Solubility in Different Solvents, Correlation, and Solvent Effect in the

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

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Solubility in Different Solvents, Correlation, and Solvent Effect in the Solvent Crystallization Process of Iohexol Zehui Yang,* Danfeng Shao,* and Guoquan Zhou

J. Chem. Eng. Data Downloaded from pubs.acs.org by LUND UNIV on 03/06/19. For personal use only.

School of Materials and Chemical Engineering, Ningbo University of Technology, Ningbo City, Zhejiang Provice, 315211, PRC ABSTRACT: The basis of purification and further theoretical studies of iohexol is the solubility in different solvents. The solubility of iohexol in 12 monosolvents (ethanol, n-propanol, isopropanol, n-butanol, acetone, acetonitrile, ethyl acetate, 1,4dioxane, cyclohexane, 2-butanone, dimethyl sulfoxide (DMSO), and toluene) and the (ethanol + ethyl acetate) solvents system was determined using a static gravimetric method, with the following conditions: temperature is T = (283.15 to 323.15) K and pressure of p = 101.2 kPa. To sum up, the solubility of iohexol in ethanol was the highest, and the solubility in cyclohexane was the lowest. The order of the solubility of iohexol from high to low is ethanol (1.690 × 10−3, 298.15 K) > npropanol (1.041 × 10−3, 298.15 K) > isopropanol (0.6738 × 10−3, 298.15 K) > nbutanol (0.4159 × 10−3, 298.15 K) > DMSO (0.3573 × 10−3, 298.15 K) > acetone (0.3082 × 10−3, 298.15 K) > 2-butanone (0.2547 × 10−3, 298.15 K) > ethyl acetate (0.2151 × 10−3, 298.15 K) > acetonitrile (0.1463 × 10−3, 298.15 K) > 1,4-dioxane (0.08301 × 10−3, 298.15 K) > toluene (0.05118 × 10−3, 298.15 K) > cyclohexane (0.01997 × 10−3, 298.15 K). Two semiempirical models (modified Apelblat equation and λh equation) served as the correlation equations to correlate the experimental solubility values of iohexol in different pure solvents. The Jouyban−Acree model, van’t Hoff/Jouyban−Acree model, and Apelblat/Jouyban−Acree models served as the binary mixture system correlation equations. Compared with the correlation results, all the correlation models can fit the experimental solubility values of iohexol in pure or mixed solvent systems very well. Consequently, for the monosolvents, the relative average deviation (RAD) and root-mean-square deviation (RMSD) values did not exceed 1.66% and 2.42 × 10−5, and the values are for the binary system are 0.66 × 10−5 and 0.60%. Moreover, interactions of solute and solvents have been researched in 12 monosolvents. The hydrogen bonds and van der Waals interaction play an important role in the dissolution process of iohexol. Particularly, the experimental solubility values and correlation results of iohexol obtained play an important role in its purification, recrystallization, and formulation development in production. medical field.9 Therefore, it has attracted a great deal of attention from synthetic chemists, and different methods for the preparation of iohexol have been extensively investigated at home and abroad.1−5,9−13 The primary production of iohexol includes a multistep chemical synthesis and is completed by a purification process. There are seventeen impurities in the quality standard of iohexol in the European Pharmacopoeia.9,10 However, every drug used in clinical studies is prescribed by pharmacopoeia, and the total content of impurities is less than or equal to 1%. Thus, controlling impurities in a safe and reasonable limit will directly affect the quality and safety of the iohexol.9 In the previous publications, it is known from the previous process that iohexol is obtained and purified by recrystallization in n-butanol, ethanol, acetone, isopropanol, and ethyl acetate or mixed solvents.1−3 In addition, 1,4-dioxane was selected as solvent priority during the preparation process of iohexol.1 Furthermore, DMSO is an important polar aprotic solvent with very low toxicity and immense biological

1. INTRODUCTION Iohexol (CAS No. 66108-95-0, Figure 1) belongs to the class of nonionic contrast media.1−3 It is one of the most used

Figure 1. Chemical structure of iohexol.

products in diagnostic X-ray procedures.4−6 It is widely used in urography, arteriography, venography, and endoscopic retrograde pancreatography1,7 since it presents a number of advantages over other contrast media, such as high safety, high visibility, and low osmotic pressure, mainly in terms of tolerability.1,8−11 As a result, iohexol has become the bestselling contrast agent in the international market and has become the standard for various kinds of contrast agents in the © XXXX American Chemical Society

Received: November 20, 2018 Accepted: February 27, 2019

A

DOI: 10.1021/acs.jced.8b01101 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Table 1. Source and Purity of the Materials Used in the Work molar mass (g·mol−1)

CAS registry no.

iohexol

821.14

66108-95-0

ethanol

46.07

64-17-5

n-propanol n-butanol isopropanol acetone ethyl acetate acetonitrile 1,4-dioxane cyclohexane 2-butanone DMSO toluene

60.10 74.12 60.10 58.08 88.11 41.05 88.11 84.16 72.11 78.13 92.14

71-23-8 71-36-3 67-63-0 67-64-1 141-78-6 75-05-8 123-91-1 110-82-7 78-93-3 67-68-5 108-88-3

chemicals

source Shanghai Macklin Biochemical Co., Ltd. Sinopharm Chemical Reagent Co.

initial mass fraction purity

final mass fraction purity

purification method

analytical method

0.983

0.994

recrystallization

HPLCa

0.997



GCb

0.995 0.997 0.995 0.995 0.995 0.994 0.996 0.996 0.994 0.996 0.994

          

GCb GCb GCb GCb GCb GCb GCb GCb GCb GCb GCb

a

High-performance liquid-phase chromatograph. bGas chromatography.

importance.14 Propanol cyclohexane 2-butanone and toluene were safe and widely used solvents in the chemical and pharmaceutical industries. On the basis of the considerations mentioned above, for the sake of optimization of conditions of reactions and provision of a fundamental basis for purifying the crude products, the static equilibrium method was used to measure the experimental solubility of iohexol in pure mixed solvent systems. The pure and mixed solvent systems comprise the (acetonitrile, ethanol, toluene, n-propanol, DMSO, isopropanol, n-butanol, acetone, ethyl acetate, 1,4-dioxane, cyclohexane, and 2-butanone) and (ethanol + ethyl acetate) systems. The temperature condition is T = (283.15 to 323.15) K. Solvent effect was also discussed. The solubility data were correlated by thermodynamic models. All model correlation results can match the experimental solubility values very well and can help to illuminate the relationship among solubility, temperature, and solvent composition.

x is mole fraction solubility of iohexol. The equation parameters A and B promulgate the effect of solution nonideality on the solute solubility and the variation of solute activity coefficient, respectively. The parameter C promulgates the influence of temperature upon the fusion enthalpy of a solute. The Jouyban−Acree model can serve as a correlation equation to correlate the solubility of iohexol in the binary system.18−20 It is shown as the following equation. ln x12 = w1 ln x1,T + w2 ln x 2,T +

2

∑ Ji (w1 − w2)i i=0

(3)

where w1 and w2 stand for the solvents 1 (ethanol) and 2 (ethyl acetate) in (ethanol + ethyl acetate) mixtures free of the solute (iohexol) in mass fraction, respectively; x12 is the solubility (x) of iohexol in the binary system at absolute temperature; x1,T and x2,T are the solubility (x) of iohexol in ethanol and ethyl acetate; and Ji are the parameters of the Jouyban−Acree model. The van’t Hoff/Jouyban−Acree model can be derived and expressed as eq 4. Parameters of A and B in this model are obtained from correlation of the van’t Hoff model.21,22

2. THERMODYNAMIC MODELS In this work, the λh equation15 and modified Apelblat equation16,17 are correlated to the experimental solubility data in monosolvents, and for binary solvent systems, the experimental data were correlated with the Jouyban−Acree model,18−20 Van’t Hoff/Jouyban−Acree model,21,22 and modified Apelblat/Jouyban−Acree model.21,22 λh Equation. Buchowski and co-workers present this equation first, and it has an excellent effect for correlating the solubility and is a semiempirical model.15 λ and h are two equation parameters, and it shown as below. É ÅÄÅ ij 1 λ(1 − x) ÑÑÑÑ 1 yzz Å lnÅÅÅ1 + − ÑÑ = λhjjj z j ÅÅÇ ÑÑÖ x Tm/K zz{ (1) k T /K

i i B1 yz B2 yz zz + w2jjjA 2 + zz ln x12 = w1jjjjA1 + z j T /K { T /K z{ k k 2 w1w2 + ∑ J (w1 − w2)i T /K i = 0 i

(4)

A similar approach can be taken for the Apelblat/Jouyban− Acree model. Substituting eq 2 into eq 3 can obtain eq 5, which is the Apelblat/Jouyban−Acree model.21,22 ÄÅ ÉÑ B1 ÅÅÅ ÑÑ ln x12 = w1ÅÅA1 + + C1 ln(T /K)ÑÑÑ ÅÅÇ ÑÑÖ T /K ÄÅ ÅÅ ÑÉÑ B2 Å Ñ + w2ÅÅÅA 2 + + C2 ln(T /K)ÑÑÑ ÅÅ ÑÑÖ T /K ÇÅ 2 w1w2 + ∑ J (w1 − w2)i T /K i = 0 i (5)

In this equation, x represents the iohexol mole fraction solubility, and Tm is the melting temperature of iohexol in absolute temperature. The correlation parameters h and λ represent the mixing enthalpy and the number association in solute molecules in the associating system. Modified Apelblat Equation. This equation is also a semiempirical equation.16,17 This equation has been used to correlate the solubility in pure solvents, which is shown as eq 2. ln x = A + B /(T /K) + C ln(T /K)

w1w2 T /K

(2) B



Article

The mole fraction solubility (xe) of iohexol in monosolvents can be calculated with eq 6.

3. EXPERIMENTAL SECTION 3.1. Materials. Iohexol with a mass fraction of 0.983 was purchased by Shanghai Macklin Biochemical Co., Ltd. (from China). The crude iohexol was crystallized in acetone three times. The purity of the ultimate iohexol used in experiment with a mass fraction was 0.994. The purity was confirmed by a high-performance liquid-phase chromatograph (HPLC). The experimental solvents (ethanol, DMSO, n-propanol, 2butanone, isopropanol, n-butanol, cyclohexane, acetone, 1,4dioxane, acetonitrile, toluene, and ethyl acetate) were purchased from Sinopharm Chemical Reagent Co., Ltd., China. The solvents were all analytical grade and used without further purification, and the purities were all greater than 0.994 in mass fraction. The detailed information on sample and solvents was presented in Table 1. 3.2. Infrared Spectroscopy Analysis. Infrared spectroscopy (IR) analysis is provided by a Perkin Elmer spectrometer. First, iohexol (2 mg) and pure dry KBr (200 mg) were mixed evenly and then pelletized at p = 10 bar in vacuum. The temperature condition for IR absorption spectrum scanning is room temperature. A Shimadzu 8400S FTIR spectrophotometer was used to test the sample, and the field frequency was from 400 to 4000 cm−1. 3.3. Solubility Determination. In this experiment, the solubility of iohexol in monosolvents and mixed solvents was measured by the static equilibrium method, and the temperature condition is T = (283.15 to 323.15) K.23−25 The reliability of verification of the experimental apparatus was verified in our previous work.26 The HPLC acted as the analytical means to test the experimental solubility data of iohexol. The mixed solvents for experiment were quantified by the analytical balance, and the model is CPA225D. The mass fraction of ethanol in the (ethanol + ethyl acetate) system varied from 0 to 1. Excessive solid sample was added into the glass vessel, and then about 40 mL of solvent was added. The sample was blended by a magnetic stirrer evenly. The experimental temperature was kept by a thermostatic watercirculator bath attached with circulating water. A mercury glass microthermometer was used to measure the actual temperature in solvent, and the standard uncertainty is 0.02 K. The equilibrium liquid phase was taken out and used by a 2 mL preheated syringe at every 2 h, and for convenience, a pore syringe filter (PTFE 0.2 μm) was connected on the preheated syringe and then analyzed by the HPLC. For all the studied systems, 13 h can make the solution reach equilibrium. When the system comes to balance, we stopped the magnetic stirrer and let the solid precipitate for about another 30 min. An amount of 2 mL of supernate was brought into a 25 mL flask with syringe preheated quickly, and then the flask was covered with a rubber stopper and weighed again. The sample was diluted to the mark, and then 1 μL was removed to analyze. The sample was analyzed by a reverse-phase column equipped on the machine, and the type of phase column is LP-C18 (250 mm × 4.6 mm). The temperature of the phase column was held at 303 K. The UV wavelength was 245 nm. Pure methanol was used as the mobile phase, and the flow rate was 1.0 mL· min−1. Each experiment was repeated three times, and final experimental results were the average values of the three measurements. The relative standard uncertainty in mole fraction solubility was 0.0186.

xe =

m1/M1 m1/M1 + m2 /M 2

(6)

where M1 and M2 are the iohexol and the solvents molar mass, and m1 and m2 are the mass of iohexol and corresponding solvents. For a briny system, the solubility (xe) of iohexol in mole fraction is obtained with eq 7, and the initial composition of the binary solvent mixture system (w) is calculated with eqs 8 and 9. m1/M1 m1/M1 + m2 /M 2 + m3 /M3

(7)

w1 =

m2 m 2 + m3

(8)

w2 =

m3 m 2 + m3

(9)

xe =

where m1 is iohexol mass; m2 is ethanol mass; m3 is the ethyl acetate mass; and M1, M2, and M3 are the corresponding molar masses.

4. RESULTS AND DISCUSSION 4.1. Infrared Spectroscopy Investigations. IR Spectroscopy (Figure 2) shows the infrared absorption peaks in the

Figure 2. Infrared spectroscopy of iohexol: (a) raw material, (b) crystallized in ethanol, (c) crystallized in n-propanol, (d) crystallized in isopropanol, (e) crystallized in n-butanol, (f) crystallized in acetone, (g) crystallized in ethyl acetate, (h) crystallized in acetonitrile, (i) crystallized in 1,4-dioxane, (j) crystallized in cyclohexane, (k) crystallized in DMSO, (l) crystallized in 2-butanone, (m) crystallized in toluene, and (n) crystallized in (ethanol + ethyl acetate).

raw material curve (a) around 3408 cm−1, 2922 cm−1, 2355 cm−1, 1643 cm−1, 1544 cm−1, 1384 cm−1, 1251 cm−1, 1039 cm−1, and 669 cm−1. From Figure 2, it can be seen that the other curve (b−n), which crystallized in different solvents, has the same infrared absorption peaks with curve (a). C



Article

Table 2. Experimental Solubility (x) of Iohexol in Mole Fraction in 12 Monosolvents at the Temperature Range from T = (283.15 To 323.15) K under 101.2 kPaa,b 1000x

1000x T/K

xexp

xApelblat

xλh

T/K

Ethanol 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 100RAD

1.132 1.304 1.484 1.690 1.924 2.168 2.440 2.739 3.061

283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 100RAD

0.7150 0.8040 0.9115 1.041 1.188 1.370 1.564 1.813 2.095

283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 100RAD

0.3886 0.4565 0.5548 0.6738 0.8062 0.9658 1.146 1.366 1.648

283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 100RAD

0.2349 0.2868 0.3425 0.4159 0.4999 0.6014 0.7225 0.8664 1.033

283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 100RAD

0.1744 0.2090 0.2557 0.3082 0.3715 0.4426 0.5264 0.6203 0.7410

283.15 288.15

0.1257 0.1500

1.133 1.301 1.487 1.693 1.920 2.169 2.441 2.738 3.061 0.11 n-Propanol 0.7132 0.8054 0.9135 1.040 1.189 1.364 1.570 1.811 2.095 0.19 Isopropanol 0.3858 0.4638 0.5572 0.6688 0.8020 0.9608 1.150 1.375 1.643 0.65 n-Butanol 0.2351 0.2848 0.3444 0.4156 0.5006 0.6018 0.7221 0.8649 1.034 0.21 Acetone 0.1738 0.2112 0.2555 0.3079 0.3695 0.4417 0.5262 0.6245 0.7388 0.37 Ethyl Acetate 0.1248 0.1506

1.141 1.303 1.484 1.686 1.910 2.159 2.435 2.742 3.084 0.36

293.15 298.15 303.15 308.15 313.15 318.15 323.15 100RAD 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 100RAD

0.6895 0.7985 0.9212 1.059 1.214 1.388 1.582 1.800 2.043 1.66

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 100RAD

0.3771 0.4609 0.5599 0.6763 0.8125 0.9713 1.156 1.370 1.618 1.07

283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 100RAD

0.2311 0.2837 0.3460 0.4195 0.5059 0.6070 0.7249 0.8619 1.021 0.97

283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 100RAD

0.1726 0.2108 0.2559 0.3088 0.3707 0.4429 0.5268 0.6239 0.7362 0.41

293.15 298.15 303.15 308.15 313.15

0.1254 0.1509

D

xexp

xApelblat

Ethyl Acetate 0.1807 0.2154 0.2555 0.3015 0.3541 0.4138 0.4814 0.21 Acetonitrile 0.08466 0.08428 0.1007 0.1016 0.1229 0.1222 0.1463 0.1466 0.1752 0.1755 0.2104 0.2098 0.2500 0.2502 0.2975 0.2977 0.3538 0.3537 0.31 1,4-Dioxane 0.05701 0.05702 0.06904 0.06893 0.08301 0.08321 0.1002 0.1003 0.1211 0.1207 0.1447 0.1450 0.1740 0.1740 0.2084 0.2084 0.13 Cyclohexane 0.009380 0.009470 0.01225 0.01220 0.01546 0.01561 0.01997 0.01982 0.02508 0.02500 0.03142 0.03133 0.03895 0.03902 0.04811 0.04832 0.05961 0.05949 0.50 2-Butanone 0.1483 0.1461 0.1784 0.1774 0.2114 0.2138 0.2547 0.2557 0.3011 0.3038 0.3579 0.3585 0.4253 0.4203 0.4902 0.4899 0.5661 0.5678 0.69 DMSO 0.2935 0.2923 0.3573 0.3556 0.4281 0.4300 0.5105 0.5171 0.6245 0.6184 0.1803 0.2151 0.2559 0.3014 0.3546 0.4137 0.4813

xλh 0.1806 0.2150 0.2548 0.3007 0.3535 0.4140 0.4833 0.27 0.08303 0.1012 0.1226 0.1478 0.1771 0.2113 0.2510 0.2969 0.3499 0.77 0.05623 0.06879 0.08365 0.1012 0.1217 0.1457 0.1737 0.2062 0.74 0.009420 0.01217 0.01560 0.01983 0.02502 0.03136 0.03905 0.04833 0.05948 0.45 0.1481 0.1783 0.2135 0.2544 0.3016 0.3560 0.4187 0.4905 0.5728 0.53 0.2930 0.3559 0.4298 0.5165 0.6176



Article

Table 2. continued 1000x

1000x exp

T/K

x

318.15 323.15 100RAD

0.7371 0.8694

283.15 288.15 293.15 298.15 303.15 308.15

0.02502 0.03223 0.04064 0.05118 0.06276 0.07567

x

Apelblat

x

λh

exp

T/K

x

313.15 318.15 323.15 100RAD

0.09188 0.1116 0.1338

DMSO

xApelblat

xλh

0.09248 0.1115 0.1336 0.70

0.09230 0.1119 0.1351 0.99

Toluene 0.7358 0.8711 0.57

0.7354 0.8722 0.54

0.02553 0.03233 0.04056 0.05045 0.06222 0.07614

0.02566 0.03230 0.04036 0.05009 0.06177 0.07572

Toluene a

x stands for the experimental mole fraction solubility of iohexol at the studied temperature T; RAD denotes the relative average deviation, respectively. bStandard uncertainties u are u(T) = 0.02 K and u(p) = 400 Pa. Relative standard uncertainty ur is ur(x) = 0.0186. xexp  experiment data, xapelblat  calculated by the Apelblat model, xλh  calculated by the λh model.

Figure 3. Solubility (x) of iohexol in mole fraction in monosolvents at different temperature: (a) ■, ethanol; ●, n-propanol; ▲, isopropanol; ▼, nbutanol; (b) ○, DMSO; ◆, acetone; ◇, 2-butanone; ★, ethyl acetate; ◀, acetonitrile; ▶, 1,4-dioxane; Δ, toluene; □, cyclohexane. Calculated curves by the modified Apelblat equation.

but also van der Waals interactions will have a great effect on the solubility behaviors of iohexol. From Figure 3 and Table 2, the solubility of iohexol in alcohol is larger than in other solvents. This may be because the H-bonds were formed between the N−H groups of iohexol and the free electron pairs of the oxygen atoms of alcohol. In addition, it is worth noting that taking the steric effect and van der Waals force into consideration is important. Iohexol’s molecular size is comparatively large, when iohexol interacts with alcohols with longer carbon chain: the longer the carbon chain is, the lower the solubility of biapenem. In order to study the effect of solvation interaction on solubility, some publications have proposed a multiple linear regression analysis (MLRA) involving various solvent parameters. Generally, previous publications have reported several solute−solvent interaction modes. It is customary to describe any property linearly related to the Gibbs energy (XYZ) of a solute−solvent system in terms of LSER by the following eq 10.28,29

Accordingly, during the experimental process, there is no solvate formation and polymorphic transformation. 4.2. Solubility Results. 4.2.1. Solubility Values in Monosolvents. The experimental solubility (x) of iohexol in mole fraction in ethyl acetate, ethanol, acetone, n-propanol, 2butanone, isopropanol, toluene, n-butanol, acetonitrile, 1,4dioxane, cyclohexane, and DMSO was measured. The temperature condition was T = (283.15 to 323.15) K. The experimental solubility data are listed in Table 2, and the data points were shown graphically in Figure 3. From Figure 3, for one solvent, the solubility of iohexol increases with increasing temperature. At a definite temperature, the experimental solubility of iohexol in mole fraction is largest in ethanol and lowest in cyclohexane. Figure 3 further shows the solubility from high to low is ethanol > n-propanol > isopropanol > nbutanol > DMSO > acetone > 2-butanone > ethyl acetate > acetonitrile > 1,4-dioxane > toluene > cyclohexane. For polar protic solvents (ethanol, n-propanol, n-butanol, and isopropanol), the order of the experimental solubility values in mole fraction are according to the polarities of the solvents,27 which shows that the polarity seems to be a significant factor to affect the solubility of iohexol in these alcohols. It can find the same tendency for the other systems, except for acetonitrile. In addition, cyclohexane has the weakest polarity, so the solubility of iohexol in cyclohexane is the lowest. Furthermore, due to the large dipole moments in the iohexol molecule, it may offer strong nonspecific dipole− dipole interactions with the solvent. Thus, solute and solvent molecules can form hydrogen bonds. In the iohexol + alcohol system, it can be speculated that not only the hydrogen bonds

XYZ = XYZ0 + cavity formation energy + Σ solute − solvent interaction energy

(10)

The term XYZ0 lies on the solute property only. The general formula of the above equation can be used as all solute− solvent interaction modes. The Gibbs free energy change of solvent-dependent reaction can be described by the Kamlet and Taft linear solvation energy relationship model, KATLSER, which is described as eq 11.30 E


Journal of Chemical & Engineering Data ln(x) = c0 + c1α + c 2β + c3π * + c4

Article

Vsδ H2 100RT

Table 4. Experimental Solubility (xeT,W × 103) of Iohexol in Mole Fraction in the Ethanol (w) + Ethyl Acetate (1 − w) System with Various Mass Fractions within T = (283.15 to 323.15) K at p = 101.1 kPaa

(11)

In this equation, α, β, and π* stand for the hydrogen bond acidity, hydrogen bond basicity, and dipolarity/polarizability of the solvent, respectively. The variable δH is the solute Hildebrand solubility parameter. Vs is molar volume of solute. The solubility of iohexol in monosolvents was examined by the KAT-LSER model at 298.15 K. Table 3 lists α, β, π*, and

w

Table 3. Hildebrand Solubility Parameters (δH) and Solvatochromic Parameters α, β, and π* for the Selected Solventsa solvent

α

β

π*

δ2H/1000 (J/cm3)

ethanol n-propanol isopropanol n-butanol acetone acetonitrile ethyl acetate 1,4-dioxane cyclohexane 2-butanone DMSO toluene

0.86 0.84 0.76 0.84 0.08 0.19 0 0 0 0.06 0 0

0.75 0.90 0.84 0.84 0.43 0.40 0.45 0.37 0 0.48 0.76 0.11

0.54 0.52 0.48 0.47 0.71 0.75 0.55 0.55 0 0.67 1.00 0.54

0.5630 0.6025 0.5630 0.5333 0.3994 0.5806 0.331 0.4194 0.02813 0.3648 0.6027 0.3334

T/K

1

0.80

0.60

0.40

0.20

0

283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

1.132 1.304 1.484 1.690 1.924 2.168 2.440 2.739 3.061

0.8996 1.023 1.159 1.332 1.540 1.730 1.968 2.216 2.499

0.6600 0.7680 0.8728 1.002 1.157 1.319 1.505 1.714 1.941

0.4411 0.5100 0.5946 0.6969 0.8037 0.9294 1.067 1.224 1.405

0.2628 0.3088 0.3552 0.4177 0.4895 0.5774 0.6646 0.7670 0.8918

0.1257 0.1500 0.1803 0.2151 0.2559 0.3014 0.3546 0.4137 0.4813

a Standard uncertainties u are u(T) = 0.02 K and u(p) = 400 Pa. Relative standard uncertainty ur is ur(x) = 0.0186. Solvent mixtures with relative standard uncertainty ur(w) = 0.03. w represents the mass fraction of ethanol in the ethanol (w) + ethyl acetate (1 − w) binary solvents system.

a

Taken from refs 29−34.

δ2H values for these monosolvents, which are taken from the literature.31−36 The results of multiple regression analysis are described as eq 12. ln(x) = −10.679 + 0.307α + 2.921β + 0.883π * + 0.099

Vsδ H2 100RT

(12)

n = 12, R = 0.95, RSS = 1.22, and F = 89.66. From eq 12, the positive signs of regression coefficients of α,

Figure 4. Solubility (x) of iohexol in mole fraction in solvent mixtures (ethanol (w) + ethyl acetate (1 − w)) at different temperature: experimental and calculated solubility data of iohexol in ethanol (w) + ethyl acetate (1 − w) mixed solutions with various mass fractions at different temperatures. Calculated surface by the Jouyban−Acree model in solvent mixtures.

Vsδ H2

β, π*, and indicate that the solubility of iohexol increases 100RT with an increase in these three parameter values. Therefore, HBA and HBD interaction of the solvent with the solute, nonspecific dipolarity/polarizability interactions, and the cavity term accounted for by Hildebrand solubility parameters are in favor of the increase of solubility. Moreover, hydrogen bond basicity, the hydrogen bond acidity, dipolarity/polarizability of the solvent, and the cavity term account for 19.62%, 2.06%, 5.93%, and 0.66% of total solvent effects, respectively. The hydrogen bond basicity has a great contribution to the total solvent effect for the studied monosolvents, and the cavity term has a small impact on total solvent effect. 4.2.2. Solubility Values in Binary Mixture Systems. The iohexol solubility (x) in mole fraction in the binary mixed solvents of (ethanol + ethyl acetate) is listed in Table 4. Simultaneously, the relationship among solubility, solvent composition, as well as temperature is plotted in Figure 4. From Table 4 and Figure 4, the mole fraction solubility (x) of iohexol is a function of solvent composition as well as temperature. The solubility (x) of iohexol in mole fraction increases with increasing ethanol mass fraction as well as temperature. From the results, it is easy to see that the

solubility of iohexol in pure ethanol has the maximum values, and minimum values are in pure ethyl acetate. 4.3. Solubility Correlation. The nonlinear regression method was used as a correlation method to calculate the experimental solubility of iohexol in studied solvents.37 The correlation function is shown as the following equation: F=

∑ (ln xie − ln xic)2 i=1

xei

(13)

xci

Here ln and ln are the logarithm of experimental data and correlated data with models, respectively. What’s more, RAD values and RMSD values calculated by the following equations are used for evaluating these five thermodynamics models. 1 RAD = N F

i |xic − xie| yz zz zz e k xi {

∑ jjjjj N

i=1

(14) DOI: 10.1021/acs.jced.8b01101 J. Chem. Eng. Data XXXX, XXX, XXX−XXX


Article

Table 5. Parameter Values Regressed by Equations as Well as RMSD Values for Iohexol in 12 Monosolvents λh equation

modified Apelblat equation solvent

A

B

C

105RMSD

λ

h

105RMSD

ethanol n-propanol isopropanol n-butanol acetone ethyl acetate acetonitrile 1,4-dioxane cyclohexane 2-butanone DMSO toluene

−5.921 −193.13 −120.61 −99.64 −49.72 −7.320 −92.79 −111.44 −23.68 28.75 −8.942 29.79

−1951.59 6296.29 2289.75 1260.45 −935.11 −2671.81 996.38 1707.84 −2989.92 −4303.88 −2873.21 −5001.37

1.068 28.99 18.54 15.38 7.857 1.376 14.15 16.91 4.015 −3.963 1.867 −4.021

0.24 0.29 0.54 0.11 0.19 0.045 0.049 0.020 0.012 0.23 0.36 0.044

0.0142 0.0122 0.0241 0.0162 0.0108 0.0056 0.0050 0.0034 0.0021 0.0067 0.0142 0.0032

141234.7 185554.0 133804.3 203044.6 297096.6 527919.8 637222.3 974000.1 2025864 442932.5 233427.9 1177286

1.00 2.42 1.20 0.57 0.22 0.093 0.17 0.10 0.011 0.33 0.37 0.071

Table 6. Parameters Values Regressed Using Three Thermodynamic Cosolvency Models Jouyban−Acree ethanol + ethyl acetate

102RAD 105RMSD

van’t Hoff/Jouyban−Acree

parameter

value

parameter

value

parameter

value

J0 J1 J2

408.79 −126.38 11.49

A1 B1 A2 B2 J0 J1 J2

1.260 −2277.97 1.934 −3093.82 409.19 −127.40 12.16

A1 B1 C1 A2 B2 C2 J0 J1 J2

−5.921 −1951.60 1.068 −7.320 −2671.81 1.376 408.26 −124.96 10.61 0.55 0.60

0.45 0.55

0.60 0.66

5. CONCLUSIONS In this research, the phase behaviors and the experimental solubility of iohexol in 12 monosolvents and the (ethanol + ethyl acetate) binary system were measured by the static equilibrium method. The experimental atmospheric pressure is about 101.2 kPa, and the temperature condition is T = (283.15 to 323.15) K. The iohexol mole fraction solubility in pure solvents increased with increasing temperature. They ranked as ethanol > n-propanol > isopropanol > n-butanol > DMSO > acetone > 2-butanone > ethyl acetate > acetonitrile > 1,4dioxane > toluene > cyclohexane. The hydrogen bonds and van der Waals interaction play an important role in the dissolution process of iohexol. From solvent effect, the hydrogen bond basicity has a great contribution to the total solvent effect for the studied monosolvents. The two semiempirical models (modified Apelblat equation and λh equation) served as the correlation equations to correlate the experimental solubility values of iohexol in different pure solvents. The RMSD and RAD values did not exceed 2.42 × 10−5 and 1.66%, respectively. What’s more, the experimental solubility values in the (ethanol + ethyl acetate) system were correlated by the Jouyban−Acree, van’t Hoff/Jouyban−Acree, and Apelblat/Jouyban−Acree models. The RMSD and RAD values do not exceed 0.66 × 10−5 and 0.60%, respectively. In brief, the selected thermodynamic models can correlate the solubility of iohexol in the monosolvents and binary solvent mixtures very well. Finally, the experimental data measured by this work and the correlation results by the thermodynamic model could be an auxiliary guide in design, separation, and purification processes of iohexol in industry.

N

RMSD =

∑i = 1 (xic − xie)2 N

Apelblat/Jouyban−Acree

(15)

Here N represents the experimental data points’ numbers, and xic and xei represent the calculated solubility values and experimental data, respectively. The melting point of iohexol is taken by ref 38. Table 5 lists λ and h parameter values regressed by the λh equation; A, B, and C parameters values are regressed by the modified Apelblat equation, as well as the RMSD values; and Ji is regressed by three cosolvency models along with the RMSD values, in Table 6. What’s more, in order to compare the experimental solubility values with the correlation solubility values, Figure 3 and Figure 4 show the correlation solubility values of iohexol using the modified Apelblat equation in monosolvents, and correlation solubility values used the Jouyban−Acree equation in the binary mixture system. In addition, the calculated RAD values for iohexol in monosolvents and solvent mixtures are presented in Tables 2 and 6, respectively. From Table 5, the highest RMSD is for the system of iohexol + n-propanol (2.78 × 10−5). However, the maximum RAD values are 1.93%. For binary solvent mixtures, the values of RAD and RMSD are listed in Table 6, and the RAD values are less than 0.60%. What’s more, the RMSDs do not exceed 0.66 × 10−5. In general, the thermodynamic models can correlate the solubility of iohexol in the monosolvents and binary mixture systems at elevated temperatures very well. G



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AUTHOR INFORMATION

Corresponding Authors

*Zehui Yang ([email protected]). *Danfeng Shao ([email protected]). ORCID

Zehui Yang: 0000-0001-7588-366X Funding

The research is supported by the China National Key Research and invention program of the 13th Five-Year Plan (No. 2017YFD0200707). The authors also want to give thanks to the Ministry of Education Scientific Research Foundation (No. XM20131225085213994) as well as Zhejiang Province Public Technology Project (No. 2013C31G2290019) and Ningbo Natural Science Foundations (No. 2013A610094 and No. 2018A610411). Notes

The authors declare no competing financial interest.

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