WO2013179194A1

WO2013179194A1 - Process for the preparation of crystalline dexlansoprazole

Info

Publication number: WO2013179194A1
Application number: PCT/IB2013/054279
Authority: WO
Inventors: Bhavin Prabhudas Thanki; Mahavir Singh Khanna; Rajesh Kumar Thaper; Mohan Prasad; Sudershan Kumar Arora
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2012-05-31
Filing date: 2013-05-23
Publication date: 2013-12-05
Anticipated expiration: 2014-11-30

Description

PROCESS FOR THE PREPARATION OF CRYSTALLINE

DEXLANSOPRAZOLE

Field of the Invention

The present invention relates to a process for the preparation of crystalline dexlansoprazole.

Background of the Invention

Dexlansoprazole is chemically described as 2-[(R)- {[3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]methyl}sulfinyl]- lH-benzimidazole as represented by Formula I.

FORMULA I

Dexlansoprazole is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintenance of healing of EE for up to 6 months, and treatment of heartburn associated with non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

U.S. Patent Nos. 6,462,058 and 7,285,668 and U.S. Publication No. 2007/0004779 describe processes for preparing crystalline forms of dexlansoprazole and its hydrates. PCT Publication No. WO 2009/1 17489 describes a process for the preparation of amorphous dexlansoprazole.

PCT Publication No. WO 2010/095144 describes the process for the preparation of crystalline dexlansoprazole using ketone and hydrocarbon solvent mixtures.

Summary of the Invention

The present inventors have found that the crystalline dexlansoprazole prepared by using an acetone and heptane mixture is not stable, as the color of this material deteriorates during storage. The present inventors have found that crystalline

dexlansoprazole can be prepared as a stable material with both the color and consistency of the material remaining stable on storage. Thus, the present invention provides a simple, efficient, and industrially preferable process for the preparation of crystalline

dexlansoprazole.

Detailed Description of the Invention

An aspect of the present invention provides a process for the preparation of crystalline dexlansoprazole, which comprises:

a) treating dexlansoprazole with a solvent selected from the group consisting of cyclic ethers, C₄_6 ketones, or mixtures thereof;

b) treating the mixture obtained in step a) with aliphatic hydrocarbons, cyclic aliphatic hydrocarbons, ethers, or mixtures thereof; and

c) isolating crystalline dexlansoprazole from the mixture.

The dexlansoprazole used as a starting material may be in any solid form and may be prepared according to the methods described in U.S. Patent No. 7,271,182, PCT Publication No. WO 201 1/121548, or PCT Publication No. WO 201 1/121546.

The dexlansoprazole is treated with a solvent selected from the group consisting of cyclic ethers, C₄-6 ketones, or mixtures thereof. The cyclic ether is selected from the group comprising tetrahydrofuran, 2-methyl tetrahydrofuran, 2,4-dimethyl tetrahydrofuran, or mixtures thereof. In a preferred embodiment of the present invention, the cyclic ether used is tetrahydrofuran or 2-methyl tetrahydrofuran. The C₄_6 ketone is selected from the group comprising methyl ethyl ketone, methyl isopropyl ketone, or mixtures thereof. In a preferred embodiment of the present invention, the C₄-6 ketone used is methyl ethyl ketone. The dexlansoprazole may be optionally treated with ammonia or organic amines. The organic amine may be, for example, diisopropylethylamine. The treatment of dexlansoprazole with the cyclic ether or C₄_6 ketone may be carried out at a temperature of about 15°C to about 50°C, for example, about 25°C to about 30°C. The treatment of dexlansoprazole with cyclic ether or C₄_6 ketone may be carried out for 10 minutes to 60 minutes, preferably 20 minutes to 40 minutes.

The reaction mixture may be treated with aliphatic hydrocarbons, cyclic aliphatic hydrocarbons, ethers, or mixtures thereof. The aliphatic hydrocarbon in step b) is selected from the group comprising pentane, n-heptane, hexane, or mixtures thereof. In a preferred embodiment of the present invention, the aliphatic hydrocarbon used is n-heptane. The cyclic aliphatic hydrocarbon in step b) is selected from the group comprising cyclohexane, cycloheptane, or mixtures thereof. In a preferred embodiment of the present invention, the cyclic aliphatic hydrocarbon used is cyclohexane. The ether in step b) is selected from the group comprising methyl tertiary butyl ether, cyclopropyl methyl ether, cyclobutyl methyl ether, diisopropyl ether, or mixtures thereof. In a preferred embodiment of the present invention, the ether used is methyl tertiary butyl ether or cyclopropyl methyl ether. The treatment of the reaction mixture with the aliphatic hydrocarbons, cyclic aliphatic hydrocarbons, ethers, or mixtures thereof is carried out at a temperature of about 15°C to about 50°C, preferably, about 25°C to about 35°C, for about 2 hours to about 7 hours, preferably for about 4 hours to about 5 hours

The crystalline dexlansoprazole may be isolated by filtration, distillation, decantation, vacuum drying, evaporation, or a combination thereof.

Brief Description of the Drawings

Figure 1 depicts the X-ray powder diffraction pattern (XRPD) of the crystalline dexlansoprazole obtained according to Example 1.

Figure 1 A provides the table of values for the XRPD pattern depicted in Figure 1.

Figure 2 depicts the X-ray powder diffraction pattern (XRPD) of the crystalline dexlansoprazole obtained according to Example 2.

Figure 2A provides the table of values for the XRPD pattern depicted in Figure 2.

Figure 3 depicts the X-ray powder diffraction pattern (XRPD) of the crystalline dexlansoprazole obtained according to Example 3.

Figure 3 A provides the table of values for the XRPD pattern depicted in Figure 3.

Figure 4 depicts the X-ray powder diffraction pattern (XRPD) of the crystalline dexlansoprazole obtained according to Example 4.

Figure 4A provides the table of values for the XRPD pattern depicted in Figure 4. Figure 5 depicts the X-ray powder diffraction pattern (XRPD) of the crystalline dexlansoprazole obtained according to Example 5.

Figure 5 A provides the table of values for the XRPD pattern depicted in Figure 5.

Figure 6 depicts the X-ray powder diffraction pattern (XRPD) of the crystalline dexlansoprazole obtained according to Example 6. Figure 6A provides the table of values for the XRPD pattern depicted in Figure 6.

Figure 7 depicts the X-ray powder diffraction pattern (XRPD) of the crystalline dexlansoprazole obtained according to Example 7.

Figure 7A provides the table of values for the XRPD pattern depicted in Figure 7.

Figure 8 depicts the X-ray powder diffraction pattern (XRPD) of the crystalline dexlansoprazole obtained according to Example 8.

Figure 8 A provides the table of values for the XRPD pattern depicted in Figure 8.

XRPD of the samples were determined by using Panalytical X'Pert Pro X-Ray Powder Diffractometer in the range 3-40 degree 2 theta and under tube voltage and current of 45 Kv and 40 mA respectively. The copper radiation of wavelength 1.54 angstroms and an Xceletor detector were used.

While the present invention has been described in terms of its specific

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.

EXAMPLES

Example 1 : Preparation of Crystalline Dexlansoprazole

2-Methyl tetrahydrofuran (75 mL) was added to dexlansoprazole (15 g) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 10 minutes to 15 minutes. Cyclohexane (75 mL) was added to the reaction mixture at 25°C to 30°C over 30 minutes. The reaction mixture was stirred at 25°C to 30°C for 2 hours. The reaction mixture was filtered and washed with cyclohexane (30 mL) under nitrogen at 25°C to 30°C. The solid obtained was dried under vacuum at 30°C to 32°C for 8 hours to 12 hours to obtain the title compound having an XRPD pattern as depicted in Figure 1.

Yield: 11.0 g

Moisture content: 0.26% Example 2: Preparation of Crystalline Dexlansoprazole

Tetrahydrofuran (100 mL) was added to dexlansoprazole (50 g) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 10 minutes to 15 minutes.

Cyclohexane (1000 mL) was added to the reaction mixture at 25°C to 30°C over 1.5 hours to 2 hours. The reaction mixture was stirred at 25°C to 30°C for 2 hours. The reaction mixture was filtered and washed with cyclohexane (100 mL) under nitrogen at 25°C to 30°C. The solid obtained was dried under vacuum at 30°C to 32°C for 8 hours to 12 hours to obtain the title compound having an XRPD pattern as depicted in Figure 2.

Yield: 48.0 g

Moisture content: 0.06%

Example 3 : Preparation of Crystalline Dexlansoprazole

Tetrahydrofuran (100 mL) was added to dexlansoprazole (50 g) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 10 minutes to 15 minutes. n-Heptane (1000 mL) was added to the reaction mixture at 25°C to 30°C over 1.5 hours to 2 hours. The reaction mixture was stirred at 25°C to 30°C for 2 hours. The reaction mixture was filtered and washed with n-heptane (100 mL) under nitrogen at 25°C to 30°C. The solid obtained was dried under vacuum at 30°C to 32°C for 8 hours to 12 hours to obtain the title compound having an XRPD pattern as depicted in Figure 3.

Yield: 49.0 g

Moisture content: 0.05%

Example 4: Preparation of Crystalline Dexlansoprazole.

2-Methyl tetrahydrofuran (125 mL) was added to dexlansoprazole (25 g) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 10 minutes to 15 minutes. n-Heptane (100 mL) was added to the reaction mixture at 25°C to 30°C over 1 hour. The reaction mixture was stirred at 25°C to 30°C for 2 hours. The reaction mixture was filtered and washed with n-heptane (50 mL) under nitrogen at 25°C to 30°C. The solid obtained was dried under vacuum at 30°C to 32°C for 8 hours to 12 hours to obtain the title compound having an XRPD pattern as depicted in Figure 4.

Yield: 20.0 g

Moisture content: 0.07% Example 5: Preparation of Crystalline Dexlansoprazole

Methyl ethyl ketone (80 mL) was added to dexlansoprazole (20 g) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 10 minutes to 15 minutes. n-Heptane (80 mL) was added to the reaction mixture at 25°C to 30°C over 45 minutes. The reaction mixture was stirred at 25°C to 30°C for 2 hours. The reaction mixture was filtered and washed with n-heptane (40 mL) under nitrogen at 25°C to 30°C. The solid obtained was dried under vacuum at 30°C to 32°C for 8 hours to 12 hours to obtain the title compound having an XRPD pattern as depicted in Figure 5.

Yield: 13.7 g

Moisture content: 0.05%

Example 6: Preparation of Crystalline Dexlansoprazole.

Tetrahydrofuran (30 mL) was added to dexlansoprazole (15 g) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 10 minutes to 15 minutes.

Cyclopropyl methyl ether (150 mL) was added to the reaction mixture at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 3 hours to 4 hours. The reaction mixture was filtered and washed with cyclopropylmethyl ether (30 mL) under nitrogen at 25°C to 30°C. The solid obtained was dried under vacuum at 30°C to 32°C for 8 hours to 12 hours to obtain the title compound having an XRPD pattern as depicted in Figure 6.

Yield: 7.2 g

Moisture content: 0.09%

Example 7: Preparation of Crystalline Dexlansoprazole

Methyl ethyl ketone (40 mL) was added to dexlansoprazole (10 g) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 10 minutes to 15 minutes.

Cyclohexane (50 mL) was added to the reaction mixture at 25°C to 30°C over 30 minutes. The reaction mixture was stirred at 25°C to 30°C for 2 hours. The reaction mixture was filtered and washed with cyclohexane (20 mL) under nitrogen at 25°C to 30°C. The solid obtained was dried under vacuum at 30°C to 32°C for 8 hours to 12 hours to obtain the title compound having an XRPD pattern as depicted in Figure 7.

Yield: 5.9 g

Moisture content: 0.09% Example 8: Preparation of Crystalline Dexlansoprazole

Tetrahydrofuran (30 mL) was added to dexlansoprazole (15 g) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 10 minutes to 15 minutes. Methyl tertiary butyl ether (150 mL) was added to the reaction mixture at 25°C to 30°C in one lot. The reaction mixture was stirred at 25°C to 30°C for 5 hours. The reaction mixture was filtered and washed with methyl tertiary butyl ether (30 mL) under nitrogen at 25°C to 30°C. The solid obtained was dried under vacuum at 30°C to 32°C for 8 hours to 12 hours to obtain the title compound having an XRPD pattern as depicted in Figure 8.

Yield: 10.2 g

Moisture content: 0.08%

Claims

We claim:

1. A process for the preparation of crystalline dexlansoprazole, which comprises: a) treating dexlansoprazole with a solvent selected from the group consisting of cyclic ethers, C₄_6 ketones, or mixtures thereof;

c) isolating crystalline dexlansoprazole from the mixture.

2. The process according to claim 1, wherein the cyclic ether is selected from the group comprising tetrahydrofuran, 2-methyl tetrahydrofuran, 2,4-dimethyl

tetrahydrofuran, or mixtures thereof.

3. The process according to claim 2, wherein the cyclic ether is tetrahydrofuran or 2- methyl tetrahydrofuran.

4. The process according to claim 1, wherein the C₄-6 ketone is selected from the group comprising methyl ethyl ketone, methyl isopropyl ketone, or mixtures thereof.

5. The process according to claim 4, wherein the C₄_6 ketone is methyl ethyl ketone.

6. The process according to claim 1, wherein the dexlansoprazole in step a) is optionally treated with ammonia or organic amines.

7. The process according to claim 6, wherein the organic amine is

diisopropylethylamine.

8. The process according to claim 1, wherein the aliphatic hydrocarbon in step b) is selected from the group comprising pentane, n-heptane, hexane, or mixtures thereof.

9. The process according to claim 8, wherein the aliphatic hydrocarbon is n-heptane.

10. The process according to claim 1, wherein the cyclic aliphatic hydrocarbon in step b) is selected from the group comprising cyclohexane, cycloheptane, or mixtures thereof.

1 1. The process according to claim 10, wherein the cyclic aliphatic hydrocarbon is cyclohexane.

12. The process according to claim 1, wherein the ether in step b) is selected from the group comprising methyl tertiary butyl ether, cyclopropyl methyl ether, cyclobutyl methyl ether, diisopropyl ether, or mixtures thereof.

13. The process according to claim 12, wherein the ether is methyl tertiary butyl ether or cyclopropyl methyl ether.