Solubility of Clopidogrel Hydrogen Sulfate (Form II) in Ethanol +

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Solubility of Clopidogrel Hydrogen Sulfate (Form II) in Ethanol + Cyclohexane Mixtures at (283.35 to 333.75) K Huai Guo, Liangcheng Song,* Chunhui Yang, Yu Tao, Yongjun Long, and Yingbei Cui School of Chemical Engineering and Technology, Harbin Institute of Technology, Harbin 150001, People’s Republic of China ABSTRACT: As the solvent system ethanol + cyclohexane is selected for the purification of clopidogrel hydrogen sulfate (Form II) [CHS(II)], the solubilities of CHS(II) in the binary solvent mixtures were measured at the temperatures ranging from (283.35 to 333.75) K. The solubility increased with both the rising temperature and mole fraction of ethanol in the binary solvent. The experimental data were well-fitted by the Jouyban−Acree model, and the thermodynamic parameters were calculated correspondingly. The result demonstrated that the dissolution process of CHS(II) in the ethanol + cyclohexane mixture was endothermic and entropy-driven.

1. INTRODUCTION Clopidogrel hydrogen sulfate (CAS Registry No. 120202-66-6; (S)-(+)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl) acetate hydrogen sulfate) is widely used in the cure of thrombotic diseases,1 whose molecular structure is shown in Figure 1. Clopidogrel hydrogen sulfate has several

As for the purification of CHS(II) by dilution crystallization from the ethanol + cyclohexane mixture, the solubilities of CHS(II) in solvent system are the crucial data for controlling the process. However, up to now, no such data have been reported in the literature. In this work, the solubilities of CHS(II) in ethanol + cyclohexane mixtures at temperatures ranging from (283.35 to 333.75) K were measured using a laser-beam synthetic method. The experimental data were correlated by the Jouyban−Acree model, and the thermodynamic parameters for the dissolution were calculated from the van’t Hoff equation.

2. EXPERIMENTAL SECTION 2.1. Materials. CHS(II) was purchased from Jinan KaiHua Chemistry Co., Ltd., China. The result of X-ray diffraction (XRD) demonstrated that the sample was Form II.3 The solvents (ethanol and cyclohexane) of analytical grade were obtained from Tianjin Chemical Reagent Co., China, which were used without any purification. Detailed information on the materials is shown in Table 1. 2.2. Apparatus and Procedures. The solubility of CHS(II) in the binary solvent was measured using the laser monitoring technique. The apparatus, illustrated in Figure 3, was similar to those in literature.6 The laser monitoring system was made up of a laser generator, a photoelectric transformer, and a light intensity display. The laser beam penetrated the solution to detect the solid in it. The solution was placed in a jacketed glass vessel which was maintained at a fixed temperature by a circulation constant temperature water bath (SHP DC-2015, China). The temperature was exactly measured by a mercury-inglass thermometer with the uncertainty of ± 0.01 K. The jacketed

Figure 1. Molecular structure of clopidogrel hydrogen sulfate.

polymorphic forms,2 among which Form II is the most stable one,3 used in the pharmaceutical industry. Clopidogrel hydrogen sulfate is prepared through reactive crystallization, and the products are always aggregates of a large number of primary particles. Contaminants can be easily introduced during the process, which directly affects the quality of the product. It was revealed that dilution crystallization is the best choice for the purification of clopidogrel hydrogen sulfate. Our previous work has demonstrated that ethanol was the excellent solvent for CHS(II).4 It has been demonstrated in the literature that ethanol and cyclohexane are completely miscible in the temperature range of interest here.5 Through systematical investigation, we found that the mixture of ethanol + cyclohexane was the suitable solvent system for the dilution crystallization process. The particles of good quality can be obtained in this solvent system, shown in Figure 2, and the main phase is some rectanglar grains with sizes of 1−5 mm. © XXXX American Chemical Society

Received: July 2, 2014 Accepted: January 7, 2015

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DOI: 10.1021/je500616v J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Figure 2. CHS(II) crystals obtained from dilution crystallization in an ethanol + cyclohexane mixture.

Table 1. Description of Materials Used in This Paper chemical name CHS(II) ethanol cyclohexane

source Jinan KaiHua Chemistry Co., Ltd., China Tianjin Chemical Reagent Co., China Tianjin Chemical Reagent Co., China

x1 =

initial mass fraction purity

m1/M1 m1/M1 + m2 /M 2

(2)

where m0, m1, and m2 represent the mass of CHS(II), ethanol, and cyclohexane, respectively. M1, M0, and M2 are the respective molecular masses.

0.990 0.997 0.995

3. RESULTS AND DISCUSSION 3.1. Solubility Data of CHS(II). The solubility data of CHS(II) in ethanol + cyclohexane mixtures at temperatures ranging from (283.35 to 333.75) K are listed in Table 2. The 3D drawing of the data is shown in Figure 4, and the solubilities in different ranges of value were printed with different colors, respectively, which graphically exhibited the trend of the data. From Figure 4, it can be seen easily that the solubility of CHS(II) increases with both the temperature and the mole fraction of ethanol in the solvent mixture. When the solvent composition is fixed, the solubility increases with the rising temperature. At a certain temperature, the solubility increases with the mole fraction of ethanol in the solvent mixture. The solubility increases sharply when the mole fraction of ethanol reaches 0.400, especially at the high temperature, and the mole fraction solubility ranges from 3.443 × 10−4 to 305.0 × 10−4. The large range of solubility in the ethanol + cyclohexane mixtures illustrates that the solvent system is a good selection for the dilution crystallization of CHS(II), through which crystals can be obtained by dropping cyclohexane (antisolvent) into the saturated solution of CHS(II) in ethanol. 3.2. Correlation of CHS(II) Solubility. Many models such as the modified Apelblat equation,4 CNIBS/Redlich−Kister model,7 NRTL equation,8 and λh equation9 have been successfully used in correlating and predicting solubility,10 most of which describe the solubility as a function of either temperature or solvent composition. The Jouyban−Acree model was proposed to provide an accurate description for solubility of a solute with the variation of both temperature and solvent composition,11 formerly known as the combined nearly ideal binary solvent/Redlich−Kister equation, in which contributions from both two-body and three-body interactions were included.12 Figure 4 shows that the solubility of CHS(II) is determined by both the temperature and the solvent composition. So the Jouyban−Acree model was employed in this work, and for the binary ethanol + cyclohexane solvent mixtures, it could be expressed as eq 3.13

Figure 3. Experimental setup for the solubility determination. 1, light intensity display; 2, condenser; 3, thermometer; 4, jacketed glass vessel; 5, photoelectric transformer; 6, magnetic stirrer; 7, laser generator; 8, water bath.

vessel was equipped with a condenser to prevent the solvent from evaporating. All of the materials were measured by an electronic balance (Mettler Toledo AB204-S, Switzerland) with the uncertainty of ± 0.0002 g. During the experiment, a certain amount of the binary solvent was introduced to the vessel, and CHS(II) was added after weighed. The solution was stirred continuously at the required temperature. The solute was added repeatedly until it could not be dissolved completely, and then the solution was saturated. The total addition was recorded. Therefore, the range of the solubility could be determined. The experiment was repeated according to the result of proceeding experiment to narrow the range of the solubility. The solubility was determined when the last addition [about (2 to 5) mg, less than 1 % of the solute dissolved] could not be dissolved in 45 min. Each experiment was repeated at least 3 times, and the mean value was used to calculate the mole fraction solubility (x0) expressed as eq 1. The composition of the solvent mixture (x1) was defined by eq 2. x0 =

m0 / M 0 m0 /M 0 + m1/M1 + m2 /M 2

(1) B

DOI: 10.1021/je500616v J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Table 2. Experimental Solubility and Fitted Errors of CHS(II) in Ethanol + Cyclohexane Mixtures at Temperature Range from T = (283.35 to 333.75) Ka T/K

x1

104 x0

104 xcal 0

100 RD

283.35

0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900

0.4037 0.8623 1.718 3.443 5.849 9.309 13.50 22.99 33.59 0.5205 1.323 2.472 5.037 7.918 12.96 21.28 32.27 52.99 0.7284 1.630 3.531 7.172 12.55 19.79 31.83 50.99 80.05 0.9868 2.535 4.982 10.99 17.79 28.65 46.85 80.46 116.2 1.463 3.354 7.537 14.99 27.06 43.28 72.89 115.0 187.0 2.099 4.945 11.00 21.94 41.49 69.70 113.0 181.8 305.0

0.3735 0.8729 1.820 3.423 5.887 9.435 14.42 21.57 32.59 0.5206 1.221 2.565 4.875 8.501 13.85 21.54 32.83 50.53 0.7283 1.713 3.622 6.951 12.28 20.29 32.08 49.73 77.82 1.027 2.422 5.153 9.978 17.83 29.87 47.94 75.49 120.0 1.458 3.447 7.372 14.40 25.99 44.12 71.80 114.7 184.9 2.175 5.152 11.08 21.82 39.84 68.51 113.1 183.5 300.2

7.488 −1.230 −5.961 0.588 −0.644 −1.357 −6.783 6.183 2.971 −0.015 7.719 −3.751 3.223 −7.360 −6.852 −1.225 −1.748 4.641 0.019 −5.091 −2.576 3.075 2.189 −2.544 −0.793 2.462 2.787 −4.095 4.441 −3.423 9.207 −0.197 −4.269 −2.333 6.172 −3.230 0.312 −2.781 2.186 3.948 3.942 −1.934 1.496 0.245 1.124 −3.611 −4.187 −0.720 0.528 3.980 1.704 −0.120 −0.947 1.567

293.35

303.15

312.95

322.75

333.75

a

Figure 4. Solubility (104x0) of CHS(II) in ethanol + cyclohexane mixtures at temperatures from (283.35 to 333.75) K.

ln x0 = x1 ln(x0)1 + x 2 ln(x0)2 +

x1x 2 T

2

∑ Ji (x1 − x2)i i=0

(3)

where x1 and x2 are the mole fraction of the binary solvent mixtures, (x0)i refers to the mole fraction solubility of the solute in pure solvent i, T is the absolute temperature, and Ji is the parameters of the model. In the binary solvent, x2 = (1 − x1). The mole fraction solubility of the solute in pure solvent 1 and 2 can be expressed by the modified Apelblat equation,14 shown as eqs 4 and 5. ln(x0)1 = a1 +

b1 + c1 ln T T

(4)

ln(x0)2 = a 2 +

b2 + c 2 ln T T

(5)

Introducing eqs 4 and 5 into eq 3 and replacing x2 with (1 − x1) results in another equation, which can be simplified as eq 6.15 A2 x x2 + A3 ln T + A4 x1 + A5 1 + A 6 1 T T T 3 4 x x + A 7 1 + A8 1 + A 9x1 ln T (6) T T

ln x0 = A1 +

where Ai is the model parameter. Equation 6 shows that, in the binary solvent, the mole fraction solubility of the solute can be expressed as a function of temperature and solvent composition. The experimental data were correlated by eq 6 and plotted in Figure 5, and the fitted errors are listed in Table 2. The relative deviation (RD), the mean percentage deviation (MPD), and the root-mean-square deviation (RMSD), defined as eqs 7, 8, and 9, respectively, were employed to evaluate the imitative effect. RD =

x0 − x0cal x0

xcal 0

x1 is the mole fraction of ethanol in the solvent mixture. x0 and represent the experimental and calculated solubility data, respectively. Standard uncertainty in temperature u(T) = 0.05 K. The relative uncertainties u are ur(x1) = 0.0004 and ur(x0) = 0.03.

MPD = C

100 N

N

∑ i=1

(7)

xi − xical xi

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Table 4. Dissolution Enthalpy, Entropy, and Molar Gibbs Energy of CHS(II) in Ethanol + Cyclohexane Mixtures

Figure 5. Nonlinear surface fit plot of (104x0) versus T and x1 for the solubility of CHS(II) in ethanol + cyclohexane mixtures. 1/2 N ⎧ (x cal − xi)2 ⎫ ⎪∑ ⎪ i=1 i ⎬ RMSD = ⎨ ⎪ ⎪ N ⎩ ⎭

T/K

x1

ΔH/(kJ·mol−1)

ΔS/(J·mol−1·K−1)

ΔG/(kJ·mol−1)

283.35

0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900

21.76 22.00 22.52 23.27 24.23 25.36 26.61 27.90 29.17 24.16 24.39 24.89 25.63 26.58 27.70 28.93 30.21 31.46 26.52 26.73 27.22 27.95 28.88 29.99 31.21 32.47 33.71 28.87 29.07 29.55 30.26 31.19 32.28 33.48 34.73 35.96 31.22 31.41 31.87 32.57 33.49 34.57 35.76 37.00 38.21 33.87 34.04 34.49 35.17 36.07 37.13 38.31 39.54 40.74

−7.96 −0.05 7.87 15.78 23.69 31.60 39.51 47.42 55.33 0.37 8.24 16.10 23.97 31.83 39.70 47.57 55.43 63.30 8.26 16.09 23.91 31.73 39.55 47.37 55.20 63.02 70.84 15.90 23.68 31.46 39.24 47.02 54.80 62.59 70.37 78.15 23.31 31.05 38.79 46.53 54.27 62.01 69.75 77.49 85.22 31.36 39.05 46.75 54.44 62.14 69.83 77.53 85.22 92.92

23.83 22.05 20.42 18.78 17.54 16.44 15.57 14.31 13.42 24.06 21.78 20.26 18.52 17.42 16.22 15.01 13.99 12.78 24.01 21.98 20.03 18.25 16.84 15.69 14.49 13.30 12.17 24.00 21.54 19.79 17.72 16.47 15.23 13.95 12.55 11.59 23.69 21.47 19.29 17.45 15.86 14.60 13.20 11.98 10.68 23.50 21.12 18.90 16.99 15.22 13.78 12.44 11.12 9.68

293.35

(9)

where N is the number of the experimental points, xcal i is the calculated value of mole fraction solubility, and xi is the experimental value. Values of the parameters from the correlation by Jouyban−Acree model were presented in Table 3, from which we

303.15

Table 3. Parameters and Fitting Errors of eq 6 from Experimental Solubility of CHS(II) in Ethanol + Cyclohexane Mixtures parameters

value

A1 A2 A3 A4 A5 A6 A7 A8 A9 MPD 104 RMSD

−194.94 5606.48 29.04 20.06 −226.14 −1738.89 4.33 485.55 −1.59 3.036 1.354

312.95

322.75

can see that the MPD value was 3.036, and RMSD value is 1.354 × 10−4. The parameter values in Table 3 demonstrate that the Jouyban−Acree model fits the solubility data quite well. The Jouyban−Acree model with the parameters obtained can be used to quantitatively describe the solubility of CHS(II) as a function of temperature and solvent composition. 3.3. Thermodynamic Parameters for CHS(II) Dissolution. The molar dissolution enthalpy ΔHd, the molar dissolution entropy of ΔSd, and molar Gibbs energy ΔGd, can be calculated by the standard expressions eqs 10 to 12.16 ⎡ ∂ ln x0 ⎤ ΔHd = RT ⎢ ⎣ ∂ ln T ⎥⎦

(10)

⎡ ∂ ln x0 ⎤ ΔSd = R ⎢ + ln x0 ⎥ ⎣ ∂ ln T ⎦

(11)

ΔGd = ΔHd − T ΔSd

(12)

333.75

ΔHd = R( −A 2 + A3T − A5x1 − A 6x12 − A 7 x13 − A8x14

Introducing the expression of ln x0 (eq 6) into eqs 10 to 12 above, eqs 13 to 15 can be obtained.

+ A 9x1T ) D

(13) DOI: 10.1021/je500616v J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Funding

This work is supported by the Fundamental Research Funds for the Central Universities (Grant No. HIT. NSRIF.2013044) and China Scholarship Council. Notes

The authors declare no competing financial interest.

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(1) Dickie, J. S.; Scott, L. J. Clopidogrel bisulfate in ST-segment elevation myocardial infarction. Am. J. Cardiovasc. Drugs 2006, 6, 407− 414. (2) Lifshitz, R.; Kovalevski-ishai, E.; Wizel, S.; Maydan, S. A.; Lidorhadas, R. Novel crystal forms III, IV, V, and novel amorphous form of clopidogrel hydrogen sulfate, processes for their preparation, processes for the preparation of form I, compositions containing the new forms and methods of administering the new forms. U.S. Patent 20,030,114,479, 2003. (3) Bousquet, A.; Castro, B.; Saint-Germain, J. Polymorphic clopidogrel hydrogenesulphate form. U.S. Patent 6,429,210 B1, 2002. (4) Song, L.; Li, M.; Gong, J. Solubility of Clopidogrel Hydrogen Sulfate (Form II) in Different Solvents. J. Chem. Eng. Data 2010, 55 (9), 4016−4018. (5) (a) Qiu, C.; Blanchard, G. J. Orientational and Vibrational Relaxation Dynamics of Perylene in the Cyclohexane−Ethanol Binary Solvent System. J. Phys. Chem. B 2014, 118 (35), 10525−10533. (b) Zereshki, S.; Figoli, A.; Madaeni, S. S.; Simone, S.; Esmailinezhad, M.; Drioli, E. Effect of polymer composition in PEEKWC/PVP blends on pervaporation separation of ethanol/cyclohexane mixture. Sep. Purif. Technol. 2010, 75 (3), 257−265. (6) (a) Zhao, Y.; Hou, B.; Jiang, X.; Liu, C.; Wang, J. Determination of Thermodynamics in Various Solvents and Kinetics of Cefuroxime Sodium during Antisolvent Crystallization. J. Chem. Eng. Data 2012, 57 (3), 952−956. (b) Yu, Q.; Black, S.; Wei, H. Solubility of Butanedioic Acid in Different Solvents at Temperatures between 283 and 333 K. J. Chem. Eng. Data 2009, 54 (7), 2123−2125. (7) Zhi, M.; Wang, J.; Jia, C.; Wang, Y. Solubility of Cloxacillin Sodium in Different Binary Solvents. J. Chem. Eng. Data 2009, 54 (3), 1084− 1086. (8) Li, R.; Yan, H.; Wang, Z.; Gong, J. Correlation of Solubility and Prediction of the Mixing Properties of Ginsenoside Compound K in Various Solvents. Ind. Eng. Chem. Res. 2012, 51 (23), 8141−8148. (9) Yan, H.; Wang, Z.; Wang, J. Correlation of Solubility and Prediction of the Mixing Properties of Capsaicin in Different Pure Solvents. Ind. Eng. Chem. Res. 2012, 51 (6), 2808−2813. (10) Tanveer, S.; Hao, Y.; Chen, C.-C. Introduction to Solid-Fluid Equilibrium Modeling. Chem. Eng. Prog. 2014, 110 (9), 37−47. (11) (a) Jouyban-Gharamaleki, A.; Acree, W. E., Jr. Comparison of models for describing multiple peaks in solubility profiles. Int. J. Pharm. 1998, 167 (1−2), 177−182. (b) Jouyban-Gharamaleki, A.; BarzegarJalali, M.; Acree, W. E., Jr. Solubility correlation of structurally related drugs in binary solvent mixtures. Int. J. Pharm. 1998, 166 (2), 205−209. (12) Acree, W. E., Jr. Mathematical representation of thermodynamic properties: Part 2. Derivation of the combined nearly ideal binary solvent (NIBS)/Redlich-Kister mathematical representation from a two-body and three-body interactional mixing model. Thermochim. Acta 1992, 198 (1), 71−79. (13) Jouyban, A. Review of the cosolvency models for predicting solubility of drugs in water-cosolvent mixtures. J. Pharm. Pharm. Sci. 2008, 11 (1), 32−57. (14) Ma, H.; Qu, Y.; Zhou, Z.; Wang, S.; Li, L. Solubility of Thiotriazinone in Binary Solvent Mixtures of Water + Methanol and Water + Ethanol from (283 to 330) K. J. Chem. Eng. Data 2012, 57 (8), 2121−2127. (15) Wang, G.; Wang, Y.; Hu, X.; Ma, Y.; Hao, H. Determination and correlation of cefoperazone solubility in different pure solvents and binary mixture. Fluid Phase Equilib. 2014, 361 (0), 223−228.

Figure 6. Molar Gibbs energy of solution as a function of solubility at different temperatures: □, T = 283.35 K; ■, T = 293.35 K; ○, T = 303.15 K; ⧫, T = 312.95 K; ◊, T = 322.75 K; ▲, T = 333.75 K.

ΔSd = R(A1 + A3 + A3 ln T + A4 x1 + A 9x1 + A 9x1 ln T ) (14)

ΔGd = −RT ln x0

(15)

With the values of the parameters given in Table 3, the values of ΔHd, ΔSd, and ΔGd were calculated and listed in Table 4. All of the values of ΔHd in Table 4 were positive, which indicated that the dissolving process of CHS(II) in each solvent mixture was endothermic. The ΔHd value increased with the mole fraction solubility (x0), while the ΔSd value increased more rapidly than that of ΔHd which made the ΔGd value decrease with the mole fraction solubility (x0). This result demonstrated that the dominant dissolution mechanism for CHS(II) in ethanol + cyclohexane mixtures was the entropy. Equation 15 showed that the molar Gibbs energy was a linear function of ln x0 at the same temperature, and it was plotted in Figure 6. It is obvious that the ΔGd value decreases as the solubility rises at the same temperature, which is coincide with the results in the previous literatures,17 the lower ΔGd value implies a more favorable dissolution process.

4. CONCLUSIONS Using the laser monitoring technique, the solubility data of CHS(II) in the ethanol + cyclohexane mixtures were obtained at temperatures ranging from (283.35 to 333.75) K. The solubility increased with both the temperature and the mole fraction of ethanol in the solvent mixture. The Jouyban−Acree model was employed to quantitatively describe the solubility of CHS(II) as a function of temperature and solvent composition. The model correlated the solubility data with a high accuracy and can be used for the optimization of crystallization process of CHS(II). Furthermore, the thermodynamic parameters were calculated. The result demonstrated that the dissolution process is endothermic, and the dominant dissolution mechanism for CHS(II) in ethanol + cyclohexane mixtures was the entropy.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; phone: +86-451-86403829; fax: +86-451-86418270. E

DOI: 10.1021/je500616v J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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DOI: 10.1021/je500616v J. Chem. Eng. Data XXXX, XXX, XXX−XXX