Solubility Modeling and Solvent Effect for Flubendazole in 12 Neat

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

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Solubility Modeling and Solvent Effect for Flubendazole in 12 Neat Solvents Jiaojiao Ma, Jinhua Liang, Jingchao Han, Min Zheng, and Hongkun Zhao*

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College of Chemistry & Chemical Engineering, YangZhou University, YangZhou, Jiangsu 225002, People’s Republic of China ABSTRACT: The method of shake-flask was used in studying the solubility of flubendazole in water, n-propanol, ethanol, isopropyl alcohol, methanol, isobutyl alcohol, n-butanol, N,N-dimethylformamide, 1,4-dioxane, 2-butanone, dimethyl sulfoxide (DMSO), and N-methyl-2-pyrrolidone. The determination was made over the temperatures from 283.15 K to 333.15 K under ambient pressure p = 101.2 kPa. The values of flubendazole solubility in mole fraction in these solvents increased with rising temperature. They were highest in DMSO and lowest in water. The gained solubility was mathematically described through the Apelblat equation. The maximum average relative deviation and root-mean-square deviation were 2.69% and 3.60 × 10−5, respectively. In addition, using the relationship analysis of linear solvation energy of solvent effect, the degree and type of solvent−solvent and solute− solvent interactions were identified.

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INTRODUCTION Knowledge of solubility is actually important in the pharmaceutical field for product design because of the effect of solubility upon efficacy, formulation development, and pharmaco-kinetics comprising transport, release, and absorption of a drug.1−3 Low aqueous solubility of a drug frequently causes low bioavailability and inadequate absorption. Alternatively, the crystallization process as a purification technique is very significant in the pharmaceutical industry and usually applied in the last step of active pharmaceutical ingredients (APIs) production.4,5 Drug solubility in neat solvents presents the significant thermodynamic knowledge desired in the crystallization procedure design and adjusting the distribution of polymorph and crystal size in mixtures.1−7 Flubendazole (IUPAC name, methyl [5-(4-fluorobenzoyl)1H-benzimidazol-2-yl]carbamate; CAS no. 31430-15-6; molar mass, 313.28) is a crucial antihelmentic substance. Its chemical structure is given as Figure 1. It is a promising drug employed

solubility, several methods such as adding tensides and solutizers, or complex formation with cyclodextrins have been employed in previous works.14−16 These techniques necessitate a great amount of accurate solubility data in neat and mixed solvents. Accordingly it is very vital to determine systematically the flubendazole solubility, which may provide an expressive description for some thermodynamic functions, physic-chemical properties. and mechanisms in relation to the physical and chemical stability of lots of pharmaceutical dissolutions. However, despite the practicality of flubendazole, its physicochemical properties in pure and mixed solvents have not yet been investigated. A comprehensive literature review demonstrates that only the flubendazole solubility in water14−16 is available as yet. It is common knowledge that solvent selection is important for pharmaceutical areas. The acceptable solvents should be commercially available, noncorrosive, nontoxic (environmentally safe), and thermally stable.17 On the basis of the discussions above, the aim of this paper is to determine the solubility of flubendazole in solvents namely isopropyl alcohol, ethanol, methanol, isobutyl alcohol, n-butanol, N,N-dimethylformamide (DMF), n-propanol, 2-butanone, 1,4-dioxane, dimethyl sulfoxide (DMSO), water, and N-methyl-2-pyrrolidone (NMP) at several temperatures.

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Figure 1. Chemical structure of flubendazole.

SOLUBILITY MODELING In the present paper, experimental flubendazole solubility in 12 neat solvents is mathematically described by using the Apelblat equation18 and KAT-LSER model.19

in the worldwide elimination programs of onchocerciasis (river blindness) and human lymphatic filariasis (elephantiasis).8−10 Onchocerciasis and lymphatic filariasis influence many people living in tropical regions.9,11,12 It is regretful that the water solubility of flubendazole is poor, which affects not only its dosage form, but also biological availability.13−16 With the purpose of overcoming the disadvantage of poor aqueous © XXXX American Chemical Society

Received: November 25, 2018 Accepted: February 14, 2019

A

DOI: 10.1021/acs.jced.8b01126 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Table 1. Detailed Information on the Materials Used in the Work molar mass g·mol−1

chemicals flubendazole methanol ethanol isopropyl alcohol isobutyl alcohol n-propanol n-butanol DMF 2-butanone 1, 4-dioxane DMSO NMP water

313.28 32.04 46.07 60.10 74.12 60.10 74.12 73.09 72.11 88.11 78.13 99.13 18.02

source

initial mass fraction purity

final mass fraction purity

purification method

0.984 0.997 0.994 0.995

0.996 0.997 0.994 0.995

recrystallization none none none

HPLCa GCb GC GC

0.994 0.995 0.994 0.995 0.994 0.995 0.994 0.995

0.994 0.995 0.994 0.995 0.994 0.995 0.994 0.995 conductivity < 2 μs·cm−1

none none none none none none none none distillation

GC GC GC GC GC GC GC GC conductivity meter

Sigma Chemical Co., Ltd. Sinopharm Chemical Reagent Co., Ltd.

our lab

analytical method

a

High-performance liquid phase chromatography. bGas chromatography.

Apelblat Equation. It is first put forward by Apelblat and co-workers,18 and provides precise description of the solubility of solid in neat solvents. The mathematical expression of the Apelblat equation is ln x = A +

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

and solvent. Vs denotes the molar volume of a solute in the hypothetical subcooled liquid state. R is the universal gas constant. The term Vsδ2H demonstrates the energy needed to destroy the attractive forces of solvent−solvent intermoleculars to provide accommodation of the solute in the cavity. The cavity term is made dimensionless through dividing it by RT. As well, with the intention of making an appropriate comparison between these variables, the Vs is divided by 100 so as to make this term have a similar range with that of the others. c0 stands for the constant at α = β = π* = δH = 0; c2 and c3 denote the solute property sensibility to the specific hydrogen bonding of solute−solvent interactions; while c1 and c4 signify the measure of the solute’s sensibility to the electrostatic interactions of solvent−solute and solvent− solvent, respectively. During the correlation procedure, the destination function is

(1)

where x refers to the solubility of flubendazole in mole fraction in pure solvents at T/K; the empirical parameters of this equation are referred to A, B, and C. The B and A refer to the variation in mixture activity coefficient and provide the information on nonideal solution effect upon solubility of flubendazole; and parameter C shows the fusion enthalpy dependence on temperature. KAT-LSER Model. The analysis of multiple linear regression (MLRA) including several parameters of a solvent is a powerful tool to investigate the solvation interactions upon solubility of a solid. In general, several linear properties relating the Gibbs energy (XYZ) of a solute−solvent system according to the LSER (linear solvation energy relationships) equation is described as eq 2.20,21

F=

Moreover, the RMSD (root average square deviation) and RAD (relative mean deviation) are also employed to evaluate the selected models. RAD =

(2)

In eq 2, XYZ0 denotes a constant which is only dependent upon the solute. The summation covers all kinds of solute− solvent interactions. The linear solvation energy relationship model proposed by Kamlet and Taft, KAT-LSER, has been used in describing the change of Gibbs energy of solutions, for instance, liquid−solid equilibrium, with physical characteristics of both solvent and solute at the molecular level upon the basis of linear contributions of different interactions between solute and solvent. The expression of KAT-LSER model is19,22 2 ji V δ zy ln(xi) = c0 + c1π * + c 2β + c3α + c4jjj s H zzz j 100RT z k {

(4)

i=1

XYZ = XYZ0 + Σsolvent−solute interaction energy + cavity formation energy

∑ (ln xTe − ln xTc)2

1 N

c e ij |x w,T − x w,T | yzz zz e z x w,T k {

∑ jjjj

(5)

N

RMSD =

c e ∑i = 1 (x w,T )2 − x w,T

N

(6)

xcT

where N denotes the experimental data number. and xeT refer to the calculated mole fraction solubility and determined value.

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EXPERIMENTAL SECTION Materials. Flubendazole was provided by Sigma Chemical Co., Ltd., China, the mass fraction purity of which was 0.984. The final content of flubendazole used in the experiment was 0.996 in mass fraction, which was purified repeatedly in neat solvent methanol and confirmed through high-performance liquid chromatography (Agilent 1260, HPLC). The organic solvents including ethanol, isopropyl alcohol, methanol, isobutyl alcohol, n-butanol, 2-butanone, n-propanol, DMF,

(3)

here α, π*, δH, and β denote, respectively, the hydrogen-bond acidity, dipolarity/polarizability, Hildebrand solubility parameter, and hydrogen-bond basicity of a solvent. The Hildebrand solubility parameter δH is termed as the energy density of cohesiveness, which denotes the interactions between solvent B



Article

Figure 2. XPRD patterns of flubendazole: (a) raw material; (b) equilibrated with methanol; (c) equilibrated with ethanol; (d) equilibrated with isopropyl alcohol; (e) equilibrated with n-propanol; (f) equilibrated with n-butanol; (g) equilibrated with isobutyl alcohol; (h) equilibrated with DMF; (i) equilibrated with 2-butanone; (j) equilibrated with 1,4-dioxane; (k) equilibrated with DMSO; (m) equilibrated with NMP; (n) equilibrated with water.

Table 2. Experimental Mole Fraction Solubility (x) of Flubendazole in Different Solvents at the Temperature Range from T = (283.15 to 333.15) K under 101.2 kPaa 105 x T/K 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15 T/K 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

methanol

ethanol

n-propanol

0.07083 0.1051 0.1570 0.2246 0.3149 0.4414 0.6314 0.8488 1.168 1.591 2.138 DMSO

0.1028 0.1559 0.2407 0.3738 0.5436 0.7733 1.007 1.413 1.938 2.554 3.328 DMF

0.7705 1.002 1.316 1.693 2.158 2.638 3.394 4.311 5.527 6.779 8.090 2-butanone

190.7 221.0 261.2 302.8 357.9 418.9 480.7 548.0 626.9

57.22 70.84 82.11 98.01 115.8 138.3 161.9 187.6 220.3 258.8 309.3

isopropyl alcohol 0.6577 0.7967 0.9581 1.144 1.345 1.630 1.931 2.221 2.652 3.119 3.562 NMP

23.17 30.48 40.08 51.57 68.19 83.66 104.5 131.8 169.6 204.0 247.9

78.03 91.80 103.3 121.6 141.7 162.4 187.6 215.2 251.9 307.5 373.3

n-butanol 1.934 2.576 3.463 4.359 5.639 7.098 8.770 11.10 14.13 17.27 21.78 1.4-dioxane

isobutyl alcohol 1.203 1.620 2.134 2.731 3.546 4.611 5.881 7.439 9.385 11.62 13.54 water

8.293 9.826 11.99 14.00 16.84 19.51 22.95 26.60 30.83 35.73

0.01033 0.01314 0.01668 0.02122 0.02602 0.03232 0.04003 0.04961 0.06065 0.07329 0.08814

a

Standard uncertainties u are u(T) = 0.02 K, u (p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.0282.

completely mixed, the flubendazole-solvent mixtures were placed in a thermostatic shaker produced by Tianjin Ounuo Instrument Co. Ltd., China. The solvent−solute mixture was shaken at a shaking speed of 100 rpm. In an attempt to get the equilibrated time, about 0.5 mL liquid phase was taken out by using a 2 mL syringe at intervals of 1 h and examined by using the Agilent 1260 HPLC. The analytical results exhibited that 19 h was sufficient for the studied systems to reach equilibrium. After that the solutions were taken out from the shaker and permitted to precipitate all solids for 3.5 h. The upper clear liquor was taken out cautiously and examined using the HPLC. Analysis of Flubendazole Using HPLC. The flubendazole composition in equilibrium liquor was confirmed with the Agilent 1260 HPLC. It comprised a UV detector (G1314F) and a quaternary pump. The separation column was a Waters

1,4-dioxane, DMSO, NMP, and water were bought from Sinopharm Chemical Reagent Co., Ltd., China, the purities of which were no smaller than 0.994 in mass fraction confirmed through a gas chromatography having a type of Smart GC2018. The conductivity of deionized water was lower than 2 μS·cm−1, which was obtained in our laboratory through distillation under normal atmospheric pressure. The detailed information on the selected materials was tabulated in Table 1. Flubendazole Solubility Determination. In this paper, the flubendazole solubilities in the 12 neat solvents were measured with the shake-flask technique,23−26 which was validated through measuring the benzoic acid solubility in toluene.24 The experiments were carried out at temperatures from 283.15 K to 333.15 K under local atmosphere pressure p = 101.2 kPa. The excessive amount of flubendazole was introduced to a neat solvent in triplicate. After they were C



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Figure 3. Mole fraction solubility (x) of flubendazole in different solvents: (a) ●, DMSO; ▲, DMF; ◆, 2-butanone; ▼, NMP; ■, 1,4-dioxane. (b) ◀, n-butanol; ◆, isobutyl alcohol; ▲, n-propanol ; ▼, isopropyl alcohol; ●, ethanol; ■, methanol; ▶, water; , calculated curves with the Apelblat equation.

C18 reverse phase column (250 mm × 4.6 mm, 5 μm). The mobile phase speed was 1 mL per minute, which consisted of a mixture of methanol and 50 mmol·L−1 KH2PO4 (pH = 3) (3:97, v/v). The temperature of the column was about 303 K, and the analysis wavelength of flubendazole was set to 246 nm.27 Before examination, the HPLC was calibrated with standard mixtures. The dependence of the HPLC area upon flubendazole concentration was constructed. Every test was performed three times. The mean value of the triple tests was regarded as the final solubility. The relative standard uncertainty of the determined mole fraction solubility was assessed to be 0.0282. Solid Characterization of Flubendazole. In an attempt to determine the possible crystallinity and transformation of flubendazole during the process of determination, the solid equilibrated with its mixture was characterized. The equilibrated solid was collected and examined with the X-ray powder diffraction (XPRD). The XPRD scans of solid with the liquid phase and raw flubendazole were gained using the HaoYuan DX-2700B instrument covering the 2θ range from 8° to 80°. The Cu was used as anode with Kα radiation, the wavelength of which was 1.54184 nm. The XPRD spectra were achieved at a tube current and voltage of 40 mA and 40 kV, respectively, with a step of 0.02°.

DMSO than of that in water at 293.15 K. It varies quickly in water solvent with increasing temperature. For example, if the temperature rises from T = 278.15 K to T = 333.15 K, the solubility of flubendazole rises from 0.00858 × 10−5 to 0.3819 × 10−5, which is an increase of nearly 44 times. By and large, the solubility of flubendazole obeys the following order in the 12 solvents: DMSO > DMF > NMP > 2-butanone >1.4dioxane > n-butanol > isobutyl alcohol > n-propanol > isopropyl alcohol > ethanol > methanol > water. For the systems of flubendazole + alcohol, the sequence of flubendazole solubility is approximately identical with the change of solvent polarity. The methanol polarity is highest among the alcohols,28 hence the solubility of flubendazole is smallest in methanol. In the same way, the water polarity is largest among these solvents, so the flubendazole solubility in water is lower than that in the other solvents. Moreover, the flubendazole exhibits larger dipole moments. The flubendazole molecule can present high interactions of dipole−dipole with solvent molecules because of the >HH group,29 which may form hydrogen bonds with the solvent molecules. The hydrogen bonds formed have significant impact upon the solubility of a solute. The flubendazole solubilities are greater in the solvents of DMF and DMSO in comparison with the other solvents. It is obvious that this case is due to the hydrogen-bonds formation between the oxygen atoms of DMF and DMSO and the >HH group of flubendazole. By and large, it is not easy to demonstrate the variation of flubendazole solubilities tabulated in Table 2 in terms of a single reason. It is perhaps resulted from several factors, such as, polarity of molecules, molecular shapes, solvent−solute interactions, sizes, and solvent−solvent interactions. It is noteworthy that the flubendazole solubility (expressed as μg·mL−1) in water at 310 K with different pH values has been reported.13−15 It is regretful that the solution densities are not found in these literature works. With the intention of comparing the reported solubility data with that obtained in the present paper, the reported solubility values are transformed to mole fraction ones through supposing that the densities of the equilibrium liquor are equal to those of the corresponding neat solvents because of their very smaller solubilities. For the system of flubendazole + water, the flubendazole solubility in mole fraction obtained by us is 7.575 × 10−7 (obtained by interpolation) at 310 K, which is much greater than 7.477 × 10−8 reported by Araujo,13 3.336 × 10−7 reported by Ceballos,14 and 1.611 × 10−7 reported by Chun.15 The difference is perhaps due to several factors, for example, purity of solute, experimental technique, equilibration time, sampling, analysis technique, and so forth.

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RESULTS AND DISCUSSION XPRD Analysis. The scans of XPRD of raw flubendazole and the solid equilibrated with the corresponding liquid phase are shown graphically in Figure 2. As can be seen, they give characteristic peaks at various 2θ values (Figure 2). The spectrum of XPRD of raw flubendazole and solid equilibrated with liquid are very similar to that reported by De Araujo,13 which suggests that flubendazole presents a pure crystalline state and no transform to polymorphic or amorphous form takes place in the experiment process. Flubendazole Solubility. The obtained mole fraction solubilities (x) of flubendazole dissolved in isopropyl alcohol, n-butanol, methanol, ethanol, isobutyl alcohol, n-propanol, DMF, 1,4-dioxane, 2-butanone, DMSO, NMP and water at pressure of p = 101.2 kPa and temperature range from 283.15 to 333.15 K are tabulated in Table 2 and given in Figure 3. Figure 3 and Table 2 show that the rising temperature leads to a significant increase of flubendazole solubility dissolved in the 12 solvents. The flubendazole solubility is largest in DMSO (9.615 × 10−3), followed by DMF (5.378 × 10−3), and smallest in water (0.3818 × 10−5) at 333.15 K. The similar behavior may also be observed at other investigated temperatures. The flubendazole solubility is 104 times greater in D



Article

here R2 refers to correlation coefficient; F denotes F-test; and RSS denotes residual sum of squares. The values presented in parentheses stand for the standard deviation of equation coefficients. As is shown from eq 7, the KAT-LSER model offers a satisfied correlation consequence for the solubility of flubendazole dissolved in pure solvents. The values of equation parameters illustrate that the contributions of solvent descriptors to flubendazole solubility are, respectively, 41.57%, 37.80%, 10.99%, and 9.64% for α, β, π*, and δH. As a result the specific interactions play an important role on the solubility of flubendazole. The hydrogen-bond acidity of the solvent has a little large contribution to the flubendazole solubility than the hydrogen-bond basicity. The interactions of polarizability/dipolarity and cavity term, which is expressed as (Vsδ2H/100RT), have a much lower contribution than the specific interactions to the flubendazole solubility. Accordingly, the flubendazole solubility is correlated with the KAT-LSER model consisting of dual-parameters of α and β by using the multiple linear regression analysis:

Solvent Effect upon Solubility. So as to obtain further information about the solvent effect upon the flubendazole solubility, the KAT-LSER model is used to inspect the solubility of flubendazole in these investigated solvents at 298.15 K. The necessary solvent parameters comprising α, β, π*, and δH can be obtained from the literature30−32 and are presented in Table 3. The flubendazole molar volume, Vs = 185.0 cm3·mol−1 (Table 4), is assessed though the method suggested by Fedors.33 Table 3. Hildebrand Solubility Parameter (δH) and Solvatochromic Parameters α, β, and π* at 298.15 K for Neat Solventsa solvent

α

β

π*

δ2H/MPa−1

methanol ethanol isopropyl alcohol n-propanol n-butanol isobutyl alcohol 1.4-dioxane DMF water DMSO 2-butanone NMP

0.98 0.86 0.76 0.84 0.84 0.79 0 0.00 1.17 0.00 0.06 0.03

0.66 0.75 0.84 0.90 0.84 0.84 0.37 0.69 0.47 0.76 0.48 0.75

0.60 0.54 0.48 0.52 0.47 0.40 0.55 0.88 1.09 1.00 0.67 0.97

29.61 26.52 23.58 24.60 23.20 22.66 20.47 24.86 47.81 26.68 19.10 22.96

ln(x) = −10.747(0.763) − 6.323(0.411)α + 5.850(1.115)β R2 = 0.96, n = 12, RSS = 3.27, F = 118.5

As a whole, the correlation results are very good for the accepted model; because r2 is greater than 0.95. The contributions of α term and β term to flubendazole solubility are, respectively, 51.94% and 48.06%. This result is rational because flubendazole is a solute with hydrogen-bond donor due to the presence of some hydrogen atoms (Figure 1). Moreover, flubendazole is also a potential hydrogen-bond acceptor solute due to the free electron pairs in the oxygen atoms of the CO group and nitrogen atoms of the >NH and N− groups (Figure 1). The negative α coefficient demonstrates that the flubendazole solubility decreases with the increase in hydrogen-bond acidity of the solvent. In contrast, the β coefficient is positive, so the flubendazole solubility rises with the increasing hydrogen-bond basicity of solvents. Solubility Correlation and Calculation. On the basis of the determined solubility of flubendazole, the equation parameters in the Apelblat equation are achieved. The attained parameters’ values are tabulated in Table 5, as well as that of RMSD and RAD. The solubility of flubendazole in the 12 solvents back-calculated according to the equation parameters is shown in Figure 3. As is shown from Table 5, the largest value of RAD is 2.69%, which is obtained for the (flubendazole + isobutyl alcohol) solution. The highest RMSD value is 3.60 × 10−5 attained for the NMP solvent. Accordingly, the Apelblat equation presents acceptable correlation results.

a

Taken from refs 30, 31, and 32.

Table 4. Application of the Fedors’ Method to Estimate Hildebrand Solubility Parameter of Flubendazole group F >CO >NH -CH3 O -N >C phenylene (P) phenyl (trisubstituted) ring closure 5 or more atoms conjugation in ring for each double bond

group number

V U (cm3·mol−1) (kJ·mol−1)

1 2 2 1 1 1 1 1 1 1 1

18.0 10.8 4.5 33.5 3.8 5.0 −5.5 52.4 33.4 16 −2.2

total solubility parameter

185.0 146.15 (146150/185)1/2 = 28.11 MPa1/2

4.18 17.35 8.36 4.70 3.34 11.70 4.31 31.89 31.89 1.05 1.67

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The determined flubendazole solubility at 298.15 K is associated with various solvent parameters using Mathcad software. The regressed consequences are expressed as eq 7 for the selected pure solvents.

CONCLUSION The equilibrium solubilities of flubendazole dissolved in water and 11 organic solvents namely isopropyl alcohol, ethanol, methanol, isobutyl alcohol, n-butanol, DMF, n-propanol, 2butanone, 1,4-dioxane, DMSO, and NMP were obtained through experiment by employing the method of shake-flask from 283.15 K to 333.15 K under local ambient pressure (101.2 kPa). The mole fraction solubility in different solvents ranked as DMSO > DMF > NMP > 2-butanone >1.4-dioxane > n-butanol > isobutyl alcohol > n-propanol > isopropyl alcohol > ethanol > methanol > water. The KAT-LSER

ln(x) = −10.879(1.319) − 5.433(1.990)α + 4.941(2.325)β + 1.437(3.318)π * ij V δ 2 yz − 1.260(2.722)jjj s H zzz j 100RT z k {

(8)

(7)

n = 12, R2 = 0.94, RSS = 3.32, F = 47.57 E



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Table 5. Parameters of the Apelblat Equation for Flubendazole Dissolved in Different Solvents solvent

A

B

C

100RAD

107RMSD

methanol ethanol n-propanol n-butanol isopropyl alcohol isobutyl alcohol DMF water DMSO 1.4-dioxane NMP 2-butanone

−27.4584 186.898 34.9650 −79.8656 −21.5698 180.467 −113.341 −12.9440 21.5109 −5.3796 −310.034 54.119

−4740.13 −14591.54 −5945.42 −594.563 −2255.68 −12737.7 2224.04 −3555.61 −3771.82 −2803.40 11431.7 −6635.72

5.3255 −26.4106 −4.5674 12.6046 3.1167 −26.0179 17.3672 1.6660 −2.6272 1.0081 46.5034 −6.9202

1.00 2.41 2.08 1.56 0.74 2.69 1.06 0.59 0.69 0.53 1.96 1.21

0.45 1.60 7.00 10.0 1.84 12.2 157 0.02 251 9.45 360 163

(9) Longo, M.; Zanoncelli, S.; Colombo, P. A.; Harhay, M. O.; Scandale, I.; Mackenzie, C.; Geary, T.; Madrill, N.; Mazue, G. Effects of the Benzimidazole Anthelmintic Drug Flubendazole on Rat Embryos in Vitro. Reprod. Toxicol. 2013, 36, 78−87. (10) Ceballos, L.; Mackenzie, C.; Geary, T.; Alvarez, L.; Lanusse, C. Exploring the Potential of Flubendazole in Filariasis Control: Evaluation of the Systemic Exposure for Different Pharmaceutical Preparations. PLoS Neglected Trop. Dis. 2014, 8, e2838. (11) Ottesen, E. A. Description, Mechanisms and Control of Reactions to Treatment in the Human. Filariasis. Ciba Found Symp. 1987, 127, 265−283. (12) Ramaiah, K. D.; Ottesen, E. A. Progress and Impact of 13 Years of the Global Programme to Eliminate Lymphatic Filariasis on Reducing the Burden of Filarial Disease. PLoS Neglected Trop. Dis. 2014, 8, e3319. (13) De Araujo, G. L. B.; Ferreira, F. F.; Bernardes, C. E. S.; Sato, J. A. P.; Gil, O. M.; De Faria, D. L. A.; Loebenberg, R.; Byrn, S. R.; Ghisleni, D. D. M.; Bou-Chacra, N. A.; Pinto, T. J. A.; Antonio, S. G.; Ferraz, H. G.; Zemlyanov, D.; Gonçalves, D. S.; Piedade, M. E. M. A New Thermodynamically Favored Flubendazole/Maleic Acid Binary Crystal Form: Structure, Energetics, and in Silico PBPK Model-Based Investigation. Cryst. Growth Des. 2018, 18, 2377−2386. (14) Ceballos, L.; Moreno, L.; Torrado, J. J.; Lanusse, C.; Alvarez, L. Exploring Flubendazole Formulations for Use in Sheep. Pharmacokinetic Evaluation of a Cyclodextrin-Based Solution. BMC Vet. Res. 2012, 8, 71−80. (15) Chun, I. K.; Park, I. S. Solubilization and Dissolution Enhancement of Benzimidazole Anthelmintic Drugs by Cyclodextrin Complexation. Yakhak Hoechi 1993, 37, 216−227. (16) Vetchy, D.; Rabiskova, M.; Sucman, E. Effect of Temperature on Drug Solubility in Complex Formation of Flubendazole and 2Hydroxypropyl-beta-cyclodextrin. Ceska Slov. Farm. 2000, 49, 239− 241. (17) Kolár,̌ P.; Shen, J. W.; Tsuboi, A.; Ishikawa, T. Solvent Selection for Pharmaceuticals. Fluid Phase Equilib. 2002, 194−197, 771−782. (18) Apelblat, A.; Manzurola, E. Solubilities of L-Aspartic, DLAspartic, DL-Glutamic, Phydroxybenzoic, o-Anistic, p-Anisic, and Itaconic Acids in Water from T = 278 K to T = 345 K. J. Chem. Thermodyn. 1997, 29, 1527−1533. (19) Taft, R. W.; Abboud, J. L. M.; Kamlet, M. I.; Abraham, M. H. Linear Solvation Energy Relations. J. Solution Chem. 1985, 14, 153− 186. (20) Carr, P. W. Solvatochromism, Linear Solvation Energy Relationships, and Chromatography. Microchem. J. 1993, 48, 4−28. (21) Kamlet, M. J.; Abboud, J. L. M.; Taft, R. W. An Examination of Linear Solvation Energy Relationships. Prog. Phys. Org. Chem. 2007, 13, 485−630. (22) Marcus, Y. Solubility and Solvation in Mixed Solvent Systems. Pure Appl. Chem. 1990, 62, 2069−2076.

concept was used to discuss the variation of solubility in relation to solvent effect. The type and importance of various intermolecular interactions were recognized. The hydrogenbond acidity and basicity played an important role upon flubendazole solubility. Furthermore, the mole fraction solubility of flubendazole was correlated by employing the Apelblat equation obtaining the RMSD values less than 3.60 × 10−5 and RAD values less than 2.69% for correlative studies.

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AUTHOR INFORMATION

Corresponding Author

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

Hongkun Zhao: 0000-0001-5972-8352 Funding

We express our thanks to the academic innovation fund for university students in Yangzhou University (Project No.: X20180220) and “Dawn Project” for innovation and entrepreneurship (Project No.: CX2018065) for their financial assistances in this paper. Notes

The authors declare no competing financial interest.

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Solubility Modeling and Solvent Effect for Flubendazole in 12 Neat

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