Article pubs.acs.org/jced
Thermodynamics of Fluconazole Solubility in Various Solvents at Different Temperatures Kapil 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 a modified Apelblat equation. The calculated results show good agreement with the experimental data.
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INTRODUCTION Fluconazole (CAS No. 86386-73-4, Figure 1), with the 2-(2,4difluorophenyl)-1,3-bis (1H-1,2,4-triazol-1-l)propan-2-ol, is a
EXPERIMENTAL SECTION Materials. Fluconazole (Figure 1), with mass fraction purity of 0.99 was purchased from Hiran orgochem Ltd. (India). The polymorph used in this study was anhydrous Fluconazole. All of the solvent were analytical grade reagents, which were purified by fractional distillation and purity was determined by using Shimadzu gas chromatography/mass spectrometry (model no. QP-2010) and was found to be greater than 99.5 %. Solubility Measurement. The gravimetric method4 was used to study the solubility. An excess mass of drug was added to a known mass of solvent. The solution was heated to a constant temperature with continuous stirring. The stirring was stopped after few hrs and the solution was allowed to approach equilibrium. This solution was then filtered and 2 mL of this solution was taken to pre weighted measuring vial (m0) by a preheated injector. The vial was quickly and tightly closed and weighted (m1) to determine the mass of the sample (m1 − m0). To prevent dust contamination, the vial was covered with a piece of filter paper. After completely drying vial mass, the vial was reweighed (m2) to determine the mass of the constant residue solid (m2 − m0). All weights were taken by electronic balance (Mettler Toledo AB204-S, Switzerland) with uncertainty of ± 0.0001 g. Thus the concentration of solid sample in the solution, mole fraction x, could be determined from equation
Figure 1. Chemical structure of Fluconazole.
novel triazole antifungistatic agent with both oral and intravenous routes and used in the excellent treatment of systemic and superficial fungal infections.1 It has established as an appropriate therapeutic record for Candida infections including oropharyngeal and esophageal candidiasis, vulvovaginal candidiasis, candidemia, and disseminated candidiasis.2 Fluconazole, like all azoles, acts by inhibiting the fungal cytochrome P-450-dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol, and its inhibition disrupts membrane synthesis in the fungal cell.3 Due to their various applications, it will be interesting to study their solubility in various solvents which may help their uses in other fields also. Further, various thermodynamic parameters have been evaluated from these solubility 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 over a temperature range of (298.15 to 323.15 K) by a gravimetric method at atmospheric pressure. © 2014 American Chemical Society
x=
(m2 − m0)/M1 (m2 − m0)/M1 + (m1 − m2)/M 2
(1)
where M1 and M2 is the molar mass of Fluconazole and solvent respectively. At each temperature, the measurement was repeated three times and an average value is given in Table 1. Received: June 4, 2013 Accepted: February 24, 2014 Published: March 4, 2014 649
dx.doi.org/10.1021/je4010257 | J. Chem. Eng. Data 2014, 59, 649−652
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Table 1. Measured Mole Fraction Solubilities (xi), Calculated Mole Fraction Solubilities (xci) and Relative Deviation (RD) of Fluconazole in Different Studied Solvents at Different Temperatures at 0.1 MPaa T/K
xi
xci
298.15 303.15 308.15 313.15 318.15 323.15
0.0141 ± 0.0002 0.0193 ± 0.0008 0.0286 ± 0.0006 0.0422 ± 0.0003 0.060 ± 0.0007 0.088 ± 0.0004
298.15 303.15 308.15 313.15 318.15 323.15
0.0115 0.0127 0.0148 0.0175 0.0210 0.0278
± ± ± ± ± ±
0.0003 0.0007 0.0005 0.0009 0.0006 0.0003
298.15 303.15 308.15 313.15 318.15 323.15
0.0121 0.0155 0.0197 0.0225 0.0273 0.0331
± ± ± ± ± ±
0.0007 0.0003 0.0002 0.0004 0.0006 0.0001
298.15 303.15 308.15 313.15 318.15 323.15
0.0135 0.0136 0.0139 0.0148 0.0160 0.0181
± ± ± ± ± ±
0.0002 0.0003 0.0008 0.0001 0.0005 0.0004
methanol 0.0140 0.0200 0.0287 0.0416 0.0606 0.0888 propan-1-ol 0.0116 0.0128 0.0148 0.0176 0.0217 0.0277 tetrahydrofuran 0.0123 0.0154 0.0191 0.0232 0.0277 0.0327 chloroform 0.0131 0.0130 0.0134 0.0142 0.0155 0.0174
xi
100RD
xci
−1.8473 1.7538 1.6093 −2.2615 −2.4012 1.4408
0.0110 0.0147 0.0170 0.0231 0.0284 0.0354
± ± ± ± ± ±
0.0001 0.0006 0.0002 0.0008 0.0003 0.0005
−0.9629 −0.6416 0.3016 −0.0539 −3.0150 0.5323
0.0058 0.0066 0.0080 0.0102 0.0132 0.0160
± ± ± ± ± ±
0.0005 0.0004 0.0008 0.0002 0.0006 0.0007
−1.2570 0.7526 3.1394 −3.1275 −1.5260 1.3829
0.0124 0.0165 0.0194 0.0219 0.0257 0.0304
± ± ± ± ± ±
0.0006 0.0009 0.0004 0.0005 0.0004 0.0005
100RD
ethanol 0.0111 0.0200 0.0287 0.0416 0.0606 0.0888 butane-1-ol 0.0061 0.0072 0.0087 0.0108 0.0136 0.0175 1,4-dioxane 0.0128 0.0159 0.0192 0.0227 0.0263 0.0299
0.6922 0.0200 0.0287 0.0416 0.0606 0.0888 2.4232 −1.7837 −1.1804 1.7816 4.2160 −1.7491 −6.7077 0.6050 −2.2123 −7.3275 −6.1395 −1.6514
2.6830 3.7356 2.9764 3.1914 2.3797 3.5249
a xi =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, 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.
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Table 2. Dielectric Constant of the Solvents at 293.15 K12
RESULTS AND DISCUSSION
The mole fraction solubilities x of Fluconazole in the selected solvents are presented in Table 1 at different temperatures [(298.15 to 323.15) K] with uncertainty of ± 0.1 K and more visually given in Figure 2. It is observed that the solubility of Fluconazole increases nonlinearly with temperature (correlation coefficient = 0.993−0.999). Further, in alcoholic solvent, solubility is maximum in methanol and minimum in butane-1ol. 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 with increase in dielectric constant of solvent. Further, in the case of alcohols, solubility is found to decrease with increase of CH2 groups in alcohols.
methanol ethanol 33.00
25.30
propan1-ol
butane1-ol
thf
1,4dioxane
chloroform
20.80
17.84
7.52
2.22
4.81
The temperature dependence of Fluconazole solubility in pure solvents was described by the modified empirical equation.5,6 ln(x) = A + B /(T /K) + C ln(T /K)
(2)
The values of parameters A, B, and C are given in Table 3. Using these parameters, mole fraction solubilities of Fluconazole (xci) were evaluated in all the solvents and are given in Table 1. Further, the relative deviations (RD) between the experimental and the calculated solubility values are calculated by eqs 3 are listed in Tables 1. 650
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Table 3. Parameters A, B, and C of eq 2, of Fluconazole in Methanol, Ethanol, Propan-1-ol, Butane-1-ol, Tetrahydrofuran, 1,4-Dioxane, and Chloroform
Table 4. Thermodynamic Parameters, Gibbs’s Energy (ΔGsol), Enthalpy (ΔHsol), and Entropy (ΔSsol) of Dissolution of Fluconazole in Different Studied Solventsa
solvent
A
B
C
solvent
ΔGsol/kJ·mol−1
ΔHsol/kJ·mol−1
ΔSsol/J·mol−1·K−1
methanol ethanol propan-1-ol butane-1-ol tetrahydrofuran 1,4-dioxane chloroform
−462.61 −87.35 −1084.32 −717.29 280.83 433.69 −793.42
15081.89 31.83 46902.37 29386.65 −16333.35 −22939.99 35407.9
71.57 14.52 161.92 107.7 −40.45 −63.38 117.65
methanol ethanol propan-1-ol butane-1-ol tetrahydrofuran 1,4-dioxane chloroform
9.36 ± 0.12 10.10 ± 0.18 10.55 ± 0.06 12.06 ± 0.10 10.03 ± 0.15 10.07 ± 0.11 10.85 ± 0.20
36.93 ± 0.62 37.21 ± 0.54 27.76 ± 0.23 33.83 ± 0.70 31.49 ± 0.42 27.23 ± 0.63 9.07 ± 0.75
88.82 ± 0.35 87.35 ± 0.44 55.44 ± 0.26 70.12 ± 0.96 69.16 ± 0.63 55.28 ± 0.12 −5.74 ± 0.25
ΔGsol is the Gibbs’s energy. ΔHsol is the enthalpy. ΔSsol is the entropy. a
RD = (xi − xci)/xi
(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 the plot of ln x versus (1/T − 1/Thm) (as shown in Figure 3). (∂ ln xi /∂(1/T − 1/Thm))P = −ΔHsol /R
compensate for the energy needed for breaking the original association bond in various solvents.8,9 The Gibbs energy of dissolution (ΔGsol) is positive for the studied solvents suggesting that the dissolution process is not spontaneous.8,10 Further, the order of ΔGsol values is the reverse of the solubility data. Comparison of solubility and ΔGsol trend for different solvents shows that the higher positive value of ΔGsol decreases the 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 of solubilization is unfavorable for solute in solution,9 whereas negative entropy is due to more order in solutions.10 This depends on the functional groups present in the drug as well as on the solvent. Owing to the fluconazole molecules containing groups of different nature like −N−, −OH, and −F, fluconazole may involve various forces such as electrostatic force, hydrogen bond, hydrophobic interaction and stereoscopic effect in the dissolving process.11 The increase in entropy may be due to the fact that the drug disrupted the alignment of solvent molecules.
(4)
where T is the experimental temperature and R is the gas constant. Thm is the mean harmonic temperature which is given as n Thm = n 1 ∑i T (5)
()
where n is the number of experimental temperatures.9 In the present 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 following relation.7 ΔGsol = −RT intercept
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CONCLUSIONS The solubility of fluconazole in the studied solvents increases nonlinearly with temperature. In alcoholic solvents solubility is higher in methanol and lower in butane-1-ol. Further, solubility decreases with increase of CH2 groups. This solubility results are 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 energy change and entropy are positive indicating thereby endothermic dissolution which is not spontaneous. The positive entropy change suggested that the entropy of solubilization is unfavorable for solute in solution. Whereas negative entropy change suggests more ordered structure in solution. Further,
(6)
Using these evaluated ΔHsol and ΔGsol values, the entropies of solutions (ΔSsol) were obtained from equation7,8 ΔSsol =
ΔHsol − ΔGsol Thm
(7)
Table 4 summarizes these thermodynamic parameters. It is found that enthalpy of dissolution (ΔHsol) is also positive for all solvents. This endothermic effect in the dissolution process of drug is may be because the interactions between drug and solvent molecules are more powerful than those between the solvent molecules. Thus, the newly formed bond energy between drug and solvent molecule is not powerful enough to
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; propan1-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. 651
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the comparison of solubility and ΔGsol trend for different solvents shows that higher positive value of ΔGsol decreases the solubility in all studied solvents.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: shipra_baluja@rediffmail.com. Notes
The authors declare no competing financial interest.
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REFERENCES
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