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 preparing Clopidogrel Hydrogen Sulfate spherical crystal form I, the method comprising the following steps: (1) Dissolving clopidogrel base in 2-butanol as a single solvent to produce a first solution having a clopidogrel base concentration of 0.020.1 g/mL, adding at 035 C. to the first solution a solution of sulfuric acid in 2-butanol to produce a second solution, wherein the solution of sulfuric acid in 2-butanol has a sulfuric acid concentration of 0.52.0 mol/L, wherein the molar ratio of sulfuric acid to clopidogrel base is 0.81.1:1, wherein the solution of sulfuric acid in 2-butanol is added to the first solution within 40 minutes; (2) adding seed Clopidogrel Hydrogen Sulfate crystal form I to the second solution, wherein the seed Clopidogrel Hydrogen Sulfate crystal form I is in an amount ranging from 1 wt % to 10 wt % of the clopidogrel base, and stirring for 48 h; and (3) filtrating, washing and drying to obtain Clopidogrel Hydrogen Sulfate spherical crystal form I.

2. The method of claim 1, wherein in step (1) the solution of sulfuric acid in 2-butanol is added to the first solution within 20 min.

3. The method of claim 1, wherein the solution of sulfuric acid in 2-butanol has a sulfuric acid concentration of 0.61.0 mol/L.

4. The method of claim 1, wherein the first solution has a clopidogrel base concentration of 0.0400.065 g/mL, and wherein the molar ratio of sulfuric acid to clopidogrel base is 0.951.05:1.

5. The method of claim 1, wherein in step (1) the solution of sulfuric acid in 2-butanol is added to the first solution within 10 min.

6. The method of claim 1, wherein in step (1) the solution of sulfuric acid in 2-butanol is added to the first solution at 1030 C.

7. The method of claim 1, wherein step (2) further comprises a step of maintaining a temperature at 2030 C. for 2-4 h, then cooling to 10-20 C. after the adding step and before the stirring step.

8. The method of claim 1, wherein the of Clopidogrel Hydrogen Sulfate crystal form I is in an amount ranging from 1 wt % to 5 wt % of the clopidogrel base.

9. The method of claim 1, further comprising a step of preparing clopidogrel base comprising the sub-steps of: (a) dissolving a clopidogrel salt in one or more organic solvents to produce a third solution; (b) adjusting pH value of the third solution with an aqueous alkaline solution, washing an organic phase with water, and removing water in the organic phase by one or more dehydrating agents; (c) concentrating the organic phase in vacuum to obtain clopidogrel base.

10. The method of claim 9, wherein in step (a), the clopidogrel salt is selected from the group consisting of a disulfate, a camphorsulfonate, a hydrochloride, and mixtures thereof; wherein the organic solvent is selected from the group consisting of dichloromethane, chloroform, ethyl acetate, and mixtures thereof; wherein in step (b), the aqueous alkaline solution comprises sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and/or potassium hydroxide; wherein the dehydrating agent is selected from the group consisting of anhydrous magnesium sulfate, anhydrous sodium sulfate, and a mixture thereof.

Description

INSTRUCTIONS FOR FIGURES

(1) FIG. 1 Clopidogrel Hydrogen Sulfate XRPD spectrogram obtained in example 1

(2) FIG. 2 Clopidogrel Hydrogen Sulfate DSC spectrogram obtained in example 1

(3) FIG. 3 Clopidogrel Hydrogen Sulfate SEM picture obtained in example 1

(4) FIG. 4 Clopidogrel Hydrogen Sulfate XRPD spectrogram obtained in comparison example 1

(5) FIG. 5 Clopidogrel Hydrogen Sulfate SEM picture obtained in comparison example 1

SPECIFIC MODE OF EXECUTION

(6) Further describe this invention combined with the following execution examples and figures, but mode of execution is not limited to it.

EXAMPLE 1

(7) 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.

(8) 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%).

(9) 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

(10) 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.

(11) 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

(12) 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.

(13) 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

(14) 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.

(15) 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

(16) 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

(17) 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

(18) 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:

(19) 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

(20) 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

(21) 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:

(22) 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

(23) 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;

(24) 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.

(25) 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.

(26) 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.

(27) 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.