Stable amorphous ticagrelor and a process for its preparation

Abstract

The present invention relates to a stable amorphous ticagrelor and a process for its preparation.

Claims

1. A process for the preparation of a stable amorphous ticagrelor comprising: a) dissolving ticagrelor in a solvent selected from dichloromethane, tetrahydrofuran, and mixtures thereof to form a solution; and adding the solution of step a) to n-heptane to obtain the stable amorphous ticagrelor.

2. The process of claim 1, wherein the stable amorphous ticagrelor shows no change in XRPD pattern when it is placed at a temperature of 25 C2 C. at relative humidity of 60% 5% for 1, 2, 3, and 6 months, and at a temperature of 5 C.3 C. for 3 and 6 months.

3. The process of claim 1, wherein the ticagrelor is dissolved in a solvent at a temperature of 40 C to 65 C.

4. The process of claim 3, wherein the ticagrelor dissolved in the solvent is added to the n-heptane precooled to 0 C to 5 C.

5. The process of claim 4, wherein the ticagrelor dissolved in the hydrocarbon solvent at a temperature of 0 C to 5 C is further stirred for about two hours to three hours to obtain a precipitate.

6. The process of claim 5, wherein the precipitate is dried under vacuum at a temperature of 25 C to 35 C to obtain the amorphous ticagrelor.

Description

BRIEF DESCRIPTION OF THE DRAWING

(1) FIG. 1 depicts the X-ray powder diffraction (XRPD) pattern of an amorphous ticagrelor.

DETAILED DESCRIPTION OF THE INVENTION

(2) The term about, as used herein, refers to any value which lies within the range defined by a number up to 10% of the value.

(3) The term stable amorphous ticagrelor, as used herein, refers to the amorphous ticagrelor for which no change was observed in an X-ray powder diffraction (XRPD) pattern when placed at a temperature of 25 C.2 C. at a relative humidity of 60% 5% for 1, 2, 3, and 6 months, and at a temperature of 5 C.3 C. for 3 and 6 months.

(4) A first aspect of the present invention provides a process for the preparation of a stable amorphous ticagrelor comprising: a) dissolving ticagrelor in a solvent selected from the group consisting of chlorinated hydrocarbons, esters, cyclic ethers, and mixtures thereof to form a solution; and b) adding the solution of step a) to a hydrocarbon solvent to obtain the stable amorphous ticagrelor.

(5) The ticagrelor used for the preparation of the stable amorphous ticagrelor of the present invention may be in any polymorphic form, for example, crystalline Forms I, II, III, or IV, and may be prepared according to the methods provided in the art, for example, PCT Publication No. WO 01/92262.

(6) Examples of chlorinated hydrocarbons include dichloromethane, dichloroethane, and chloroform.

(7) An example of an ester is ethyl acetate.

(8) Examples of cyclic ethers include tetrahydrofuran and dioxane.

(9) The solution of ticagrelor is added to the hydrocarbon solvent and the reaction mixture is stirred at a temperature of from about 10 C. to about 15 C., for example, from about 5 C. to about 10 C., for about 45 minutes to about 6 hours, for example, for about 1 hour to about 4 hours.

(10) Examples of hydrocarbon solvents include n-pentane, n-hexanes, n-heptane, and cyclohexane.

(11) The isolation of the stable amorphous ticagrelor from the reaction mixture may be carried out by cooling, precipitation, washing, filtration, or combinations thereof. The stable amorphous ticagrelor may further be dried by using known methods, for example, drying under reduced pressure, vacuum drying, or air drying.

(12) The stable amorphous ticagrelor prepared by the process of the present invention shows no change in XRPD pattern when it is placed at a temperature of 25 C.2 C. at relative humidity of 60% 5% for 1, 2, 3, and 6 months, and at a temperature of 5 C.3 C. for 3 and 6 months.

(13) A second aspect of the present invention provides a stable amorphous ticagrelor.

(14) While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.

(15) Methods

(16) The X-ray powder diffraction (XRPD) pattern was recorded using a PANalytical X'pert PRO with X'celerator as the detector.

EXAMPLES

Example 1

Preparation of an Amorphous Ticagrelor

(17) Ticagrelor (0.5 g) was dissolved in dichloromethane (17 mL) by heating at 40 C. to obtain a solution. The solution was added to precooled n-heptane (125 mL) at 0 C. to 5 C. The reaction mixture was stirred at 0 C. to 5 C. for 2 hours to obtain a precipitate. The precipitate was filtered, and then dried under vacuum at 25 C. to 30 C. for 4 hours to obtain the amorphous ticagrelor.

(18) Yield: 0.28 g

Example 2

Preparation of an Amorphous Ticagrelor

(19) Ticagrelor (5 g) was dissolved in dichloromethane (100 mL) at 40 C. to 45 C. to obtain a solution. The solution was added to precooled n-heptane (730 mL) at 0 C. to 5 C. The reaction mixture was stirred at 0 C. to 5 C. for 2 hours to obtain a precipitate. The precipitate was filtered, and then dried under vacuum at 25 C. to 30 C. for 8 hours to obtain the amorphous ticagrelor.

(20) Yield: 3 g

Example 3

Preparation of an Amorphous Ticagrelor

(21) Ticagrelor (25 g) was dissolved in dichloromethane (487.5 mL) and tetrahydrofuran (12.5 mL) at 40 C. to 45 C. to obtain a solution. The solution was distilled to recover the dichloromethane (250 mL). The solution was added to precooled n-heptane (2500 mL) at 0 C. to 5 C. over a period of 2 hours to 3 hours. The resultant slurry was stirred at 0 C. to 5 C. for 2 hours to obtain a precipitate. The precipitate was filtered, then washed with n-heptane (100 mL), and then dried under vacuum at 25 C. to 30 C. for 6 hours to obtain the amorphous ticagrelor.

(22) Yield: 22 g

Example 4

Preparation of an Amorphous Ticagrelor

(23) Ticagrelor (2 g) was dissolved in dichloromethane (10 mL) and tetrahydrofuran (2 mL) to obtain a solution. The solution was added to precooled n-heptane (96 mL) at 0 C. to 5 C. The resultant slurry was stirred for 2 hours at 0 C. to 5 C. to obtain a precipitate. The precipitate was filtered, and then dried under vacuum at 25 C. to 30 C. to obtain the amorphous ticagrelor.

(24) Yield: 1.5 g

Example 5

Preparation of an Amorphous Ticagrelor

(25) Ticagrelor (0.5 g) was dissolved in ethyl acetate (4 mL) by heating at 65 C. to obtain a solution. The solution was added to pre-cooled cyclohexane (50 mL) at 0 C. to 5 C. The reaction mixture was cooled to 0 C. to 5 C. for 3 hours, then filtered, and then dried under vacuum at 25 C. to 30 C. for 2 hours to obtain the amorphous ticagrelor.

(26) Yield: 0.25g

Example 6

Preparation of an Amorphous Ticagrelor

(27) Ticagrelor (2 Kg) was dissolved in dichloromethane (40 L) and tetrahydrofuran (1 L) at 40 C. to 45 C. to obtain a solution. The solution was distilled to recover the dichloromethane (20 L). The solution was added to precooled n-heptane (200 L) at 0 C. to 5 C. over a period of 2 hours to 3 hours. The reaction mixture was stirred at 0 C. to 5 C. for 2 hours to obtain a precipitate. The precipitate was filtered, then washed with n-heptane (20 L), and then dried under vacuum at 30 C. to 35 C. for 6 hours to obtain the amorphous ticagrelor.

(28) Yield: 1.82 Kg

(29) HPLC purity (initial and at stability at a temperature of 25 C.2 C. at relative humidity of 60% 5% for 1, 2, 3, and 6 months): 99.8%

(30) HPLC purity (initial and at stability at a temperature of 5 C.3 C. for 3 and 6 months): 99.9%

(31) When amorphous ticagrelor was placed at a temperature of 25 C.2 C. at a relative humidity of 60% 5% for 1, 2, 3, and 6 months, and at a temperature of 5 C.3 C. for 3 and 6 months, no change was observed in the XRPD pattern, showing that the amorphous ticagrelor obtained by following the present invention is stable.