Experimental Measurements and Modeling of the Solubility of

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Experimental Measurements and Modeling of the Solubility of Aceclofenac in Six Pure Solvents from (293.35 to 338.25) K Jin-Qiang Liu,* Ye Wang, Hui Tang, Sha Wu, Yao-Yao Li, Li-Yue Zhang, and Qiao-Yun Bai College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022, People’s Republic of China

Xun Liu Zhejiang Jianye Chemical Co., Ltd., Hangzhou, Zhejiang, China ABSTRACT: The solubility of aceclofenac in six pure solvents from (293.35 to 338.25) K was experimentally measured using a synthetic method. The experimental results indicate obviously that the solubility of aceclofenac in the selected solvents increases with elevated temperature. Furthermore, the experimental solubility data were fitted with modified Apelblat and Wilson models. The results show that the data calculated by the two models agree with the measured data with RMSD values of no more than 2.75 %.

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Alvarez-Larena et al.,6 Kun et al.,7 and Murphy et al.8 reported purifying aceclofenac from toluene. Jiang et al.9 used methanol as the recrystallization solvent to purify aceclofenac. In this paper, the solubility of aceclofenac in methanol and toluene as well as in other four common solvents (ethanol, 2-propanone, ethyl acetate, and 2-propanol) whose polarity values were between that of toluene and methanol was measured from (293.35 to 338.35) K at atmospheric pressure. The modified Apelblat and Wilson equations were chosen to correlate the measured solubility data.

INTRODUCTION Aceclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of arylacetic acid type with remarkable anti-inflammatory, antipyretic, and analgesic properties.1,2 Because of its preferential cox-2 blockade, aceclofenac is the most well-tolerated drug among all the NSAIDs with a relatively lower incidence of gastrointestinal and cardiovascular adverse effects.3,4 The molecular structure of aceclofenac (CAS Registry No. 8979699-6) is illustrated in Figure 1.

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EXPERIMENTAL SECTION Materials. Aceclofenac (melting temperature, Tm, 424.55 K3) was supplied by Hubei Xinyuanshun Pharmaceutical Chemical Co., Ltd., China. The aceclofenac had a mass purity of > 0.98 and was recrystallized from methanol to obtain a purified sample with a mass purity no less than 0.995, analyzed by high performance liquid chromatography (HPLC, type Shimadzu LC-10AT, Japan). All of the organic solvents used in the experiments including methanol, ethanol, 2-propanone, ethyl acetate, 2-propanol, and toluene (purchased from Tianjin Kaitong Chemical Reagents Co., Ltd., China) were of analytical reagent grade with mass purity greater than 0.995. Detailed information on all materials used in the experiments is given in Table 1. Apparatus and Procedure. In this contribution, the solubility of aceclofenac in methanol, ethanol, 2-propanone,

Figure 1. Molecular structure of aceclofenac.

In the industrial manufacturing processes of aceclofenac, crystallization from a suitable solution is one of the key procedures which not only can affect the final yield but also can determine the quality of the final product to a certain extent. Although the solubility data of aceclofenac are very imperative in the design, operation, and optimizing of the crystallization processes, to the best of the authors’ knowledge, the data have been quite scarcely reported in the literature. Only the solubility data of aceclofenac in the pure water at 301.15 K and in the mixture of ethanol (25%) + water (75%) at 303.15 K were studied.3,5 Another literature reported the solubility of aceclofenac in pure water and 1-octanol at 278.15 K, 298.15 K, and 310.15 K.21 © 2014 American Chemical Society

Received: January 12, 2014 Accepted: April 9, 2014 Published: April 17, 2014 1588

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Table 1. Detailed Information of Materials

a

materials

sources

initial mass purity

purification method

final mass purity

analysis method

aceclofenac methanol (AR) ethanol (AR) 2-propanone (AR) ethyl acetate (AR) 2-propanol (AR) toluene (AR)

a b b b b b b

0.98 ≥ 0.995 ≥ 0.997 ≥ 0.995 ≥ 0.995 ≥ 0.995 ≥ 0.995

recrystallization none none none none none none

≥ 0.995

HPLC GC GC GC GC GC GC

Hubei Pharmaceutical & Chemical Co., Ltd. Xinyuan Shun, China. bTianjin Kaitong Chemical Reagents Co., Ltd., China.

where A, B, and C stand for adjustable empirical equation parameters and T is the Kelvin temperature. In accordance with the basic thermodynamic theory,16 a universal solubility model can be expressed as

ethyl acetate, 2-propanol, and toluene was measured by the synthetic method.10 The experimental procedure in detail was explained in our previous works,11−13 so we just described it in brief here. The experimental facility includes a jacketed glass vessel with a volume of about 200 mL, a magnetic stirrer (type 85-2, China), a mercury-in-glass thermometer (uncertainty of ± 0.05 K, type WLB, China), a condenser, a constant pressure funnel, a constant-temperature bath (typeCS501, China), and a laser detector. At the beginning of each experiment, a known mass of aceclofenac and a predetermined mass of a solvent weighed by an electronic analytical balance (type Sartorius BS210S, Germany) with uncertainty of ± 0.0001 g were added into the glass vessel, and then the mixture was stirred by a magnetic stirrer and kept at a constant temperature by a constant-temperature bath. The intensity of the laser beam penetrating the glass vessel and the solution increased with the dissolution of the solute. When the solute dissolved completely, the intensity of the laser beam reached the peak value, then an additional (2 to 5) mg of aceclofenac was added into the vessel. This procedure was repeated until the last addition of aceclofenac was not completely dissolved in 60 min, and the intensity of the laser beam reached 90 % of the peak at most. At this point, the liquid−solid equilibrium was considered to be reached. Then, the total mass of aceclofenac dissolved was recorded. The solubility (x1) of aceclofenac in different pure solvents was calculated by eq 1. x1 =

m1/M1 m1/M1 + m2 /M 2

ln x1γ1 =

where γ1, ΔCp, and ΔV denote the activity coefficient of solute, difference of the molar heat capacity of solute between the solid and the liquid at constant pressure, and the volume difference between the solid and the liquid, respectively; ΔHtp, Ttp and Ptp represent enthalpy, temperature, and pressure of the triple point. For many substances, the difference between temperature of the triple point and the the melting temperature is small, so ΔHtp and Ttp can be replaced by enthalpy of melting ΔHfus and melting temperature Tm. The terms containing ΔCp and ΔV are very small, so they can be ignored.17,18 On the basis of the above, eq 3 can be simplified as ln x1 =

(1)

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(4)

⎞ ⎛ Λ12 Λ 21 ln γ1 = −ln(x1 + Λ12x 2) + x 2⎜ − ⎟ x 2 + Λ 21x1 ⎠ ⎝ x1 + Λ12x 2

RESULTS AND DISCUSSION The solubility data of aceclofenac in methanol, ethanol, 2-propanone, ethyl acetate, 2-propanol, and toluene at temperatures ranging from (293.35 to 338.25) K were determined and listed in Table 2. The experimental solubility data of aceclofenac in the selected pure solvents were regressed by the modified Apelblat and Wilson models. These models are widely used in correlating solubility data of a solute in pure solvent. The parameters of these models are of potential interest in industrial application. The modified Apelblat equation is a semiempirical equation, stems from Williamson equation14,15 and is shown as eq 2, B + C ln T T

ΔHfus ⎛ 1 1⎞ − ⎟ − ln γ1 ⎜ R ⎝ Tm T⎠

The enthalpy of fusion (ΔHfus) of the solute was needed to use this equation. However, our endeavor to measure it using differential scanning calorimetry (DSC) resulted in failure because it decomposed before melting. Thus, ΔHfus was estimated by the widely used group-contribution method19 at a value of 52.03 kJ/mol. The Wilson equation, a local composition model, was used to derive γ1. In the binary system, the Wilson equation can be expressed as

where m1 and m2 are the total mass of aceclofenac and the selected solvent, respectively. M1 and M2 denote the corresponding molecular weights. Each data point was determined three times with the relative uncertainty less than 1 %.

ln x1 = A +

⎞ ΔHtp ⎛ 1 Ttp 1 ⎞ ΔCp ⎛ Ttp ⎜⎜ − ⎟⎟ − − + 1⎟ ⎜ln R ⎝ Ttp T⎠ R ⎝ T T ⎠ ΔV − (P − Ptp) (3) RT

(5)

where ⎛ λ − λ11 ⎞ ν2 ⎟; exp⎜ − 12 ⎝ RT ⎠ ν1 ⎛ λ − λ 22 ⎞ ν ⎟ Λ 21 = 1 exp⎜ − 21 ⎝ RT ⎠ ν2

Λ12 =

(6)

In eq 5, x2 is the mole fraction of the selected solvent. In eq 6, Δλ12 = λ12 − λ11 and Δλ21 = λ21 − λ22 are two binary cross interaction parameters which are independent of composition and temperature; ν1 and ν2 represent the molar volumes of solute and pure solvent, respectively.

(2) 1589

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Table 2. Solubility of Aceclofenac in Methanol, Ethanol, 2-Propanone, Ethyl Acetate, 2-Propanol, and Toluene at (293.35 to 338.25) K at 0.1 MPaa

a

T/K

103x1

294.25 299.05 303.25 308.75 313.15 317.95 323.65 328.65 333.25

8.09 10.25 13.03 16.96 21.93 28.19 38.55 51.97 68.84

293.85 301.95 302.85 308.15 313.95 318.75 323.35 328.45 333.25 337.95

8.53 12.84 13.55 17.42 23.96 30.64 39.31 50.91 68.43 90.30

293.35 298.95 303.15 308.25 314.15 318.55 323.25

53.24 60.79 67.77 76.57 88.16 97.89 109.04

293.55 298.25

30.25 34.03

103x1calcd,Apel

102RD

103x1calcd,Wil

102RD

T/K

103x1

8.18 10.26 12.97 16.89 21.84 28.12 38.54 52.01 68.94

−1.10 −0.07 0.47 0.45 0.40 0.23 0.05 −0.08 −0.15

304.05 307.95 313.35 318.45 322.95 328.55 332.75 338.25

40.22 45.03 53.21 60.81 68.35 80.46 90.07 104.71

8.65 12.81 13.50 17.35 23.86 30.56 39.26 50.90 68.48 90.42

−1.36 0.22 0.33 0.42 0.39 0.26 0.13 0.00 −0.08 −0.13

293.75 298.65 303.05 307.95 312.35 317.65 322.75 328.55 333.25 338.05

5.97 6.95 8.23 9.71 11.56 14.22 17.49 22.32 27.48 35.19

53.24 60.80 67.77 76.56 88.15 97.89 109.05

−0.01 −0.01 0.01 0.01 0.01 0.00 −0.01

298.15 303.35 308.15 313.55 317.85 323.05 327.55 334.75

0.43 0.55 0.65 0.89 1.11 1.60 2.24 4.42

30.26 34.05

−0.03 −0.05

Methanol 8.12 −0.42 10.32 −0.62 12.79 1.83 17.10 −0.81 21.70 1.06 28.29 −0.38 39.05 −1.29 52.11 −0.27 68.24 0.87 Ethanol 8.61 −0.96 12.79 0.42 13.38 1.26 17.52 −0.56 23.72 0.99 30.65 −0.04 39.36 −0.12 52.17 −2.48 68.29 0.20 89.20 1.22 2-Propanone 53.14 0.18 61.05 −0.42 67.65 0.18 76.55 0.03 88.14 0.02 97.79 0.10 109.15 −0.10 Ethyl Acetate 30.02 0.77 34.32 −0.84

103x1calcd,Apel

102RD

103x1calcd,Wil

102RD

40.22 45.02 53.18 60.79 68.34 80.45 90.08 104.74

−0.01 0.02 0.05 0.03 0.01 0.01 −0.01 −0.02

5.98 6.97 8.23 9.71 11.54 14.19 17.47 22.31 27.48 35.21

−0.14 −0.28 0.03 0.00 0.13 0.15 0.12 0.04 −0.03 −0.08

0.42 0.54 0.69 0.89 1.12 1.58 2.22 4.44

2.38 2.66 −5.09 −0.22 −0.35 1.11 0.68 −0.36

Ethyl Acetate 40.46 −0.59 45.17 −0.31 52.58 1.18 60.65 0.27 68.74 −0.58 80.28 0.22 90.14 −0.07 104.80 −0.09 2-Propanol 5.98 −0.24 7.00 −0.71 8.14 1.11 9.72 −0.06 11.49 0.59 14.18 0.22 17.53 −0.22 22.53 −0.93 27.81 −1.20 34.68 1.43 Toluene 0.45 −3.56 0.53 4.20 0.65 0.43 0.87 2.47 1.13 −1.71 1.63 −1.75 2.31 −3.21 4.30 2.80

Standard uncertainties u are u(T) = 0.05K, ur(p) = 0.05, ur(x) = 0.01.

Table 3. Parameters of the Models Used in This Study for Solubility of Aceclofenac and the rsmd Values between Measured Solubility Data and Calculated Resultsa modified Apelblat

Wilson

solvent

A

B

C

methanol ethanol 2-propanone ethyl acetate 2-propanol toluene

−387.619 −357.533 −59.210 −94.954 −397.063 −2386.707

13245.006 12016.135 646.927 1926.347 14955.963 106971.840

59.424 54.880 9.517 14.939 60.012 354.651

2

10 rmsd

Apel

0.96 1.08 0.19 0.60 0.81 2.75

Δλ12

Δλ21

102rmsdwil

15623.328 16290.684 12298.541 14447.508 17944.615 25798.972

26070.037 25446.245 27046.174 26623.467 26013.788 25798.972

0.46 0.49 0.01 0.03 0.13 2.25

a rmsdApel and rmsdWil are the root-mean-square deviations between measured data and computed results fitted respectively by modified Apelblat and Willson equations.

The least-squares method was employed to fit all the parameters in a modified Apelblat equation and Wilson model with the objective function (OF) of:

The regressed parameter values of A, B, and C in eq 2 and Δλ12 and Δλ21 in eq 6 were collected in Table 3 with the values of root-mean-square deviation (rmsd), expressed as

n

OF =

⎡ 1 rmsd = ⎢⎢ N ⎣

∑ |xiexp − xical| 1

where xiexp and xical are experimental and calculated mole fractions of the solute aceclofenac, and n is the number of experimental points.

⎛ x calcd − x exp ⎞2 ⎤ ∑ ⎜⎜ 1,i exp 1,i ⎟⎟ ⎥⎥ x1, i ⎠⎦ i=1 ⎝ N

1/2

(7)

where N represents the number of experimental solubility data points determined in one solvent; x1,icalcd and x1,iexp stand for the 1590

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the solubility of aceclofenac is not only affected by the polarity of the solvent, but also influenced by several other solvent properties, including the dipole moment, dielectric constant, and solubility parameters and so on. The solubility behavior of aceclofenac in these solvents is thought to be the net contribution of these factors. From Tables 2 and 3, it can be seen that all the absolute values of RDs are no more than 5.09 %; all the rmsd values are less than 2.75 %. These indicate that the modified Apelblat and Wilson models can both be appropriate for fitting the measured solubility of aceclofenac.

calculated solubility computed by eq 2 or 4 and the experimental solubility, respectively. The relative deviation (RD) is defined as RD =

calcd x1,exp i − xi

x1,exp i

(8)

and the values are also presented in Table 2. The experimental solubility data points and the fitted curves are shown in Figure 2 and Figure 3.

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CONCLUSIONS The solubility data of aceclofenac in methanol, ethanol, 2-propanone, ethyl acetate, 2-propanol, and toluene in temperatures ranging from (293.35 to 338.25) K were measured by a synthetic method. It is found that the solubility of aceclofenac in the six pure solvents increases with rising temperature. The better solvents for dissolving aceclofenac are 2-propanone and ethyl acetate, but for the recrystallization, methanol and ethanol are suitable solvents. The calculated data of aceclofenac by the modified Apelblat and Wilson models are consistent with the experimental values, with the absolute values of RD and the value of rmsd no more than 5.09 % and 2.75 %, respectively.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +86-379-65523821. Fax: +86-379-65523821. E-mail: [email protected].

Figure 2. Solubility of aceclofenac in six selected solvents: ●, methanol; ◇, ethanol; ◆, 2-propanone; ▽, ethyl acetate; ∗, 2-propanol; ▲, toluene. Solid line, computed data based on the modified Apelblat equation.

Funding

This work was financially funded by the National Natural Science Foundation of Henan Province (21172105) and The Low Carbon Fatty Amine Engineering Research Center of Zhejiang Province (2012E10033). Notes

The authors declare no competing financial interest.

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REFERENCES

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Figure 3. Solubility of aceclofenac in six selected solvents: ●, methanol; ◇, ethanol; ◆, 2-propanone; ▽, ethyl acetate; ∗, 2-propanol; ▲, toluene. Dashed line, computed data based on the Wilson equation.

It can be seen from Table 2 and Figures 2 and 3 that the solubility of aceclofenac in all the tested solvents increases with the elevated temperature. Especially, the solubility of aceclofenac in methanol and ethanol has much more significant change with temperature than in other solvents, which suggests the two solvents have potential advantage in the recrystillization of aceclofenac. Furthermore, the solubility of aceclofenac in different solvents are basically in the order of 2-propanone > ethyl acetate > methanol ≈ ethanol > 2-propanol > toluene, which is not exactly in accordance with the polarity sequence of the six solvents (polarity: methanol > ethanol > 2-propanol > 2propanone > ethyl acetate > toluene).20 The result means that 1591

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