Method For Preparing Spherical Clopidogrel Hydrogen Sulfate Polymorph I

Abstract

This invention provides a new preparation method of Clopidogrel Hydrogen Sulfate spherical crystal form I, using single 2-butanol as solvent, controlling the concentration, addition way and addition speed of sulfuric acid used to salify to shorten the process time, thus separating out Clopidogrel Hydrogen Sulfate from solution system stably with spherality. And the Clopidogrel Hydrogen Sulfate obtained complies with the requirements of the follow-up process on residual solvent, bulk density and mobility.

Claims

1. A method for the preparation of Clopidogrel Hydrogen Sulfate spherical crystal form I includes the following steps: (1) Dissolve clopidogrel free alkali into 2-butanol to get free alkali solution with the concentration of 0.020.1 g/mL, rapidly add 2-butanol solution with sulfuric acid 0.52.0 mol at 035 C., and the molar ratio of sulfuric acid and clopidogrel free alkali added is 0.81.1:1; (2) Keep the temperature in step (1), add Clopidogrel Hydrogen Sulfate crystal form I with mass ratio to clopidogrel free alkali 110 wt % as crystal seeds, and keep the temperature and stir for 48 h; (3) Filtrate, wash and dry to obtain Clopidogrel Hydrogen Sulfate spherical crystal form I; characterized by the addition time of sulfuric acid and 2-butanol solution in step (1) is controlled within 40 min.

2. According to the preparation method of Clopidogrel Hydrogen Sulfate spherical crystal form I in claim 1, wherein addition time of sulfuric acid and 2-butanol solution in step (1) is controlled within 20 min.

3. According to the preparation method of Clopidogrel Hydrogen Sulfate spherical crystal form I in claim 1, wherein the concentration of sulfuric acid and 2-butanol solution is 0.61.0 mol/L.

4. According to the preparation method of Clopidogrel Hydrogen Sulfate spherical crystal form I in claim 1, wherein the concentration of free alkali solution is 0.0400.065 g/mL and the molar ratio of sulfuric acid and clopidogrel free alkali is 0.951.05:1.

5. According to the preparation method of Clopidogrel Hydrogen Sulfate spherical crystal form I in claim 1, wherein the addition time of sulfuric acid and 2-butanol solution in step (4) is controlled within 10 mm.

6. According to the preparation method of Clopidogrel Hydrogen Sulfate spherical crystal form I in claim 1, wherein the temperature in step (1) is 1030 C.

7. According to the preparation method of Clopidogrel Hydrogen Sulfate spherical crystal form I in claim 1, wherein in step (2), it keeps at 2030 C. for 24 h, then cools to 1020 C. and stir for crystallization.

8. According to the preparation method of Clopidogrel Hydrogen Sulfate spherical crystal form I in claim 1, wherein the mass ratio of Clopidogrel Hydrogen Sulfate crystal form I and clopidogrel free alkali is 15 wt %.

9. According to the preparation method of Clopidogrel Hydrogen Sulfate spherical crystal form I in claim 1, wherein the method mentioned further includes the preparation step of clopidogrel base: (1) Dissolve clopidogrel salt in organic solvent; (2) Adjust pH value of the system with alkali, wash the organic phase with a little water and remove water in the organic phase by dehydrating agent; (3) Concentrate organic phase in vacuum to obtain clopidogrel free alkali.

10. According to the preparation method of Clopidogrel Hydrogen Sulfate spherical crystal form in claim 9, wherein in step (1), clopidogrel salt is preferably one of disulfate, camphorsulfonates and hydrochloride, or mixture of more than one above in various amounts; and purity of clopidogrel salt is above 95%; organic solvents are the mixture of one or mixture of more than one in various amounts of dichloromethane, chloroform, ethyl acetate; in step (2), the alkalis mentioned are sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide; the dehydrating agents mentioned are anhydrous magnesium sulfate and anhydrous sodium sulfate.

Description

INSTRUCTIONS FOR FIGURES

[0023] FIG. 1 Clopidogrel Hydrogen Sulfate XRPD spectrogram obtained in example 1

[0024] FIG. 2 Clopidogrel Hydrogen Sulfate DSC spectrogram obtained in example 1

[0025] FIG. 3 Clopidogrel Hydrogen Sulfate SEM picture obtained in example 1

[0026] FIG. 4 Clopidogrel Hydrogen Sulfate XRPD spectrogram obtained in comparison example 1

[0027] FIG. 5 Clopidogrel Hydrogen Sulfate SEM picture obtained in comparison example 1

SPECIFIC MODE OF EXECUTION

[0028] Further describe this invention combined with the following execution examples and figures, but mode of execution is not limited to it.

Example 1

[0029] Dissolved 760 g of clopidogrel hydrosulfate weighed (Purity>99.0%) into the mixing solution of 10 L of dichloromethane and 5 L of water, added solid sodium bicarbonate to water phase till pH>7. Kept still, washed the organic phase with water (1 L2), and removed water with anhydrous magnesium sulfate till the solution was clear.

[0030] Filtrated the organic phase and evaporated in vacuum rotary evaporator till the mass didn't change. Dissolved the residuum in 10.5 L of 2-butanol, and kept the solution at 25 C. Dissolved 100 ml of concentrated sulfuric acid (181 g) in 2.5 L of 2-butanol, added into the system within 10 min, and dispersed 10 g of crystal form I into 1 L of 2-butanol, and added mixture into the system together. Kept it at 25 C. for 2.5 h, reduced the temperature to 15 C. and kept for 3 h. Performed suction filtration, washed filter cake with ethyl acetate, vacuum drying at 40 C. for 1.0 h to get 610 g of the product (residual 2-butanol<0.2%).

[0031] XRPD spectrogram of the product obtained was as shown in FIG. 1, DSC spectrogram was as shown in FIG. 2 and SEM picture was as shown in FIG. 3.

Example 2

[0032] Added 1000 g of clopidogrel camphorsulfonates (Purity>99.0%) into the mixing solution of 10 L of dichloromethane and 5 L of water, added solid sodium bicarbonate to water phase till pH>7. Kept still, washed the organic phase with water (1 L2), and removed water with anhydrous magnesium sulfate till the solution was clear.

[0033] Filtrated the organic phase and evaporated in vacuum rotary evaporator till the mass didn't change. Dissolved the residuum into 10.5 L of 2-butanol, and kept the solution at 25 C. Dissolved 100 ml of concentrated sulfuric acid (181 g) into 2.5 L of 2-butanol, added mixture into the system within 10 min, and dispersed 12 g of crystal I into 1 L of 2-butanol, and added into the system together. Kept at 25 C. for 2.5 h, reduced the temperature to 15 C. and kept for 3 h. Performed suction filtration, washed filter cake with ethyl acetate, vacuum drying at 40 C. for 1.0 h to get 605 g of the product (residual 2-butanol<0.2%). It is tested to be Clopidogrel Hydrogen Sulfate spherical crystal form I.

Comparison Example 1

[0034] Dissolved 760 g of clopidogrel hydrosulfate (Purity>99.0%) in the mixing solution of 10 L of dichloromethane and 5 L of water, added solid sodium bicarbonate to water phase till pH>7. Kept still, washed the organic phase with water (1 L2), and removed water with anhydrous magnesium sulfate till the solution was clear.

[0035] Filtrated the organic phase and evaporated in vacuum rotary evaporator till the mass didn't change. Dissolved the residuum into 10.5 L of 2-butanol, and kept the solution at 25 C. Dissolved 100 ml of concentrated sulfuric acid (181 g) into 2.5 L of 2-butanol, added into the system within 10 min, and dispersed 10 g of crystal I into 1 L of 2-butanol, and added the mixture into the system together. Kept at 25 C. for 2.5 h, reduced the temperature to 15 C. and kept for 3 h. Performed suction filtration, washed filter cake with ethyl acetate, vacuum drying at 40 C. for 1.0 h to get 608 g of the product (residual 2-butanol<0.2%). XRPD spectrogram of the product obtained was as shown in FIG. 4, and SEM picture was as shown in FIG. 5. Seen from FIG. 4, the product obtained was the mixture of Clopidogrel Hydrogen Sulfate crystal forms I and II, and seen from FIG. 5, the product form existed as irregular sphere.

Example 3

[0036] Used the same ratio and operation as example 1, but different addition time of sulfuric acid to study the relationship between addition time of sulfuric acid and product form and crystal form.

TABLE-US-00001 Time No. (min) Form Crystal form Bulk density 1 15 Spherical Form I 0.77 2 20 Spherical Form I 0.76 3 30 Spherical Form I 0.75 4 40 Spherical Form I 0.75 5 80 Spherical-like Mixed crystal form I/II 0.68 6 120 Spherical-like Mixed crystal form I/II 0.65 7 180 Spherical-like Mixed crystal form I/II 0.58

[0037] As can be seen, on the premise other process condition was same, addition time of sulfuric acid related with product form and crystal form. In detail, as addition time of sulfuric acid was prolonged, the product showed a crystal transformation tendency and this tendency increased as time was prolonged. And the product obtained was mixed crystal form when the additional time was prolonged to be more than 40 min

[0038] It also observed in the study that as addition time of sulfuric acid was prolonged, bulk density of the product reduced correspondingly, form changed as well and became bad uniformed. When the addition time of sulfuric acid was controlled within 20 min, bulk density and form were better; when the addition time of sulfuric acid was controlled within 10 min, evaluation of comprehensive yield, bulk density and form was optimized.

Example 4

[0039] Used Malvern-3000 granulometer to test the form and homogeneity of products obtained in examples 1 and 2, and the test results were as shown in the following table:

TABLE-US-00002 Form d(0.1) d(0.5) d(0.9) Example 1 Spherical 58.24 m 70.67 m 113.10 m Example 2 Spherical 46.46 m 62.48 m 90.60 m

[0040] As can be seen, the Clopidogrel Hydrogen Sulfate spherical crystals obtained in examples 1 and 2 had a homogeneous form. A further test of preparation dissolution found that the dissolution rate of the preparation prepared by the spherical crystal in this invention was faster than that of marketed products.

Example 5

[0041] Tested respectively the angle of repose and bulk density of products obtained in examples 1 and 2 by using fixed-funnel method and measuring-cylinder-knocking method, and the test results were as shown in the following table:

TABLE-US-00003 Angle of repose () Bulk density (g/ml) Example 1 28 0.78 Example 2 30 0.77 Power Regular and uniform Regular and uniform sphere sphere

[0042] As can be seen, angles of repose in examples 1 and 2 were all between 2532, so the mobility of spherical crystals obtained was far superior to powder product;

Bulk density of examples 1 and 2 was between 0.75 and 0.80 g/ml, which was far higher than the powder product, so the electrostatic effect of the spherical crystals obtained reduced greatly.

[0043] In conclusion, the spherical crystal obtained in this invention was more complied with the commonly used preparation process of current technology of Clopidogrel Hydrogen Sulfate and would contribute to further improvement of the process.

[0044] A further scale-up study showed that the process to prepare Clopidogrel Hydrogen Sulfate spherical crystal form I in examples 13 had the same effect to the execution example when used in large scale production, so the corresponding process was applicable to large-scale production as well.

[0045] The execution examples above are better mode of execution of this invention, but not limited by the execution examples, and any changes, ornament, replacement, combination and simplification without violation the spirit and principle of this invention shall be all equivalent substitute mode, and included in the protection range of this invention.