Solubility and Preferential Solvation of Carbazochrome in Solvent

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

pubs.acs.org/jced

Solubility and Preferential Solvation of Carbazochrome in Solvent Mixtures of N,N‑Dimethylformamide Plus Methanol/Ethanol/ n‑Propanol and Dimethyl Sulfoxide Plus Water Yanqing Zhu,† Chao Cheng,‡ and Hongkun Zhao*,‡ †

School of Environmental & Municipal Engineering, North China University of Water Resources and Electric Power, ZhengZhou, He’nan 450011, People’s Republic of China ‡ College of Chemistry & Chemical Engineering, YangZhou University, YangZhou, Jiangsu 225002, People’s Republic of China S Supporting Information *

ABSTRACT: The carbazochrome (3) solubility in solvent mixtures of DMF (N,N-dimethylformamide, 1) + methanol (2), DMF (1) + ethanol (2), DMF (1) + n-propanol (2), and dimethyl sulfoxide (DMSO, 1) + water (2) was measured by the static method within the temperature range from (278.15 to 318.15) K under atmospheric pressure, p = 101.0 kPa. The solubility of carbazochrome increased with rising mass fraction of DMF or DMSO and temperature. The Jouyban−Acree, van’t Hoff−Jouyban−Acree, and Apelblat−Jouyban−Acree models were used to correlate the obtained solubility, and the Apelblat−Jouyban−Acree model provided better correlation results. The parameters of preferential solvation (δx1,3) were acquired from the mixture properties with the method of inverse Kirkwood−Buff integrals. The values of δx1,3 changed nonlinearly with the DMF/DMSO (1) proportion in the studied mixed solvents. The carbazochrome was solvated preferentially by alcohol or water in alcohol or water-rich solutions and preferentially solvated by DMF/DMSO in DMF/DMSO-rich mixtures. It could be speculated that in DMF/DMSO-rich mixtures the interaction by acidic hydrogen bonding with the basic sites of carbazochrome played a significant role in carbazochrome solvation.

■

INTRODUCTION The solubility of drugs in mixed solvents plays a vital role and is still a challenging topic in the pharmaceutical industry and developing liquid dosage forms.1,2 Mixed solvents have wider uses than monosolvents because they may provide an extensive choice of mixtures with suitable properties. The drugs’ solubility in mixed solvents as a function of temperature and composition is very important for the purposes of designing liquid dosage forms, raw material purification, and understanding the mechanisms regarding the chemical and physical stability of drug dissolutions.2,3 Therefore, the drugs’ solubility is an essential property in designing pharmaceuticals because it influences the drug efficacy, affecting some pharmacokinetic and biopharmaceutical properties.4,5 In addition, the dependence of solubility on temperature and composition permits the calculation of the preferential solvation of a solute in mixed solvents, which is a powerful tool in understanding the molecular interactions in relation to the dissolution processes of a drug.6,7 Carbazochrome (IUPAC name {[(5Z)-3-hydroxy-1-methyl6-oxo-2,3,5,6-tetrahydro-1H-indol-5-ylidene]amino}urea; CAS no. 69-81-8) is orange-red crystalline or a crystalline powder. Its chemical structure is given in Figure S1 of the Supporting Information. Carbazochrome is a hemostatic or antihemorrhagic agent which will stop blood flow by leading to the © XXXX American Chemical Society

adhesion and aggregation of platelets to form a platelet plug.8−10 With troxerutin, it can be used to cure hemorrhoids.11,12 The drug’s solubility in water is one of the key properties in the pharmaceutical field. Allowing for the use of drugs, the dissolution of a drug in the blood plays an important role in the absorption and distribution of the drug in the body. Thus, the solubility of a poorly water-soluble drug such as carbazochrome 13−17 is significant in the pharmaceutical field. Furthermore, knowing the aqueous solubility is useful in investigating the improvement direction of the drug. Nevertheless, no solubility data of carbazochrome has been detemined in previous work. Although several semiempirical and theoretical models may be employed to predict drug solubility in mixed solvents, the availability of solubility data by experiment is still essential to pharmaceutical scientists.1,2 Since the solubility of carbazochrome is low in neat water,13−16 some mixed solvents may be used to increase the drug solubility. For the above reasons, there is an intense demand to measure systematically the solubility of a drug in solvent mixtures and construct better Received: November 11, 2017 Accepted: February 14, 2018

A

DOI: 10.1021/acs.jced.7b00982 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Table 1. Source and Properties of Carbazochrome and the Selected Solvents molar mass

a

chemicals

g·mol−1

carbazochrome

236.23

DMF

73.10

methanol ethanol n-propanol DMSO water

32.04 46.07 60.10 78.13 18.02

source

initial mass fraction purity

Shanghai Beilang Biological Technology Co., Ltd., China Sinopharm Chemical Reagent Co., Ltd., China

our laboratory

final mass fraction purity

purification method recrystallization

analytical method HPLCa

0.986

0.995

0.994

0.994

GCb

0.995 0.994 0.993 0.993

0.995 0.994 0.993 0.993 conductivity DMF > methanol > (water, ethanol) > n-propanol. For the carbazochrome + alcohol systems, the order of the mole fraction solubility of carbazochrome is consistent with the polarity of methanol, ethanol, and n-propanol.39 The solvent polarities appear to be a chief factor affecting the carbazochrome solubility in these alcohols. The polarity of the carbazochrome molecule is relative strong, thus the carbazochrome solubility is larger in methanol than in the other alcohols. It should be noted that the carbazochrome solubility in water and ethanol crosses at about 313.5 K. If the temperature is less than 313.15 K, then the solubility of carbazochrome is greater in water than in ethanol, C



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and if the temperature is greater than 313.15 K, then the solubility of carbazochrome is greater in ethanol than in water. Carbazochrome has large dipole moments owing to the −NH2 group and −NH− group and hence can give strong dipole−dipole interactions and form H-bonds with the solvent.40 These H-bonds also have an effect on the solubility. The carbazochrome solubilities are larger in DMSO and DMF than in the other studied solvents, obviously owing to the Hbonds formed between the N−H groups of carbazochrome and the free electron pairs of oxygen atoms in DMSO and DMF molecules. The H-bonds formed between the NH group and several solvents have been confirmed using infrared spectroscopy. 41 The H-bonds may also be formed between carbazochrome and esters, ketones, alcohols, and nitriles. As a result, the solubility of carbazochrome is larger in DMSO and DMF than in the other solvents at a given temperature. It may also be found from Figure 1 that for the sequence of solubility in neat solvents DMSO, DMF, ethanol, water, methanol, and npropanol that the water molecule is interrupting the sequence of solubility within the alcohol series. The reason is unclear and needs further study. In general, it is too complex to explain the solubility behavior contained in Tables S1−S4 for one reason. This may be a result of numerous factors, e.g., molecule polarity, solute−solvent interactions, molecular shapes, and solvent−solvent interactions and sizes. Solubility Data in Mixed Solvents. Tables S1−S4 present the measured solubility of carbazochrome in binary mixtures (DMF + methanol), (DMF + ethanol), (DMF + n-propanol), and (DMSO + water), respectively. In order to compare the solubility data, the dependence of the mole fraction solubility on solvent composition and temperature is given in Figures 2−5 as well. It can be observed that, for the four solvent solutions, the carbazochrome solubility is a function of solvent composition and temperature. The solubilities of carbazochrome increase with increasing mass fraction of DMF/DMSO and temperature for systems (DMF + methanol), (DMF + ethanol), (DMF + n-propanol), and (DMSO + water). The

Figure 3. Mole fraction solubility x of carbazochrome in DMF (w) + ethanol (1 − w) with various mass fractions at different temperatures: ▽, w = 0; Δ, w = 0.1000; ○, w = 0.2000; □, w = 0.3000; ★, w = 0.4000; ▶, 0.5000; ◀, w = 0.6000; ▼, w = 0.7000; ▲, w = 0.8000; ●, w = 0.9000; and ■, w = 1. Solid line, calculated by the Jouyban−Acree model.

Figure 4. Mole fraction solubility x of carbazochrome in DMF (w) + n-propanol (1 − w) with various mass fractions at different temperatures: ▽, w = 0; Δ, w = 0.1000; ○, w = 0.2000; □, w = 0.3000; ★, w = 0.4000; ▶, 0.5000; ◀, w = 0.6000; ▼, w = 0.7000; ▲, w = 0.8000; ●, w = 0.9000; and ■, w = 1. Solid line, calculated by the Jouyban−Acree model.

largest solubility of carbazochrome is found in pure DMF and DMSO. Solubility Modeling. Along with the experiment to determine the solid solubility in solvent mixtures, numerous solubility models have been put forward to correlate the solid solubility in mixed solvents.2,17 In the present work, three equations are used to fit the carbazochrome solubility in (DMF + methanol), (DMF + ethanol), (DMF + n-propanol), and (DMSO + water) mixtures at different temperatures, which correspond to the Jouyban−Acree equation,17,42 a combination of Jouyban−Acree equition with van’t Hoff equation,43,44 and a combination of Jouyban−Acree equation with Apelblat equation.43,44

Figure 2. Mole fraction solubility x of carbazochrome in DMF (w) + methanol (1 − w) with various mass fractions at different temperatures: ▽, w = 0; Δ, w = 0.1000; ○, w = 0.2000; □, w = 0.3000; ★, w = 0.4000; ▶, 0.5000; ◀, w = 0.6000; ▼, w = 0.7000; ▲, w = 0.8000; ●, w = 0.9000; and ■, w = 1. Solid line, calculated by the Jouyban−Acree model. D



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⎡ ⎤ B ln xw , T = w1⎢A1 + 1 + C1 ln(T /K )⎥ ⎣ ⎦ T /K ⎡⎛ ⎤ B2 ww + w2⎢⎜A 2 + + C2 ln(T /K )⎥ + 1 2 ⎦ T /K ⎢⎣⎝ T /K

2

∑ Ji (w1 − w2)i i=0

(8)

The determined solubilities of carbazochrome in the four mixed solvents are correlated by using eqs 4−8, and the values of the equation parameters are acquired by minimizing the objective function described as F=

∑ ∑ (ln xwe ,T − ln wwc ,T )2 i

j

i

j

(9)

i=1 j=1

Here, ln xew,T is the logarithm of solute solubility obtained in the present work, and ln xcw,T is calculated via the corresponding model. Additionally, the root-mean-square deviation (RMSD) and relative average deviation (RAD) are also employed to estimate the selected models, which are expressed as eqs 10 and 11.

Figure 5. Mole fraction solubility (x) of carbazochrome in DMSO (w) + water (1 − w) mixed solutions with various mass fractions at different temperatures: ▽, w = 0; Δ, w = 0.1000; ○, w = 0.2000; □, w = 0.3000; ★, w = 0.4000; ▶, w = 0.5000; ◀, w = 0.6000; ▼, w = 0.7000; ▲, w = 0.8000; ●, w = 0.9000; and ■, w = 1. w, mass fraction of DMSO; , curves calculated by the Jouyban−Acree model.

RAD =

1 N

2

∑ Ji (w1 − w2)i i=0

(4)

Here, xw,T denotes the solubility of the solute in mole fraction in mixed solvents at temperature T/K; w1 and w2 are the mass fractions of solvents 1 (DMF or DMSO) and 2 (ethanol, methanol, n-propanol, or water) free of the solute (carbazochrome), respectively; x1,T and x2,T are the solute solubilities in pure solvent; and Ji denotes the Jouyban−Acree model parameters. The van’t Hoff equation (eq 5) expresses the dependence of the solubility on the reciprocal of temperature. ln x = A +

B T

(5)

The Apelblat equation has been widely employd to express a nonlinear relationship between solute solubility (ln xw,T) in neat solvent or solvent mixtures and 1/T. This equation is expressed as eq 6. ln x = A +

B + C ln(T /K) T /K

(6)

In eqs 5 and 6, A, B, and C are corresponding model constants. Equations 7 and 8 may be derived by substituting eqs 5 and 6 into eq 4, respectively.43,44 ⎛ ⎛ B ⎞ B2 ⎞ ww ⎟+ 1 2 ln xw , T = w1⎜A1 + 1 ⎟ + w2⎜A 2 + ⎝ ⎝ T /K ⎠ T /K ⎠ T /K

∑i = 1 (xwc , T − xwe , T )2 N

(11)

Here, N denotes the number of solubility data points. During the regression procedure, the solubility data points for certain mixed solvents within the whole range of compositions at all investigated temperatures are selected for the selected models. In terms of the determined solubility values, the equation parameters in eqs 4−8 are attained with Mathcad software. The acquired values of model parameters along with the RMSD and RAD values are listed in Table S5 of the Supporting Information. The determined solubility is analyzed with the Kruskal−Wallis analysis of variance, and Bonferroni’s correction is employed for posthoc analysis. The statistical analysis is carried out with the SPSS 15.0 software package (SPSS Inc., Chicago, IL). The obtained p values are also presented in Table S5. The solubility of carbazochrome in the solvent mixtures of (DMF + methanol), (DMF + ethanol), (DMF + n-propanol), and (DMSO + water) is calculated on the basis of the values of the parameters. Moreover, the evaluated solubility values with the Jouyban−Acree model are shown in Figures 2−5. For the four binary mixed solvents, the RAD values between the computed and determined solubility data are all lower than 4.39 × 10−2, and the RMSD values are all smaller than 0.98 × 10−4. For the comparison with the other two equations, the values of RMSD and RAD acquired using the Jouyban−Acree equation are relatively small. In general, the three equations may all be used to correlate the carbazochrome solubility in the binary (DMF + methanol), (DMF + ethanol), (DMF + n-propanol), and (DMSO + water) mixtures, and the Jouyban−Acree equation offers better results than do the other two equations. Preferential Solvation of Carbazochrome. IKBI is a powerful tool for calculating the preferential solvation of solid in mixed solvents.6,7 It expresses the local solvent composition around a solute compared to the global solutions composition. This action depends on the standard molar Gibbs energies of transfer of solute from neat alcohol or water to mixed solvents of DMF (1) + alcohol (2) or DMSO (1) + water (2) and the excess molar Gibbs energy of mixing for the mixed solvents. As is well known, the preferential solvation study provides useful

The Jouyban−Acree model expressed as eq 4 is a precise description of the solubility dependence upon both solvent composition and temperature for solvent mixtures.17,42 w1w2 T

(10)

N

RMSD =

ln xw , T = w1 ln x1, T + w2 ln x 2, T +

⎛ |xwc , T − xwe , T | ⎞ ⎟⎟ ∑ ⎜⎜ xwe , T ⎠ ⎝

2

∑ Ji (w1 − w2)i i=0

(7) E



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previous publications, it is assumed to be similar to the molar volume of carbazochrome.30,45−47 In this manner, the molar volume of carbazochrome (3) is evaluated with the Fedors group contribution method49 as 107.7 cm3·mol−1 (Table S6 in the Supporting Information). Therefore, the radius of the carbazochrome molecule in eq 16 is computed using eq 18 as 0.350 nm.

information concerning the solvent distribution around a solute molecule and molecular interactions in mixed solvents.6,7,30,45−47 In solvent mixtures such as DMF (1) + ethanol (2), DMF (1) + methanol (2), DMF (1) + n-propanol (2), and DMSO (1) + water (2) mixtures, the preferential solvation parameter of carbazochrome (3) by DMSO or DMF (1) is expressed as6,7,30,45−47 L δx1,3 = x1,3 − x1 = −δx 2,3

r3 =

(12)

In eq 12, xL1,3 is the local mole fraction of DMSO/DMF in the environment close to carbazochrome (solvation sphere), and x1 is the mole fraction of DMSO/DMF employed in the bulk mixed solution. Parameter δx1,3 signifies the deficiency or excess of DMSO/DMF in the DMSO/DMF mixture in the local area. When carbazochrome is preferentially solvated by DMSO (DMF) (1), δx1,3 > 0 and for δx1,3 < 0, carbazochrome is preferentially solvated by alcohol or water (2). However, for |δx1,3| < 0.01, the preferential solvation procedure may be negligible, while for xL1,3 ≈ 1 the carbazochrome is completely solvated by DMSO/DMF. Needed parameter δx1,3 in DMSO/ DMF systems may be attained from the IKBI method for the single solvent component based on the equations as follows.6,7,30,45−47 δx1,3 =

with x 2 V2D Q

(14)

G2,3 = RTκT − V3 +

x1V1D Q

(15)

L L Vcor = 2522.5[r3 + 0.1363(x1,3 V1̅ + x 2,3 V2)1/3 − 0.085]3

(16)

Here, κT denotes the isothermal compressibility of the DMF (1) + ethanol (2), DMF (1) + methanol (2), DMF (1) + npropanol (2), and DMSO (1) + water (2) mixtures (in GPa−1). The dependence of κT upon composition is not reported for many systems. Instead, because of the slight contribution of RTκT to the IBKI, the dependence of κT upon composition can be computed approximately by assuming additive behavior from the isothermal compressibilities of individual components based on eq 176,7,30,45−47 κT =

x1κTo,1

+

x 2κTo,2

(18)

V1 = V + x 2

dV dx1

(19)

V2 = V − x1

dV dx1

(20)

Here, V denotes the molar volume of the solutions computed as V = (x1M1 + x2M2)/ρ. M1 is 46.07 g·mol−1 for ethanol, 32.04 g·mol−1 for methanol, 60.10 g·mol−1 for n-propanol, and 18.02 for water, and M2 is 73.1 g·mol−1 for DMF and 78.13 g·mol−1 for DMSO. In eqs 14 and 15, function D (eq 21) is the derivative of the standard molar Gibbs energies of transfer of carbazochrome from neat ethanol, methanol, n-propanol, or water to DMF (1) + alcohol (2) and DMSO (1) + water (2) mixtures with regard to the DMF/DMSO composition (expressed in kJ·mol−1). The function Q (eq 22) includes the second derivative of the excess molar Gibbs energy of mixing of the neat solvents (G1exc+ 2) with regard to the ethanol, methanol, n-propanol, or water proportion in the solutions (expressed in kJ·mol−1).6,7,30,45−47

(13)

G1,3 = RTκT − V3 +

3 × 1021V3 4πNAV

where r3 is the molecular radius of carbazochrome and NAv refers to Avogadro’s number. The partial molar volumes of two neat solvents in the solutions may be computed according to eqs 19 and 20 from the density of DMF (1) + alcohol (2) and DMSO (1) + water (2) solutions at the temperatures under investigation by Yang for DMF + ethanol and DMF + methanol mixtures,50 by Páez for DMF + n-propanol mixtures,51 and by Grande for DMSO (1) + water (2) solutions.52

x1x 2(G1,3 − G2,3) x1G1,3 + x 2G2,3 + Vcor

3

o ⎞ ⎛ ∂Δtr G(3,2 → 1 + 2) ⎟ D=⎜ ∂x1 ⎠T , P ⎝

(21)

⎡ ∂ 2G exc ⎤ 1+2 ⎥ Q = RT + x1x 2⎢ 2 ⎣ ∂x 2 ⎦T , p

(22)

G1exc + 2

The mixing excess molar Gibbs energies should be needed to compute the values of Q. But the value is reported at 298.15 K for DMSO (1) + water (2) mixtures, 313.15 K for DMF (1) + ethanol (2) and DMF (1) + methanol (2) solutions,6 and 353.15 K for DMF (1) + n-propanol (2) mixtures.53 Therefore, it is required to calculate the data at −1 other temperatures. Gexc 1+2 (J·mol ) values are computed on the basis of eqs 23 and 24 for the DMF (1) + ethanol (2) and DMF (1) + methanol (2) mixtures at 313.15 K, respectively, and at 298.15 K using eq 25 for the DMSO (1) + water (2) mixtures.6 For the DMF (1) + n-propanol (2) solutions, the −1 Gexc 1+2 (J·mol ) values are derived from the isothermal vapor− liquid equilibrium data at 353.15 K53 and correlated to a polynomial as a function of mole fraction of DMF as eq 26. Instead, the Gexc 1+2 values at the other temperatures are obtained

(17)

where xi is the mole fraction of component i in the mixed solvents and κoT,i stands for the isothermal compressibility of the pure solvent, i. The RTκT values in DMF (1) + ethanol (2), DMF (1) + methanol (2), DMF (1) + n-propanol (2), and DMSO (1) + water (2) solutions are evaluated by using eq 17 with κoT,i values of 0.653, 1.248, 1.153, 1.025, 0.524, and 0.457 GPa−1 for DMF, methanol, ethanol, n-propanol, DMSO, and water, respectively.48 In eqs 14−16, V1 and V2 denote the partial molar volumes of solvents 1 and 2, respectively, in the solutions (in cm3·mol−1), and V3 denotes the partial molar volume of carbazochrome in the solvent mixtures. Since no partial molar volume of carbazochrome (3) in the solvent mixtures is given in the F



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Figure 6. δx1,3 values of carbazochrome (3) transfer from methanol (ethanol, n-propanol and water) to DMF (1) + methanol (2), DMF (1) + ethanol (2), DMF (1) + n-propanol (2), and DMSO (1) + water (2) mixtures at several temperatures.

with eq 27, where Hexc 1+2 denotes the excess molar enthalpy of the DMF solutions, T1 is 298.15 K for DMSO (1) + water (2) mixtures, 313.15 K for DMF (1) + ethanol (2) and DMF (1) + methanol (2) solutions, and 353.15 K for DMF (1) + npropanol (2), and T2 denotes the studied temperature. Hexc 1+2 values for DMSO (1) + water (2) solutions and DMF (1) + ethanol (2) and DMF (1) + methanol (2) solutions (eqs 28−30) are cited in ref 6, and for DMF (1) + n-propanol (2) solutions, they are cited in ref 54 and also correlated to a polynomial as a function of the mole fraction of DMF described as eq 31. The relevant values are considered to change in 0.05 mole fraction of DMSO or DMF. G1exc + 2 = x1(1 − x1)[ − 1264 + 67(1 − 2x1)] G1exc +2

H1exc + 2 = x1(1 − x1)[ − 10 372 + 6922(1 − 2x1) − 2466(1 − 2x1)2 ]

H1exc + 2 = x1(1 − x1)[ − 428 + 47(1 − 2x1) − 126(1 − 2x1)2 ]

− 292(1 − 2x1)2 ]

− 16.683x13 − 1.219 × 103x14

G1exc + 2 = x1(1 − x1)[ − 4909 + 2168(1 − 2x1) (25)

⎛ x3,2 ⎞ 0 ⎟⎟ Δtr G3,2 ⎜ → 1 + 2 = RT ln⎜ ⎝ x3,1 + 2 ⎠

3 3 2 G1exc + 2 = − 0.0184 − 1.414 × 10 x1 + 1.714 × 10 x1

G1exc + 2(T2)

=

G1exc + 2(T1)

−T

∫T

T2

1

≈

H1exc +2

(26)

(32)

The ΔtrG03,2→1+2 values are regressed using eq 33 for DMF (1) + methanol (2) and DMSO (1) + water (2) solutions and using eq 34 for DMF (1) + ethanol (2) and DMF (1) + npropanol (2) solutions. Figure S9 in the Supporting Information presents the Gibbs energy of transfer at several temperatures, while the obtained values are listed in Tables S7

⎛1⎞ d⎜ ⎟ ⎝T ⎠

⎛ T2 exc T2 ⎞ G1 + 2(T1) + H1exc ⎟ + 2 ⎜1 − T1 T1 ⎠ ⎝

(31)

The standard molar Gibbs energies of transfer of carbazochrome from pure ethanol (2), methanol (2), npropanol (2), and water (2) to DMF (1) + ethanol (2), DMF (1) + methanol (2), DMF (1) + n-propanol (2), and DMSO (1) + water (2) solutions are calculated from the solubility values with eq 32.

(24)

− 344.90x13 + 45.168x14

(30)

3 3 2 H1exc + 2 = − 0.624 + 2.412 × 10 x1 − 1.176 × 10 x1

(23)

= x1(1 − x1)[−506 + 85(1 − 2x1) + 34(1 − 2x1)

− 5(1 − 2x1)2 ]

(29)

H1exc + 2 = x1(1 − x1)[1612 − 447(1 − 2x1)

2

+ 27(1 − 2x1)3 ]

(28)

(27) G



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δx1,3 = 1.488 × 10−2 to 1.517 × 10−2 for DMSO (1) + water (2). It may also be found from Figure 6 that the temperature has a slight effect on the preferential solvation magnitudes of carbazochrome in the four solvent mixtures. It is noteworthy that several δx1,3 values are smaller than 1.0 × 10−2. Hence these values are qualitative owing to uncertainty propagation influences.55,56 On the basis of a functional group and structural analysis, carbazochrome may behave as a Lewis acid in the mixture because of the capacity of the acidic hydrogen atom in −OH and −NH2 (Figure S1 of Supporting Information) to form hydrogen bonds with proton-acceptor functional groups such as oxygen atoms or nitrogen groups in DMF and DMSO. Moreover, carbazochrome may also behave as a Lewis base due to the free electron pairs in the oxygen atom of O and the nitrogen atom of >N−, which can interact with acidic hydrogen atoms of ethanol, methanol, n-propanol, or water. On the basis of the preferential solvation analysis, we can surmise that in the regions (δx1,3 > 0) of 0.35 < x1 < 1.00 for DMF (1) + methanol (2) solutions, 0.43 < x1 < 1.00 for DMF (1) + ethanol (2) solutions, 0.50 < x1 < 1.00 for DMF (1) + npropanol (2) solutions, and 0.21 < x1 < 1.00 for DMSO (1) + water (2) solutions, carbazochrome acts as a Lewis acid with DMSO or DMF molecules, although DMF is less basic than npropanol or ethanol, as expressed by the Kamlet−Taft hydrogen bond acceptor parameters, i.e., β = 0.66 for methanol, β = 0.69 for DMF, β = 0.90 for n-propanol, β = 0.75 for ethanol, β = 0.76 for DMSO, and β = 0.47 for water,50,57,58 while in the other regions for the studied mixed solvents, where carbazochrome is preferentially solvated by ethanol, methanol, n-propanol, or water, carbazochrome acts mainly as a Lewis base with ethanol, methanol, n-propanol, or water because the solvents are more acidic than DMF/DMSO molecules as expressed by the Kamlet−Taft hydrogen bond donor parameters, i.e., α = 0 for DMF and DMSO, α = 0.850 for ethanol, α = 0.990 for methanol, α = 0.766 for n-propanol, and α = 1.17 for water.48,58,59

and S8 of the Supporting Information. The attained coefficients for equations are contained in Tables S9 and S10. −x1/ t1 0 Δtr G3,2 + A 2 e−x1/ t2 → 1 + 2 = A 0 + A1e

(33)

0 2 3 4 5 Δtr G3,2 → 1 + 2 = a + bx1 + cx1 + dx1 + ex1 + fx1

(34)

Thus, the values of D are acquired from the first derivative of eqs 33 and 34 solved on the basis of the DMSO/DMF solution composition varying by 0.05 in mole fraction of DMSO/DMF. The achieved values of D are contained in Tables S11 and S12 of the Supporting Information. Moreover, the computed G1,3 and G2,3 values are given in Tables S13−S16 of the Supporting Information. It may be observed that the values of G1,3 and G2,3 are all negative. This case demonstrates that carbazochrome shows an affinity for the two solvents in the DMF (1) + ethanol (2), DMF (1) + methanol (2), DMF (1) + n-propanol (2), and DMSO (1) + water (2) solutions. The definitive correlation volume relates to the local mole fractions near the carbazochrome; therefore, it requires iteration. This process is made by substituting δx1,3 and Vcor into eqs 12, 13, and 16 to re-evaluate xL1,3 until a constant value of Vcor is acquired. The obtained data of Vcor and δx1,3 are, respectively, contained in Tables S17−S20 of the Supporting Information for DMF (1) + methanol (2), DMF (1) + ethanol (2), DMF (1) + n-propanol, and DMSO (1) + water (2) solutions. Morever, the relationship between δx1,3 values and DMF/DMSO composition is shown in Figure 6. It reveals that the δx1,3 values change nonlinearly with the DMF/DMSO (1) proportion in all of the mixed solvents. Introducing DMF/ DMSO makes negative the δx1,3 values of carbazochrome (3) transfer from pure ethanol, methanol, n-propanol, and water to the mixture with composition x1 = 0.43 for DMF (1) + ethanol (2), x1 = 0.35 for DMF (1) + methanol (2), x1 = 0.50 for DMF (1) + n-propanol (2), and x1 = 0.21 for DMSO (1) + water systems. The largest negative values are attained in solution x1 = 0.10 with δx1,3 = −1.832 × 10−2 to −1.762 × 10−2 for DMF (1) + methanol (2), x1 = 0.10 with δx1,3 = −2.754 × 10−2 to −2.406 × 10−2 for DMF (1) + ethanol (2), x1 = 0.20 with δx1,3 = −3.083 × 10−2 to −2.724 × 10−2 for DMF (1) + n-propanol (2), and x1 = 0.05 with δx1,3 = −1.859 × 10−2 to −1.673 × 10−2 for DMSO (1) + water (2), respectively. Perhaps the structuring of ethanol, methanol, n-propanol, or water molecules around the nonpolar aromatic group of carbazochrome makes the net δx1,3 values negative in the ethanol, methanol, n-propanol, or water-rich solutions. In the DMF (1) + methanol (2) solution with composition 0.35 < x1 < 1.00, DMF (1) + ethanol (2) solution with composition 0.43 < x1 < 1.00, DMF (1) + n-propanol (2) solution with composition 0.50 < x1 < 1.00, and DMSO (1) + water (2) solution with composition 0.21 < x1 < 1.00, the local mole fractions of DMSO/DMF are greater than that of the solutions; consequently, the δx1,3 values are positive, which shows that carbazochrome is preferentially solvated by DMSO or DMF. The DMSO/DMF action to enhance the solubility of the solute is perhaps related to breaking the ordered structure of water, ethanol, methanol, or n-propanol around the nonpolar moieties of carbazochrome, which increases the solvation of the drug showing the largest value in x1 = 0.70 with δx1,3 = 0.950 × 10−2 to 1.016 × 10−2 for DMF (1) + methanol (2), x1 = 0.70 with δx1,3 = 1.358 × 10−2 to 1.511 × 10−2 for DMF (1) + ethanol (2), x1 = 0.75−0.80 with δx1,3 = 1.358 × 10−2 to 1.502 × 10−2 for DMF (1) + n-propanol (2), and x1 = 0.45−0.50 with

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CONCLUSIONS The carbazochrome solubility in four mixed solvents of DMF + methanol, DMF + ethanol, DMF + n-propanol, and DMSO + water with different compositions was obtained within the temperature range from 278.15 to 318.15 K by using the static method under 101.0 kPa. For the four mixed solvents, with the rise in temperature, the solubility of carbazochrome in mole fraction increased. At the same temperature, they increased with the increase in mass fractions of DMF and DMSO. The dependence of carbazochrome solubility upon solvent composition and temperature was correlated using the Jouyban−Acree equation, Apelblat−Jouyban−Acree equation, and van’t Hoff−Jouyban−Acree equation. The computed solubility with the selected equations all provided good agreement with the experimental data. The standard molar Gibbs energy of transfer of carbazochrome decreased with increasing composition of DMF (1) and DMSO (1) and had a strong dependency on DMSO in DMSO (1) + water (2) solvent mixtures. The local mole fractions of ethanol (methanol, n-propanol, or water) and DMF/DMSO around the carbazochrome were quantitatively deduced on the basis of the IKBI approach. Carbazochrome was preferentially solvated by alcohol/water in alcohol/water-rich solutions and preferentially solvated by DMSO/DMF in DMSO/DMF-rich mixtures. H



Article

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For the latter case, carbazochrome might be behaving as a Lewis acid with DMF or DMSO molecules.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.7b00982. Chemical structure of carbazochrome, experimental apparatus, XPRD patterns, DSC/TG scan, van’t Hoff plots, Gibbs energy of transfer, solubilities in mixed solvents, parameters of equations, Fedors’ method to estimate the molar volume and Hildebrand solubility parameter, Gibbs energy of transfer, coefficients of equations, D values, G1,3 and G2,3 values, correlation volume, and δx1,3 values (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel: + 86 514 87975568. Fax: + 86 514 87975244. E-mail: [email protected]. ORCID

Hongkun Zhao: 0000-0001-5972-8352 Funding

This work was supported by the Science and Technology Research Key Project of the Education Department of Jiangsu Province (project number SJCX17_0621) and the Practice Innovation Project of Jiangsu Province for Post Graduate Students (project number XKYCX17_039). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors express their gratitude to the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Solubility and Preferential Solvation of Carbazochrome in Solvent

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