Solubility and preferential solvation of econazole nitrate in binary solvent mixtures of methanol, ethanol and 1,4-dioxane in water

J. Chem. Thermodynamics 111 (2017) 228–237

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Solubility and preferential solvation of econazole nitrate in binary solvent mixtures of methanol, ethanol and 1,4-dioxane in water Gaoquan Chen, Jiao Chen, Chao Cheng, Yang Cong, Cunbin Du, Hongkun Zhao ⇑ School of Chemistry & Chemical Engineering, YangZhou University, YangZhou, Jiangsu 225002, People’s Republic of China

a r t i c l e

i n f o

Article history: Received 28 February 2017 Received in revised form 25 March 2017 Accepted 31 March 2017 Available online 3 April 2017 Keywords: Econazole nitrate Solubility Jouyban-Acree model Inverse Kirkwood–Buff integrals IKBI Preferential solvation

a b s t r a c t The solubility of econazole nitrate in binary mixed solvents of (methanol + water, ethanol + water and 1,4-dioxane + water) were measured experimentally via the isothermal dissolution equilibrium method in the temperature range of (278.15–318.15) K under 101.2 kPa. For the (1,4-dioxane + water) system, at a certain composition of 1,4-dioxane, the solubility of econazole nitrate increased with an increase in temperature; nevertheless at the same temperature, they increased at first and then decreased with an increase in mass fraction of 1,4-dioxane. At the same temperature and mass fraction of methanol, ethanol or 1,4-dioxane, the solubility of econazole nitrate was greater in (methanol + water) than in the other two mixed solvents. The solubility values were correlated by using Jouyban-Acree model, and the dissolution enthalpies of the dissolution process were computed. Preferential solvation parameters of econazole nitrate were also derived by means of the inverse Kirkwood-Buff integrals method. The preferential solvation parameter by water dx1,3 is negative in water-rich mixtures but positive in compositions from 0.31 to 1.0 in mole fraction of methanol and from 0.24 to 1.0 in mole fraction of ethanol. It is conjecturable that in intermediate composition of alcohol and alcohol-rich mixtures the interaction by acidic hydrogen-bonding by methanol/ethanol on the basic sites of econazole nitrate played a relevant role in the drug solvation. However in 1,4-dioxane (1) + water (2) mixtures with 0.18 < x1 < 0.50 positive dx1,3 values were observed, but with 0.50 < x1 < 1.0 negative dx1,3 values were observed again. The solubility data presented in this work expand the physicochemical information about drugs in binary aqueous-co-solvent mixtures. Ó 2017 Published by Elsevier Ltd.

1. Introduction The solubility behaviour of drugs in co-solvent mixtures as a function of composition and temperature is assessed essentially for the purposes of raw material purification, design of liquid dosage forms, and understanding of the mechanisms relating to the physical and chemical stability of pharmaceutical dissolutions [1,2]. Thus, the solubility of active ingredients is an important physicochemical property to be considered in pharmaceutical design because it affects the drug efficacy, influencing several biopharmaceutical and pharmacokinetic properties [3,4]. On the other hand, temperature-dependence of the solubility allows performing a thermodynamic analysis to insight into the molecular mechanisms relating to the drug dissolution processes [5]. Moreover, drug solubility in co-solvent systems is employed to estimate the preferential solvation of the solute by the solvent components in mixtures. This information provides a powerful tool in the under⇑ Corresponding author. E-mail address: [email protected] (H. Zhao). http://dx.doi.org/10.1016/j.jct.2017.03.038 0021-9614/Ó 2017 Published by Elsevier Ltd.

standing of molecular interactions relating to the drug dissolution processes [6,7]. Econazole nitrate (CAS Reg. No. 24169-02-6; chemical structure shown in Fig. 1) is an essential class of chemical drugs. It is an efficient and safe broad-spectrum antifungal drug [8–10]. This drug has shown important microbiological activities against fungal infections, such as dermatophytoses and microzyme, and it has been used in treatment of majority mycosis like the jock itch, foot moss, tinea versicoeor and the Candida dermatitis [11–14]. Due to its good properties, econazole nitrate has been received great attention. Nevertheless, despite the usefulness of this drug, physicochemical properties of econazole nitrate in solution have been studied but the data on its solubility in aqueous and organic media are still not complete [14,15]. Up to yet, only Xie and co-workers determine the econazole nitrate solubility in several pure organic solvent [15]. Its solubility data in co-solvent mixtures have not been reported in the previous works. Some theoretical and semi-empirical models can be employed to predict drug solubilities in solvent mixtures. However the availability of experimental data is still fundamental for the pharma-

G. Chen et al. / J. Chem. Thermodynamics 111 (2017) 228–237

Cl

Cl N

N

O . HNO 3

Cl

229

Electronic CO., Ltd., China. The true temperature of solution was displayed by a mercury glass micro thermometer (standard uncertainty: 0.02 K) inserted in the inner chamber of the jacket glass vessel. A condenser was connected with the glass vessel to prevent the solvent from escaping. An analytical balance (model: BSA224S) having a standard uncertainty of 0.0001 g was provided by Satorius Scientific Instrument (Beijing), which was employed to determine the mass of the solute, solvent, and saturated solution. Before experiment, the reliability of experimental apparatus was verified by measuring the benzoic acid solubility in toluene [24,25]. 2.2. Preparation of solvent mixtures

Fig. 1. The chemical structure of econazole nitrate.

ceutical scientists [16]. Because the solubility of econazole nitrate in neat water is too low [14], some aqueous and non-aqueous mixtures may be employed to increase the solubility of the drug. Although co-solvency as the drug solubilizing technique has been widely used in pharmacies long ago, recently the mechanisms involving in the increase or decrease in drugs’ solubility start to be approached from a deep thermodynamic point of view, including the analysis of the preferential solvation of solute by the components of mixtures [5–7,17,18]. In this way, the main goal of this article is to determine the equilibrium solubility of ECN (3) in several mixtures of {methanol (1) + water (2)}, {ethanol (1) + water (2)} and {1,4-dioxane (1) + water (2)} at different temperatures to evaluate the preferential solvation of this drug, based on well-established thermodynamic definitions [17,18]. It is important to keep in mind that methanol and 1,4-dioxane is not used to develop liquid medicines due to its high toxicity. But in some instances methanol is used in drug purification procedures [19], as well as solvent in some drug microencapsulation techniques [20]. Moreover, methanol is widely used as mobile phase in high performance liquid chromatography [21]. Besides, 1,4-dioxane is widely used as a model co-solvent because it is miscible with water in all the range of compositions although it exhibits a low polarity as described by its dielectric constant, i.e. 2.21 at 298.15 K [22]. Even more, the Jouyban–Acree model has been used to correlate the solubility of a lot of drugs in {methanol/1,4-dioxane (1) + water (2)} mixtures [23]. 2. Experimental 2.1. Materials and apparatus Econazole nitrate was purchased from ScienMax Precision Industrial Co., Ltd, China with a mass fraction of 0.975. It was purified three times via crystallization in methanol. The final content of econazole nitrate employed for solubility measurement was 0.996 in mass fraction, which was confirmed by using a highperformance liquid chromatography (HPLC, Agilent 1260). The solvents of methanol, ethanol, and 1,4-dioxane were provided by Sinopharm Chemical Reagent Co., Ltd., China. The purity of these solvents was all higher than 0.995 in mass fractions determined by gas chromatography ((GC Smart (GC-2018))). The water was twice distilled water prepared in our lab, which conductivity was less than 2 lS
cm1. The detailed information of these chemicals used in this work is presented in Table 1. The experimental apparatus used in this work for the solubility determination was given in Fig. 2. It included a 100 mL jacketed glass vessel with a magnetic stirrer and a circulating (water + isopropanol) system used for keeping the system temperature. The temperature of circulating (water + isopropanol) was controlled by a thermostatic bath (Model: QYHX-1030) with a standard uncertainty of 0.05 K, which was purchased from Shanghai Joyn

The solvent mixtures were prepared by using the analytical balance (model: BSA224S) in this experiment. The mixed solvents in the glass vessel were near to 50 g. The mass fractions of methanol, ethanol or 1,4-dioxane in the binary mixtures varied from 0 to 0.9. The glass vessel was covered with a stopper to prevent the solvent from escaping. The local atmosphere pressure was about 101.2 kPa during the experiment. 2.3. Solubility determination In this work, the solubility of econazole nitrate in binary solvent mixtures of (methanol + water), (ethanol + water) and (1,4dioxane + water) were determined by an isothermal dissolution equilibrium method [26–29], and the high-performance liquid phase chromatograph (HPLC, Agilent-1260) was employed to determine the solubility of econazole nitrate in equilibrium liquid phase. Saturated solutions of econazole nitrate were prepared in the jacketed glass vessel for each experiment. Excessive econazole nitrate was added into the jacketed glass vessel filled with about 50 g solvent mixtures accompanied by continuous stirring, which was obtained by using a magnetic stirrer at a fixed temperature in order to mix the suspension intensively. The system was kept at a desired temperature by circulating (water + isopropanol) from the smart thermostatic bath through the outer jacket. In order to determine the equilibration time of the studied systems, about 1 ml liquid phase was extracted out every one hour using a 2 mL of preheated syringe equipped with a pore syringe filter (PTFE 0.2 lm), and then analysed by the high-performance liquid phase chromatograph (Agilent-1260). Once the content of liquid phase didn’t vary, the system was assumed to be in equilibrium. In order to ensure that sampling was performed at equilibrium conditions, two types of experiments were performed, one starting from a supersaturated solution, in which the solid phase precipitated to reach equilibrium and the other starting from a non-saturated solution, in which solid dissolved to reach equilibrium. Results showed that 24 h was sufficient to make the system equilibrium. Once the equilibrium was reached, stirring was ceased for 30 min before sampling to allow any solid to be precipitated out of the solution. The upper liquid phase was taken out with the 2 mL of preheated or precooled syringe attached with a filter (PTFE 0.2 lm), and transferred quickly to a 25 mL pre-weighed volumetric flask equipped with a rubber stopper. The volumetric flask filled with sample was weighed again by using the analytical balance. Subsequently, the sample was diluted to 25 mL with methanol, and 1 lL of the solution was taken out for analysis using the high-performance liquid chromatography. 2.4. Analysis method The compositions determination of the equilibrium liquid phase was carried out on an Agilent 1260 HPLC system (Agilent Technologies, USA) equipped with a quaternary pump with a vacuum

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Table 1 Detailed information of all chemical materials used in this work.

a b

Chemicals

Molar mass g
mol1

Source

Initial mass fraction purity

Final mass fraction purity

Purification method

Analytical method

Econazole nitrate Methanol Ethanol 1,4-Dioxane Water

444.70

ScienMax Precision Industrial Co., Ltd., China Sinopharm Chemical Reagent Co., Ltd., China

0.975

0.996

Recrystallization

HPLCa

0.996 0.995 0.995 Conductivity <2 lS
cm1

– – – Distillation

GCb GC GC Conductivity meter

32.04 46.07 88.11 18.02

Our lab

High-performance liquid chromatography. Gas chromatography.

VII II III

VI V

I IV

temperature and mass fraction of methanol, ethanol and 1,4dioxane for the binary systems of (methanol + water), (ethanol + water) and (1,4-dioxane + water). Apparently, the maximum solubility of econazole nitrate is observed in pure methanol or ethanol for the binary systems of (methanol + water), (ethanol + water). However, for the binary system of (1,4-dioxane + water), the econazole nitrate solubility reaches a maximum in the mixture with x1 = 0.80. Tables 2–4 also show that the solubility of econazole nitrate in (methanol + water) is greater than those in (ethanol + water) or (1,4-dioxane + water) at the same temperature and solvent composition except for in pure 1,4-dioxane. The polarity of econazole nitrate molecule is relative strong. At the same composition, the polarities of the (methanol + water) mixtures are larger than those in ethanol + water and 1,4-dioxane + water mixtures [2]. Consequently, the solubility of econazole nitrate is greater in (methanol + water) than in the other two mixed solvents. 3.2. Thermodynamic modelling

Fig. 2. Schematic diagram of experimental apparatus: I, smart thermostatic water bath; II, mercury-in-glass thermometer; III, magnetic stirrer; IV, stirrer controller; V, jacketed glass vessel; VI, sampling port; VII, condenser.

degasser itself (type G1311C), an auto-sampler (type G1329B) and an UV detector (type G1314F). The detection wavelength of econazole nitrate was 229 nm, which was determined by continuous UVScanning. The separation column was a unimicro Kromasil C18, 5 lm (250 mm  4.6 mm) with a mobile phase of pure methanol at a flow rate of 1 ml
min1. Each experiment was repeated at least three times to check the repeatability and three samples were taken for each solution at a given temperature. The average value was considered as final solubility data point. The relative uncertainty of the experimental solubility data was estimated to be 6.5% in mole fraction.

3. Results and discussion 3.1. Solubility results The measured mole fraction solubility of econazole nitrate in binary solvent mixtures of (methanol + water), (ethanol + water) and (1,4-dioxane + water) are presented in Tables 2, 3 and 4, respectively. It is noteworthy that values of the mole fraction solubility of econazole nitrate in pure methanol, ethanol and 1,4dioxane are also tabulated in corresponding tables, which are taken from Ref. [15]. Furthermore, the relationship between the mole fraction solubility and temperature and solvent composition are demonstrated graphically in Figs. 3–5. It can be seen from Tables 2–4 that the econazole nitrate solubility data is a function of temperature and solvent composition for the all solvent mixtures. The solubility of econazole nitrate increase with increasing

Several thermodynamic models have been employed to correlate the solubility of component in mixed solvents in many publications. In this work, JouybanAcree model [5,16,18,23] are used to correlate the solubility of econazole nitrate in the binary solvent mixtures of (methanol + water), (ethanol + water) and (1,4dioxane + water) at different temperatures. Thhis model can offer accurate mathematical description for the dependence of solute solubility on both temperature and solvent composition for binary and ternary mixed solvents [5,16,18,23]. The expression of Jouyban-Acree model is described as Eq. (1).



 B1 B2 þ w2 A2 þ ln xw;T ¼ w1 A1 þ T=K T=K þ

2 w1 w2 X J ðw1  w2 Þi T=K i¼0 i

ð1Þ

where xw,T denotes the mole fraction solubility of solute in solvent mixtures at absolute temperature T in Kelvin; w1 and w2 are the mass fraction of solvents 1 (methanol, ethanol or 1,4-dioxane) and 2 (water) in the absence of the solute (econazole nitrate), respectively; x1;T and x2;T are the solute solubility in mole fraction in pure solvent; and J i are the Jouyban-Acree model parameters. In order to compute the model parameters, the model requires the solute solubility in pure solvent at the highest and lowest temperatures. The experimental solubility of econazole nitrate in the selected solvent mixtures are correlated and calculated with Eq. (1) by using the method of non-linear regression. During the regression process, the objective function is defined as

F¼

X

ln xew;T  ln xcw;T

2

ð2Þ

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Table 2 Experimental mole fraction solubility (xeT;w  103 ) of econazole nitrate in mixed solvent of methanol (w) + water (1  w) with various mass fractions within the temperature range from T = (278.15–318.15) K at 101.2 kPa.a T/K

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

w xeT;w  103 0

0.0964

0.1994

0.2936

0.3993

0.4996

0.6028

0.6968

0.7995

0.8984

1b

0.01674 0.02049 0.02469 0.02934 0.03441 0.03984 0.04559 0.05159 0.05776

0.09423 0.1126 0.1329 0.1548 0.1786 0.2036 0.2297 0.2567 0.2839

0.2648 0.3128 0.3661 0.4229 0.4861 0.5519 0.6207 0.6924 0.7646

0.4263 0.5024 0.5882 0.6798 0.7844 0.8935 1.009 1.131 1.256

0.5479 0.6475 0.7620 0.8850 1.030 1.183 1.348 1.526 1.710

0.6288 0.7461 0.8840 1.033 1.215 1.408 1.620 1.855 2.100

0.7351 0.8758 1.045 1.229 1.459 1.707 1.984 2.296 2.628

0.8954 1.070 1.282 1.516 1.814 2.140 2.508 2.928 3.382

1.160 1.389 1.673 1.987 2.398 2.850 3.368 3.970 4.6268

1.439 1.727 2.092 2.496 3.038 3.640 4.339 5.163 6.073

1.501 1.813 2.214 2.664 3.279 3.972 4.788 5.773 6.869

a Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.065. Solvent mixtures were prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.003. w represents the mass fraction of methanol in mixed solvents of methanol + water. b Taken from Ref. [15].

Table 3 Experimental mole fraction solubility (xeT;w  103 ) of econazole nitrate in mixed solvent of ethanol (w) + water (1  w) with various mass fractions within the temperature range from T = (278.15–318.15) K at 101.2 kPa.a T/K

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

w xeT;w  103 0

0.1002

0.2003

0.2980

0.3985

0.4985

0.5998

0.6987

0.7990

0.9004

1b

0.01674 0.02049 0.02469 0.02934 0.03441 0.03984 0.04559 0.05159 0.05776

0.04807 0.05822 0.06967 0.08205 0.09558 0.1101 0.1256 0.1416 0.1582

0.09552 0.1152 0.1378 0.1618 0.1883 0.2171 0.2482 0.2802 0.3139

0.1469 0.1773 0.2127 0.2500 0.2919 0.3381 0.3886 0.4410 0.4971

0.1966 0.2380 0.2872 0.3388 0.3977 0.4639 0.5376 0.6145 0.6985

0.2424 0.2946 0.3582 0.4246 0.5018 0.5901 0.6902 0.7957 0.9130

0.2905 0.3548 0.4349 0.5183 0.6170 0.7320 0.8646 1.006 1.166

0.3453 0.4239 0.5237 0.6275 0.7523 0.9002 1.074 1.260 1.475

0.4050 0.4994 0.6223 0.7498 0.9058 1.094 1.318 1.560 1.845

0.4419 0.5517 0.6939 0.8575 1.050 1.307 1.616 1.982 2.366

0.5256 0.6561 0.8319 1.015 1.246 1.533 1.886 2.277 2.751

a Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.065. Solvent mixtures were prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.003. w represents the mass fraction of ethanol in mixed solvents of ethanol + water. b Taken from Ref. [15].

Table 4 Experimental mole fraction solubility (xeT;w  103 ) of econazole nitrate in mixed solvent of 1,4-dioxane (w) + water (1  w) with various mass fractions within the temperature range from T = (278.15–318.15) K at 101.2 kPa.a T/K

288.15 293.15 298.15 303.15 308.15 313.15 318.15

w xeT;w  103 0

0.1008

0.2007

0.2980

0.4001

0.4996

0.6002

0.6968

0.8008

0.8998

1b

0.02469 0.02934 0.03441 0.03984 0.04559 0.05159 0.05776

0.1004 0.1172 0.1356 0.1550 0.1756 0.1968 0.2188

0.1930 0.2241 0.2589 0.2957 0.3354 0.3765 0.4198

0.2493 0.2899 0.3366 0.3864 0.4415 0.4992 0.5614

0.2812 0.3282 0.3839 0.4442 0.5126 0.5853 0.6657

0.3194 0.3743 0.4409 0.5140 0.5988 0.6900 0.7935

0.3921 0.4606 0.5459 0.6404 0.7523 0.8742 1.015

0.4996 0.5878 0.7002 0.8258 0.9773 1.144 1.340

0.6002 0.7083 0.8494 1.009 1.205 1.423 1.685

0.5349 0.6362 0.7716 0.9268 1.121 1.342 1.612

0.2619 0.3172 0.3929 0.4819 0.5964 0.7294 0.8966

a Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.065. Solvent mixtures were prepared by mixing different masses of the solvents with relative standard uncertainty ur(w) = 0.003. w represents the mass fraction of 1,4-dioxane in mixed solvents of 1,4-dioxane + water. b Taken from Ref. [15].

In order to estimate the different models, the relative average deviation (RAD) and root-mean-square deviation (RMSD) are used, the expression of which are described as Eqs. (3) and (4).

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

RMSD ¼

vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi uP  2 u N t i¼1 xcw;T  xew;T N

ð3Þ

ð4Þ

where xew;T stands for the experimental solubility values in mole fraction; and xcw;T is the mole fraction solubility calculated using sol-

ubility model; N represents the number of experimental data points. The values obtained for the model parameters are listed in Table 5, together with the RAD and the RMSD values. The solubility of econazole nitrate in the three binary mixtures of (methanol + water, ethanol + water and 1,4-dioxane + water) was evaluated based on the regressed parameters’ values. The calculated solubility values are plotted in Figs. 3–5. Table 5 shows that for the selected binary solvent mixtures, the maximum value of relative average deviations (RAD) between the calculated and experimental values is 1.22%, which is obtained for the system of (ethanol + water). Besides, the root-mean-square deviations (RMSD) are no greater than 1.5  105. On the whole, the Jouyban–Acree model can be employed to correlate the solubility of econazole nitrate

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G. Chen et al. / J. Chem. Thermodynamics 111 (2017) 228–237

0.0016

0.0060 0.0012

x

0.0045

x

0.0008

0.0030

0.0004

0.0015 320

310

300

T/K 290

280

0.0

0.2

1.0 0.8 0.6 0.4

320

T/K 300

w

Fig. 3. Mole fraction solubility (x) of econazole nitrate in methanol (w) + water (1  w) mixed solutions with various mass fractions at different temperatures: w, mass fraction of methanol; ✰, w = 1 (Taken from Ref. [15]); 4, w = 0.8984; s, w = 0.7995; h, w = 0.6968; w, w = 0.6028; }, w = 0.4996; r, w = 0.3993; ., w = 0.2936; N, w = 0.1994; d, w = 0.0964; j, w = 0; —, calculated curves by the Jouyban  Acree model.

0.6

310

0.4 0.2

0.8

1.0

w

290 0.0

Fig. 5. Mole fraction solubility (x) of econazole nitrate in 1,4-dioxane (w) + water (1  w) mixed solutions with various mass fractions at different temperatures: w, mass fraction of 1,4-dioxane; ✰, w = 1 (Taken from Ref. [15]); 4, w = 0.8998; s, w = 0.8008; h, w = 0.6968; w, w = 0.6002; }, w = 0.4996; r, w = 0.4001; ., w = 0.2980; N, w = 0.2007; d, w = 0.1008; j, w = 0; —, calculated curves by the Jouyban  Acree model.

Table 5 Values of parameters obtained using the thermodynamic model.

0.0025 J0 J1 J2 RAD
102 RMSD
104

0.0020

x

0.0015 0.0010 0.0005 320

310

0.4

300

T/K

0.2

290 280

0.6

1.0 0.8

w

0.0

in the binary mixtures of (methanol + water, ethanol + water and 1,4-dioxane + water) at all composition ranges. 3.3. Dissolution property for the dissolution During the dissolution process, thermodynamic properties of solute dissolved in solvent mixtures can provide important information. The standard dissolution enthalpy (DHosol ) for dissolution process of econazole nitrate in solvent mixtures can be obtained from the famous Van’t Hoff analysis [30].



 @ ln xw;T @ ln xw;T ¼ R @ð1=TÞ p @½ð1=TÞ  ð1=T hm Þ p

Ethanol + water

1,4-Dioxane + water

1533.6 1771.9 1796.8 0.43 0.03

1065.19 903.63 591.38 1.22 0.15

1590.5 420.11 2790.8 0.87 0.09

here R is the universal gas constant having a value of 8.314 J
K1
mol1; T hm is the mean harmonic temperature which may be obtained via Eq. (6).

N T hm ¼ PN

1 i¼1 T i

Fig. 4. Mole fraction solubility (x) of econazole nitrate in ethanol (w) + water (1  w) mixed solutions with various mass fractions at different temperatures: w, mass fraction of ethanol; w = 1 (Taken from Ref. [15]); 4, w = 0.9004; s, w = 0.7990; h, w = 0.6987; w, w = 0.5998; }, w = 0.4985; r, w = 0.3985; ., w = 0.2980; N, w = 0.2003; d, w = 0.1002; j, w = 0; —, calculated curves by the Jouyban–Acree model.

DHosol ¼ R

Methanol + water

ð5Þ

ð6Þ

The dissolution standard enthalpy of econazole nitrate in (methanol + water), (ethanol + water) and (1,4-dioxane + water) are computed from the slope of the curves of ln xw;T vs ð1=T  1=T hm Þ. The calculated values in the studied mixed solutions are tabulated in Table 6. It can be found that the values of standard molar enthalpy of dissolution are all positive, which show that the dissolution process of econazole nitrate in the three binary solvent solutions is endothermic, and the entropy is the driving force for the dissolution process. 3.4. Preferential solvation of econazole nitrate The preferential solvation parameter of econazole nitrate (compound 3) by the co-solvent (compound 1) in {co-solvent (1) + water (2)} mixtures is defined as [6,17,18]:

dx1;3 ¼ xL1;3  x1 ¼ dx2;3

ð7Þ

where xL1;3 is the local mole fraction of co-solvent (1) in the environment near to econazole nitrate (3) and x1 is the bulk mole fraction composition of co-solvent (1) in the initial binary solvent. If dx1,3 > 0 then the solute is preferentially solvated by co-solvent (1); on the contrary, if dx1,3 is <0 the solute is preferentially solvated by water (2). Values of dx1,3 are obtainable from the inverse Kirkwood-Buff integrals for the individual solvent components analyzed according

233

G. Chen et al. / J. Chem. Thermodynamics 111 (2017) 228–237 Table 6 Standard enthalpy change of econazole nitrate in mixed solvents of methanol (w) + water (1  w), ethanol (w) + water (1  w) and 1,4-dioxane (w) + water (1  w). Methanol + water

Ethanol + water

DHosol

w

kJ
mol 0 0.0964 0.1994 0.2936 0.3993 0.4996 0.6028 0.6968 0.7995 0.8984 1

22.76 20.30 19.56 19.96 21.06 22.35 23.63 24.68 25.72 26.80 28.32

w 1

kJ
mol 0 0.1002 0.2003 0.2980 0.3985 0.4985 0.5998 0.6987 0.7990 0.9004 1

x1 x2 ðG1;3  G2;3 Þ ¼ x1 G1;3 þ x2 G2;3 þ V cor

ð8Þ

with,

G1;3 ¼ RT jT  V 3 þ

x2 V 2 D Q

ð9Þ

G2;3 ¼ RT jT  V 3 þ

x1 V 1 D Q

ð10Þ

V cor

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

ð11Þ

Here jT is the isothermal compressibility of the {co-solvent (1) + water (2)} solvent mixtures (expressed in GPa1); V1 and V2 are the partial molar volumes of the solvents in the mixtures (expressed in cm3
mol1); similarly, V3 is the partial molar volume of econazole nitrate in these mixtures (expressed in cm3
mol1). The function D in (Eq. (12)) is the derivative of the standard molar Gibbs energies of transfer of econazole nitrate from neat water (2) to {co-solvent (1) + water (2)} mixtures with respect to the solvent composition (expressed in kJ
mol1, as is RT). The function Q (Eq. (13)) involves the second derivative of the excess molar Gibbs energy of mixing of the two solvents (GExc 1þ2 ) with respect to the water proportion in the mixtures (also expressed in kJ
mol1) [6,17,18]. Vcor is the correlation volume and r3 is the molecular radius of econazole nitrate calculated by means of Eq. (14) with NAv as the Avogadro’s number.

D¼

@ Dtr Goð3;2!1þ2Þ @x1 "

Q ¼ RT þ x1 x2

!

ð12Þ T;P

@ 2 GExc 1þ2 @x22

sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 21 3 3  10 V3 r3 ¼ 4pNAV

kJ
mol

# ð13Þ T;p

0 0.1008 0.2007 0.2980 0.4001 0.4996 0.6002 0.6968 0.8008 0.8998 1

1

21.59 19.78 19.75 20.64 21.92 23.14 24.20 25.11 26.27 28.07 31.32

jT ¼ x1 joT;1 þ x2 joT;2

ð15Þ o

where xi is the mole fraction of component i in solution and kT;i is the isothermal compressibility of the pure component i. Values of the solubility of econazole nitrate (3) in {methanol (1) + water (2), ethanol (1) + water (2) and 1,4-dioxane (1) + water (2)} mixtures are taken from Ref. [15]. The standard molar Gibbs energy of transfer of econazole nitrate from neat water (2) to {methanol (1) + water (2), ethanol (1) + water (2) and 1,4-dioxane (1) + water (2)} mixtures is computed and correlated to regular quartic polynomials from the solubility values by using Eq. (16).




Dtr G03;2!1þ2 ¼ RT ln



DHosol

w 1

22.76 21.89 21.88 22.42 23.33 24.42 25.59 26.75 27.96 31.13 30.52

to some thermodynamic quantities as shown in the following equations [6,17,18]:

dx1;3

1,4-Dioxane + water

DHosol

x3;2 x3;1þ2



ð16Þ

The values of Dtr G03;2!1þ2 are correlated according to polynomial presented as Eq. (17). Fig. 6 shows the Gibbs energy of transfer behaviour at five temperatures, whereas Tables S1 and S2 of Supplementary material give the behaviour. The polynomial coefficients obtained are shown in Table S3 of Supplementary material. 2

3

2:5 4 Dtr G03;2!1þ2 ¼ a þ bx1 þ cx1:5 1 þ dx1 þ ex1 þ fx1 þ gx1

ð17Þ

Thus, D values are calculated from the first derivative of polynomial models (Eq. (17)) solved according to the co-solvent mixture composition varying by 0.05 in mole fraction of methanol (1), ethanol (1) or 1,4-dioxane (1). The obtained D values are reported in Table S4 of Supplementary material. 2

1:5 3 D ¼ b þ 1:5cx0:5 1 þ 2dx1 þ 2:5ex1 þ 3fx1 þ 4gx1

ð18Þ

In order to calculate the Q values, the excess molar Gibbs energies of mixing GExc 1þ2 at all the temperatures considered are required. Nevertheless, these values are reported only at one temperature, i.e. normally at 298.15 K. For this reason, it is necessary to calculate these values at the other temperatures required. In this way, GExc 1þ2 values are calculated at 298.15 K using Eqs. (19), (20) and (21) for {methanol (1) + water (2), ethanol (1) + water (2) and 1,4dioxane (1) + water (2)} co-solvent mixtures, respectively, as reported by Marcus [6]. On the other hand, the GExc 1þ2 values at the

ð14Þ

Because of the dependence of jT on composition, this term is not known for all the systems investigated. Moreover, due to the small contribution of RTjT to the inverse Kirkwood-Buff integral, the dependence of jT on composition will be calculated approximated as an additive property by using the mixtures compositions and the reported values for neat solvents by [6,17,18]:

other temperatures are calculated using Eq. (22), where HExc 1þ2 is the excess molar enthalpy of the co-solvent mixtures, T1 is 298.15 K and T2 is one of the other temperatures under consideration [6]. In turn, HExc 1þ2 values are calculated by using Eqs. (23), (24) and (25) at 298.15 K for {methanol (1) + water (2), ethanol (1) + water (2) and 1,4-dioxane (1) + water (2)} co-solvent mixtures, respectively, as also reported by Marcus [6].

h i 2 GExc 1þ2 ¼ x1 ð1  x1 Þ 1200  87ð1  2x1 Þ  330ð1  2x1 Þ

ð19Þ

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G. Chen et al. / J. Chem. Thermodynamics 111 (2017) 228–237

0

0

Go3,2/kJ mol-1

Go3,2/kJ mol-1

293.15 K 298.15 K 303.15 K 308.15 K 313.15 K

-6

-9

-12 0.0

ethanol (1) + water (2)

-2

methanol (1) + water (2)

-3

-4

293.15 298.15 303.15 308.15 313.15

K K K K K

-6 -8

-10

0.2

0.4

x1

0.6

0.8

1.0

0.0

0.2

0.4

0.6

0.8

1.0

x1 0

Go3,2/kJ mol-1

-2

1,4-dioxane (1) + water (2) 293.15 K 298.15 K 303.15 K 308.15 K 313.15 K

-4 -6 -8 0.0

0.2

0.4

0.6

0.8

1.0

x1 Fig. 6. Gibbs energy of transfer (kJ
mol1) of econazole nitrate (3) from neat water (2) to methanol (1) + water (2), ethanol (1) + water (2) and 1,4-dioxane (1) + water (2) mixtures at several temperatures.

h i 2 GExc 1þ2 ¼ x1 ð1  x1 Þ 2907  777ð1  2x1 Þ þ 494ð1  2x1 Þ

ð20Þ

h i 2 GExc 1þ2 ¼ x1 ð1  x1 Þ 3835  973ð1  2x1 Þ  421ð1  2x1 Þ

ð21Þ


 1 ¼ T T T1
 T2 T2 Exc  GExc 1þ2 ðT 1 Þ þ H1þ2 1  T1 T1 Z

GExc 1þ2 ðT 2 Þ

GExc 1þ2 ðT 1 Þ

T2

HExc 1þ2 d

ð22Þ

HExc 1þ2 ¼ x1 ð1

h i  x1 Þ 3102 þ 2040ð1  2x1 Þ  2213ð1  2x1 Þ2

ð23Þ

HExc 1þ2 ¼ x1 ð1

h i  x1 Þ 1300  3567ð1  2x1 Þ  4971ð1  2x1 Þ2

h i 2 HExc 1þ2 ¼ x1 ð1  x1 Þ 611 þ 6006ð1  2x1 Þ  1712ð1  2x1 Þ

ð24Þ ð25Þ

It is noteworthy that quartic regular polynomials of GExc 1þ2 , as a function of the mole fraction of water, were obtained. Q values at different temperatures are shown in Table S5 of Supplementary material. On the other hand, Table S6 of Supplementary material presents the RTjT values calculated with the reported jT values for methanol (1.248 GPa1), ethanol (1.153 GPa1), 1,4-dioxane (0.738 GPa1) and water (0.457 GPa1) at 298.15 K, taken as independent of the temperature [31]. In similar way, the partial molar volumes of both solvents in the mixtures are calculated from the reported density values of the {co-solvent (1) + water (2)} mixtures at the studied temperatures under study by Mikhail and Aliaj for (methanol + water) mixtures [32,33], by Khattab for (ethanol + water) mixtures [34], and by Ruidiaz for (1,4-dioxane + water) mixtures [35] by using Eqs. (26) and

(27). In these equations V is the molar volume of the mixtures calculated as V = (x1
M1 + x2
M2)/q. Here, M1 is 32.04 g
mol–1 for methanol, 46.07 g
mol1 for ethanol, 88.11 g
mol1 for 1,4dioxane and M2 is 18.02 g
mol1 for water.

V 1 ¼ V þ x2

dV dx1

ð26Þ

V 2 ¼ V  x1

dV dx1

ð27Þ

Because no partial molar volumes of econazole nitrate (3) in these mixtures are reported in the literature, in this work this property is considered as similar to that for the pure compound as a good approximation [36]. In this way, the molar volume of econazole nitrate (3) is calculated by using Advanced Chemistry Development (ACD/Labs) Software V 11.02 (sc1994-2016 ACD/ Labs) as 286.7 cm3
mol1. From this volume value, solute radius value (r3) is calculated using Eq. (14) as 0.484 nm. The values of G1,3 and G2,3 shown in Tables S7–S9 of Supplementary material are negative in all cases, except for (1,4-dioxane + water) mixtures in compositions of 0.55  x1  1.0 where positive values of G2,3 are found. This behaviour indicates that econazole nitrate exhibits affinity for both solvents in the (methanol + water) and (ethanol + water) mixtures. Definitive correlation volume requires iteration because it depends on the local mole fractions around the solute. This iteration is done by replacing dx1,3 and Vcor in the Eqs. (7), (8) and (11) to recalculate xL1;3 until a non-variant value of Vcor is obtained. The obtained values of correlation volume Vcor and dx1,3 are tabulated in Tables S10–S12 of Supplementary material for {methanol (1) + water (2), ethanol (1) + water (2) and 1,4-dioxane (1) + water (2)} co-solvent mixtures, respectively. In addition, the dependence of dx1,3 values on co-solvent composition in mole fraction is shown graphically in Fig. 7. It shows that the values of dx1,3 vary nonlinearly with the co-solvent (1) proportion in all the aqueous mix-

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G. Chen et al. / J. Chem. Thermodynamics 111 (2017) 228–237

2 2

methanol (1) + water (2)

ethanol (1) + water (2)

1

x1,3

x1,3

1

0

-2 0.0

0

293.15 K 298.15 K 303.15 K 308.15 K 313.15 K

-1

0.2

0.4

x1

0.6

293.15 K 298.15 K 303.15 K 308.15 K 313.15 K

-1

0.8

-2 0.0

1.0

2

0.2

0.4

x1

0.6

0.8

1.0

1,4-dioxane (1) + water (2)

x1,3

0 -2 293.15 K 298.15 K 303.15 K 308.15 K 313.15 K

-4 -6 -8 -10 0.0

0.2

0.4

x1

0.6

0.8

1.0

Fig. 7. dx1,3 values of econazole nitrate (3) in methanol (1) + water (2), ethanol (1) + water (2) and 1,4-dioxane (1) + water (2) mixtures at several temperatures.

2.0 1.8

x1,3

tures. According to Fig. 7, addition of co-solvent (1) makes negative the dx1,3 values of econazole nitrate (3) from the pure water to the mixture with composition x1 = 0.31 for {methanol (1) + water (2)}, x1 = 0.24 for {ethanol (1) + water (2)} and x1 = 0.18 for {1,4-dioxane (1) + water (2)} systems. Maximum negative values are obtained in the mixture x1 = 0.05 for the three co-solvent mixtures. Probably the structuring of water molecules around the nonpolar aromatic group of econazole nitrate (i.e. hydrophobic hydration of aromatic rings group) contributes to lowering of the net dx1,3 to negative values in these water-rich mixtures. In the {methanol (1) + water (2)} mixtures with composition 0.31 < x1 < 1.00, ethanol (1) + water (2) mixtures with composition 0.24 < x1 < 1.0 and {1,4-dioxane (1) + water (2)} mixtures with composition 0.18 < x1 < 0.50, the local mole fractions of methanol (ethanol or 1,4-dioxane) are higher than those of the mixtures and therefore the dx1,3 values are positive indicating preferential solvation of econazole nitrate by the co-solvents. The co-solvent action to increase the solute solubility may be related to the breaking of the ordered structure of water around the nonpolar moieties of econazole nitrate which increases the solvation having maximum values near to x1 = 0.60 for {methanol (or ethanol) (1) + water (2)} mixtures and x1 = 0.40 for {1,4-dioxane (1) + water (2)} mixtures. However in {1,4-dioxane (1) + water (2)} mixtures with composition 0.50 < x1 < 1.0 negative dx1,3 values are observed again. This is because the maximum solubility of econazole nitrate is observed in a mixture instead of neat 1,4-dioxane. It is important to note that if the absolute value of dx1,3 is lower than 1.0  102 the result is a consequence of the effect of uncertainties propagation instead of the preferential solvation [37–39]. Fig. 8 shows the linear temperature-dependence of dx1,3 in the mixtures with maximum variations of these values, i.e. x1 = 0.60 (methanol and ethanol) and x1 = 0.40 (1,4-dioxane) for preferential solvation by methanol, ethanol or 1,4-dioxane and water, respectively. It is noteworthy that for the {methanol (ethanol) (1) + water (2)} mixtures, in the first case, the preferential solvation by methanol (ethanol) increases with increasing temperature, but in the sec-

1.6 1.4 1.2 295

300

T/K

305

310

Fig. 8. dx1,3 values of econazole nitrate (3) in methanol (1) + water (2), ethanol (1) + water (2) and 1,4-dioxane (1) + water (2) mixtures with composition: x1 = 0.60 for methanol and ethanol and x1 = 0.45 for 1,4-dioxane as a function of the temperature. j, methanol; d, ethanol; N, 1,4-dioxane.

ond case, the preferential solvation by water decreases with increasing temperature (it is important to keep in mind that dx2,3 = dx1,3). However, for the {1,4-dioxane (1) + water (2)} mixtures, in the first case, the preferential solvation by 1,4-dioxane decreases with increasing temperature, but in the second case, the preferential solvation by water increases with increasing temperature. Econazole nitrate can act as a Lewis acid in solution due to the ability of the acidic hydrogen atom in its HNO3 group (Fig. 1) to establish hydrogen bonds with proton-acceptor functional groups of the co-solvents (oxygen atoms in AOA and AOH groups). In addition, econazole nitrate can also act as a Lewis base because of the free electron pairs in oxygen atoms of AOA and AN

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G. Chen et al. / J. Chem. Thermodynamics 111 (2017) 228–237

(Fig. 1), which interact with acidic hydrogen atoms of water. According to the preferential solvation results, it is conjecturable that in the region of 0.31 < x1 < 1.00 for methanol, 0.24 < x1 < 1.0 for ethanol and 0.18 < x1 < 0.50 for 1,4-dioxane, econazole nitrate is acting as a Lewis acid with methanol, ethanol or 1,4-dioxane molecules, because these co-solvents are more basic than water, as described by the Kamlet–Taft hydrogen bond acceptor parameters, i.e. b = 0.66 for methanol, 0.75 for ethanol, 0.37 for 1,4dioxane, and 0.47 for water [31,40]. On the other hand, in waterrich mixtures, where econazole nitrate is preferentially solvated by water, econazole nitrate could be acting mainly as a Lewis base in front to water because these solvents are more acidic than methanol or ethanol as described by the Kamlet–Taft hydrogen bond donor parameters, i.e. a = 1.017 for water, 0.990 for methanol, 0.850 for ethanol and 0.00 for 1,4-dioxane, respectively [31,41]. Fig. 9 compares the preferential solvation of econazole nitrate in {methanol (1) + water (2), ethanol (1) + water (2) and 1,4-dioxane (1) + water (2)} at 298.15 K. The preferential solvation magnitudes of econazole nitrate by water in water-rich region are similar in the three co-solvent mixtures. For the three binary co-solvent mixtures under study in intermediate composition, the preferential solvation magnitude of econazole nitrate by the co-solvent is highest in 1,4-dioxane mixtures, followed by ethanol mixtures, and finally, by methanol mixtures, although the compositions of maxima are obtained in different co-solvent proportions, i.e. x1 = 0.60, dx1,3 = 1.234  102 and dx1,3 = 1.502  102 for {methanol (1) + water (2)} and {ethanol (1) + water (2)}, respectively; and x1 = 0.40, dx1,3 = 1.95  102 for {1,4-dioxane (1) + water (2)}. 4. Conclusion The solubility of econazole nitrate in three binary mixed solvents of (methanol + water), (ethanol + water) and (1,4-dioxane + water) with various compositions was acquired experimentally via the isothermal dissolution equilibrium method within the temperature range of (278.15–318.15) K under pressure of 101.3 kPa. The maximum solubility of econazole nitrate was observed in pure methanol or ethanol for (methanol + water), (ethanol + water) mixtures, while the econazole nitrate solubility reaches a maximum in the mixture with x1 = 0.80 for (1,4-dioxane + water). The dependence of econazole nitrate solubility on temperature and solvent composition was correlated with the Jouyban-Acree model. The values of relative average deviations and root-mean-square

2

x1,3

0 -2 -4 -6 -8 0.0

0.2

0.4

x1

0.6

0.8

1.0

Fig. 9. dx1,3 values of econazole nitrate (3) in methanol (1) + water (2), ethanol (1) + water (2) and 1,4-dioxane (1) + water (2) mixtures at at 298.15 K. j, methanol (1) + water (2); d, ethanol (1) + water (2); N, 1,4-dioxane (1) + water (2).

deviations were no greater than 1.22% and 0.15  104, respectively. The standard dissolution enthalpy for dissolution process of econazole nitrate in solvent mixtures was obtained from the Van’t Hoff analysis. Quantitative values relative to the local mole fraction of methanol, ethanol or 1,4-dioxane and water around econazole nitrate were derived on the basis of the IKBI method at several temperatures. Some differences between the behaviour of econazole nitrate in {methanol (or ethanol) (1) + water (2)} and the {1,4-dioxane (1) + water (2)} mixtures were found. The econazole nitrate was first solvated preferentially by water in water-rich mixtures and then preferentially solvated by methanol in {methanol (1) + water (2)} and {ethanol (1) + water (2)} mixtures. However in {1,4-dioxane (1) + water (2)} mixtures with 0.18 < x1 < 0.50 positive dx1,3 values are observed, but with 0.50 < x1 < 1.0 negative dx1,3 values are observed again. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jct.2017.03.038. References [1] J.T. Rubino, Co-solvents and cosolvency, in: J. Swarbrick, J.C. Boylan (Eds.), Encyclopedia of Pharmaceutical Technology, 3, Marcel Dekker, New York, NY, 1988. [2] A. Jouyban, Handbook of Solubility Data for Pharmaceuticals, CRC Press, BocaRaton, FL, 2010. [3] M.E. Aulton, Pharmaceutics, The Science of Dosage Forms Design, second ed., Churchill Livingstone, London, 2002. [4] A. Avdeef, Absorption and drug development, solubility, in: Permeability and Charge State, Wiley-Interscience, Hoboken, NJ, 2003. [5] D.P. Pacheco, F. Martínez, Thermodynamic analysis of the solubility of naproxen in ethanol + water co-solvent mixtures, Phys. Chem. Liq. 45 (2007) 581–595. [6] Y. Marcus, Solvent Mixtures: Properties and Selective Solvation, Marcel Dekker Inc., New York, NY, 2002. [7] Y. Marcus, Preferential solvation in mixed solvents, in: P.E. Smith, E. Matteoli, J.P. O’Connell (Eds.), Fluctuation Theory of Solutions: Applications in Chemistry, Chemical Engineering, and Biophysics, CRC, Press, Taylor & Francis Group, BocaRaton, FL, 2013. [8] A. Fleischer Jr., I. Raymond, Econazole nitrate foam 1% improves the itch of tinea pedis, J. Drugs Dermatol. 15 (2016) 1111–1114. [9] A.H. Al-Marzouqi, H.M. Elwy, I. Shehadi, A. Adem, Physicochemical properties of antifungal drug–cyclodextrin complexes prepared by supercritical carbon dioxide and by conventional techniques, J. Pharm. Biomed. Anal. 49 (2009) 227–233. [10] Z. Hu, J. Zhang, X. Cheng, Antifungal efficiency of miconazole and econazole and the interaction with transport protein: a comparative study, Pharm. Biol. 53 (2014) 1–11. [11] M. Jug, N. Mennini, K.E. Kövér, P. Mura, Comparative analysis of binary and ternary cyclodextrin complexes with econazole nitrate in solution and in solid state, J. Pharm. Biomed. Anal. 91 (2014) 81–91. [12] C.S. Wu, Y.H. Deng, J.S. Hao, J.M. Zheng, Determination of the drug content in econozole nitrate liposome by HPLC and study on its physical properties, Chin. Hosp. Pharm. J. 24 (2004) 606–607. [13] V. Cavrini, A.M.D. Pietra, R. Gatti, Analysis of miconazole and econazole in pharmaceutical formulations by derivative UV spectroscopy and liquid chromatography, J. Pharm. Biomed. Anal. 7 (1989) 1535–1543. [14] L. Chen, J.H. Cui, C. Jiang, Preparation and in vitro evaluation of thermosensitive gel containing econazole nitrate, Chin. J. New Drugs 17 (2008) 1607–1611 (Chinese). [15] Y. Xie, S. Han, H.W. Shi, C.B. Du, Y. Cong, H.K. Zhao, Measurement and modelling of econazole nitrate in twelve pure organic solvents at temperatures from 278.15 K to 318.15 K, J. Chem. Thermodyn. 103 (2016) 59–68. [16] A. Jouyban, Review of the cosolvency models for predicting solubility of drugs in water-co-solvent mixtures, J. Pharm. Pharm. Sci. 11 (2008) 32–58. [17] Y. Marcus, On the preferential solvation of drugs and PAHs in binary solvent mixtures, J. Mol. Liq. 140 (2008) 61–67. [18] D.M. Cristancho, A. Jouyban, F. Martínez, Solubility, solution thermodynamics, and preferential solvation of piroxicam in ethyl acetate + ethanol mixtures, J. Mol. Liq. 221 (2016) 72–81. [19] B. Chen, Y. Du, H. Wang, Study on enantiomeric separation of basic drugs by NACE in methanol-based medium using erythromycin lactobionate as a chiral selector, Electrophoresis 31 (2010) 371–377. [20] A.J. Thote, R.B. Gupta, Formation of nanoparticles of a hydrophilic drug using supercritical carbon dioxide and microencapsulation for sustained release, Nanomedicine 1 (2005) 85–90.

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JCT 17-169