Thermodynamics of Fluconazole Solubility in Various Solvents atDifferent TemperaturesKapil Bhesaniya, Kajal Nandha, and Shipra Baluja*

Physical Chemistry Laboratory, Department of Chemistry, Saurashtra University, Rajkot 360005 Gujarat, India

ABSTRACT: The solubility of Fluconazole in pure methanol, ethanol, propan-1-ol, butane-1-ol, chloroform, tetrahydrofuran,and 1,4-dioxane was measured by gravimetric method over a temperature range (298.15 to 323.15) K at atmospheric pressure.The solubility increases nonlinearly with temperature in all seven solvents. The experimental data were correlated with amodified Apelblat equation. The calculated results show good agreement with the experimental data.

■ INTRODUCTIONFluconazole (CAS No. 86386-73-4, Figure 1), with the 2-(2,4-difluorophenyl)-1,3-bis (1H-1,2,4-triazol-1-l)propan-2-ol, is a

novel triazole antifungistatic agent with both oral andintravenous routes and used in the excellent treatment ofsystemic and superficial fungal infections.1 It has established asan appropriate therapeutic record for Candida infectionsincluding oropharyngeal and esophageal candidiasis, vulvovagi-nal candidiasis, candidemia, and disseminated candidiasis.2

Fluconazole, like all azoles, acts by inhibiting the fungalcytochrome P-450-dependent enzyme lanosterol 14-α-deme-thylase. This enzyme functions to convert lanosterol toergosterol, and its inhibition disrupts membrane synthesis inthe fungal cell.3 Due to their various applications, it will beinteresting to study their solubility in various solvents whichmay help their uses in other fields also. Further, variousthermodynamic parameters have been evaluated from thesesolubility data.Thus, in the present study, the solubilities of Fluconazole in

methanol, ethanol, propan-1-ol, butane-1-ol, chloroform,tetrahydrofuran, and 1,4-dioxane have been determined overa temperature range of (298.15 to 323.15 K) by a gravimetricmethod at atmospheric pressure.

■ EXPERIMENTAL SECTIONMaterials. Fluconazole (Figure 1), with mass fraction purity

of 0.99 was purchased from Hiran orgochem Ltd. (India). Thepolymorph used in this study was anhydrous Fluconazole. All ofthe solvent were analytical grade reagents, which were purifiedby fractional distillation and purity was determined by usingShimadzu gas chromatography/mass spectrometry (model no.QP-2010) and was found to be greater than 99.5 %.

Solubility Measurement. The gravimetric method4 wasused to study the solubility. An excess mass of drug was addedto a known mass of solvent. The solution was heated to aconstant temperature with continuous stirring. The stirring wasstopped after few hrs and the solution was allowed to approachequilibrium. This solution was then filtered and 2 mL of thissolution was taken to pre weighted measuring vial (m0) by apreheated injector. The vial was quickly and tightly closed andweighted (m1) to determine the mass of the sample (m1 − m0).To prevent dust contamination, the vial was covered with apiece of filter paper. After completely drying vial mass, the vialwas reweighed (m2) to determine the mass of the constantresidue solid (m2 − m0). All weights were taken by electronicbalance (Mettler Toledo AB204-S, Switzerland) with un-certainty of ± 0.0001 g. Thus the concentration of solidsample in the solution, mole fraction x, could be determinedfrom equation

=−

− + −x

m m Mm m M m m M

( )/( )/ ( )/

2 0 1

2 0 1 1 2 2 (1)

where M1 and M2 is the molar mass of Fluconazole and solventrespectively. At each temperature, the measurement wasrepeated three times and an average value is given in Table 1.

Received: June 4, 2013Accepted: February 24, 2014Published: March 4, 2014

Figure 1. Chemical structure of Fluconazole.

Article

pubs.acs.org/jced

© 2014 American Chemical Society 649 dx.doi.org/10.1021/je4010257 | J. Chem. Eng. Data 2014, 59, 649−652

■ RESULTS AND DISCUSSION

The mole fraction solubilities x of Fluconazole in the selectedsolvents are presented in Table 1 at different temperatures[(298.15 to 323.15) K] with uncertainty of ± 0.1 K and morevisually given in Figure 2. It is observed that the solubility ofFluconazole increases nonlinearly with temperature (correla-tion coefficient = 0.993−0.999). Further, in alcoholic solvent,solubility is maximum in methanol and minimum in butane-1-ol. The order of solubility is: methanol > ethanol > propan-1-ol> butane-1-ol. Whereas in the selected nonalcoholic solvents,order is tetrahydrofuran > 1,4-dioxane > chloroform.The comparison of results with dielectric constants of the

solvents (Table 2) suggests that solubility of drug increase withincrease in dielectric constant of solvent. Further, in the case ofalcohols, solubility is found to decrease with increase of CH2

groups in alcohols.

The temperature dependence of Fluconazole solubility inpure solvents was described by the modified empiricalequation.5,6

= + +x A B T C Tln( ) /( /K) ln( /K) (2)

The values of parameters A, B, and C are given in Table 3.Using these parameters, mole fraction solubilities of Flucona-zole (xci) were evaluated in all the solvents and are given inTable 1. Further, the relative deviations (RD) between theexperimental and the calculated solubility values are calculatedby eqs 3 are listed in Tables 1.

Table 1. Measured Mole Fraction Solubilities (xi), Calculated Mole Fraction Solubilities (xci) and Relative Deviation (RD) ofFluconazole in Different Studied Solvents at Different Temperatures at 0.1 MPaa

T/K xi xci 100RD xi xci 100RD

methanol ethanol298.15 0.0141 ± 0.0002 0.0140 −1.8473 0.0110 ± 0.0001 0.0111 0.6922303.15 0.0193 ± 0.0008 0.0200 1.7538 0.0147 ± 0.0006 0.0200 0.0200308.15 0.0286 ± 0.0006 0.0287 1.6093 0.0170 ± 0.0002 0.0287 0.0287313.15 0.0422 ± 0.0003 0.0416 −2.2615 0.0231 ± 0.0008 0.0416 0.0416318.15 0.060 ± 0.0007 0.0606 −2.4012 0.0284 ± 0.0003 0.0606 0.0606323.15 0.088 ± 0.0004 0.0888 1.4408 0.0354 ± 0.0005 0.0888 0.0888

propan-1-ol butane-1-ol298.15 0.0115 ± 0.0003 0.0116 −0.9629 0.0058 ± 0.0005 0.0061 2.4232303.15 0.0127 ± 0.0007 0.0128 −0.6416 0.0066 ± 0.0004 0.0072 −1.7837308.15 0.0148 ± 0.0005 0.0148 0.3016 0.0080 ± 0.0008 0.0087 −1.1804313.15 0.0175 ± 0.0009 0.0176 −0.0539 0.0102 ± 0.0002 0.0108 1.7816318.15 0.0210 ± 0.0006 0.0217 −3.0150 0.0132 ± 0.0006 0.0136 4.2160323.15 0.0278 ± 0.0003 0.0277 0.5323 0.0160 ± 0.0007 0.0175 −1.7491

tetrahydrofuran 1,4-dioxane298.15 0.0121 ± 0.0007 0.0123 −1.2570 0.0124 ± 0.0006 0.0128 −6.7077303.15 0.0155 ± 0.0003 0.0154 0.7526 0.0165 ± 0.0009 0.0159 0.6050308.15 0.0197 ± 0.0002 0.0191 3.1394 0.0194 ± 0.0004 0.0192 −2.2123313.15 0.0225 ± 0.0004 0.0232 −3.1275 0.0219 ± 0.0005 0.0227 −7.3275318.15 0.0273 ± 0.0006 0.0277 −1.5260 0.0257 ± 0.0004 0.0263 −6.1395323.15 0.0331 ± 0.0001 0.0327 1.3829 0.0304 ± 0.0005 0.0299 −1.6514

chloroform298.15 0.0135 ± 0.0002 0.0131 2.6830303.15 0.0136 ± 0.0003 0.0130 3.7356308.15 0.0139 ± 0.0008 0.0134 2.9764313.15 0.0148 ± 0.0001 0.0142 3.1914318.15 0.0160 ± 0.0005 0.0155 2.3797323.15 0.0181 ± 0.0004 0.0174 3.5249

axi =measured mole fraction solubility. xci = calculated mole fraction solubility. RD = relative deviation. Standard uncertainty ur(T) = 0.1 K, ur(P) =0.05 and ur(x) = 0.02.

Figure 2. Variation of mole fraction solubilities (x) with temperature (T) for Fluconazole in different studied solvents. [A] In methanol, bluediamond; ethanol, red square; propan-1-ol, green triangle; butane-1-ol, purple cross. [B] In chloroform, green triangle; tetrahydrofuran, red square;and 1,4-dioxane, blue diamond. Corresponding lines are from the calculated values by eq 2.

Table 2. Dielectric Constant of the Solvents at 293.15 K12

methanol ethanolpropan-1-ol

butane-1-ol thf

1,4-dioxane chloroform

33.00 25.30 20.80 17.84 7.52 2.22 4.81

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= −x x xRD ( )/i i ic (3)

where xci is the solubility calculated by eq 2.From these solubility data, enthalpies of solution (ΔHsol),

Gibb’s energy of dissolution (ΔGsol), and entropy of solutions(ΔSsol) have also been evaluated.The enthalpies of solution (ΔHsol) was calculated by

modified van’t Hoff equation,7,8 i.e., from the slope of theplot of ln x versus (1/T − 1/Thm) (as shown in Figure 3).

∂ ∂ − = −Δx T T H R( ln / (1/ 1/ )) /i hm P sol (4)

where T is the experimental temperature and R is the gasconstant. Thm is the mean harmonic temperature which is givenas

=∑ ( )

Tn

in

T

hm 1(5)

where n is the number of experimental temperatures.9 In thepresent case, the Thm value obtained is only 310.41 K.From the intercepts of these plots, Gibbs energy change

(ΔGsol) for the solubility process was evaluated by the followingrelation.7

Δ = −G RT interceptsol (6)

Using these evaluated ΔHsol and ΔGsol values, the entropiesof solutions (ΔSsol) were obtained from equation7,8

Δ =Δ − Δ

SH G

Tsolsol sol

hm (7)

Table 4 summarizes these thermodynamic parameters. It isfound that enthalpy of dissolution (ΔHsol) is also positive for allsolvents. This endothermic effect in the dissolution process ofdrug is may be because the interactions between drug andsolvent molecules are more powerful than those between thesolvent molecules. Thus, the newly formed bond energybetween drug and solvent molecule is not powerful enough to

compensate for the energy needed for breaking the originalassociation bond in various solvents.8,9 The Gibbs energy ofdissolution (ΔGsol) is positive for the studied solventssuggesting that the dissolution process is not spontaneous.8,10

Further, the order of ΔGsol values is the reverse of the solubilitydata. Comparison of solubility and ΔGsol trend for differentsolvents shows that the higher positive value of ΔGsol decreasesthe solubility in all studied solvents. The entropy of dissolution(ΔSsol) is also positive in studied solvents except in chloroform.The positive entropy change indicates that the entropy ofsolubilization is unfavorable for solute in solution,9 whereasnegative entropy is due to more order in solutions.10 Thisdepends on the functional groups present in the drug as well ason the solvent. Owing to the fluconazole molecules containinggroups of different nature like −N−, −OH, and −F, fluconazolemay involve various forces such as electrostatic force, hydrogenbond, hydrophobic interaction and stereoscopic effect in thedissolving process.11 The increase in entropy may be due to thefact that the drug disrupted the alignment of solvent molecules.

■ CONCLUSIONSThe solubility of fluconazole in the studied solvents increasesnonlinearly with temperature. In alcoholic solvents solubility ishigher in methanol and lower in butane-1-ol. Further, solubilitydecreases with increase of CH2 groups. This solubility resultsare also correlated with dielectric constant of alcoholic solvents.Thus, as dielectric constant of alcoholic solvent increase,solubility increases. However, in nonalcoholic solvents,solubility order is tetrahydrofuran > 1,4-dioxane > chloroform.The thermodynamic parameters such as enthalpy, Gibbs energychange and entropy are positive indicating thereby endothermicdissolution which is not spontaneous. The positive entropychange suggested that the entropy of solubilization isunfavorable for solute in solution. Whereas negative entropychange suggests more ordered structure in solution. Further,

Table 3. Parameters A, B, and C of eq 2, of Fluconazole inMethanol, Ethanol, Propan-1-ol, Butane-1-ol,Tetrahydrofuran, 1,4-Dioxane, and Chloroform

solvent A B C

methanol −462.61 15081.89 71.57ethanol −87.35 31.83 14.52propan-1-ol −1084.32 46902.37 161.92butane-1-ol −717.29 29386.65 107.7tetrahydrofuran 280.83 −16333.35 −40.451,4-dioxane 433.69 −22939.99 −63.38chloroform −793.42 35407.9 117.65

Figure 3. Plot of ln x versus (1/T − 1/Thm) for fluconazole in different studied solvents [A] in methanol, blue diamond; ethanol, red square; propan-1-ol, green triangle; butane-1-ol, purple cross. [B] In chloroform, green triangle; tetrahydrofuran, red square; and 1,4-dioxane, blue diamond.Corresponding lines are from the calculated values by eq 2.

Table 4. Thermodynamic Parameters, Gibbs’s Energy(ΔGsol), Enthalpy (ΔHsol), and Entropy (ΔSsol) ofDissolution of Fluconazole in Different Studied Solventsa

solvent ΔGsol/kJ·mol−1 ΔHsol/kJ·mol−1 ΔSsol/J·mol−1·K−1

methanol 9.36 ± 0.12 36.93 ± 0.62 88.82 ± 0.35ethanol 10.10 ± 0.18 37.21 ± 0.54 87.35 ± 0.44propan-1-ol 10.55 ± 0.06 27.76 ± 0.23 55.44 ± 0.26butane-1-ol 12.06 ± 0.10 33.83 ± 0.70 70.12 ± 0.96tetrahydrofuran 10.03 ± 0.15 31.49 ± 0.42 69.16 ± 0.631,4-dioxane 10.07 ± 0.11 27.23 ± 0.63 55.28 ± 0.12chloroform 10.85 ± 0.20 9.07 ± 0.75 −5.74 ± 0.25

aΔGsol is the Gibbs’s energy. ΔHsol is the enthalpy. ΔSsol is theentropy.

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the comparison of solubility and ΔGsol trend for differentsolvents shows that higher positive value of ΔGsol decreases thesolubility in all studied solvents.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: shipra_baluja@rediffmail.com.NotesThe authors declare no competing financial interest.

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