Article pubs.acs.org/jced
Measurement and Correlation of the Solubility of Febuxostat in Four Organic Solvents at Various Temperatures Lei Zhang,*,† Zhiping Huang,‡ Xiaoran Wan,‡ Jing Li,† and Jing Liu‡ †
School of Bioscience and Engineering and ‡School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China
ABSTRACT: The solubility of febuxostat in ethyl acetate, methanol, ethanol, and acetone was determined respectively by the gravimetric method from (293.15 to 328.15) K under atmospheric pressure, and the experimental data were well-correlated by the Apelblat and van’t Hoff equations. The experimental solubility data and their correlation equation obtained would be useful for the solvent selection of febuxostat crystallization.
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INTRODUCTION Febuxostat, 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (shown in Figure 1), is a thiazole-
because of the narrow temperature range and methanol/water ratio for the pure phase of Form A. A new crystalline form of febuxostat (designated as Form H) was invented through simply desolving methanol (or ethanol) solvate of febuxostat in the temperature range of (303.15 to 323.15) K under vacuum. Form H of febuxostat is very stable under a variety of conditions employed for the formulation and less hygroscopic upon storage. The solubility is very crucial for the formulation and for the solvent selection of the crystallization process. The common methods to measure solubility are the gravimetric method7 and synthetic method (laser scattering method).8,9 Laser scattering is one of important technologies applied to the synthetic method, which is mainly applicable to the substance which is fast dissolution to reach the equilibrium. But the gravimetric method is based on the establishment of solid−liquid equilibrium. In this paper, the solubilities of febuxostat for crystalline Form H in four different solvents at different temperatures are measured by gravimetric method and the experiment data are correlated by regression model.
Figure 1. Chemical structure of febuxostat.
carboxylic acid derivative used as a selective nonpurine inhibitor of xanthine oxidoreductase (XOR) for the management of hyperuricemia in adults with gout which was approved in February 2009 by the US Food and Drug Administration. XOR can catalyze the last two reactions of uric acid formation through oxidizing hypoxanthine to xanthine and xanthine to uric acid at the molybdopterin center with concomitant reduction of NAD+ to NADH at the FAD cofactor in human purine catabolism.1,2 Polymorphism is an important phenomenon observed in febuxostat, and five forms were observed in the literature.3 Febuxostat has three polymorphs (namely, Form A, Form B, and Form C) and two solvates (BH and D). The crystallization process for the preferred Form A is described in detail by Kitamura and co-workers4−6 and is very difficult to control © 2012 American Chemical Society
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EXPERIMENTAL SECTION Materials. All of the solvents (ethyl acetate, methanol, ethanol, and acetone) were analytical grade reagents. Febuxostat was gifted by Shanghai Hotmed Sciences Co., Ltd. and recrystallized by 0.937 mass fraction ethanol. The
Received: July 6, 2012 Accepted: October 1, 2012 Published: October 10, 2012 3149
dx.doi.org/10.1021/je300647k | J. Chem. Eng. Data 2012, 57, 3149−3152
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Table 1. Purity of Chemicals Used in This Study and Their Details chemical name
source
initial mass fraction purity
purification method
final mass fraction purity
analysis method
febuxostat ethyl acetate ethanol acetone methanol
Shanghai Hotmed Sciences Co., Ltd. Sinopharm Chemical Reagent Co., Ltd. Sinopharm Chemical Reagent Co., Ltd. Sinopharm Chemical Reagent Co., Ltd. Sinopharm Chemical Reagent Co., Ltd.
0.988 0.995 0.997 0.995 0.995
recrystallization none none none none
0.993
HPLCa
a
High-performance liquid chromatography.
purity of febuxostat was found to be greater than 0.993 (mass fraction). In the experiments, distilled−deionized water was used. Table 1 lists a summary of chemicals used in this work and their details. A powder X-ray diffraction (PXRD) spectrum was recorded on a Bruker D8 ADVANCE diffractometer with the uncertainty of 0.2°, and IR spectrum was recorded on a Bruker Vector 33 spectrophotometer with the uncertainty of 2 cm−1. Solubility Measurements. The apparatus used for the solubility determination was a small glass cell (50 mL) fitting with a calibrated thermometer with an uncertainty of 0.02 K and a magnetic stirrer. Then the equilibrium cell was heated to a constant temperature with continuous stirring. The amount of febuxostat varied in the range of (1 to 5) g in the solvent (10 mL), and the size of febuxostat is about 120 μm (D50). To prevent solvent evaporation, the cell was sealed using a rubber plug. After stirring for about 3 h to achieve the thermodynamic equilibrium of the mixture, stirring was then stopped, and the cell was kept undisturbed for 2 h to ensure that the solid crystal powder deposited sufficiently. For each measurement, an amount of the sedimentation of crystal was left in the lower portion of the cell; about 2 mL of the upper clean portion was extracted by a preheated injector and taken into another weighted measuring vial (m1). The vial was weighed (m2) and put in a vacuum oven to evaporate the solvent (313 K). After the solvent was completely dried, the vial was reweighed (m3). All of the weights were measured using an electronic balance (BS224S, Sartorius) with an uncertainty of 0.1 mg. The mole fraction of solubility of the febuxostat, x, can be determined from eq 1. x=
(m3 − m1)/Msolute (m3 − m1)/Msolute + (m2 − m3)/Msolvent
Figure 2. PXRD pattern of crystalline Form H of febuxostat (insert: the PXRD patterns of BH and D obtained from ref 5).
(1) Figure 3. IR spectrum of Form H of febuxostat.
where m1, m2, and m3 are the masses of the vial, the vial containing the sample, and the vial containing the solid solute, and Msolute and Msolvent stand for the molecular weights of febuxostat and solvent.
and 1425) cm−1 are attributed to the vibration of phenyl and/ or thiazolyl rings. Experimental Data. The experimental solubility data of sodium chloride in water were measured to prove the feasibility of the experimental method mentioned above. The experimental data, along with literature values, are given in Table 2. The comparison indicates that the experimental method is reasonable and reliable. The relative deviations (RD) between the experimental and the calculated values of solubility are calculated by eq 2, and the relative average deviations (RAD) and root-mean-square deviations (σ) are calculated by eqs 3 and 4. The mole fractions of experimental solubility data for febuxostat are listed in Table 3 and shown in Figure 4, where x is the experimental data and xcal is the calculated value from eq 5; both x and xcal are mole fractions. x − xcal RD = (2) x
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RESULTS AND DISCUSSION Physical Characterization of Crystalline Form H of Febuxostat. The crystalline Form H of febuxostat was characterized by powder X-ray diffraction using Cu Kα radiation, and the PXRD pattern of Form H is shown in Figure 2. The significant 10 peaks with relative intensity at 2θ angle are 6.67 (24.4 %), 7.24 (60.1 %), 12.88 (100 %), 13.33 (5.4 %), 16.53 (5.4 %), 19.65 (3.8 %), 23.07 (3.0 %), 23.87 (4.0 %), 25.92 (8.9 %), and 26.74° (8.2 %). The Form H is very stable and is not decomposed until 482.5 K. The FTIR spectrum (Figure 3) shows the characteristic absorption peaks at 2231 cm−1 (ν−CN), 1677 cm−1 (ν−COOH), 1276 cm−1, 1116 cm−1, and 1011 cm−1 (ν−C−O−C). The peaks of (1605, 1515, 3150
dx.doi.org/10.1021/je300647k | J. Chem. Eng. Data 2012, 57, 3149−3152
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Table 2. Comparison of the Solubility Data of NaCl in Water between Literature (xref) and This Work (x), at Temperature T and Pressure p = 0.1 MPaa T/K
x/g·(100 g water)−1
xref/g·(100 g water)−1
100 RD
100 RAD
293.15 303.15 313.15 323.15 333.15
36.14 36.32 36.69 37.12 37.36
36.0 36.3 36.6 37.0 37.3
0.3874 0.0551 0.2453 0.3233 0.1606
0.2343
a x and xcal are the experimental solubility and reference solubility, respectively. The uncertainty of determining the temperature and pressure is up to ± 0.02 K and 0.005 MPa.
Table 3. Experimental Mole Fraction Solubility (x) and Calculated Mole Fraction Solubility (xcal) of Febuxostat in Different Solvents at Temperature T and Pressure p = 0.1 MPaa 103 x
T/K 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15
3.7617 4.5649 5.1627 6.4304 7.3172 8.2839 9.7472 11.3923
± ± ± ± ± ± ± ±
293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15
1.2245 1.7652 2.6885 4.0089 5.8393 8.3615 10.9366 14.2563
± ± ± ± ± ± ± ±
293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15
6.2333 7.4284 9.2127 10.6826 12.8785 14.6646 16.1533 17.0634
± ± ± ± ± ± ± ±
293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15
0.5239 0.8563 1.1689 1.6167 2.2928 3.2455 4.5040 6.8492
± ± ± ± ± ± ± ±
Ethyl Acetate 0.1151 0.1374 0.1987 0.1344 0.1022 0.1823 0.1161 0.1394 Ethanol 0.01735 0.02869 0.03205 0.08177 0.02920 0.09580 0.02535 0.03192 Acetone 0.1221 0.1141 0.07450 0.05220 0.03225 0.03974 0.07442 0.08258 Methanol 0.02066 0.03273 0.01871 0.01037 0.04714 0.1167 0.1142 0.2092
103 xcal
100 RD
3.7754 4.4843 5.2956 6.2193 7.2659 8.4464 9.7719 11.2543
−0.3642 1.7656 −2.5742 3.2828 0.7011 −1.9616 −0.2534 1.2113
1.1817 1.8297 2.7528 4.0315 5.7554 8.0209 10.9267 14.5680
3.4953 −3.6540 −2.3917 −0.5638 1.4368 4.0734 0.0905 −2.1864
6.0773 7.5590 9.1699 10.8658 12.5939 14.2967 15.9151 17.3929
2.5027 −1.7581 0.4646 −1.7149 2.2099 2.5088 1.4746 −1.9310
0.5542 0.7981 1.1450 1.6367 2.3310 3.3077 4.6769 6.5898
−5.7836 6.7967 2.0447 −1.2371 −1.6661 −1.9165 −3.8388 3.7873
Figure 4. Experimental mole fraction solubility of febuxostat in different solvents obtained from Table 3: ▲, acetone; ■, ethyl acetate; △, ethanol; □, methanol.
Table 4. Correlative Parameters A, B, and C and Correlation Coefficient (R2) and Root-Mean-Square Deviations (σ) of eq 5 for Febuxostat in Different Solvents
N
∑ i=1
x − xcal x
B
C
R2
104 σ
ethyl acetate ethanol acetone methanol
7.552 363.015 438.368 −185.466
−3135.017 −22831.166 −22838.668 2450.666
−0.429 −51.380 −64.352 29.857
0.997 0.999 0.997 0.998
1.30 1.82 1.25 0.98
ΔHd solvent ethyl acetate ethanol acetone methanol
ΔSd
−1
kJ·mol 24.95 57.40 23.95 56.56
± ± ± ±
0.66 1.22 1.22 1.43
⎡ N (x − x )2 ⎤1/2 cal ⎥ σ = ⎢∑ ⎢⎣ i = 1 N − 1 ⎥⎦
Maximum relative standard deviation of the experimental solubility is about ± 4.0 %. x and xcal are the experimental solubility and calculated solubility from the Apelblat equation, respectively. The uncertainty of determining the temperature and pressure is up to ± 0.02 K and 0.005 MPa.
1 N
A
Table 5. Dissolution Enthalpy and Entropy of Form H of Febuxostat in Four Solvents Obtained from eq 7
a
RAD =
solvent
kJ·mol−1·K−1 38.71 140.11 39.81 130.31
± ± ± ±
2.15 3.93 3.94 4.62
R2 0.997 0.997 0.981 0.996
(4)
where N is the number of experimental points. In this study, the solubility data of the febuxostat were measured three times, and then the average values with standard deviations are given in Table 3. It revealed that the obtained data points were reproducible within the maximum relative standard deviation of ± 4.0 %.
(3)
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The calculated values are shown in Table 5 and Figure 5. From these data, we can divide the four solvents into two groups: the first group contains ethyl acetate and acetone, which has the similar value of ΔHd and ΔSd with about 24 kJ·mol−1 and 38 J·mol−1·K−1, respectively. The other groups are methanol and ethanol, which have higher values of ΔHd and ΔSd than the first group, which may be caused by strong solute−solvate interaction in the solution state. The experimental solubility data of febuxostat in four solvents were precisely measured by the gravimetric method, and the solubility data of febuxostat are well-correlated by the Apelblat and van’t Hoff equations. The experimental solubility data and correlation equation in this work can not only provide essential data for the crystallization and separation of febuxostat but also highlight that solute−solvate interaction increases the enthalpy.
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Figure 5. van't Hoff plot of logarithm mole fraction solubility of febuxostat in different solvents: ▲, value for acetone from Table 3; ■, value for ethyl acetate from Table 3; △, value for ethanol from Table 3; □, value for methanol from Table 3. The lines were obtained from eq 7 and Table 5.
*E-mail:
[email protected]. Fax: 86-20-3938 0678. Funding
This work was financially supported by the Guangdong Provincial Department of Science and Technology (2012B050600013). Notes
Data Correlation. The Apelblat equation, as shown in eq 5, is widely used to correlate solid−liquid equilibrium data ln x = A + B /(T /K) + C ln(T /K)
The authors declare no competing financial interest.
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(5)
ΔHfus ΔSfus + RT R
(6)
where x is the mole fraction of solute in the solvent, ΔHfus is the mole enthalpy of fusion of the solute, ΔSfus is the mole entropy of fusion, T is the corresponding absolute temperature, and R is the gas constant. However, the most real solution exhibits nonideal behavior in practice, so the solvent effect should be considered, and the enthalpy and entropy must be taken into account by replacing ΔHfus with ΔHd (enthalpy of dissolution) and ΔSfus with ΔSd (entropy of dissolution) to generate eq 7.11 ln x = −
ΔHd ΔSd + RT R
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where x is the mole fraction of solubility of febuxostat, T is the absolute temperature, and A, B, and C are correlative parameters. The correlation results are shown in Table 4. The calculated values are shown in Table 3. All relative deviations were less than 7.0 %, indicating that calculated solubility of febuxostat at different temperatures in all studied solvents was in good agreement with the experimental data. It is observed that the solubility increases with increasing temperature, and the whole increase is nonlinear except for the acetone solvent. Further, in ethanol, the solubility is largely affected by the increasing temperature. The solubility in ethanol is larger than in ethyl acetate above 320 K. The solubility in other three solvents is in the order: acetone > ethyl acetate > methanol. The van’t Hoff equation (eq 6) was also applied to the four systems to evaluate the thermodynamic parameters because it relates the logarithm of mole fraction of a solute in an ideal solution as a linear function of the reciprocal of the absolute temperature.10 ln x = −
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dx.doi.org/10.1021/je300647k | J. Chem. Eng. Data 2012, 57, 3149−3152
