Solubility of Amorphous Clopidogrel Hydrogen Sulfate in Different

Article pubs.acs.org/jced

Solubility of Amorphous Clopidogrel Hydrogen Sulfate in Different Pure Solvents Yan Liu,† Zhi-Peng Zhao,† Jingbin Cui, and Guobin Ren* Laboratory of Pharmaceutical Crystal Engineering & Technology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, People’s Republic of China ABSTRACT: At the temperature range (273.15 to 308.15) K, the solubility of amorphous clopidogrel hydrogen sulfate (CHS) in pure 1-butanol, 2-butanol, 2-propanol, methyl acetate, ethyl acetate, acetone, and methyl tert-butyl ether (MTBE) were experimentally measured. The order of solubility of amorphous CHS is 1-butanol > acetone > 2-propanol > 2-butanol > methyl acetate > ethyl acetate > MTBE, which is in good agreement with the orders of CHS crystalline forms in the literature. However, the solubility of the amorphous ones is dozens of times higher than that of crystals, respectively. In addition, the modified Apelblat equation was used to correlate the temperature with the mole fraction solubility. Finally, the thermodynamic parameters were calculated by the fitting parameters of the modified Van’t Hoff equation.

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INTRODUCTION Clopidogrel hydrogen sulfate (CAS registry no. 120202-66-6), with its chemical name, (S)-(+)-methyl 2-(2- chlorophenyl)-2(6,7-dihydro-4H-thieno[3,2-c] pyridine-5-yl) acetate hydrogen sulfate,1 a selective and irreversible inhibitor of adenosine-5′diphosphate (ADP)-induced platelet aggregation, was widely used in the clinical treatment of atherosclerosis, acute coronary syndrome, and other vascular diseases. Among the several different polymorphs of CHS, forms I and II were employed in the pharmaceutical industry. Form I was first employed in the pharmaceutical industry, and then form II was more widely used after it was born because of its greater thermodynamic stability.2 Crystallization is necessary in the manufacture of CHS, and appropriate solvents should be selected to purify CHS. First, CHS is soluble in some solvents, such as methanol, ethanol, and acetic acid. However, these solvents usually result in unstable product, low yield, high content of impurities, etc. In addition, other solvents with low solubility to CHS, such as 2-propanol, 1-butanol, and ethyl acetate, were also selected. A great amount of solvents were used during the crystallization, which led to a series of problems on cost and environment. Finally, in order to obtain supersaturated solution of CHS during crystallization, the complex reactive method was invented, which clopidogrel base was first prepared by reacting suspension of CHS with saturated solution of sodium hydroxide or sodium carbonate, dissolved in solvent, and then reacted with sulfuric acid.3−8 After a series of operations, lots of impurities may be produced. The solubility of the amorphous active pharmaceutical ingredient (API) was usually higher than crystalline ones, because of larger surface free energy and lower solution heat.9 Saturated solution of CHS was first gained by using amorphous ones in this work, and problems mentioned above were improved. It provides a new idea for the industrial preparation of CHS. Solubility data of amorphous CHS is significant on crystallization. In this © 2015 American Chemical Society

paper, the solubility of amorphous CHS in 1-butanol, 2-butanol, 2-propanol, methyl acetate, ethyl acetate, acetone, and MTBE at temperature range from (273.15 to 308.15) K and under atmospheric pressure was experimentally measured by using a dynamic method via a laser monitoring observation technique,10 and the data obtained was correlated by the Apelblat equation. In addition, some other thermodynamic properties of amorphous CHS, such as the molar enthalpy, the molar entropy, and the molar Gibbs energy of the dissolution were calculated by the modified Van’t Hoff equation.

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EXPERIMENTAL SECTION Materials. Form II and amorphous CHS was supplied from the Tianma Specialty Chemicals Co., Ltd., China (mass fraction purity >99%, determined by high-performance liquid chromatography, HPLC), and the crystalline forms were verified by powder X-ray diffraction (see Figure 1). Solvents used in the experiments (from the Sinopharm Chemical Reagent Co., Ltd., China) were of analytical reagent grade, whose mass fraction purity is greater than 99.5%. Apparatus and Procedures. The solubility of CHS in different pure solvents was measured with a dynamic method. The apparatus for the measurement are similar to those described in the literature.2 All solubility experiments were performed in a 100-ml EasyMax vessel (from Mettler Toledo, Switzerland) in conjunction with the iControl Easymax software. The accuracy of temperature control of this system is ± 0.01 K, and the vessel was stirred with an overhead stirrer. A condenser was used to prevent evaporation of solvent. The solute were weighed by an analytical Received: April 1, 2015 Accepted: July 9, 2015 Published: July 22, 2015 2442

DOI: 10.1021/acs.jced.5b00306 J. Chem. Eng. Data 2015, 60, 2442−2446

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Table 1. Experimental Solubility of CHS (Form II) in 1-Butanol and Solubility of Amorphous Ones in Acetone at Atmospheric Pressurea solubility of CHS (form II) in 1-butanol 104·X1

T/K 293.15 295.65 298.15 300.65 303.15 305.65 308.15 310.65 313.15 315.65 318.15

Figure 1. X-ray diffraction patterns of clopidogrel hydrogen sulfate: amorphous and II, respectively.

balance (Mettler Toledo XS105, Switzerland) with an accuracy of ± 0.01 mg. A laser monitoring system consisting of a laser generator, a photoelectric convertor, and a light intensity display was used to determine the disappearance of the last crystal in the mixtures. In experiments, a predetermined mass of amorphous CHS and pure solvent were added to the vessel. The amount of solvent was slightly in excess. The contents of the vessel were continuously stirred at the desired temperature. When the last solute just disappeared, the maximum of penetrated light intensity was reached. Then a certain amount of solute was weighed by the balance and added to the vessel. This step of measurement was repeated until the last addition of solute could not be dissolved completely, and according to the preceding experiments fewer times of addition reduced the accumulated error and shortened the dissolving time. The mass of the solute consumed in the experiment would be recorded. Through all of the experiments in this work, polymorphic transformation was not observed by X-ray powder diffraction. Together with the mass of the solute, the saturated mole fraction solubility (X1) of CHS was obtained from eq 1.11 X1 =

m1/M1 m1/M1 + m2 /M 2

104·Xlit 1

100·(X1 − X1lit)/X1

12.62 17.10 14.29 18.86 16.20 20.24 18.34 22.55 20.76 23.65 23.47 25.72 26.51 28.26 29.91 30.49 33.73 33.48 37.99 38.03 42.76 46.54 solubility of amorphous CHS in acetone

26.19 24.25 19.98 18.64 12.22 8.75 6.19 1.88 −0.73 0.09 8.11

T/K

104·X1

104·Xlit 1 (form II)

X1(amorphous)/Xlit 1 (form II)

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15

188.17 261.69 339.42 436.16 473.98 567.02 671.68 601.30

3.28 3.80 4.36 5.03 5.90 6.93 8.28 9.69

57.35 68.83 77.94 86.68 80.30 81.88 81.14 62.07

a

Standard uncertainties u for temperature T and pressure P are u(T) = 0.01 K and u(P) = 5 kPa. The relative standard uncertainty ur for the mole fraction solubilities x is ur(x) = 0.5%.

solubility of the amorphous ones in three solvents. The solubility was fitted by the modified Apelblat equation,12 eq 2 B ln x1 = A + + C ln(T ) (2) T where x1 is the mole fraction solubility of CHS, T is the absolute temperature. A, B, and C are empirical constants. The correlated values of A, B, and C of different pure solvents were listed in Table 3. The root-mean-square deviation (RMSD) is defined as follows N

(1)

RMSD =

where m1 and m2 represent the mass of the solute and the solvent, respectively. M1 and M2 are the respective molecular masses. All of the experiments were run at least three times, and the relative uncertainties of the experimental data were within 0.5%, obtained from the mass ratio of the additional solute to the dissolved solute.

∑i = 1 (x1exp − x1cal) N

(3)

xexp 1

where N is the number of experimental points and and xcal 1 represent the experimental and calculated values of the solubility, respectively. The RMSDs of different pure solvents were also listed in Table 3. According to the literature, the molar enthalpy ΔHd (J·mol−1), the molar entropy ΔSd (J·K−1·mol−1), and the molar Gibbs energy ΔGd (J·mol−1) of the dissolution were calculated by the following equations:13

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RESULTS AND DISCUSSION At the beginning, solubility of CHS (form II) in 1-butanol and the solubility of amorphous CHS in acetone were measured to compare with literature data, respectively, which were listed in Table 1. The experimental data of CHS (form II) in 1-butanol was in a good agreement with the literature reports, while the experimental data of amorphous CHS in acetone was 57 to 86 times higher than relative crystal ones in literature. The solubility of amorphous CHS in 1-butanol, 2-butanol, 2-propanol, methyl acetate, ethyl acetate, acetone and MTBE at temperatures range from (273.15 to 308.15) K are listed in Table 2 and plotted in Figure 2. Figure3 was close-up of the lower

⎛ ∂ ln x1 ⎞ ⎟ = R( −B + CT ) ΔHd = RT ⎜ ⎝ ∂ ln T ⎠

(4)

⎤ ⎡ ∂ ln x1 ΔSd = R ⎢ + ln x1⎥ = R[A + C(1 + ln T )] ⎦ ⎣ ∂ ln T

(5)

ΔGd = ΔHd − T ΔSd

(6)

The values of ΔHd, ΔSd, and ΔGd of dissolution at the points of measured solubility were calculated and listed in the Table 4. 2443

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Table 2. Solubility of Amorphous CHS in 1-Butanol, 2-Butanol, 2-Propanol, Methyl Acetate, Ethyl Acetate, Acetone, and MTBE from (273.15 to 308.15) K at Atmospheric Pressurea T/K

104·X1exp

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15

502.15 560.38 654.71 686.14 771.05 799.87 869.50 952.36

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15

188.17 261.69 339.42 436.16 473.98 567.02 671.68 760.30

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15

81.47 112.88 131.92 198.13 237.25 305.30 381.68 463.00

273.15 278.15 283.15 288.15

37.69 52.79 67.84 96.06

104·X1cal 1-Butanol 505.06 568.95 632.24 694.94 757.05 818.56 879.50 939.85 Acetone 192.74 262.02 335.56 413.04 494.13 578.55 666.04 756.35 2-Propanol 83.62 106.75 141.47 186.96 242.46 307.28 380.77 462.33 2-Butanol 37.50 51.64 71.15 95.64

100·(X1exp − X1cal)/X1exp

T/K

104·X1exp

−0.58 −1.53 3.43 −1.28 1.82 −2.34 −1.15 1.31

293.15 298.15 303.15 308.15

127.15 160.16 191.11 238.46

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15

9.59 10.28 11.19 12.24 13.34 15.07 18.78 21.41

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15

2.78 3.25 3.42 4.01 4.57 5.11 5.43 6.19

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15

0.62 0.65 0.75 0.86 1.01 1.10 1.22 1.25

−2.43 −0.12 1.14 5.30 −4.25 −2.03 0.84 0.52 −2.64 5.43 −7.24 5.64 −2.20 −0.65 0.24 0.14 0.52 2.17 −4.88 0.44

104·X1cal

100·(X1exp − X1cal)/X1exp

2-Butanol 124.76 158.18 195.61 236.77 methyl acetate 9.92 10.07 10.77 11.98 13.67 15.81 18.37 21.31 ethyl acetate 2.80 3.16 3.57 4.01 4.50 5.02 5.57 6.15 MTBE 0.58 0.68 0.78 0.88 0.98 1.08 1.19 1.29

1.88 1.23 −2.36 0.71 −3.44 2.03 3.76 2.10 −2.49 −4.96 2.22 0.50 −0.44 2.90 −4.27 −0.06 1.60 1.74 −2.57 0.70 5.90 −5.13 −3.86 −2.41 3.27 1.83 2.51 −3.01

a Standard uncertainties u for temperature T and pressure P are u(T) = 0.01 K and u(P) = 5 kPa. The relative standard uncertainty ur for the mole fraction solubilities x is ur(x) = 0.5%.

Figure 3. Mole fraction solubility (x1) of amorphous CHS in three solvents. left pointing triangle, methyl acetate; right pointing triangle, ethyl acetate; ◊, methyl tert-butyl ether (MTBE).

energy of amorphous CHS in seven solvents calculated by eq 6 was plotted with the temperature in Figure 4. The results indicate that at the higher temperature, the lower value of ΔGd is reached. It is of note that, at a given temperature, the order of ΔGd is 1-butanol < acetone < 2-propanol < 2-butanol < methyl acetate < ethyl acetate < MTBE. This is exactly opposite to the order of solubility of amorphous CHS. This fact may be due to the largest

Figure 2. Mole fraction solubility (x1) of amorphous CHS in seven different solvents. □, 1-butanol; ○, acetone; ▽, 2-butanol; Δ, 2propanol; left pointing triangle, methyl acetate; right pointing triangle, ethyl acetate; ◊, methyl tert-butyl ether (MTBE).

At the experimental temperature range, the dissolving process of amorphous CHS is endothermic (ΔHd > 0). The molar Gibbs 2444

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Table 4. continued

Table 3. Parameters of eq 3 for Amorphous CHS in Different Solvents solvent

A

B

C

10 000·rmsd

1-butanol acetone 2-propanol 2-butanol methyl acetate ethyl acetate MTBE

141.93 545.53 125.30 333.66 −533.98 −2.38 87.07

−7548.50 −26609.60 −9191.07 −18496.23 21294.66 −1853.60 −5798.70

−20.91 −80.58 −17.20 −48.40 80.05 0.18 −13.47

13.54 12.02 6.03 2.38 0.40 0.09 0.03

solvent

MTBE

T (K)

ΔHd (J·mol−1)

ΔSd (J·mol−1·K−1)

ΔGd (J·mol−1)

303.15 308.15 273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15

15852.55 15859.84 17618.27 17058.29 16498.30 15938.31 15378.33 14818.34 14258.35 13698.36

−10.01 −9.99 −16.43 −18.47 −20.46 −22.42 −24.35 −26.24 −28.11 −29.94

18887.36 18937.35 22107.45 22194.72 22292.06 22399.28 22516.22 22642.71 22778.60 22923.72

Table 4. Molar Enthalpy, Molar Entropy, and the Molar Gibbs Energy of Dissolution with Different Solvents from (273.15 to 308.15) K solvent

T (K)

ΔHd (J·mol−1)

ΔSd (J·mol−1·K−1)

ΔGd (J·mol−1)

1-butanol

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 273.15 278.15 283.15 288.15 293.15 298.15

15280.53 14411.45 13542.37 12673.29 11804.21 10935.14 10066.06 9196.98 38234.69 34884.93 31535.16 28185.40 24835.64 21485.87 18136.11 14786.35 37365.12 36650.32 35935.52 35220.72 34505.92 33791.12 33076.32 32361.53 43856.31 41844.20 39832.09 37819.98 35807.88 33795.77 31783.66 29771.56 4746.94 8074.62 11402.29 14729.96 18057.64 21385.31 24712.98 28040.66 15808.84 15816.13 15823.41 15830.70 15837.98 15845.27

31.11 27.96 24.86 21.82 18.83 15.89 13.00 10.16 107.16 95.00 83.07 71.34 59.82 48.49 37.34 26.38 96.79 94.20 91.65 89.15 86.69 84.27 81.89 79.56 114.07 106.77 99.60 92.55 85.63 78.82 72.13 65.55 −40.30 −28.23 −16.37 −4.72 6.72 17.98 29.05 39.94 −10.16 −10.14 −10.11 −10.08 −10.06 −10.04

6782.34 6634.69 6502.66 6385.97 6284.37 6197.60 6125.39 6067.53 8964.80 8459.49 8014.40 7628.46 7300.65 7029.98 6815.48 6656.24 10926.31 10448.85 9984.24 9532.26 9092.67 8665.29 8249.88 7846.27 12698.92 12146.89 11631.03 11150.70 10705.29 10294.20 9916.86 9572.70 15755.98 15927.22 16038.65 16091.31 16086.23 16024.38 15906.73 15734.19 18584.79 18635.54 18686.16 18736.64 18787.01 18837.24

acetone

2-propanol

2-butanol

methyl acetate

ethyl acetate

Figure 4. Molar Gibbs energy of dissolution from T= (273.15 to 308.15) K. □, 1-butanol; ○, acetone; Δ, 2-propanol; ▽ 2-butanol; left pointing triangle, methyl acetate; right pointing triangle, ethyl acetate; ◊, methyl tert-butyl ether (MTBE).

Figure 5. Molar Gibbs energy of dissolution at T = 278.15 K as a function of the solubility values. □, 1-butanol; ○, acetone; Δ, 2-propanol; ▽, 2-butanol; left pointing triangle, methyl acetate; right pointing angle, ethyl acetate; ◊, methyl tert-butyl ether (MTBE).

polarity by alcohol, which leads to the strongest interactions between CHS and alcohol molecules and then the low value of ΔGd. In esters and ethers, fewer hydrogen bonds exist between CHS and the solvent, and hence much more energy is required to break the original associated bonds among either solute or solvent molecules, which results in high values of ΔGd. In acetone which has water of condensation and an interconversion between the keto form and enol one, acidulous CHS solute facilitates keto to enol; thus, the polarity of acetone changes, which results in a lower ΔGd. The molar Gibbs energy of CHS at 278.15 K in seven solvents is plotted with the solubility in Figure 5. It is indicated that a linear correlation exists between the molar Gibbs energy of dissolution and ln x1. The trend of ΔGd with the solubility is similar to the previous literature. Comparing the calculated the molar Gibbs energy, the lower the value of ΔGd, the larger the solubility of CHS. 2445

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(7) Kumar, A.; Bhayani, P. J.; Doshi, V. C.; Saxena, A.; Pathak, G. P.; Abhyankar, R.; Purohit, M. Process for the preparation of crystalline clopidogrel hydrogen sulphate Form I. U.S. Patent Application 12,010,581, 2008. (8) Lifshitz-Liron, R.; Kovalevski-Ishai, E.; Wizel, S.; Avhar-Maydan, S.; Lidor-Hadas, R. Polymorphs of clopidogrel hydrogensulfate. U.S. Patent 7,074,928, 2006. (9) Lv, Y.; Du, G. H. Polymorphic Drugs (in Chinese); People’s Medical Publishing House: Bei Jing, 2009. (10) Liu, Y.; Wang, J.; Wang, X.; Pang, F. Solubility of Valsartan in Ethyl Acetate + Hexane Binary Mixtures from (278.15 to 313.15) K. J. Chem. Eng. Data 2009, 54, 1412−1414. (11) Wang, J.; Gao, L.; Liu, Y. Solubility of Captopril in 2-Propanol, Acetone, Acetonitrile, Methyl Acetate, Ethyl Acetate, and Butyl Acetate. J. Chem. Eng. Data 2010, 55, 966−967. (12) Wang, L. C.; Wang, F. A. Solubility of Niacin in 3-Picoline + Water from (287.65 to 359.15) K. J. Chem. Eng. Data 2004, 49, 155− 156. (13) Zhang, H.; Yin, Q.; Liu, Z.; Gong, J.; Bao, Y.; Zhang, M.; Xie, C. Measurement and correlation of solubility of dodecanedioic acid in different pure solvents from T=(288.15 to 323.15) K. J. Chem. Thermodyn. 2014, 68, 270−274. (14) Smallwood, I. M. Handbook of organic solvent properties; Arnold: London, 1996.

CONCLUSIONS Because of the low solubility of crystalline CHS in appropriate crystallization solvents, the amorphous ones were first used to improve its solubility. The solubility of amorphous ones was measured by dynamic method in different pure solvents and was fitted by modified Apelblat equation. In addition, some other thermodynamic properties of amorphous CHS, such as the molar enthalpy, the molar entropy, and the molar Gibbs energy of the dissolution were also calculated by the modified Van’t Hoff equation. According to above results, the following conclusions can be drawn: (1) The solubility of amorphous CHS in seven solvents increases with temperature increasing. (2) The solubility of amorphous CHS is ranked as 1-butanol > acetone > 2-propanol > 2-butanol > methyl acetate > ethyl acetate > MTBE. This could be caused by the ion-dipole type interaction between the solvents and the solute, which gets stronger with the increase of the polarity of the solvents [polarity: 1-butanol (60.2) > 2-propanol (54.6) > 2-butanol (50.6) > methyl acetate (29.0) > ethyl acetate (23.0) > MTBE (14.8)].14 Remarkablely, the curve of solubility in acetone differs from those in alcohols. That could be the result of interconversion between the keto form and enol form of acetone. (3) The correlation equation was in a good agreement with the experimental data, and the molar enthalpy, the molar entropy and the molar Gibbs energy of the dissolution were also calculated. This study provided fundamental data and a new perspective for the upscale of industrial preparation of CHS.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: +86 (0)21-64253406. Author Contributions †

Y.L. and Z.-P.Z. are cofirst authors; they contributed equally to this work. Notes

The authors declare no competing financial interest. Funding

The authors would like to thank the Shanghai Committee of Science and Technology (Grant 12DZ1930702) for financial support.

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ACKNOWLEDGMENTS We are very grateful to Tianma Specialty Chemicals Co., Ltd. of China for supplying the experimental material.

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REFERENCES

(1) Song, L.; Gao, Y.; Gong, J. Measurement and correlation of solubility of clopidogrel hydrogen sulfate (metastable form) in lower alcohols. J. Chem. Eng. Data 2011, 56, 2553−2556. (2) Song, L.; Li, M.; Gong, J. Solubility of clopidogrel hydrogen sulfate (Form II) in different solvents. J. Chem. Eng. Data 2010, 55, 4016−4018. (3) Badorc, A.; Frehel, D. Clopidogrel and salts such as clopidogrel hydrogen sulfate; anticoagulants. U.S. Patent 4,847,265, 1989. (4) Bousquet, A.; Castro, B.; Saint-Germain, J. Polymorphic form of clopidogrel hydrogen sulphate. U.S. Patent 6,504,030, 2003. (5) Bousquet, A.; Castro, B.; Saint-Germain, J. Orthorombic polymorph of clopidogrel hydrogen sulfate with improved stability and lower solubility; antithrombotic agent; specific crystal structure and thermodynamic properties. U.S. Patent 6,429,210, 2002. (6) Mukarram, M. S. J.; Merwade, Y. A.; Khan, R. A. Process for the manufacture of (+)-(s)-clopidogrel bisulfate form-1. U.S. Patent 7,291,735, 2007. 2446

DOI: 10.1021/acs.jced.5b00306 J. Chem. Eng. Data 2015, 60, 2442−2446