyl formate > methyl acetate > ethyl acetate > propyl acetate > butyl acetate; and the cohesion energy density was ethanol > 1-propanol > acetonitrile > DMF > acetone > methyl acetate > ethyl formate > 2-butanone > methyl propionate > ethyl acetate > 4-methyl-2-pentanone > propyl acetate > butyl acetate.

Table 3. Values of π*, μ, ε, α, β, and δH for the 13 Pure Solvents at 298.15 K.

solvents bp (°C)a π*b μb εb αb βb δHc (J1/2/cm3/2)
acetonitrile 81 0.75 3.92 35.69 0.07 0.32 24.09
DMF 153 0.88 3.82 37.22 0.00 0.74 23.97
acetone 56.5 0.71 2.88 20.49 0.04 0.49 19.77
2-butanone 79.6 0.67 2.78 18.25 0.00 0.51 18.80
4-methyl-2-pentanone 117 0.65 2.81 12.89 0.00 0.51 17.83
ethyl formate 53 0.61 1.90 8.33 0.00 0.38 18.94
methyl acetate 57 0.60 1.72 6.86 0.00 0.45 19.44
ethyl acetate 76.5 0.55 1.78 5.99 0.00 0.45 18.35
propyl acetate 102 0.50 1.80 5.52 0.00 0.45 17.67
butyl acetate 124 0.46 1.90 4.99 0.00 0.45 17.58
methyl propionate 79 0.55         18.63
ethanol 78.3 0.54 1.69 24.85 0.37 0.48 26.42
1-propanol 97 0.52 1.55 20.52 0.37 0.48 24.56
Open in a new tab
a

The values of bp were provided by the supplier.

b

The values of π*, μ, ε, α, and β were obtained from the literature.40

c

The values of δH were obtained from the literature.17

However, the experimental results were inconsistent with the above four orders, indicating that there was no obvious correlation between the solubility of EP and the above orders of the physical properties of solvents. This phenomenon showed that the dissolution process of EP in different solvents was very complicated. The solubility of EP was not affected by a single factor but may be influenced by many factors. These factors may include the physical and chemical properties of solute and solvents, intermolecular forces (such as hydrogen bond, dispersion force, induction force, orientation force), molecular structure, and stereoscopic effects.

4.3. Evaluations of Models

The adjusted R2, model parameters, ARD, and RMSD of the four models are shown in Tables 4–6. As can be seen from Tables 4–6, the adjusted R2 of the four models was close to 1, and the maximum ARD values were 3.27 × 10–2, 4.70 × 10–2, 4.68 × 10–2, and 2.37 × 10–2, respectively. The maximum RMSD values were 1.664 × 10–4, 2.95 × 10–4, 2.392 × 10–4, and 1.006 × 10–4, respectively. The above data indicated that the four models can effectively describe the relationship between the solubility of EP and temperature. In combination with the total ARD and RMSD, the polynomial empirical model exhibited higher fitting accuracy and smaller error compared to the modified Apelblat model, van′t Hoff model, and λh model. However, some parameters in the modified Apelblat model, van′t Hoff model, and polynomial empirical model were not significant and did not have statistical significance, and all parameters were significant when all solubility data were only fitted with the λh model. Therefore, the λh model was selected as the predictive model for the solubility of EP in this study.

Table 4. Parameters of the Modified Apelblat Model and the van′t Hoff Model (P = 101.3 kPa)a,b.

  modified Apelblat model
 van′t Hoff model
solvents 100R2 A1 B1 C1 100R2 A2 B2
acetonitrile 99.77 –106.82 ± 16.53 3396.67 ± 1131.17 16.04 ± 2.48 99.39 0.95 ± 0.14 –1484.66 ± 41.52
DMF 99.94 –65.61 ± 30.79 0* 10.86 ± 4.51 99.93 7.48 ± 0.13 –3828.24 ± 40.78
acetone 99.68 –86.57 ± 52.09 0* 13.52 ± 7.71 99.67 4.39 ± 0.23 –3232.60 ± 70.09
2-butanone 99.97 0* –2506.98 ± 1102.63 2.83 ± 3.45 99.97 5.93 ± 0.07 –3377.46 ± 21.22
4-methyl-2-pentanone 98.97 –108.79 ± 41.50 3192.74 ± 2873.15 16.22 ± 6.25 98.81 0* –1749.62 ± 68.62
ethyl formate 99.86 –187.05 ± 20.95 5307.10 ± 2006.01 28.59 ± 3.14 99.67 5.32 ± 0.25 –3478.56 ± 76.20
methyl acetate 99.47 126.86 ± 41.01 –8277.07 ± 2843.43 –18.36 ± 6.28 99.40 3.38 ± 0.25 –2654.48 ± 77.18
ethyl acetate 99.76 –67.66 ± 27.58 0* 10.13 ± 4.12 99.69 0.45 ± 0.12 –1887.69 ± 37.64
propyl acetate 99.77 –250.72 ± 14.54 8728.10 ± 1739.13 37.76 ± 2.22 99.22 3.22 ± 0.30 –2840.19 ± 93.01
butyl acetate 99.91 153.83 ± 21.11 –10380.31 ± 1599.96 –22.14 ± 3.26 99.81 4.86 ± 0.20 –3573.26 ± 60.79
methyl propionate 99.72 –126.51 ± 20.50 3925.53 ± 1516.63 18.88 ± 3.09 99.38 0.40 ± 0.17 –1831.21 ± 51.68
ethanol 99.80 96.15 ± 55.84 –8608.78 ± 3381.69 –13.34 ± 8.58 99.81 6.35 ± 0.26 –4489.01 ± 80.02
1-propanol 99.70 –223.79 ± 47.10 0* 34.60 ± 7.00 99.65 9.36 ± 0.45 –5557.32 ± 138.58
Open in a new tab
a

Standard uncertainty u(P) = 0.3 kPa.

b

0* indicates that the parameter has no significance and is not statistically significant.

Table 6. Deviations of the Modified Apelblat Model, van′t Hoff Model, λh Model, and Polynomial Empirical Model (P = 101.3 kPa)a.

  modified Apelblat model
 van′t Hoff model
 λh model
 polynomial empirical model
solvents 102ARD 105RMSD 102ARD 105RMSD 102ARD 105RMSD 102ARD 105RMSD
acetonitrile 0.72 16.64 1.23 29.47 0.92 23.92 0.43 9.19
DMF 1.42 7.05 1.47 8.53 1.47 8.50 0.51 3.75
acetone 2.45 4.34 2.73 4.74 2.70 4.67 1.54 3.49
2-butanone 0.62 4.01 0.73 4.18 0.70 4.11 0.53 3.48
4-methyl-2-pentanone 1.82 8.38 1.93 9.72 1.81 9.07 1.17 5.91
ethyl formate 1.54 3.50 3.20 5.78 3.10 5.64 1.35 3.08
methyl acetate 2.04 11.18 1.96 12.91 2.03 13.38 1.76 10.06
ethyl acetate 0.84 3.52 1.30 4.29 1.09 3.82 0.78 3.34
propyl acetate 1.61 3.57 3.77 7.15 3.62 6.86 0.80 1.67
butyl acetate 1.14 1.40 2.20 2.14 2.26 2.21 0.99 1.32
methyl propionate 0.97 4.21 1.66 6.73 1.41 5.85 1.04 4.17
ethanol 2.15 0.57 2.79 0.61 2.81 0.61 2.37 0.56
1-propanol 3.27 0.55 4.70 0.64 4.68 0.64 2.28 0.50
Open in a new tab
a

Standard uncertainty u(P) = 0.3 kPa.

Table 5. Parameters of the λh Model and the Polynomial Empirical Model (P = 101.3 kPa)a,b.

  λh model
 polynomial empirical model
solvents 100R2 λ h 100R2 A3 B3 C3 D3
acetonitrile 99.60 0.08 ± 5.88 × 10–3 15759.56 ± 601.45 99.92 –2.78 ± 0.73 0.03 ± 7.20 × 10–3 –9.46 × 10–5 ± 2.38 × 10–5 1.07 × 10–7 ± 2.61 × 10–8
DMF 99.93 0.93 ± 0.05 4130.14 ± 182.22 99.98 –2.04 ± 0.30 0.02 ± 2.94 × 10–3 –7.35 × 10–5 ± 9.70 × 10–6 8.57 × 10–8 ± 1.07 × 10–8
acetone 99.68 0.13 ± 0.01 25325.73 ± 1859.73 99.75 0* 0* 0* 0*
2-butanone 99.97 0.46 ± 0.01 7268.96 ± 162.94 99.97 0* 2.42 × 10–3 ± 2.72 × 10–3 –1.05 × 10–5 ± 8.99 × 10–6 1.51 × 10–8 ± 9.89 × 10–9
4-methyl-2-pentanone 98.97 0.02 ± 3.07 × 10–3 61218.96 ± 4271.03 99.39 –1.14 ± 0.47 0.01 ± 4.63 × 10–3 –3.82 × 10–5 ± 1.53 × 10–5 4.27 × 10–8 ± 1.68 × 10–8
ethyl formate 99.69 0.20 ± 0.02 17198.95 ± 1367.28 99.87 0* 2.41 × 10–3 ± 2.41 × 10–3 –9.27 × 10–6 ± 7.97 × 10–6 1.19 × 10–8 ± 8.77 × 10–9
methyl acetate 99.35 0.14 ± 0.02 19040.70 ± 1617.46 99.49 1.02 ± 0.79 –9.95 × 10–3 ± 7.88 × 10–3 3.21 × 10–5 ± 2.60 × 10–5 –3.40 × 10–8 ± 2.8610–8
ethyl acetate 99.76 0.03 ± 1.57 × 10–3 65461.72 ± 2368.57 99.74 0* 0* 0* 0*
propyl acetate 99.28 0.08 ± 0.01 34341.12 ± 3247.92 99.94 0.20 ± 0.13 –1.71 × 10–3 ± 1.31 × 10–3 0* 0*
butyl acetate 99.80 0.11 ± 9.14 × 10–3 33568.65 ± 2257.24 99.90 0* 7.82 × 10–4 ± 1.03 × 10–3 0* 3.83 × 10–9 ± 3.76 × 10–9
methyl propionate 99.53 0.03 ± 2.22 × 10–3 60923.82 ± 2964.81 99.67 0* 0* 0* 0*
ethanol 99.80 0.08 ± 8.53 × 10–3 56639.38 ± 5003.79 99.77 0* 0* 0* 1.80 × 10–9 ± 1.59 × 10–9
1-propanol 99.65 0.20 ± 0.04 28025.26 ± 4390.36 99.69 –0.12 ± 0.04 1.25 × 10–3 ± 3.95 × 10–4 –4.34 × 10–6 ± 1.30 × 10–6 5.03 × 10–9 ± 1.43 × 10–9
Open in a new tab
a

Standard uncertainty u(P) = 0.3 kPa.

b

0* indicates that the parameter has no significance and is not statistically significant.

4.4. KAT-LSER Model

In this research, the KAT-LSER model was used to investigate the solvent effect of the dissolution process of EP in pure solvents and then to analyze the impact of the solvent effect on the solubility of EP. The values of π*, α, β, and δH for the pure solvents are presented in Table 3.

The solubility data of EP in pure solvents measured at 298.15 K was fitted to each property of the solvents using the KAT-LSER model. The model was obtained as

4.4. 19

where n is the number of solvent species, R2 is adjusted R2, F is the F-test, and RSS is the residual sum of squares.

The above results were output directly by the statistical analysis software. The above data denoted that the KAT-LSER model fitted the solubility data of EP well, but the Hildebrand solubility parameter (δH) was not significant in this model and had no statistical significance, so δH was excluded. And from the fitting model, the regression coefficient c1 of π* was positive, which implied that the solubility of EP was positively correlated with this parameter. This indicated that the nonspecific polarity/dipolarity of solvents contributed to the dissolution of EP. The negative regression coefficients of α and β indicated that the solubility of EP decreased with the increase of hydrogen bond donor capacity and hydrogen bond acceptor capacity of solvents. That is, the solve–solvent interaction through specific hydrogen bond was not conducive to the dissolution process of EP. From the regression coefficients of π*, α, and β, the contribution of each parameter to the total solvent effect can be calculated by eq 20, and the following results were obtained: polarity/dipolarity 27.01%, hydrogen bond donor capacity 24.25%, and hydrogen bond acceptor capacity 19.55%. In conclusion, the sum of these coefficients accounted for up to 70.81% of the total solvent effect, demonstrating that the parameters of the KAT-LSER model played a decisive role in the solubility of EP in the selected solvents. Specifically, the solubility of EP in the selected solvents mainly depended on nonspecific polarity/dipolarity.

4.4. 20

where λi is the contribution rate of each parameter.

4.5. Thermodynamic Properties of the Solution

According to the van’t Hoff model, it could be seen that there was a linear relationship between the logarithm of molar solubility of EP (ln x1) and (1/T – 1/Tav), so the linear fitting was plotted with ln x1 as the vertical coordinate and (1/T – 1/Tav) as the horizontal coordinate, and then the slope (−ΔsolH°)/R and the intercept b were obtained. The specific results are shown in Figure 6 and Table 7. Table 7 shows that the adjusted R2 of the models was close to 1, which meant a good fit of the model to the data.

Figure 6.

Figure 6

Open in a new tab

Relationship between the logarithm of the molar solubility (ln x1) and the reciprocal of temperature (1/T – 1/Tav) for EP in 13 pure solvents.

Table 7. Thermodynamic Parameters of the Dissolution Process of EP in 13 Pure Solvents (P = 101.3 kPa)a.

solvents 100R2 intercept slope ΔsolS° (J/(mol·K)) ΔsolH° (kJ/mol) ΔsolG° (kJ/mol) ξH/% ξTS/%
acetonitrile 99.52 –3.95 ± 5.02 × 10–3 –1454.32 ± 35.55 7.06 12.09 9.95 84.96 15.04
DMF 99.87 –5.14 ± 6.73 × 10–3 –3804.11 ± 47.68 61.58 31.63 12.96 62.88 37.12
acetone 99.21 –6.27 ± 0.01 –3142.01 ± 98.82 34.02 26.12 15.81 71.69 28.31
2-butanone 99.96 –5.21 ± 3.25 × 10–3 –3354.22 ± 23.02 48.71 27.89 13.12 65.38 34.62
4-methyl-2-pentanone 99.06 –5.56 ± 8.38 × 10–3 –1719.20 ± 59.33 0.96 14.29 14.00 98.01 1.99
ethyl formate 99.44 –6.15 ± 0.01 –3319.20 ± 87.94 39.89 27.60 15.50 69.53 30.47
methyl acetate 99.61 –5.38 ± 8.45 × 10–3 –2704.92 ± 59.83 29.46 22.49 13.56 71.58 28.42
ethyl acetate 99.61 –5.77 ± 5.82 × 10–3 –1857.99 ± 41.20 2.97 15.45 14.55 94.49 5.51
propyl acetate 98.54 –6.15 ± 0.02 –2667.20 ± 114.76 22.05 22.18 15.49 76.84 23.16
butyl acetate 99.73 –6.94 ± 9.66 × 10–3 –3704.77 ± 68.41 43.94 30.80 17.48 69.81 30.19
methyl propionate 99.36 –5.64 ± 7.16 × 10–3 –1783.94 ± 50.75 2.05 14.83 14.21 95.98 4.02
ethanol 99.72 –8.47 ± 0.01 –4556.31 ± 85.20 54.56 37.88 21.34 69.61 30.39
1-propanol 99.66 –8.95 ± 0.02 –5320.97 ± 109.63 71.49 44.24 22.57 67.12 32.88
Open in a new tab
a

Standard uncertainty u(P) = 0.3 kPa.

The thermodynamic parameters of EP in 13 pure solvents could be calculated from the fitting results, and the detailed results are displayed in Table 7. From Table 7, it could be observed that ΔsolH°, ΔsolS°, and ΔsolG° were all positive during the dissolution process of EP, manifesting that the dissolution process of EP in the 13 pure solvents was endothermic, nonspontaneous, and entropy-increasing. In addition, it was also noted that the value of ξH/% of 13 pure solvents was greater than the value of ξTS/%, indicating that ΔsolH° was the main contributor to ΔsolG° during the dissolution of EP.

Furthermore, this study has identified certain limitations that warrant further improvement and extension in subsequent research. Regarding thermodynamic modeling, various types of models can be selected to correlate and fit the solubility data of EP. Examples of such models include the Wilson model and the NRTL model. For thermodynamic analysis of solutions, molecular dynamics simulations can be employed to investigate the interactions between eplerenone and solvent molecules, which can dynamically elucidate the relationship between solubility of EP and solvent properties.

5. Conclusions

The solubility of EP in 13 pure solvents (acetonitrile, DMF, acetone, 2-butanone, 4-methyl-2-pentanone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, ethanol, and 1-propanol) was determined by the gravimetric method at atmospheric pressure and temperature of 283.15 to 323.15 K. The following conclusions were drawn from the work. The solubility of EP in the selected solvents was positively correlated with the thermodynamic temperature. In the experimental range, EP had the highest molar solubility in acetonitrile (2.67 × 10–2, 323.15 K) and the lowest in 1-propanol (3.65 × 10–5, 283.15 K). The modified Apelblat model, van’t Hoff model, λh model, and polynomial empirical model correlated well with the solubility data of EP, but the best model was the λh model, with a minimum ARD of 7.0 × 10–3 and a minimum RMSD of 6.1 × 10–6. Parameters such as polarity/dipolarity, hydrogen bond donor capacity, and hydrogen bond acceptor capacity accounted for 70.81% of the total solvent effect in KAT-LSER model but mainly depended on nonspecific polarity/dipolarity. The thermodynamic properties (ΔsolH°, ΔsolS°, and ΔsolG°) of the dissolution process of EP in 13 pure solvents were all positive, indicating that the dissolution process of EP was endothermic, nonspontaneous, and entropy-increasing.

This study provides valuable data on the solubility, dissolution characteristics, and thermodynamic parameters of EP. It offers important insights for the production, crystallization, and purification processes of EP, as well as guidance for optimizing the crystallization of EP in industry.

Acknowledgments

The authors are thankful to Wuhan Research Institute of Materials Protection for providing DSC equipment. The authors are also thankful to Li Yinhua for experimental guidance.

Author Contributions

J.L.: Project administration, funding acquisition, writing—review and editing, and supervision. T.L.: Conceptualization, data curation, and writing—original draft. R.Z.: Visualization and investigation. S.Y.: Software and validation. Y.Z.: Methodology. C.Y.: Supervision. S.P.: Data curation. Q.Y.: Resources.

The authors declare no competing financial interest.

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